Polycyclic compounds and uses thereof

Abstract

The present invention relates to polycyclic compounds and their uses.Specifically, the compounds of the present invention have the structure shown in formula I, wherein the definitions of each group and substituent are as described herein, and the present invention further discloses the preparation method of said compounds and their use in regulating and treating the related diseases caused by the abnormal activity of YAP / TEAD. [Formula 1] JPEG2024530956000247.jpg2362

Description

[Technical field]

[0001] The present invention relates to the field of pharmaceutical technology, in particular to polycyclic compounds used to regulate the Hippo pathway, which are mainly used for the treatment or prevention of proliferative diseases (e.g., cancer), in particular for the regulation and treatment of related diseases due to the abnormal activity of YAP / TEAD, and their preparation methods and uses. [Background technology]

[0002] The Hippo pathway is essentially composed of a core kinase cascade, which includes the Ste-20 family of protein kinases MST1-2, the scaffolding proteins Salvador and the large tumor inhibitory kinase LATS1-2, and the inhibitory transcriptional coactivators YAP (Yes1-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motifs). YAP and TAZ are the main effectors of the Hippo signaling pathway, which act as transcription factors together with TEAD (transcriptionally enhanced binding domain) in the nucleus, thereby increasing the expression of target genes such as CTGF (connective tissue growth factor), CYR61, etc. The Hippo pathway is a key regulator of cell growth, proliferation and migration. TEAD transcription factors are located at the core of the Hippo pathway and are crucial for regulating organ growth and wound repair. Dysregulation of TEAD and its regulatory cofactor Yes-associated protein (YAP) are involved in many human cancers and hyperproliferative pathological processes, and dysregulation of the pathway is frequently detected in human cancers. Similar to TEAD proteins, activation of YAP and TAZ has been confirmed in many human tumors and is important for tumor initiation, progression and metastasis; for example, elevated YAP expression exists in patients with breast, ovarian, colon, liver and pancreatic cancer, and is associated with reduced survival. Consistent with this, activation or overexpression of YAP or TAZ enhances TEAD-dependent gene expression (e.g., CCN1, CTGF, ITGB2 and Birc5 / Survivin), promoting cell proliferation and migration in many cell types. Conversely, blocking the signal for YAP / TAZ-TEAD complex formation or intervening to prevent the expression of many mitogenic TEAD target genes can significantly reduce cell proliferation and oncogenic transformation activity. In addition, the Hippo pathway also cross-talks with other signaling pathways, such as Wnt, Notch, Hedgehog and MAPK, thereby affecting various biological functions, and its functional dysregulation may be involved in many human diseases in addition to cancer. Therefore, the YAP-TEAD complex is a promising therapeutic target. Summary of the Invention [Problem to be solved by the invention]

[0003] It is an object of the present invention to provide compounds according to formula I, as well as processes for their preparation and use. [Means for solving the problem]

[0004] A first aspect of the present invention provides a compound according to formula I, or a pharma- ceutically acceptable salt, solvate or prodrug thereof: [ka] Where: A is, [ka] is selected from L1 is selected from absent or CR3R4, B is selected from a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, and a C5-C10 cycloalkyl group; X is selected from O, NH, CR3R4 or S; X1, X2, X3, X4, X5, X6 and X7 are each independently selected from CR3, (CR3)2, N, O, S, SR3, SR3R4, NR4, CR3R4, (CR3R4)2; R1 is independently H, D, halogen, CN, NH2, a urea group, a carboxy group, a urethane group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; [ka] wherein NH2, an ester group, a urea group, a urethane group, an amide group, C1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R; Each of R2, R3, R4 and R5 is independently H, D, halogen, CN, NH2, -CO-(C 1-6 alkyl), =O, -C(=O)-O-(C1-C6 alkyl), -C(=O)-O-OBi, -S(=O)2-NR6R7, [ka] Ester group, urea group, urethane group, amide group, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, SF5, where NH2, an ester group, a urea group, a urethane group, an amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 A cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R, or X1 and X7 are each independently CR3R4, X1 and X7 share one R3, and R3 is a C1-C6 alkylene group; R6 and R7 are each independently hydrogen, D, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C6-C10 aryl groups, NH2, NH(C 1-6 alkyl), N(C 1-6alkyl)2, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, -S(O)2-(C 1-6 alkyl), -S(O)2-(C 2-6 alkenyl), where C 1-6 Alkyl group, C 3-6 a cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R, or R6 and R7 form a 3-7 membered carbocyclic ring, or R6 and R7 form a 3-7 membered heterocyclic ring containing N, O or S; R8 is, [ka] is selected from Each R is halogen, CN, OH, -(C 1-6 Alkylene)-N(C 1-6 alkyl), NH, NH(C 1-6 alkyl), ester group, urea group, urethane group, amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, C 2-6 Alkenyl group, C 2-6 R' is independently selected from an alkynyl group, a C6-C10 aryl group, a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or an R' substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy groups, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl), CN, halogen, =O; each m and n is independently selected from 1, 2, 3, or 4; p is selected from 0, 1 or 2. In another preferred embodiment, A is [ka] is selected from L1 is selected from absent or CR3R4, B is selected from a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, and a C5-C10 cycloalkyl group; X is selected from O, NH or S; X1, X2, X3, X4 and X5 are each independently selected from CR3, (CR3)2, N, O, S, NR4, CR3R4, (CR3R4)2; R1 is H, halogen, CN, NH2, urea group, carboxy group, urethane group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; [ka] wherein NH2, an ester group, a urea group, a urethane group, an amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R; Each of R2, R3, R4 and R5 is independently H, halogen, CN, NH2, -CO-(C 1-6 alkyl), ester group, urea group, urethane group, amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, SF5, where NH2, an ester group, a urea group, a urethane group, an amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R; R6 and R7 are each independently hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C6-C10 aryl groups, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, -S(O)2-(C 1-6 alkyl), -S(O)2-(C 2-6 alkenyl), where C 1-6 Alkyl group, C 3-6 a cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R, or R6 and R7 form a 3-7 membered carbocyclic ring, or R6 and R7 form a 3-7 membered heterocyclic ring containing N, O or S; Each R is halogen, CN, OH, -(C 1-6 Alkylene)-N(C 1-6 alkyl), NH, NH(C 1-6 alkyl), ester group, urea group, urethane group, amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, C 2-6 Alkenyl group, C 2-6R' is independently selected from an alkynyl group, a C6-C10 aryl group, a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or an R' substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy groups, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl), CN, and halogen; each m and n is independently selected from 1, 2, 3, or 4; p is selected from 0, 1 or 2.

[0005] In another preferred embodiment, A is [ka] is selected from L1 is selected from absent or CR3R4, B is selected from a C6-C10 aryl group or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; X is selected from O, NH or S; X1, X2, X3 and X4 are each independently selected from CR3, N, O, S or NR4; R1 is H, halogen, CN, NH2, urea group, carboxy group, urethane group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; [ka] wherein NH2, an ester group, a urea group, a urethane group, an amide group, C 1-6 Alkyl group, C 1-6Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R; Each of R2, R3, R4 and R5 is independently H, halogen, CN, NH2, -CO-(C 1-6 alkyl), ester group, urea group, urethane group, amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, where NH2, an ester group, a urea group, a urethane group, an amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R; R6 and R7 are each independently hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C6-C10 aryl groups, 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, -S(O)2-(C 1-6 alkyl), -S(O)2-(C 2-6 alkenyl), where C 1-6 Alkyl group, C 3-6 a cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R, or R6 and R7 form a 3-7 membered carbocyclic ring, or R6 and R7 form a 3-7 membered heterocyclic ring containing N, O or S; Each R is a halogen, CN, OH, NH2, ester group, urea group, urethane group, amide group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, C 2-6 Alkenyl group, C 2-6 independently selected from an alkynyl group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; each m and n is independently selected from 1, 2, 3, or 4; p is selected from 0, 1 or 2.

[0006] In another preferred embodiment, A is [ka] is selected from L1 is selected from absent or CR3R4, B is a C6-C10 aryl group; X is O, X1, X2, X3, X4, X6 and X7 are each independently selected from CR3, N, CR3R4, or NR4; R1 is, [ka] is selected from Each of R2, R3, R4 and R5 is independently H, halogen, CN, NH2, -CO-(C 1-6 Alkyl), C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 cycloalkoxy groups, C6-C10 aryl groups, 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, where NH2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R; R6 and R7 are each independently hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C6-C10 aryl groups, 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, -S(O)2-(C 1-6 alkyl), -S(O)2-(C 2-6 alkenyl), where C 1-6 Alkyl group, C 3-6 a cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R, or R6 and R7 form a 3-7 membered carbocyclic ring, or R6 and R7 form a 3-7 membered heterocyclic ring containing N, O or S; R8 is, [ka] is selected from Each R is halogen, CN, OH, NH2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, C 2-6 Alkenyl group, C 2-6 independently selected from an alkynyl group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; each m and n is independently selected from 1, 2, 3, or 4; p is selected from 0, 1 or 2.

[0007] In another preferred embodiment, A is [ka] is selected from L1 is selected from absent or CR3R4, B is a C6-C10 aryl group; X is O, X1, X2, X3 and X4 are each independently selected from CR3, N, or NR4; R1 is, [ka] is selected from Each of R2, R3, R4 and R5 is independently H, halogen, CN, NH2, -CO-(C 1-6 Alkyl), C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 cycloalkoxy groups, C6-C10 aryl groups, 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, where NH2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R; R6 and R7 are each independently hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C6-C10 aryl groups, 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, -S(O)2-(C 1-6 alkyl), -S(O)2-(C 2-6 alkenyl), where C 1-6 Alkyl group, C 3-6a cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R, or R6 and R7 form a 3-7 membered carbocyclic ring, or R6 and R7 form a 3-7 membered heterocyclic ring containing N, O or S; Each R is halogen, CN, OH, NH2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, C 2-6 Alkenyl group, C 2-6 independently selected from an alkynyl group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; each m and n is independently selected from 1, 2, 3, or 4; p is selected from 0, 1 or 2.

[0008] In another preferred embodiment, A is [ka] is selected from L1 is selected from absent or CR3R4, B is a C6-C10 aryl group; X is O, X1, X2, X3 and X4 are each independently selected from CR3, N, or NR4; R1 is, [ka] is selected from Each of R2, R3, R4 and R5 is independently H, halogen, CN, NH2, -CO-(C 1-6 Alkyl), C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6cycloalkoxy groups, C6-C10 aryl groups, 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, where NH2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 a cycloalkoxy group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R; R6 and R7 are each independently hydrogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C6-C10 aryl groups, 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, -S(O)2-(C 1-6 alkyl), -S(O)2-(C 2-6 alkenyl), where C 1-6 Alkyl group, C 3-6 a cycloalkyl group, a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, optionally substituted by 1, 2 or 3 R, or R6 and R7 form a 3-7 membered carbocyclic ring, or R6 and R7 form a 3-7 membered heterocyclic ring containing N, O or S; Each R is halogen, CN, OH, NH2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, C 2-6 Alkenyl group, C 2-6 independently selected from an alkynyl group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; each m and n is independently selected from 1, 2, 3, or 4; p is selected from 0, 1 or 2.

[0009] In another preferred embodiment, the compound is [ka] [ka] is selected from the group consisting of Here, each group is as defined above.

[0010] In another preferred embodiment, the compound is [ka] is selected from the group consisting of Here, each group is as defined above.

[0011] In another preferred embodiment, the compound is [ka] is selected from the group consisting of Here, each group is as defined above.

[0012] In another preferred embodiment, the compound is [ka] is selected from the group consisting of R1 is CN, a urea group, a urethane group, [ka] is selected from Here, each group is as defined above.

[0013] In another preferred embodiment, R1 is CN, a urea group, a urethane group, [ka] is selected from.

[0014] In another preferred example, R2 is selected from a trifluoromethyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a cyclopentyl group, or a cyclohexyl group, or a sulfur pentafluoride group. In another preferred example, R2 is selected from a trifluoromethyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a cyclopentyl group, or a cyclohexyl group.

[0015] In another preferred embodiment, [ka] is an aromatic group or an unsaturated group. In another preferred embodiment, [ka] is a non-aromatic or saturated group. Similar formal groups have similar meanings. In another preferred embodiment, [ka] indicates that the structure containing it is an aromatic group or an unsaturated group.

[0016] In another preferred embodiment, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0017] A second aspect of the present invention provides a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a safe and effective amount of one or more compounds according to the first aspect of the invention or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

[0018] A third aspect of the present invention provides the use of a pharmaceutical composition according to the second aspect of the present invention for use in the preparation of a medicament for the prevention and / or treatment of a disease associated with dysregulation of the Hippo pathway.

[0019] A fourth aspect of the present invention provides the use of a pharmaceutical composition according to the second aspect of the present invention for use in the preparation of a medicament for the prevention and / or treatment of an associated disease due to YAP or TAZ or YAP / TAZ or YAP / TEAD or YAP / TAZ / TEAD dysregulation. In another preferred embodiment, the disease is selected from the group consisting of lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, renal cancer, esophageal cancer, uterine cancer, and pleural mesothelioma.

[0020] A fifth aspect of the invention provides a combination of a compound according to the first aspect of the invention, or a pharma- ceutically acceptable salt, solvate or prodrug thereof, with a second drug for use in the preparation of a medicament for the prevention and / or treatment of cancer, The second drug is selected from the group consisting of an ERK inhibitor, a MEK inhibitor, a KRAS inhibitor, a BRAF inhibitor, an EGFR inhibitor, a Wnt inhibitor, a PD-1 inhibitor, or a combination thereof. Effect of the Invention

[0021] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] After a long and detailed study, the present inventors unexpectedly prepared a compound with excellent YAP / TEAD inhibitory activity, based on which the present inventors have completed the present invention.

[0023] term In the present invention, unless otherwise specified, the terms used have their ordinary meanings known to those skilled in the art. In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0024] In the present invention, the term "C1-C6 alkyl group" refers to an alkyl group containing from 1 to 6 carbon atoms, either straight or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, t-pentyl, or the like. 1-6 The term "alkyl group" has an analogous meaning.

[0025] In the present invention, the term "C2-C6 alkenyl group" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and one double bond, including, but not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups. 2-6 The term "alkenyl group" has an analogous meaning.

[0026] In the present invention, the term "C2-C6 alkynyl group" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, including one triplet, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.2-6 The term "alkynyl group" has an analogous meaning.

[0027] In the present invention, the term "C3-C8 cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms on the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. 3-8 Cycloalkyl group, C 3-6 Cycloalkyl group, C 5-10 The term "cycloalkyl group" has an analogous meaning.

[0028] In the present invention, the term "C1-C6 alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group. A C1-C4 alkoxy group is preferred. 1-6 The term "alkoxy group" has an analogous meaning.

[0029] In the present invention, the term "heterocyclic group" means [ka] and the like. A 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, including but not limited to:

[0030] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and are preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and not containing a heteroatom on the ring, such as a phenyl group, a naphthyl group, etc.

[0031] In the present invention, the terms "aromatic heterocycle" or "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one to several heteroatoms. For example, a "C3-C10 heteroaryl group" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and 3 to 10 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl group, a heterocyclic group, or a cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0032] In the present invention, the term "halogenated" refers to substitution with halogen. In the present invention, the term "deuterated" refers to substitution with deuterium.

[0033] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above as appropriate in the present specification or the substituent described in each example. Unless otherwise specified, a substituted group may have one substituent selected from the specific groups at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically achievable combinations. The substituents include, but are not limited to, halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, etc.

[0034] In the present invention, the term 1 to 6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms each independently have an analogous meaning. The term "ester group" has the structure -C(O)-O-R' or R'-C(O)-O-, where R' independently represents a hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C6-C10 aryl group, a heteroaryl group, or a heterocyclic group, as defined above.

[0035] The term "urea group" refers to [ka] wherein Ra, Rb are each independently selected from H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, and a C6-C10 aryl group.

[0036] The term "urethane group" means [ka] wherein Ra, Rb are each independently selected from H, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, and a C6-C10 aryl group.

[0037] The term "amide group" refers to a group having the structure -CONRR', where R and R' can each independently represent hydrogen, an alkyl group or a substituted alkyl group, a cycloalkyl group or a substituted cycloalkyl group, an aryl group or a substituted aryl group, a heterocycle or a substituted heterocycle, as defined above. R and R' can be the same or different in a dialkylamine moiety.

[0038] The term "aralkyl group" refers to an alkyl group substituted with an aryl group or a heteroaryl group, where the aryl group, heteroaryl group, and alkyl group are as defined herein. Typically, the aryl group can have 6 to 14 carbon atoms, the heteroaryl group can have 5 to 14 ring atoms, and the alkyl group can have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl groups.

[0039] When a group is simultaneously present at several different positions in a compound, its definition at each position is independent of each other and may be the same or different, i.e. the term "selected from the group consisting of:" has the same meaning as the term "each independently selected from the group consisting of:".

[0040] compound The present invention provides a compound according to formula I, or a pharma- ceutically acceptable salt, solvate or prodrug thereof: [ka] Here, each group is as defined above. In another preferred embodiment, A, L1, B, R1, R2, m, and n are each independently a group corresponding to each specific compound of the present invention.

[0041] As used herein, the term "pharmaceutical acceptable salt" refers to a medicament-compatible salt formed by the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salt formed by the compound of the present invention and an acid. Acids compatible with salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, etc., and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc.

[0042] Further preferred salts are salts formed by the compounds of the present invention with bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanol ammonium salts and other pharma- ceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, t-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0043] The term "solvate" refers to a complex formed when a compound of the present invention is coordinated with a solvent molecule in a specific ratio. The term "hydrate" refers to a complex formed when a compound of the present invention is coordinated with water.

[0044] Furthermore, the compounds of the present invention further include prodrugs of the compounds shown in formula I. The term "prodrug" includes compounds that may be biologically active or inactive themselves, and that are converted into the compounds of formula I, or salts or solutions of the compounds of formula I, by metabolism or chemical reaction in the human body after administration in an appropriate manner. The prodrugs include, but are not limited to, carboxylates, carbonates, phosphates, nitrates, sulfates, sulfonates, sulfoxides, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and other forms of the compounds.

[0045] Pharmaceutical Compositions and Methods of Administration The present invention further provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and a safe and effective amount of one or more of the above compounds or a pharma- ceutically acceptable salt, solvate or prodrug thereof.

[0046] Because the compound of the present invention has excellent antitumor activity, the compound of the present invention and its various crystal forms, pharma- ceutically acceptable inorganic or organic salts, hydrates or solvates, as well as pharmaceutical compositions containing the compound of the present invention as a main active ingredient, can be used to treat, prevent and alleviate tumor-related diseases.

[0047] The pharmaceutical composition of the present invention contains the compound of the present invention or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient or carrier within a safe and effective amount. Here, the term "safe and effective amount" refers to an amount of the compound sufficient to clearly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound / agent of the present invention, more preferably 10-1000 mg of the compound / agent of the present invention. Preferably, the "one agent" is one capsule or tablet.

[0048] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances, which must be suitable for human use, have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the ability of each component of the composition to be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween R), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0049] The pharmaceutical composition is in the form of an injection, a capsule, a tablet, a pill, a powder or a granule. The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0050] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as, for example, sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, (c) humectants, such as glycerin, (d) agar, calcium carbonate, potato tempura, (e) glyceryl stearate, and (f) glyceryl stearate. The pharmaceutical composition is mixed with ingredients such as potato starch or tapioca starch, alginic acid, certain complex silicates, and disintegrating agents such as sodium carbonate, (e) retarding solvents such as paraffin, (f) absorption promoters such as quaternary amine compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include buffering agents.

[0051] Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coating and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0052] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0053] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar-agar, or mixtures of these substances.

[0054] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0055] Dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required.

[0056] The compounds of the present invention can be administered alone or in combination with other pharma- ceutically acceptable compounds (eg, anti-tumor drugs). The therapeutic methods of the present invention can be used alone or in combination with other therapeutic procedures or therapeutic agents.

[0057] When the pharmaceutical composition is used, a safe and popular amount of the compound of the present invention is applied to a mammal (e.g., human) in need of treatment, where the dosage at the time of administration is the effective dosage considered, and for a person weighing 60 kg, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the health condition of the patient, all of which are within the skill of a skilled physician.

[0058] Compared with the prior art, the present invention has the following advantages: (1) The compound has excellent YAP, TAZ and / or TEAD inhibitory activity. (2) The compounds have excellent pharmacokinetic properties.

[0059] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods that do not show specific conditions usually follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or those suggested by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the method of the present invention. The preferred implementation methods and materials described herein are used for demonstration purposes only.

[0061] Example T-1 Compounds synthesized according to the present invention: [ka]

[0062] The synthetic route is as follows: [ka]

[0063] The experimental process is as follows. (1) Synthesis of Compound 2 50mg (1.0eq) of compound 1, 150mg (3.0eq) of 4-trifluoromethylbenzeneboronic acid, 60mg (2.4eq) of anhydrous copper acetate, 64mg (2.0eq) of DIPEA, 10ml of solvent 1,6-dioxane and 1g of 4A molecular sieves are mixed homogeneously, substituted with nitrogen gas three times, protected with oxygen gas and reacted at room temperature for 18 hours. TLC and LC-MS show that the product is mainly the product and the raw material remains slightly, and the reaction solution is quenched by adding water and then extracted with EA. The organic phase is dried, spin-dried, separated and purified by a separation plate to obtain 1.91mg of compound 2. HPLC purity: 98.01%.

[0064] (2) Synthesis of compound T-1 30mg (1.0eq) of compound 2 and 12mg (3.0eq) of anhydrous lithium hydroxide are added to a solvent (tetrahydrofuran / methanol / water=6:3:1) (10ml) and mixed uniformly. After replacing with nitrogen gas three times, react at room temperature overnight. TLC shows that the raw material has disappeared, and LC-MS detects that it is mainly the product. The reaction solution is quenched with 2N hydrochloric acid and the pH is adjusted to 4, and then extracted with EA. The organic phase is dried, spin-dried, and separated and purified by a separation plate to obtain 1.87mg of compound T-1. HPLC purity: 97.20%.

[0065] Example T-3 Compounds synthesized according to the present invention: [ka]

[0066] The synthetic route is as follows: [ka]

[0067] The experimental process is as follows. Synthesis of compound T-3 100mg (1.0eq) of T-1, 53mg (3.0eq) of isopropylamine, 343mg (3.0eq) of HATU, 388mg (10.0eq) of DIPEA, 5ml of solvent DMF are mixed uniformly, and after replacing with nitrogen gas three times, the mixture is reacted at room temperature under nitrogen gas protection for 18 hours. The reaction solution is quenched by adding water and then extracted with EA. The organic phase is combined, then washed with saturated saline, then the organic phase is dried, spin-dried, and separated and purified by a separation plate to obtain 15mg of compound T-3. HPLC purity: 95.80%.

[0068] The following compounds are synthesized with reference to the synthesis methods of Examples T-1 and T-3. [Table 1-1] [Table 1-2] [Table 1-3]

[0069] Example T-4 Compounds synthesized according to the present invention: [ka]

[0070] The synthetic route is as follows: [ka]

[0071] The experimental process is as follows. (1) Synthesis of compound SM2 Mix 1.0g (1.0eq) of raw material compound SM1, 5ml (8.2eq) of DMF-DMA, 0.13g (0.1eq) of p-toluenesulfonic acid monohydrate, and 5ml of solvent toluene evenly, replace with nitrogen gas three times, protect with nitrogen gas, heat the oil bath to reflux, and react for 18 hours. TLC shows that no raw material remains, and directly spin evaporate the reaction solution to dryness to obtain 1.3g of crude product compound SM2.

[0072] (2) Synthesis of compound SM3 Mix 1.2g (1.0eq) of SM2, 0.85g (1.2eq) of p-trifluoromethylaniline, and 12ml (10 times the volume) of the solvent toluene evenly, replace with nitrogen gas three times, protect with nitrogen gas, heat the oil bath to reflux, and react for 18 hours. TLC shows that the raw material remains, and LCMS shows that it is accurate. Stir the reaction solution directly and pass it through a column to obtain 70mg of SM3.

[0073] (3) Synthesis of compound SM4 Mix 70mg (1.0eq) of SM3 and 2ml of DMF solvent evenly, replace with nitrogen gas three times, protect with nitrogen gas, cool ice-water bath to 0℃, add 10mg of NaH in batches, warm to room temperature after addition, stir for 15 minutes, warm oil bath to 100℃, react for 18 hours. TLC shows no raw material remaining, LCMS shows accuracy, cool the reaction solution, quench with water, extract with EA, separate and purify the EA phase by separation plate to obtain 15mg of SM4.

[0074] (4) Synthesis of compound SM5 Mix 500mg (1.0eq) of SM4, 518mg (1.5eq) of pinacol diborate, 400mg (3.0eq) of potassium acetate, 100mg (0.1eq) of Pd(dppf)Cl2, and 5ml (10x volume) of dioxane solvent homogeneously, then replace with nitrogen gas three times, heat to 90℃, and react for 18 hours. TLC detects that the raw materials have completely reacted. Purify by PE:EA=1:1 column chromatography to obtain 200mg of SM5.

[0075] (5) Synthesis of compound T-4 200mg of SM5 (1.0eq), 5mg of palladium acetate (0.05eq), 19mg of triphenylphosphine (0.15eq), 210mg (2.0eq) of di-t-butyl dicarbonate, and 1ml of dioxane were added to the reaction system, which was then purged with nitrogen gas three times. After reacting at 100°C for 18 hours, the completion of the reaction was detected by TLC, and the product was purified by liquid phase separation to obtain 30mg of T-4, with a purity of 99.9%. 1 H NMR (400MHz, chloroform-d) δ 9.04(d,J=2.1Hz,1H),7.92(d,J=8.3Hz,2H),7.61-7.54(m,3H),6.99(d,J=8.9Hz,1H),6.43(d,J=7.9Hz,1H),1.62(s,9H).

[0076] Example T-5 Compounds synthesized according to the present invention: [ka]

[0077] The synthetic route is as follows: [ka]

[0078] The experimental process is as follows. (1) Synthesis of compound SM6 Raw material compound SM4 (5g, 1.0eq), palladium acetate (0.3g, 0.1eq), dppf (1.5g, 0.2eq), triethylamine (9ml, 5eq), solvent ethanol (10ml), DMF (15ml) were mixed uniformly, replaced with nitrogen gas three times, replaced with CO three times, protected under positive pressure using a CO balloon, reacted at 40°C, and reacted for 18 hours. TLC showed that no raw material remained, and the reaction solution was directly concentrated, extracted with water and EA, separated, and the EA phase was concentrated and purified by column to obtain 2.5g of compound SM6. HPLC purity: 97.16%. 1 H NMR(400MHz,chloroform-d)δ 9.12(d,J=2.1Hz,1H),8.15(dd,J=8.9,2.1Hz,1H),7.93(d,J=8.2Hz,2H),7.59(dd,J=8.1,2.7Hz ,3H),7.01(d,J=9.0Hz,1H),6.44(d,J=7.9Hz,1H),4.42(q,J=7.1Hz,2H),1.42(t,J=7.1Hz,3H).

[0079] (2) Synthesis of compound T-5 The raw material compound SM6 (2.4g, 1.0eq), lithium hydroxide (0.84g, 3.0eq), solvent tetrahydrofuran (29ml), methanol (14ml), and water (5ml) were mixed uniformly, and the mixture was replaced with nitrogen gas three times, and then reacted at room temperature for 18 hours. TLC showed that no raw material remained, and the reaction solution was directly concentrated, followed by adding 50ml of water, and about 10ml of 2N hydrochloric acid was added dropwise, after which a large amount of solid was precipitated. The reaction solution was filtered by suction, and the filter cake was dissolved in ethyl acetate and then concentrated to obtain 2.3g of compound T-5. HPLC purity: 98.10%. 1 H NMR(400MHz,DMSO-d6)δ 8.80(d,J=2.1Hz,1H),8.15-8.04(m,4H),7.11(d,J=8.9Hz,1H),6.28(d,J=7.8Hz,1H).

[0080] Example T-6 Compounds synthesized according to the present invention: [ka]

[0081] The synthetic route is as follows: [ka]

[0082] The experimental process is as follows. Synthesis of compound T-6 Mix T-5 (30mg, 1.0eq), isopropylamine (22mg, 2.0eq), HATU (52mg, 1.5eq), DIPEA (46.5mg, 4.0eq), and solvent DMF (1ml) uniformly, purge with nitrogen gas three times, protect with nitrogen gas, and react at room temperature for 18 hours. TLC shows that no raw material remains, and LCMS shows that it is accurate. Add water to the reaction solution to quench, then extract with EA. Separate and purify the EA phase by a separation plate to obtain 12mg of compound T-6. HPLC purity: 99.3%. 1 H NMR(400MHz,chloroform-d)δ 8.67(d,J=2.2Hz,1H),8.18(dd,J=8.9,2.2Hz,1H),7.92(d,J=8.2Hz,2H),7.60(dd,J=13.7,8.0Hz,3H),7. 07(d,J=8.9Hz,1H),6.46(d,J=7.8Hz,1H),6.35(d,J=7.9Hz,1H),4.38-4.25(m,1H),1.30(d,J=6.6Hz,7H).

[0083] The following compounds are synthesized with reference to the synthesis method of Example T-6. [Table 2-1] [Table 2-2]

[0084] Examples T-7 & T-15 Compounds synthesized according to the present invention: [ka]

[0085] The synthetic route is as follows: [ka]

[0086] The experimental process is as follows. (1) Synthesis of compound 2: 5.0g (1.0eq) of compound 1 is taken in a 250mL flask, 60mL of DCM and 2.85g (1.03eq) of 4-methoxy-N-methylbenzylamine are added, then 11.5g (5eq) of DIPEA are slowly added dropwise, and the mixture is reacted at room temperature for 2 hours. After the reaction is complete, 60mL of water is added, extracted with DCM, the organic phase is combined, evaporated to dryness, and passed through a column to obtain 6.8g of compound 2. HPLC purity: 95.3%.

[0087] (2) Synthesis of compound 3: 3.33g (1.0eq) of p-trifluoromethylaniline is placed in a flask, 80mL of DMF is added, and 2.48g (3.0eq) of NaH is added under ice bath conditions and reacted for 10 minutes. Then 8.0g (1.0eq) of compound 2 is added, and the temperature is slowly raised to room temperature and reacted. After the reaction is completed, the reaction is quenched by adding water, extracted with EA, evaporated to dryness, and passed through a column to obtain 5.3g of compound 2.

[0088] (3) Synthesis of compound 4: 1.0g of compound 3 is taken in a flask, 4.0mL of TFA and 12mL of DCM are added, and the mixture is reacted at room temperature. After the reaction is completed, water is added, the mixture is extracted with DCM, evaporated to dryness, and passed through a column to obtain 0.65g of compound 2.

[0089] (4) Synthesis of compound 5: 430mg (1.0eq) of compound 4 is taken in a flask, 6mL of dioxane, 402mg (1.5eq) of pinacol diborate, 206mg (2.0eq) of KOAc and 39mg (0.05eq) of Pd(dppf)Cl2 are added, and the mixture is reacted under N2 protection at 100°C. After the reaction is complete, water is added, the mixture is extracted with EA, evaporated to dryness, and passed through a column to obtain compound 3, and the crude product is used directly in the next step.

[0090] (5) Synthesis of compound T-15: 200mg (1.2eq) of compound 5 is taken in a flask, 4mL of dioxane, 0.4mL of water, 85mg (1.0eq) of 4-bromo-1-methyl-5-ethoxycarbonylimidazole, 21mg (0.05eq) of Pd(PPh3)4 and 100mg (2.0eq) of K2CO3 are added, and the mixture is reacted at 100℃ under N2 protection. After the reaction is complete, water is added, the mixture is extracted with EA, evaporated to dryness, and passed through a column to obtain 120mg of compound T-15. HPLC: 97.7%. 1 H NMR(400MHz,DMSO-d6)δ 8.57(d,J=2.4Hz,1H),8.43(s,1H),8.06(d,J=8.4Hz,2H),7.79-7.65(m,3 H),7.60(m,1H),6.78(d,J=8.8Hz,1H),4.06(s,3H),2.41(d,J=5.2Hz,3H).

[0091] (6) Synthesis of compound T-7: 100mg (1.0eq) of T-15 was placed in a flask, 3mL of ultra-dry THF was added, and 46mg (5.0eq) of LiAlH4 was added in an ice bath, and the mixture was allowed to react by slowly warming to room temperature. After the reaction was completed, water was added and the mixture was extracted with EA to obtain 36mg of compound T-7. HPLC: 95.1%. 1H NMR(400MHz,DMSO-d6)δ 7.86(d,J=2.4Hz,1H),7.82(d,J=8.4Hz,2H),7.74(s,1H),7.57(d,J=8.4Hz,2 H),7.29(m,1H),6.82(d,J=8.8Hz,1H),5.17(s,2H),3.63(s,3H),2.39(s,3H).

[0092] The following compounds are synthesized with reference to the synthesis methods of Examples T-7 & T-15. [Table 3-1] [Table 3-2]

[0093] Examples T-18 & T-31 Compounds synthesized according to the present invention: [ka]

[0094] The synthetic route is as follows: [ka]

[0095] The experimental process is as follows. (1) Synthesis of compound SM2: Add SM1 (6.57 g, 39 mmol, 1.0 eq), CuBr (11.12 g, 78 mmol, 2.0 eq) in acetonitrile (245 mL), protect with nitrogen gas, then cool to 0 °C and add isoamyl nitrite (13.39 g, 105 mmol, 2.7 eq). Warm to 50 °C and react overnight. TLC (PE:EA = 5:1) shows the raw materials are completely reacted. Concentrate the reaction solution, then add 300 mL of water and 300 mL of ethyl acetate. Filter through diatomaceous earth, separate the organic layer, and extract the aqueous layer twice with 300 mL of ethyl acetate. Combine the organic layers, wash twice with 300 mL of water, wash twice with 300 mL of brine, dry over anhydrous sodium sulfate, filter, concentrate to obtain the crude product, pass through a silica gel column to obtain 5.5 g of product. 1 HNMR (400MHz, MeOD) δ 8.13 (s, 1H), 4.27 (q, 2H), 3.88 (s, 3H), 1.33 (t, 3H).

[0096] (2) Synthesis of compound T-31: SM2 (169 mg, 0.73 mmol, 1.0 eq), SM3 (400 mg, 0.87 mmol, 1.2 eq), Pd(PPh3)4 (84 mg, 0.073 mol, 0.1 eq), potassium carbonate (201.4 mg, 1.46 mmol, 2.0 eq) are added to 1,4-dioxane (5 mL) and water (0.5 mL) and protected with nitrogen gas. The mixture is then reacted at 105 °C overnight, and LCMS shows a product peak. The reaction is cooled to room temperature, the solvent is removed under reduced pressure, and 30 mL of water and 50 mL of ethyl acetate are added. The organic layer is separated, the aqueous layer is extracted twice with 50 mL of ethyl acetate, the organic layers are combined, washed once with 20 mL of water, and washed twice with 20 mL of saturated saline. Dry over anhydrous sodium sulfate and pass through a concentration column to obtain 100 mg of product. 1 HNMR(400MHz,CDCl3)δ 8.70(d,1H),8.18(s,1H),7.87(m,2H),7.67(dd,1H),7.42-7.36(m,2H),6.63(d,1H),4.43(m,1H),4.13(s,3H),2.63(d,3H).

[0097] (3) Synthesis of compound T-18: 100mg (1.0eq) of T-31 is taken in a flask, 5mL of ultra-dry THF is added, and 46mg (5.0eq) of LiAlH4 is added in an ice bath, the temperature is slowly raised to room temperature, and then the mixture is refluxed. After the reaction is completed, water is added and the mixture is extracted with EA to obtain 16mg of compound T-18. HPLC: 95.1%.

[0098] Examples T-19 & T-32 Compounds synthesized according to the present invention: [ka]

[0099] The synthetic route is as follows: [ka]

[0100] The experimental process is as follows. (1) Synthesis of compound SM2: Dissolve SM1 (5.7 g, 29 mmol, 1.0 eq) in methanol (100 mL), cool to 0° C., add concentrated sulfuric acid (3.5 g, 1.9 mL, 1.2 eq) dropwise, then warm to 70° C. and reflux overnight. LCMS shows complete reaction of the starting material. Cool to room temperature and concentrate to remove methanol. Add saturated sodium bicarbonate, then extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to give the product (5.6 g) as a white solid. 1 HNMR (400MHz, MeOD) δ 7.79 (s, 1H), 3.91 (s, 3H).

[0101] (2) Synthesis of compound SM4: Add NaH (0.39 g, 9.8 mmol, 2.0 eq) to THF (20 mL), cool to 0° C., add SM2 (1 g, 4.9 mmol, 1.0 eq) and stir for 20 min. Then add iodomethane (0.9 g, 0.4 ml, 6.4 mmol, 1.3 eq) dropwise. Allow to warm slowly to room temperature and stir overnight. Pour the reaction mixture into ice water (100 ml), extract with 50 mL ethyl acetate three times, and wash with saturated brine. Dry over anhydrous sodium sulfate, filter, and concentrate to give the product (1.0 g, white solid). 1 HNMR (400MHz, MeOD) δ 8.13 (s, 1H), 4.8 (s, 3H), 3.88 (s, 3H).

[0102] (3) Synthesis of compound T-32: SM4 (169 mg, 0.73 mmol, 1.0 eq), SM3 (400 mg, 0.87 mmol, 1.2 eq), Pd(PPh3)4 (84 mg, 0.073 mol, 0.1 eq), potassium carbonate (201.4 mg, 1.46 mmol, 2.0 eq) are added to 1,4-dioxane (5 mL) and water (0.5 mL) and protected with nitrogen gas. The mixture is then reacted at 105 °C overnight, and LC-MS shows a product peak. The reaction is cooled to room temperature, the solvent is removed under reduced pressure, and 30 mL of water and 50 mL of ethyl acetate are added. The organic layer is separated, the aqueous layer is extracted twice with 50 mL of ethyl acetate, the organic layers are combined, washed once with 20 mL of water, and washed twice with 20 mL of saturated saline. Dry over anhydrous sodium sulfate and pass through a concentration column to obtain 80 mg of product. 1 HNMR(400MHz, CDCl3)δ 8.70(d,1H),8.19(s,1H),7.84(d,2H),7.67(d,1H),7.39(d,2H),6.63(d,1H),4.36(q,1H),4.13(s,3H),2.63(d,3H).

[0103] (4) Synthesis of compound T-19: 50mg (1.0eq) of T-32 is taken in a flask, 3mL of ultra-dry THF is added, and 25mg (5.0eq) of LiAlH4 is added in an ice bath, the temperature is slowly raised to room temperature, and then the mixture is refluxed. After the reaction is complete, water is added and the mixture is extracted with EA to obtain 12mg of compound T-19. HPLC: 97.2%.

[0104] The following compounds are synthesized by referring to the synthesis methods of Examples T-18, T-19, T-31 & T-32. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0105] Example T-61 Compounds synthesized according to the present invention: [ka]

[0106] The synthetic route is as follows: [ka]

[0107] The experimental process is as follows. (1) Synthesis of SM2: SM1 (50g, 183mmol, 1.0eq), N-(4-methoxybenzyl)-N-methylamine (28g, 185mmol, 1.01eq) are added to DCM (500ml), DIEA (28.33g, 219.6mmol, 1.2eq) is added dropwise, protected with nitrogen gas, and the temperature is maintained at 30℃, and LC (PE:EA=2:1) ​​shows that the raw materials are completely reacted. The reaction solution is washed with NaCl (300ml), 70g of silica gel is added, stirred, and passed through a column to obtain 74.2g of product.

[0108] (2) Synthesis of SM3: SM2 (5 g, 122 mmol, 1.0 eq), B2Pin2 (34.1 g, 134.2 mmol, 1.1 eq), Pd(dppf)Cl2 (4.46 g, 6.1 mmol, 0.05 eq), KOAc (35.9 g, 366 mmol, 3 eq) are added to 1,4-dioxane (764 ml), protected with nitrogen gas, then heated to 105 °C and reacted for 1.5 h. LCMS shows that the product is already obtained and relatively pure. The reaction is diluted with 1 L of EA, filtered through 100 g of diatomaceous earth, spin-dried, added with 250 ml of toluene and 400 ml of ethanol, spin-dried, added with 250 ml of toluene and 400 ml of ethanol, spin-dried, added with PE, washed to give 48 g of SM3.

[0109] (3) Synthesis of SM4: SM3 (4.93 g, 11.33 mmol, 1.2 eq), ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate (2.2 g, 9.44 mmol, 1.0 eq), K2CO3 (2.61 g, 18.88 mmol, 2.0 eq), Pd(dppf)Cl2 (0.345 g, 0.47 mmol, 0.05 eq) and mixed solvent (ethanol, 1,4-dioxane, water 5:2:1, total 35.2 mL) were added to the reaction flask, evacuated and purged with nitrogen gas three times, then heated to 95 °C and reacted for 3 h. TLC (PE:EA=2:1) ​​showed that the raw materials were completely reacted. Cool to room temperature, add 200mL EtOAc and 30mL water, add diatomaceous earth and filter, separate the EA layer, then wash with saturated brine (30mL*1), dry over anhydrous sodium sulfate, concentrate to obtain the crude product, then pass through a column to obtain 2g of oily product.

[0110] (4) Synthesis of SM5: Add SM4 (2 g), dioxane (20 mL), and aqueous ammonia (15 mL) to the autoclave, evacuate and replace with nitrogen gas three times, then heat to 100 °C and react for 24 hours. TLC shows that the raw materials have reacted completely. Cool to room temperature, suction filter, wash the filter cake with water, wash with methanol, wash with petroleum ether, and dry in vacuum to obtain 0.8 g of product.

[0111] (5) Synthesis of SM6: SM5 (100 mg, 0.2424 mmol, 1 eq), phenylboronic acid (59.1 mg, 0.4848 mmol, 2 eq), Cu(OAc)2 (4.4 mg, 0.02424 mmol, 0.1 eq), TEA (49 mg, 0.4848 mmol, 2 eq) were added to DCM (3 ml) and 3 g of molecular sieves, protected with oxygen gas, and allowed to react overnight. When TLC (PE:EA=1:2) showed the reaction was nearly complete, the reaction was diluted with DCM and water, filtered through diatomaceous earth, extracted with DCM, washed with saturated NaCl, dried over anhydrous sodium sulfate, and the sample was stirred and passed through a column to give 25 mg of SM6.

[0112] (6) Synthesis of T-61: Add SM6 (25 mg, 0.051 mmol, 1 eq), 0.83 ml of TFA to 4.2 ml of DCM, protect with nitrogen gas, and react overnight. TLC (PE:EA=1:3) shows the conversion of the starting material is nearly complete, add saturated NaHCO3 solution to the reaction until the solution is basic, extract with DCM, wash with saturated NaCl, dry with anhydrous sodium sulfate, vortex the sample, and pass through a column to obtain 20 mg of T-61. 1 H NMR(400MHz,DMSO-d6)δ 8.82-8.77(m,1H),8.56(d,J=2.2Hz,1H),7.76(m,J=8.9,2.3Hz,1H),7.74-7.66(m,2H),7.7 0-7.56(m,2H),7.48-7.40(m,2H),6.73(d,J=8.9Hz,1H),4.21(s,3H),2.47(d,J=5.0Hz,3H).

[0113] The following compounds are synthesized with reference to the synthesis method of Example T-61. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

[0114] Examples T-86, T-100 & T-110 Compounds synthesized according to the present invention: [ka]

[0115] The synthetic route is as follows: [ka]

[0116] The experimental process is as follows. (1) Synthesis of SM2 Mix 50g (1.0eq) of SM1, 72g (1.5eq) of cesium carbonate, 22g (0.25eq) of Xantphos, 1.64g (0.05eq) of palladium acetate and 1L of 1,4-dioxane uniformly, slowly add 31g of 4-(trifluoromethyl)aniline, evacuate, replace with nitrogen gas, and reflux at 105°C for 16 hours, TLC shows that the raw material has reacted completely. Dilute with 1L of EA, then suction filter with diatomaceous earth, add silica gel to the filtrate, stir the sample, and obtain 38g of SM2 by column chromatography. 1 H NMR(400MHz,Chloroform-d)δ 8.25(d,J=1.9Hz,1H),7.87(dd,J=8.6,1.9Hz,1H),7.64-7.58(m,2H),7.29(dd,J=8.5,5.7Hz,4H),6.58(s,1H),3.90(s,3H).

[0117] (2) Synthesis of SM3 Mix 24g (1.0eq) of SM2, 21.5g (1.3eq) of B2Pin2, 12.6g (2.0eq) of KOAc, 2.4g (0.05eq) of Pd(dppf)d2 and 300ml of 1,4-dioxane homogeneously, protect with nitrogen gas, and react at reflux at 105°C for 1.5 hours. Cool to room temperature, add 500mL of EA, then suction filter with diatomaceous earth. Then ultrasonically mix using toluene: absolute ethanol = 5:8, stir for 5 minutes, and spin evaporate. Repeat this process until the solid is spin evaporated, then mix the solid with an appropriate amount of PE until the solid is precipitated. Suction filter, collect the solid, and dry to obtain 20g of SM3. 1 H NMR(400MHz,DMSO-d6)δ 8.47(s,1H),8.22(d,J=2.2Hz,1H),7.94(dd,J=8.7,2.3Hz,1H),7.65(d,J=8.4Hz,2H),7.35(t,J=8.5Hz,2H),3.85-3.71(m,3H),3.36(s,12H).

[0118] (3) Synthesis of T-100 18g (1.2eq) of SM3, 21.5g (1.3eq) of ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate, 15.0g (2.0eq) of K2CO3, 1.3g (0.05eq) of Pd(dppf)d2 and 250ml of 1,4-dioxane / water / anhydrous methanol=5:2:1 are mixed homogeneously, protected with nitrogen gas, and refluxed at 105°C for 1.5 hours, after which TLC shows that the product is formed. Cool to room temperature, then suction filter through diatomaceous earth, spin dry, quench with water, and extract with EA. 9.5g of T-100 is obtained by column chromatography. 1 H NMR(400MHz,DMSO-d6)δ 8.73(s,1H),8.68(d,J=2.1Hz,1H),8.03(d,J=8.3Hz,2H),7.89(dd,J=8.9,2. 1Hz, 1H), 7.71-7.64 (m, 2H), 6.61 (d, J=8.9Hz, 1H), 4.14 (s, 3H), 3.87 (s, 3H).

[0119] (4) Synthesis of T-110 4.5g (1.0eq) T-100, 1.42g (3.0eq) LiOH monohydrate and 50ml THF / water / anhydrous methanol=2:1:4 are mixed homogeneously, protected with nitrogen gas, reacted at 50℃ for 2-5 hours, TLC shows the product is formed, cooled to room temperature, spin-dried, quenched with water, extracted with EA, organic impurities are removed, the aqueous phase is adjusted to pH=2, and extracted with EA to obtain 3.6g T-110. 1 H NMR(400MHz,Methanol-d4)δ 8.90(d,J=2.0Hz,1H),8.51(s,1H),8.02-7.90(m,3H),7.59(d,J=8.2Hz,2H),6.68(d,J=8.9Hz,1H),4.21(s,3H).

[0120] (5) Synthesis of T-86: Dissolve T-110 (387 mg, 1 eq), DIPEA (258 mg, 2 eq) and HATU (380 mg, 1 eq) in DCM, stir at room temperature for 10 min, add isopropylamine (71 mg, 1.2 eq) and continue to react for 12 h. After completion of the reaction, monitor the completion of the reaction of T-110 by TLC (pure EA). Dilute with about 10 times DCM, wash off DIPEA with 0.05% citric acid, then wash with saturated NaCl solution, then dry and spin dry, after which the crude product is dissolved in DCM and methanol, then purified by PTLC or column chromatography to obtain 302 mg of T-86. 1 H NMR(400MHz,chloroform-d)δ 8.49(s,J=2.2Hz,1H),8.25(s,1H),7.87(dd,J=17.7,8.4Hz,3H),7.46(d,J=8.0Hz,2H),6.65( d,J=8.8Hz,1H),6.10(d,J=7.6Hz,1H),4.36-4.28(m,1H),4.21(s,3H),1.29(d,J=6.5Hz,6H).

[0121] The compounds shown in the following table are synthesized by referring to the synthesis methods of Examples T-86, T-100 & T-110. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15] [Table 6-16] [Table 6-17] [Table 6-18] [Table 6-19] [Table 6-20] [Table 6-21] [Table 6-22] [Table 6-23] [Table 6-24] [Table 6-25] [Table 6-26] [Table 6-27] [Table 6-28] [Table 6-29]

[0122] Example T-170 Compounds synthesized according to the present invention: [ka]

[0123] The synthetic route is as follows: [ka]

[0124] The experimental process is as follows. (1) Synthesis of SM2: Mix 50g (1.0eq) of SM1, 72g (1.5eq) of cesium carbonate, 22g (0.25eq) of xantphos, 1.64g (0.05eq) of palladium acetate and 1L of 1,4-dioxane uniformly, slowly add 31g of 4-(trifluoromethyl)aniline, evacuate, replace with nitrogen gas, and react at 105℃ for 16 hours under reflux, TLC shows that the raw material is completely reacted. Dilute with 1L of EA, then suction filter with diatomaceous earth, add silica gel to the filtrate, stir the sample, and obtain 38g of SM2 by column chromatography. 1 H NMR (400MHz, chloroform-d) δ 8.25(d,J=1.9Hz,1H),7.87(dd,J=8.6,1.9Hz,1H),7.64-7.58(m,2H),7.29(dd,J=8.5,5.7Hz,4H),6.58(s,1H),3.90(s,3H).

[0125] (2) Synthesis of SM3: Mix 24g (1.0eq) of SM2, 21.5g (1.3eq) of B2Pin2, 12.6g (2.0eq) of KOAc, 2.4g (0.05eq) of Pd(dppf)d2 and 300ml of 1,4-dioxane homogeneously, protect with nitrogen gas, and react at reflux at 105°C for 1.5 hours. Cool to room temperature, add 500mL of EA, then suction filter with diatomaceous earth. Then ultrasonically mix using toluene: absolute ethanol = 5:8, stir for 5 minutes, and spin evaporate. Repeat this process until the solid is spin evaporated, then mix the solid with an appropriate amount of PE until the solid is precipitated. Suction filter, collect the solid, and dry to obtain 20g of SM3. 1H NMR(400MHz,DMSO-d6)δ 8.47(s,1H),8.22(d,J=2.2Hz,1H),7.94(dd,J=8.7,2.3Hz,1H),7.65(d,J=8.4Hz,2H),7.35(t,J=8.5Hz,2H),3.85-3.71(m,3H),3.36(s,12H).

[0126] (3) Synthesis of SM4: 18g (1.2eq) of SM3, 21.5g (1.3eq) of ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate, 15.0g (2.0eq) of K2CO3, 1.3g (0.05eq) of Pd(dppf)d2 and 250ml of 1,4-dioxane / water / anhydrous methanol=5:2:1 are mixed homogeneously, protected with nitrogen gas, and refluxed at 105°C for 1.5 hours, after which TLC shows that the product is formed. Cool to room temperature, then suction filter through diatomaceous earth, spin dry, quench with water, and extract with EA. 9.5g of SM4 is obtained by column chromatography. 1 H NMR(400MHz,DMSO-d6)δ 8.73(s,1H),8.68(d,J=2.1Hz,1H),8.03(d,J=8.3Hz,2H),7.89(dd,J=8.9,2. 1Hz, 1H), 7.71-7.64 (m, 2H), 6.61 (d, J=8.9Hz, 1H), 4.14 (s, 3H), 3.87 (s, 3H).

[0127] (4) Synthesis of SM5: 4.5g (1.0eq) SM4, 1.42g (3.0eq) LiOH monohydrate and 50ml THF / water / anhydrous methanol=2:1:4 were mixed homogeneously, protected with nitrogen gas, reacted at 50℃ for 2-5 hours, TLC showed the product was formed, cooled to room temperature, spin-dried, quenched with water, extracted with EA, removed organic impurities, adjusted the aqueous phase to pH=2, and extracted with EA to obtain 3.6g SM5. 1H NMR(400MHz,Methanol-d4)δ 8.90(d,J=2.0Hz,1H),8.51(s,1H),8.02-7.90(m,3H),7.59(d,J=8.2Hz,2H),6.68(d,J=8.9Hz,1H),4.21(s,3H).

[0128] (5) Synthesis of SM6: Mix 1.0g (1.0eq) SM5, 0.4g (1.5eq) TEA and 20ml t-BuOH homogeneously, protect with nitrogen gas, reflux at 80℃, add 0.85g (1.2eq) DPPA dropwise, react for 2 hours, TLC shows the product is formed, cool to room temperature, spin dry, quench with water, extract with EA, and obtain 2.3g SM6 by column chromatography.

[0129] (6) Synthesis of SM7: 2.3g SM6, 23ml TEA and 30ml DCM are mixed homogeneously, protected with nitrogen gas, reacted at room temperature overnight, spin-dried, quenched with water, extracted with DCM and subjected to column chromatography to obtain 280mg SM7. 1 H NMR(400MHz,Methanol-d4)δ 8.40(s,1H),7.93(d,J=8.2Hz,2H),7.58(t,J=7.9Hz,1H),7.54-7.48(m,4H),7.22-7.12(m,1H),4.16(s,3H).

[0130] (7) Synthesis of T-170: Mix 2-pyridinecarboxylic acid (147.6 mg, 1.2 eq), HATU (465.6 mg, 1.2 eq), DIPEA (490 mg, 4.0 eq) and 2 ml of anhydrous dichloromethane and react at room temperature for 20 minutes, then add compound SM7 (394 mg, 1.0 eq) to the reaction solution and react at room temperature for 18 hours. TLC shows that the raw material has disappeared and LCMS shows that it is accurate, and the reaction solution is quenched by adding water after spin drying, extracted with EA, and the EA phase is washed once with 0.5% citric acid and dried with anhydrous sodium sulfate. The EA phase is separated and purified by a separation plate to obtain product T-170. 1 H NMR(400MHz,Methanol-d4)δ 8.96(d,1H),8.74(d,J=2.5Hz,1H),8.68(s,1H),8.18-8.16(d,H),8.10-8.06(m,1H),8.01-7.99(d,1H),7.76-7.60(m,4H),4.14(s,3H).

[0131] Example T-172 Compounds synthesized according to the present invention: [ka]

[0132] The synthetic route is as follows: [ka]

[0133] The experimental process is as follows. Synthesis of T-172: Mix SM7 (394 mg, 1.0 eq), DIPEA (490 mg, 4.0 eq) and 2 ml of anhydrous dichloromethane and react at room temperature for 20 minutes, then add compound acryloyl chloride (108 mg, 1.2 eq) to the reaction solution and react at room temperature for 18 hours. TLC shows that the raw material has disappeared, and LCMS shows that it is accurate. After spin-drying the reaction solution, add water to quench, extract with EA, wash the EA phase once with 0.5% citric acid, and dry with anhydrous sodium sulfate. Separate and purify the EA phase by preparative liquid phase to obtain product T-172. 1 H NMR(400MHz,DMSO-d6)δ 10.35(s,1H),8.73(d,J=2.5Hz,1H),8.68(s,1H),8.00(d,J=8.3Hz,2H),7.62(d,J=8.1Hz,2H),7.45(dd,J= 9.1,2.5Hz,1H),6.51-6.36(m,2H),6.27(dd,J=17.0,2.1Hz,1H),5.77(dd,J=10.0,2.1Hz,1H),4.13(s,3H).

[0134] Example T-186 Compounds synthesized according to the present invention: [ka]

[0135] The synthetic route is as follows: [ka]

[0136] The experimental process is as follows. Synthesis of T-186: SM7 (394 mg, 1.0 eq), pyridine (237 mg, 3.0 eq), benzenesulfonyl chloride (352 mg, 2.0 eq) and 2 ml of solvent anhydrous dichloromethane are mixed homogeneously and reacted at room temperature for 18 hours. TLC shows that the raw material has disappeared and LCMS shows that it is accurate, the reaction solution is quenched by adding water after spin drying, extracted with EA, the EA phase is washed once with 0.5% citric acid and dried with anhydrous sodium sulfate. The EA phase is separated and purified by a separation plate to obtain the product T-186. 1 H NMR(400MHz,Methanol-d4)δ 8.39(s,1H),8.00-7.87(m,5H),7.87-7.69(m,3H),7.60-7.36(m,1H),7.0 8(dd,J=9.1,2.6Hz,1H),6.44(d,J=9.1Hz,1H),5.50(s,1H),4.15(s,3H).

[0137] The following compounds are synthesized with reference to the synthesis methods of Examples T-170, T-172 & T-186. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8]

[0138] Example T-243 Compounds synthesized according to the present invention: [ka]

[0139] The synthetic route is as follows: [ka]

[0140] (1) Synthesis of SM1 Dissolve 25 g (1 eq) of 5,6-dibromonicotinic acid, 23.13 g (2 eq, if d is hydrochloride, 3 eq) of DIPEA and 34.083 g (1 eq) of HATU in DCM (250 ml), stir at room temperature for 10 min, add 13.14 g (1.2 eq) of compound pyridine ethylamine, and continue to react for 1.5 h. After the reaction is complete, monitor that 5,6-dibromonicotinic acid has reacted completely by TLC (pure EA), add 5 times DCM to dilute, wash off DIPEA with 0.1 mol hydrochloric acid, dry with saturated NaCl solution, stir the sample with 2-2.5 times silica gel, pass through column PE:EA=3:1 to obtain 30.7 g of yellow viscous liquid SM1.

[0141] (2) Synthesis of SM2 Sequentially, 30.7 g (1 eq) of SM1, 52.2 g (2 eq) of Cs2CO3, 4.6 g (0.1 eq) of Xantphos and 12.9 g (1 eq) of p-fluoroaniline are dissolved in ultra-dry 1,4-dioxane solution (300 ml) and placed in a round-bottom flask. 0.9 g (0.05 eq) of Pd(OAc)2 is added, purged with nitrogen gas 2-3 times, heated to 105 °C, and reacted for 1.5 hours. After the reaction is complete, monitor the complete reaction of the raw materials by TLC (PE:EA = 1:1). Dilute with 10 times solvent EA, suction filter with diatomaceous earth, stir the sample, separate it by chromatography column, pass through PE:EA = 2:1 to obtain 15.2 g of product yellow solid SM2.

[0142] (3) Synthesis of SM3 Sequentially, 13.2 g (1 eq) of SM2, 14.5 g (2 eq) of pinacol diborate and 1.04 g (0.05 eq) of Pd(dppf)Cl2 are dissolved in 1,4-dioxane solution (132 ml), put into a round-bottom flask and stirred, add 5.6 g (2 eq) of KOAc, replace with nitrogen gas 2-3 times, heat the oil bath pot to 105 ° C and react for 3 hours. After the reaction is completed, monitor the complete reaction of the raw materials by TLC (PE: EA = 1: 1.5), and fumigate with the color developer alizarin, and SM3 appears yellow. Dilute with 10 times the solvent EA, suction filter with diatomaceous earth, and spin dry the solvent. Add 5:8 toluene and ethanol solution and stir for 5 minutes, then spin dry the solvent. Repeat the above steps and spin dry the solvent. Add a small amount of PE, shake thoroughly, and suction filter to obtain 13.1 g of a gray-brown solid, SM3.

[0143] (4) Synthesis of TM Dissolve SM3 (1eq) in 1,4-dioxane solution, add K2CO3 (3eq), Pd(dppf)Cl2 (0.16eq) and ethyl 4-bromo-1-methylpyrazole-3-carboxylate (1eq) in a round-bottom flask, replace with nitrogen gas 2-3 times, heat to 105 °C, and react for 1 hour. After the reaction is complete, monitor by TLC (PE:EA = 3:1) that SM3 has completely reacted, and the polarity of the product is relatively high. Monitor by TLC (PE:EA = 1:1) that SM4 has completely crawled out from the distance. Filter by suction, add EA, stir the sample, and run it through a chromatography column (PE:EA = 1:1) to obtain 24 mg of a beige-brown solid product.

[0144] The following compounds are synthesized with reference to the synthesis method of Example T-243. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11] [Table 8-12] [Table 8-13] [Table 8-14] [Table 8-15]

[0145] Example T-276 Compounds synthesized according to the present invention: [ka]

[0146] The synthetic route is as follows: [ka]

[0147] The experimental process is as follows. Synthesis of SM3: In a 50ml round bottom flask, protect it with nitrogen gas, add SM2 (2g, 5.362mmol, 1eq), crotonic acid (1.154g, 13.4mmol, 2.5eq), DIEA (6.92g, 53.62mmol, 10eq), THF (10ml) to the original round bottom flask, evacuate the nitrogen gas, add Pd(PHCN)3Cl2 (102.8mg, 0.268mmol, 0.05eq), tri(o-tolyl)phosphine (81.6g, 0.26mmol, 0.05eq), acetic anhydride (1.68ml), protect it with nitrogen gas, heat it to 70℃, reflux, and react overnight. TLC (PE:EA=10:1) shows that all the raw materials have reacted completely. Cool, extract by adding 20 ml of 2N HCl, 10 ml of water, and 50 ml of EA, wash with NaHCO3, extract with EA (20 ml x 3), wash with saturated sodium chloride (20 ml x 2), dry over anhydrous sodium sulfate, vortex the sample, and pass through a column to obtain 892 mg of SM5.

[0148] Synthesis of SM4: SM3 (85 mg, 0.235 mmol, 1 eq), LiOH (16.9 mg, 0.705 mmol, 3 eq), MeOH (1.2 ml), HO (0.3 ml), THF (0.6 ml) were reacted under nitrogen gas for 4.5 h, which was shown to be complete by LC-MS. The reaction was cooled, spin evaporated, DCM was added and spin dried to give 80 mg of product.

[0149] Synthesis of SM5: SM4 (640 mg, 1.458 mmol, 1 eq), tributyl(1-ethoxyethylene)tin (789.8 mg, 52.187 mmol, 1.5 eq), Pd(PPh3)Cl2 (102.3 mg, 0.1458 mmol, 0.1 eq), DMF (13 ml) are placed in a round bottom flask, protected with nitrogen gas, heated to 120 °C, and refluxed for 30 min. TLC (PE:EA = 3:1) shows complete reaction of raw materials. Cool, add 15 ml water, filter through diatomaceous earth, extract with EA (30 ml x 3), wash with saturated sodium chloride (40 ml x 2), dry over anhydrous sodium sulfate, stir the sample, and pass through a column to obtain 363 mg of SM4.

[0150] Synthesis of SM6: SM5 (363 mg, 0.842 mmol, 1 eq), methanol (10 ml), HCl.1,4-dioxane (10 ml) were placed in a round bottom flask and protected with nitrogen gas at 25°C for 2.5 hours. TLC (PE:EA=3:1) showed complete reaction of the raw materials. Spin dry to give 312 mg of SM6.

[0151] Synthesis of SM7: SM6 (312 mg, 0.774 mmol, 1 eq), LiOH (55.6 mg, 2.322 mmol, 3 eq), MeOH (6 ml), HO (1.5 ml), THF (3 ml) were reacted overnight under nitrogen gas at 25° C. and TLC (DCM:MeOH=10:1) showed complete reaction. The reaction was cooled, spin-evaporated, 5 ml water and 2 ml 2N HCl were added, a large amount of white solid precipitated, filtered, and the filtrate was extracted with EA, washed with saturated NaCl, dried over anhydrous sodium sulfate, and spin-dried to give 280 mg of SM7.

[0152] Synthesis of T-276: SM7 (280mg, 0.72mmol, 1eq), pyridineethylamine (105.4mg, 0.864mmol, 1.2eq), HATu (237.8mg, 0.72mmol, 1eq), DIEA (185.8mg, 1.44mmol, 2eq) were added to 5ml DCM, protected with nitrogen gas, and reacted at room temperature overnight, TLC (EA) showed that the raw materials were completely reacted and the product was produced. The reaction solution was extracted with water and EA, washed with 0.5% citric acid, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and passed through a column to obtain 335mg of product. HPLC: 97%. 1 H NMR(400MHz,Methanol-d4)δ 8.55(d,J=2.0Hz,1H),8.50(dd,J=5.0,1.8Hz,1H),7.97(dd,J=8.5,2.8Hz,3H),7.80(td,J=7.7,1.8Hz,1H),7.58(d,J=8.1Hz,2H),7.46(d ,J=7.9Hz,1H),7.29(dd,J=7.6,5.0Hz,1H),6.74(d,J=8.9Hz,1H),5.27(q,J=7.1Hz,1H),2.58(s,3H),2.53(s,3H),1.60(d,J=7.1Hz,3H).

[0153] The following compounds are synthesized with reference to the synthesis method of Example T-276. [Table 9]

[0154] Example T-281 Compounds synthesized according to the present invention: [ka]

[0155] The synthetic route is as follows: [ka]

[0156] The experimental process is as follows. Synthesis of SM4: SM3 (2.54 g, 6.02 mmol, 1.2 eq), o-bromoacetophenone (1 g, 5.02 mmol, 1 eq), Pd(dppf)Cl2 (183.7 mg, 0.251 mmol, 0.05 eq), K2CO3 (1.385 mg, 10.04 mmol, 2 eq), methanol (10 ml), water (5 ml), and 1,4-dioxane (25 ml) were placed in a round-bottom flask, protected with nitrogen gas, heated to 90 °C, refluxed, and reacted overnight. TLC (PE:EA = 3:1) showed that most of the raw materials had reacted. Cool, add 15 ml of water, filter through diatomaceous earth, extract with EA (50 ml × 3), wash with saturated sodium chloride (50 ml × 2), dry over anhydrous sodium sulfate, stir the sample, and pass through a column to obtain 161 mg of SM4.

[0157] Synthesis of SM5: SM4 (161 mg, 0.393 mmol, 1 eq), Pd(OH)2 (20 mg, 0.142 mmol, 0.36 eq), and ethanol (3 ml) were placed in a round bottom flask, protected with nitrogen gas, and allowed to react at room temperature overnight. TLC (PE:EA=5:1) showed complete reaction of the raw materials. Filter through diatomaceous earth, stir the sample, and pass it through a column to obtain 100 mg of SM5.

[0158] Synthesis of SM6: SM5 (100 mg, 0.252 mmol, 1 eq), LiOH (18.1 mg, 0.756 mmol, 3 eq), MeOH (2 ml), HO (0.5 ml), THF (1 ml) were placed under nitrogen gas at 25° C. overnight and shown to be complete by TLC (DCM:MeOH=10:1). The reaction was cooled, spin evaporated, water and 2N HCl were added and a large amount of white solid precipitated, which was filtered to give 85 mg of SM6.

[0159] Synthesis of T-281 SM6 (85mg, 0.222mmol, 1eq), pyridineethylamine (32.5mg, 0.2664mmol, 1.2eq), HATu (84.4mg, 0.222mmol, 1eq), DIEA (57.3mg, 0.444mmol, 2eq) were added to 2ml DCM, protected with nitrogen gas, and reacted at room temperature overnight, TLC (PE:EA=1:3) showed that the raw materials were completely reacted and the product was produced. The reaction solution was extracted with water and EA, washed with 0.5% citric acid, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and 62mg of product was obtained by TLC. HPLC: 99.03%. 1 H NMR(400MHz,chloroform-d)δ 8.59(t,J=5.3Hz,1H),8.42(s,1H),7.93(d,J=7.8Hz,1H),7.78(d,J=7.2H z,1H),7.68(dt,J=15.6,6.7Hz,2H),7.54(d,J=8.4Hz,2H),7.44-7.38(m, 1H),7.32(q,J=8.6Hz,5H),7.13(d,J=7.5Hz,1H),5.38(dt,J=12.6,6.2Hz ,1H),5.03(q,J=6.7Hz,1H),1.62(d,J=6.7Hz,3H),1.40(d,J=6.7Hz,3H).

[0160] Example T-282 Compounds synthesized according to the present invention: [ka]

[0161] The synthetic route is as follows: [ka]

[0162] The experimental process is as follows. Synthesis of Sm2: SM1 (15 g, 59.18 mmol, 1.0 eq), p-trifluoromethylbenzeneboronic acid (16.86 g, 88.77 mmol, 1.5 eq), Mo(CO)6 (15.62 g, 39.18 mmol, 1.0 eq), potassium carbonate (24.54 g, 177.54 mmol, 3.0 eq), palladium acetate (398.59 mg, 1.78 mmol, 0.03 eq), and anisole (150 ml) were added in sequence to a 500 ml three-neck flask, evacuated, purged with nitrogen, and then heated to 105 °C and reacted for 16 hours. TLC (PE:EA=10:1, UV) showed that the raw materials were consumed.

[0163] Cool to room temperature, add 300ml of methanol to dilute the reaction system, then use a Buchner funnel to add diatomaceous earth and suction filter, wash the filter cake with methanol. After concentrating the filtrate at 45 degrees, add 300ml of EA and 300ml of water, separate the organic layer, extract the aqueous layer with EA (300ml x 2), combine the organic layers, add saturated sodium chloride to wash, and dry with sodium sulfate. After concentration, add 40g of silica gel, stir the sample, and pass it through a column to obtain 2.8g of SM2 (yellow oil).

[0164] Synthesis of SM3 SM2 (2.8g, 0.009mol, 1.0eq), cuprous bromide (2.68g, 0.0186mol, 2.0eq), and acetonitrile (50ml) are added to a 100ml reaction flask, and isoamyl nitrite (2.87g, 3.3ml, 0.0243mol, 2.7eq) is added dropwise at 0°C, then the mixture is heated to 50°C and reacted for 16 hours. TLC shows that a small amount of SM2 remains. The reaction is cooled to room temperature, diluted with EA (200 ml), and filtered using a Buchner funnel with the addition of diatomaceous earth. Water (200 ml) is added to the filtrate, the EA layer is separated, the aqueous layer is extracted with EA (200 ml x 2), the organic layers are combined and dried over saturated sodium sulfate, then concentrated and passed through a column to give 2.2 g of product SM3.

[0165] Synthesis of Sm4 SM3 (2.0 g, 5.5 mmol, 1.0 eq), pinacol borate (1.7 g, 6.6 mmol, 1.2 eq), anhydrous potassium acetate (1.6 g, 16.5 mmol, 3.0 eq), Pd(dppf)Cl2 (0.201 g, 0.28 mmol, 5%), and ultra-dry dioxane (20 ml) are added to a reaction flask, which is then evacuated, replaced with nitrogen gas, and heated to 100 °C for 16 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate, diatomaceous earth is added, and the mixture is suction filtered. The filtrate is concentrated, and then toluene:ethanol (6:1) is added in sequence and concentrated to give 2.2 g of SM4.

[0166] Synthesis of SM5 SM4 (1.38 g, 4.8 mmol, 1.0 eq), t-butyl (2-bromobenzyl)carbamate (2.8 g, 6.8 mmol, 1.4 eq), potassium carbonate (1.33 g, 9.7 mmol, 2.0 eq), Pd(dppf)Cl2 (0.177 g, 0.24 mmol, 5% eq) and dioxane / water (50 ml:5 ml) are added to the reaction flask, evacuated, replaced with nitrogen gas and reacted overnight. LCMS shows that the raw materials have reacted completely. Cool to room temperature, add EA (100 ml) and water (50 ml), separate the organic layer, extract the aqueous layer with EA (100 ml x 2), combine the organic layers, wash with saturated brine, dry, concentrate and pass through a column to obtain 800 mg of product.

[0167] Synthesis of SM6: Dissolve SM5 (540 mg) in methanol (2 ml), then add hydrochloric acid / dioxane (10 ml) and stir at room temperature overnight. TLC shows that the raw material has reacted completely (PE:EA=5:1). Dry the reaction solution, add saturated sodium bicarbonate solution, extract with EA, separate the organic layer, dry, concentrate and pass through a column to obtain 300 mg of product SM6.

[0168] Synthesis of SM7 Add SM6 (300 mg, 0.806 mmol, 1.0 eq), triethylamine (244 mg, 334 μL, 2.4 mmol, 3.0 eq), Pd(dppf)Cl2 (30 mg, 0.0403 mmol, 5%), and ethanol (35 ml) to the autoclave, then evacuate and replace with carbon monoxide. Heat to 100 °C and react for 24 hours. TLC shows that a small amount of raw material still remains. Cool to room temperature, add diatomaceous earth using a Buchner funnel, add EA to the filtrate to dilute it, then add silica gel (100-200 mesh, 3 g), stir the sample, and then use the host machine to separate and purify to obtain 200 mg of SM7 and 80 mg of raw SM6.

[0169] SM8 Synthesis Add SM7 (200mg, 0.) to the reaction flask, add THF / MeOH / H2O (4ml:2ml:1ml), then add lithium hydroxide (35.2mg, 1.46mmol, 3.0eq), then stir at room temperature overnight. TLC shows that the raw materials have reacted completely. Cool to room temperature, then add 5ml of water, add a few drops of concentrated hydrochloric acid to adjust the pH to acidic, and a white solid is precipitated, which is suction filtered to obtain 150mg of white solid.

[0170] TM synthesis: SM9 (150mg, 0.39mmol, 1.0eq), HATU (147.38mg, 0.387mmol, 1.0eq), DIEA (100mg, 141μL, 0.775mmol, 2.0eq), DCM (2ml) are added to the reaction tube and stirred at room temperature for 10 minutes, then (S)-1-(pyridin-2-yl)ethan-1-amine (56.82mg, 0.465mmol, 1.2eq) is added and reacted at room temperature overnight. Lcms indicates that the raw materials have reacted completely. The reaction is diluted with DCM (10ml), then washed with 0.5% citric acid and saturated saline. Dry, concentrate and pass through a column to obtain 161mg of a white solid. 1HNMR(400MHz,MeOD)δ 8.55-8.50(t,1H),8.39-8.35(d,1H),7.96-7.89(m,2H),7.86-7.78(m,1H),7.70-7.68(d,2H),7.61-7.59(d,2H) ,7.55-7.47(m,4H),7.43-7.41(d,1H),7.34-7.31(m,1H),5.33-5.31(q,1H),3.98-3.96(d,1H),1.64-1.62(q,3H)

[0171] Example T-283 Compounds synthesized according to the present invention: [ka]

[0172] The synthetic route is as follows: [ka]

[0173] The experimental process is as follows. Synthesis of SM2 SM1 (5.3 g, 0.05 mol, 1.0 eq), benzaldehyde (9.46 g, 0.055 mol, 1.1 eq) and ethanol (75 ml) are added to the reaction flask, evacuated, replaced with nitrogen gas, then heated to 80 °C and reacted for 3.5 hours, cooled to room temperature, added NaBH4 (2.28 g, 0.06 mol, 1.2 eq) in batches under ice bath, then stirred at room temperature overnight. The reaction system is poured into a 1 L Erlenmeyer flask, slowly added with 1N HCl (200 ml), extracted with EA (150 ml × 3), washed with saturated saline, dried, concentrated to obtain the crude product. Then 20 ml of methanol and 100 ml of HCl / dioxane solution are added, stirred at room temperature overnight, and the solvent is spin-dried after removing the hydrochloric acid gas with a water pump to obtain SM2 (11.6 g, white solid SM2).

[0174] Synthesis of SM3 Using an electric heating mantle, distill the purchased dicyclopentadiene at 180 °C under atmospheric pressure and collect the 40-42 °C fraction to obtain cyclopentadiene monomer for the synthesis of SM3. Add SM2 (5.5g), methanol (55ml) and cyclopentadiene (3.3g) and formaldehyde aqueous solution (2.86g) into a 250ml three-neck flask at about 0℃, then react at room temperature for 72 hours, TLC (PE:EA=10:1) shows that the raw materials are completely reacted and white solids are precipitated. Suction filter using a sand core funnel, and dry the filter cake using a vacuum drying oven at 25℃ to obtain the target product (about 2.6g).

[0175] Synthesis of SM4: 2 batches. SM3 (425mg, 1.25mmol, 1.0eq), anhydrous potassium phosphate (1.59g, 7.49mmol, 5.0eq), palladium acetate (20.19mg, 0.09mmol, 8%), (S)-1-(pyridin-2-yl)ethan-1-amine (457.79mg, 3.75mmol, 3.0eq), DMAP (302.72mg, 2.5mmol, 2.0eq), Mo(CO)6 (108.16mg, 0.409mmol, 0.32eq), Xantphos (106.96mg, 0.184mmol, 14%eq), dioxane (10ml) were added to a 30ml microwave reaction tube, then reacted at 120°C for 20 minutes, TLC (PE:EA=1:1) shows the raw materials are completely reacted. Cool to room temperature and combine the two batches of reaction liquids. Add EA (100 ml) and water (50 ml), separate the EA layer, extract the aqueous layer with EA (50 ml x 2), combine the organic layers, wash with saturated sodium chloride solution, dry over sodium sulfate, concentrate, and pass through a host machine column to obtain 630 mg of SM4 (yellow solid).

[0176] Synthesis of SM5 SM4 (200 mg) is added to ethanol (10 ml), then palladium hydroxide (30 mg, w / w 15%) is added, 0.2 ml of 2N HCl is added, and the mixture is evacuated and purged with nitrogen gas three times, then evacuated and purged with hydrogen gas three times (hydrogen balloon). The mixture is heated to 80°C and refluxed for 19 hours, and TLC shows that the raw materials are completely reacted (PE:EA=1:1). The mixture is cooled to room temperature, EA (30 ml) is added, diatomaceous earth is added, and the mixture is filtered with suction, then silica gel is added to the filtrate, the sample is stirred, and the mixture is passed through a column using a column passer to obtain SM5 (60 mg, white solid).

[0177] Synthesis of T-283 SM5 (60mg, 0.186mmol, 1.0eq), p-trifluoromethylbromobenzene (50.4mg, 0.224mol, 1.2eq), cesium carbonate (121.64mg, 0.373mmol, 2.0eq), palladium acetate (2.1mg, 0.01mmol, 5%eq), Xantphos (10.8mg, 0.018mmol, 10%eq) and anhydrous dioxane (1ml) were added to the reaction tube, then heated to 105°C for 16 hours, TLC shows that the raw materials were completely reacted. The reaction solution was cooled to room temperature, 1ml water was added, extracted with EA (6ml x 2), then separated by PTLC to give SM6 (28mg, white solid). 1 HNMR(400MHz,CDCl3)δ 8.50-8.49(d,1H),8.39-8.35(d,1H),7.71-7.51(m,2H),7.49-7.44(m,3 H),7.41-7.36(d,1H),7.257.23(d,2H),7.157.12(m,2H),6.926.86(m,1H ),5.295.25(m,1H),4.04-3.50(m,1H),3.20-3.07(d,1H),2.43-2.26(m, 2H),1.96-1.87(m,2H),1.74-1.60(m,2H),1.49(m,3H),1.40-1.26(m,2H)

[0178] Example T-285 Compounds synthesized according to the present invention: [ka]

[0179] The synthetic route is as follows: [ka]

[0180] The experimental process is as follows. Synthesis of SM2: Compound SM1 (1g, 1.0eq), p-trifluoroaniline (728mg, 1.28eq), Cs2CO3 (1.71g, 1.5eq), Pd(OAc)2 (39mg, 0.05eq), and Xantphos (506mg, 0.25eq) are dissolved in dioxane (20mL) and stirred at 105℃ for 14 hours under N2 protection, until the raw materials are almost completely reacted. Work-up: Add EA to the reaction solution to dilute, add a small amount of water, and extract with EA to obtain an organic phase, wash with saturated saline, dry with anhydrous sodium sulfate, and concentrate the filtrate to dryness to obtain crude product SM3 (1.02g).

[0181] Synthesis of SM3 Compound SM2 (200 mg, 1.0 eq), crotonic acid (137 mg, 2.5 eq), DIEA (813 mg, 10 eq) were added to THF, and after replacing with N2, Pd(PhCN)2Cl2 (12 mg, 0.05 eq) and 3(tolyl)phosphorus (10 mg, 0.05 eq) were added and reacted at 70 ° C overnight. The raw material was almost completely reacted, but many uncyclized products were generated, so acetic anhydride (0.2 mL) was added to promote the ring-closing reaction, and after 1 hour, most of the products were ring-closed. LCMS shows that it was accurate. Work-up: The reaction solution was diluted with EA, a small amount of water was added, and the organic phase was obtained, washed with saturated saline, dried with anhydrous sodium sulfate, and the filtrate was concentrated to dryness to obtain crude product SM3 (126 mg).

[0182] Synthesis of SM4 Compound SM3 (6.0 g, 1.0 eq) and NBS (7.13 g, 2 eq) were added to acetonitrile (60 mL), and after replacing with N2, the mixture was reacted at 90 ° C overnight. The raw materials were almost completely reacted, and LCMS showed that the reaction was accurate. Work-up: The reaction solution was diluted with EA, a small amount of water was added, and the organic phase was extracted with EA. The organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, and SM4 (7.42 g) was obtained by column chromatography PE → PE:EA = 50:1 → 20:1 → 10:1.

[0183] Synthesis of SM5 Compound SM4 (4g, 1.0eq), tributyl(1-ethoxyethylene)tin (5.67g, 1.5eq), Pd(PPh3)Cl2 (738mg, 0.1eq) were added to DMF (40mL) and reacted at 120℃ overnight after replacing with N2. The raw materials were almost completely reacted and the LCMS showed accurate. Work-up: The reaction solution was diluted with EA, a small amount of water was added, and the organic phase was extracted with EA, washed with saturated saline, dried with anhydrous sodium sulfate, and passed through a column (PE:EA=5:1) to obtain SM5 (970mg). 1 The accuracy is shown by HNMR.

[0184] Synthesis of SM6 Compound SM5 (970 mg, 1.0 eq) was added to MeOH (10 mL), and hydrochloric dioxane (10 mL) was added. After overnight reaction at room temperature, the raw material was almost completely reacted and the LCMS showed accurate. Work-up: The reaction solution was directly spin-dried to obtain crude product SM6 (728 mg).

[0185] Synthesis of SM7 Compound SM6 (728 mg, 1.0 eq) was added to MeOH (5 mL), sodium borohydride (200 mg, 2.5 eq) was added under ice bath, and the mixture was allowed to react at room temperature. The subsequent reaction did not proceed, so sodium borohydride was added up to 10 equivalents. After 30 minutes, the raw material was almost completely reacted, and LCMS showed that the reaction was accurate. Work-up: The reaction solution was diluted with EA, a small amount of water was added, and the organic phase was extracted with EA, which was washed with saturated saline and dried over anhydrous sodium sulfate to obtain crude product SM7 (734 mg). 1H NMR showed that the reaction was accurate.

[0186] SM8 Synthesis Compound SM7 (690 mg, 1.0 eq), phthalimide (438 mg, 1.5 eq), triphenylphosphine (1.563 g, 3 eq) are added to THF (15 mL), DEAD (865 mg, 2.5 eq) is added under ice bath, and the mixture is allowed to react at room temperature. After the weekend, the raw materials are almost completely reacted and a new point is generated. Work-up: The reaction solution is directly spin-dried and passed through a column (PE:EA = 5:1) to obtain product SM8 (2.55 g).

[0187] Synthesis of SM9 Compound SM8 (2.5 g, 1.0 eq) and hydrazine hydrate (2.683 g, 10 eq) were added to EtOH (25 mL) and refluxed overnight. Work-up: The reaction solution was directly spin-dried and subjected to column chromatography to obtain crude product SM9 (327 mg).

[0188] Synthesis of T-285 Compound SM9 (166 mg, 1.0 eq), TEA (145 mg, 3 eq) were added to DCM (1 mL), and acryloyl chloride (50 mg, 1.15 eq) was added dropwise under ice bath, and the mixture was allowed to react at room temperature overnight. The reaction materials were almost completely reacted, and the reaction was performed accurately by LCMS. Work-up: The reaction solution was directly spin-dried, and the product T-285 (33 mg) was obtained by column chromatography (PE → PE:EA = 5:1 → PE:EA = 2:1 → 1:1).

[0189] 1H NMR (400MHz, chloroform-d) δ 7.89(ddd,J=7.7,6.2,2.1Hz,3H),7.71(d,J=9.4Hz,1H),7.50-7.39(m,2H),7 .35(ddd,J=8.5,7.1,1.5Hz,1H),7.31-7.28(m,1H),6.61(dd,J=8.3,1.3Hz,1H ),6.26(dd,J=17.0,1.6Hz,1H),6.06(dd,J=16.9,10.2Hz,1H),5.83(dq,J=9.4 ,7.0Hz,1H),5.60(dd,J=10.2,1.5Hz,1H),2.72(s,3H),1.54(d,J=7.0Hz,3H).

[0190] Example T-412 Compounds synthesized according to the present invention: [ka]

[0191] The synthetic route is as follows: [ka]

[0192] The experimental process is as follows. Synthesis of T-412-2 Compound T-412-1 (20 g, 1.0 eq), p-trifluoroaniline (12.12 g, 1.28 eq), Cs2CO3 (28.75 g, 1.5 eq), Pd(OAc)2 (660 mg, 0.05 eq), and Xantphos (850 mg, 0.25 eq) are dissolved in dioxane (400 mL) and stirred at 105 °C for 14 hours under N2 protection, until the raw materials are almost completely reacted. Work-up: Add EA to the reaction solution to dilute, add a small amount of water, and extract with EA to obtain an organic phase, wash with saturated saline, dry with anhydrous sodium sulfate, and concentrate the filtrate to dryness, and purify (PE → PE:EA = 50:1) to obtain the crude product T-412-2 (20.7 g). Note: If the purity of T-412-2 is not sufficient, hydrolysis and esterification strategies can be adopted, and the 1H NMR shows that it is accurate.

[0193] Synthesis of T-412-3 Compound T-412-2 (10.6 g, 1.0 eq), crotonic acid (6.11 g, 2.5 eq), DIEA (36.09 g, 10 eq) were added to THF (53 mL), and after replacing with N2, Pd(PhCN)2Cl2 (545 mg, 0.05 eq) and 3(tolyl)phosphorus (432 mg, 0.05 eq) were added and reacted at 70 ° C overnight. The raw material was almost completely reacted, but many uncyclized products were generated, so acetic anhydride (8.9 mL) was added to activate and promote the ring closure of the reaction, and after 2 hours, all the ring-closed products were generated. LCMS shows that it was accurate. Work-up: Add EA to dilute, add a small amount of water, extract with EA to obtain the organic phase, wash with saturated saline, dry with anhydrous sodium sulfate, and concentrate the filtrate to dryness, pass through a column (PE:EA = 5:1) to obtain the crude product T-412-3 (4.6 g).

[0194] Synthesis of T-412-4 Compound T-412-3 (4.6g, 1.0eq), LiOH (917.5mg, 3.0eq) was dissolved in MeOH / THF / H2O (76ml / 38mL / 19mL), protected with N2 at 50℃, stirred at room temperature for 14 hours, the raw material was almost completely reacted, and LCMS showed accurate. Workup: Add EA to the reaction solution to dilute, add a small amount of water, separate to obtain aqueous layer (in this case, the product in the aqueous phase is a salt), add 1NHCl to the aqueous phase to adjust to about ph=3, extract with EA to obtain organic phase (in this case, the product is in the organic phase), wash with saturated saline, dry with anhydrous sodium sulfate, and concentrate the filtrate to dryness to obtain crude product T-412-4 (3.9g). LCMS accurate.

[0195] Synthesis of T-412-5 Compound T-412-4 (3.9 g, 1.0 eq), DPPA (4.33 g, 1.4 eq), Et3N (2.04 g, 1.8 eq) were added to t-butanol (80 mL) and reacted at 90 °C overnight, and the raw materials were almost completely reacted, and the LCMS showed that the reaction was accurate. Work-up: The reaction solution was diluted with EA, a small amount of water was added, and the organic phase was extracted with EA, washed with saturated saline, dried with anhydrous sodium sulfate, and passed through a column (PE:EA = 5:1) to obtain T-412-5 (944 mg). The 1H NMR showed that the reaction was accurate.

[0196] Synthesis of T-412-6 Compound T-412-5 (944 mg, 1.0 eq) was added to MeOH (15 mL), and 4M hydrochloric acid dioxane (15 mL) was added under ice bath, and the reaction was allowed to proceed overnight until the raw material was almost completely reacted. Work-up: Directly spin-dried to obtain crude product T-412-6 (709 mg).

[0197] Synthesis of T-412 Compound T-412-6 (709 mg, 1.0 eq), TEA (684 mg, 3 eq) are added to DCM (15 mL), acryloyl chloride (244 mg, 1.15 eq) is added dropwise under ice bath, and the mixture is allowed to react at room temperature overnight, showing that the raw material is almost completely reacted and accurate by LCMS. Work-up: The reaction solution is directly spin-dried, and the product T-425 (536 mg) is obtained by column chromatography. After purification, 363 mg of 93.3% purity is obtained, and after crystallization, 160 mg of 97.6% purity is obtained, and the remaining mixed product is 220 mg. 1 H NMR(400MHz,DMSO-d6)δ 10.30(s,1H),8.15(d,J=2.4Hz,1H),8.00(d,J=8.2Hz,2H),7.93(d,J=1.4Hz,1H),7.60(d,J=8.1Hz,2H),7.49(dd,J=9.1,2.4Hz, 1H),6.47(d,J=9.3Hz,1H),6.45-6.37(m,1H),6.26(dd,J=17.0,2.1Hz,1H),5.76(dd,J=10.0,2.1Hz,1H),2.15(d,J=1.2Hz,3H).

[0198] The following compounds are synthesized with reference to the synthesis methods of Examples T-243 and T-412. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

[0199] The experimental process of the biological activity test is as follows: Test Example 1. Cell proliferation inhibition experiment Measurement of YAP-TEAD inhibitor compounds for growth inhibition of human pleural mesothelioma cells NCI-H226 Experimental materials and equipment: Human pleural mesothelioma cells NCI-H226 are purchased from Cobioer Biosciences C., LTD. RPMI-1640 medium (Bio-Channel), DMSO (dimethyl sulfoxide), CCK8 (WST-8) cell analysis kit (Beyotime), 0.25% EDTA-trypsin (trypsin digestion solution), 1xPBS (phosphate buffer, PH7.2), 96-well plate (Corning), fetal bovine serum (FBS), 10000U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF5810R), enzyme-linked immunosorbent assay detector (Tecan Spark).

[0200] Experimental preparation: 1. Cell plating A) Under conditions of 37 °C, 5% CO2 and saturated humidity, tumor cells are cultured in RPMI-1640 (containing 10% FBS and 100 U / mL penicillin-G / streptomycin) to a density of 80-90%. B) Removal of medium from the 10 cm culture dish. C) Rinse the cells once with 10 ml of 1xPBS. D) Add 4 ml of 0.25% EDTA-trypsin, place in a 37°C, 5% CO2 incubator to digest trypsin for 5 minutes, transfer to a 15 ml centrifuge tube, centrifuge at 200 g for 5 minutes, discard the supernatant, and obtain cell pellets. E) Resuspend in 4 ml of DMEM medium, count and adjust to 10,000 cells / ml. F) The cell suspension is added to a 96-well plate at a volume of 100 μL per well and incubated overnight in a 37° C., 5% CO2 incubator.

[0201] 2. Compound Treatment Compound dilution A) Preparation of gradient dilution solution of test compound: Test compound is prepared as 1 mM stock solution. Then 1.5 μl of stock solution is dissolved in 1.5 ml of DMSO-free medium, and serial dilution is performed with 0.1% DMSO medium for 3 times total 9 concentrations, and the concentration of the compound after dilution is as follows: 333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM, 0.15nM B) After thorough mixing, take 100 μL of each compound solution and replace the culture medium in the cell culture plate, and prepare four duplicate wells for each concentration. C) The cells are transferred to an incubator and incubated for 3 days.

[0202] 3. Analysis and detection of CCK8 (WST-8) cells A) Take out the cell culture plate and add 10 μL of CCK-8 (WST-8) solution to each well in a biosafety cabinet. B) The cell culture plate was returned to the incubator and incubated for another 3 hours. C) Measure the absorbance value by selecting a wavelength of 450 nm with a TECAN enzyme-linked immunosorbent assay detector.

[0203] 4. Data Analysis Calculate % Cell Viability using the following formula: Cell viability (%) = [A(medication) - A(blank)] / [A(0-medication) - A(blank)] x 100 A (Dosing): Absorbance of wells with cells, CCK8 solution and drug solution A (blank): absorbance of wells with medium and CCK8 solution but no cells A (0 dose): Absorbance of wells with cells, CCK8 solution but no drug solution Cell viability:cell proliferation or cytotoxicity activity are curve fitted using GraphPad Prism 8 software to obtain IC50 values.

[0204] Experimental Example 2. Nanoluciferase method for detecting YAP-TEAD inhibitor activity (1) Experimental materials and equipment: 293T cells are purchased from Cobioer Biosciences C., LTD. DMEM medium (high sugar, no phenol red, Bio-Channel), DMSO (dimethyl sulfoxide), Lipo6000TM transfection reagent (Beyotime), pGL3B-8xGTiiC-nLuc-CMV-fLuc plasmid, 0.25% EDTA-trypsin (trypsin digestion solution), 1xPBS (phosphate buffer, PH7.2), 96-well white cell culture plate (PerkinElmer), fetal bovine serum (FBS), 10000U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF5810R), 37℃, CO2 incubator, Vi-cellR cell counter, Envision microplate reader (PerkinElmer).

[0205] reagent [Table 11]

[0206] (2) Transient transfection of 293T cells Seed the recovered 293T cells into a 10 cm culture dish and place them in a 5% CO incubator and culture them at a constant temperature of 37 °C. To ensure transfection efficiency, cells that are in the logarithmic phase (cell density approximately 50%-70%) should be used.

[0207] The day before transfection, digest log-phase cells with trypsin-EDTA, add media to stop the reaction, and mix by pipetting to prepare a cell suspension. Measure cell concentration using Vi-cell and dilute to a suspension of 5 x 10^5 cells per mL. After preparing the cell suspension, mix gently and add 10 mL of liquid to a 10 cm culture dish. Thus, the number of cells per 10 cm culture dish is 5 x 10^6. Incubate for 1 day at a constant temperature of 37°C in a 5% CO2 incubator.

[0208] Take two clean sterile centrifuge tubes and add 750 μL of antibiotic- and serum-free opti-MEM Medium to each, then add 15 μg of plasmid (pGL3B-8xGTiiC-nLuc-CMV-fLuc) to one of the tubes and mix by gently pipetting with a pipette, add Lipo6000 transfection reagent to the other tube and mix by gently pipetting with a pipette. After leaving it at room temperature for 5 minutes, gently add the DNA-containing culture to the Lipo6000 transfection reagent-containing culture, gently mix by inverting the centrifuge tube, and leave it at room temperature for 5 minutes. The above mixture was evenly dropped onto a 10 cm culture dish and cultured for 6 hours, after which the medium was replaced with fresh complete medium.

[0209] (3) Plating on 96-well plates One day after transfection, digest the cells with trypsin-EDTA, add medium to stop the reaction, and mix by pipetting up and down to prepare a cell suspension. Measure cell concentration using Vi-cell and dilute to a suspension of 20,000 cells per mL. After preparing the cell suspension, mix gently and add 100 μL to each well of a 96-well plate, and the density of cells to be tested is 2000 cells per well.

[0210] (4) Addition of compounds The seeded cell culture plates are placed in an incubator for incubation and the gradient compounds are added after approximately 24 hours. Dilute 10 mM compound stock solutions to 50 μM with medium, and sequentially add 50 μM compound solutions to the third column of a deep-well plate, and then add 216 μL of 0.5% DMSO-containing medium to columns 4 to 11. Gradient dilution: Take 100 μL of the solution from column 3 and add it to column 4, mix well, then take 100 μL of the solution from column 4 and add it to column 5, and repeat the process up to column 11. Using a multichannel pipette, remove 25 μL of compound solution from the deep well plate and add it to a 96-well culture plate, repeating each compound four times in the 96-well plate, and finally form a 1:3.16 concentration gradient on the 96-well plate with a maximum concentration of 10,000 nM.

[0211] (5) Addition of nanoluciferase detection reagent and reading The 96-well plates are incubated in a 5% CO2 incubator at a constant temperature of 37° C. for 48 hours, then removed and equilibrated to room temperature for 10 minutes. Add 100 μL of detection reagent to each well and shake on a horizontal shaker at low speed for 10 minutes to completely lyse the cells. Detect the fluorescence value of each well using a PerkinElmer Envision microplate reader.

[0212] (6) Calculation of results 0 nM was used as a control, and the values ​​for each well were converted to percentages. Nonlinear fitting was performed using [Inhibitor] vs. response (three parameters) in GrahpPad prism software to obtain the IC 50 Calculate.

[0213] As shown in Table 1, where A≦1 μM, 1 μM <B<5μM、C≧5μM [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8] [Table 12-9] [Table 12-10] [Table 12-11] [Table 12-12] [Table 12-13] [Table 12-14] [Table 12-15] [Table 12-16]

Table 12-17

Table 12-18

Table 12-19

Table 12-20

Table 12-21

Table 12-22

Table 12-23

Table 12-24

Table 12-25

Table 12-26

Table 12-27

Table 12-28

Table 12-29

Table 12-30

Table 12-31

Table 12-32

Table 12-33

Table 12-34

Table 12-35

Table 12-36

Table 12-37

Table 12-38

Table 12-39

Table 12-40

Table 12-41

Table 12-42

Table 12-43

Table 12-44

Table 12-45

Table 12-46

Table 12-47

Table 12-48

Table 12-49

Table 12-50

Table 12-51

Table 12-52

Table 12-53

Table 12-54

Table 12-55

Table 12-56

Table 12-57

Table 12-58

Table 12-59

Table 12-60

Table 12-61

Table 12-62

Table 12-63

Table 12-64

Table 12-65

Table 12-66

[0214] As can be seen from Table 1, most of the compounds of the present invention have very good inhibitory effects on human pleural mesothelioma cells NCI-H226.

[0215] Test Example 3. Pharmacokinetics of Compounds Pharmacokinetic study of the compounds of the present invention T-32 / T-105 / T-253 / T-272 / T-273 / T-277.

[0216] Pharmacokinetics Experimental Protocol in Rat (1) Animals required: 3 healthy adult SD rats, male, 6-8 weeks old, weighing 200-300 g. (2) Equipment required: analytical balance, animal weighing scale, magnetic stirrer, refrigerated centrifuge, single-channel manual pipette, etc. (3) Required reagents: EDTA-Na2 anticoagulant, etc. Weigh out 11.2 g of EDTA-Na2 and place it in a reagent bottle, add 100 mL of saline, and shake until completely dissolved. After preparation, place 20 uL into each 1.5 mL centrifuge tube to collect whole blood samples.

[0217] (3) Accurately weigh out approximately 10 mg of test sample, dissolve in 5% DMSO after conversion, add 30% PEG400 and 65% (10% Hp-β-CD in PBS), sonicate, and vortex to mix to obtain a solution with a concentration of 1 mg / mL, and prepare fresh before use. (4) A 0.1 mL sample is taken in a 1.5 mL centrifuge tube, stored at -80°C, and used to analyze the concentration of the dosing solution.

[0218] (5) The animals are kept in rat cages and fasted (for at least 10 hours) from the day before the test, but water is not prohibited. On the day of the test, each animal is weighed and its tail is marked. Blank blood is collected from each animal before administration. Blood is collected from the tail vein. (6) Route of administration: intragastric administration (po), dosage: 10 mg / kg, dosage volume: 10 mL / kg.

[0219] (7) Procedure: Hold the rat upright with the left hand wearing a bite-resistant glove, insert a No. 16 gavage needle into its mouth and throat, test the needle under the condition that no obvious resistance is encountered, and inject the drug into the stomach. (8) Before administration and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration, 0.2 ml of whole blood is collected from the test animals into EDTA-Na2 anticoagulant tubes, mixed by inverting upside down 3 to 4 times, centrifuged at 10,000 g for 5 minutes at 4°C, to separate the plasma, which is then stored at -80°C until testing. Blood is collected via the tail vein.

[0220] (9) Establish an LC-MS / MS method to measure the drug substance concentration in plasma, plot the blood drug concentration-time curve, and calculate the main pharmacokinetic parameters using a noncompartmental model. (10) The pharmacokinetic parameters of T-32 / T-105 / T-253 / T-272 / T-273 / T-277 are specifically as shown in Table 2 below. [Table 13]

[0221] Here, the control compound 1 is a compound with the most excellent properties disclosed in Patent WO2020097389A1, and the structural formula of the compound is as follows: [ka]

[0222] All documents mentioned in the present invention are incorporated by reference in this application as if each document was incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalents are also included in the scope defined by the appended claims of this application.

Claims

1. A compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, 【Chemistry 1】 Where: A has the following formula: 【Chemistry 2】 is selected from L １ is absent, B is selected from a C6-C10 aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, and a C5-C10 cycloalkyl group; X is O; X １ is selected from CR 3 and N; X ２ is selected from CR 3 , N, O, S, and NR 4 ; X ３ is selected from CR 3 and N; X ４ is selected from CR 3 and N; X ６ is selected from CR 3 and N; X ７ is selected from CR 3 and N; R １ are each independently represented by the following formula: 【Chemistry 3】 is selected from Each R ２ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, and SF 5 ; Each R ３ and R4 are each independently H, D, halogen, CN, NH ２ , -CO-(C １－６ alkyl), =O, -C(=O)-O-(C1-C6 alkyl), -S(=O) ２ -NR ６ R ７ , based on the following formula: 【Chemistry 4】 Urea group, C １－６ Alkyl group, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ Cycloalkoxy groups, C6-C10 aryl groups, 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O and S, and SF ５ wherein NH ２ , urea group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ Cycloalkoxy groups, C6-C10 aryl groups, and 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O and S are optionally substituted by 1, 2 or 3 R; R ６ and R ７ are each independently hydrogen, D, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C6-C10 aryl group, NH ２ , NH(C １－６ Alkyl), N(C １－６ Alkyl) ２ , a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, -S(O) ２ - (C １－６ alkyl), and -S(O) ２ - (C ２－６ alkenyl), wherein C １－６ Alkyl group, C ３－６ Cycloalkyl groups, and C6-C10 aryl groups are optionally substituted by 1, 2 or 3 R or R ６ and R ７ forms a 3- to 7-membered carbocyclic ring, or R ６ and R ７ forms a 3- to 7-membered heterocyclic ring containing N, O or S, Each R is a halogen, CN, OH, -(C １－６ alkylene)-N(C １－６ Alkyl) ２ , N.H. ２ , NH(C １－６ alkyl), urea group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ Cycloalkoxy group, C ２－６ Alkenyl group, C ２－６ alkynyl groups, C6-C10 aryl groups, 5-10 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O and S, and R' substituted or unsubstituted 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O and S, where R' is independently selected from C １－６ Alkyl groups, halogenated C １－６ Alkyl group, C １－６ Alkoxy group, NH ２ , NH(C １－６ Alkyl), N(C １－６ Alkyl) ２ , CN, halogen, and ═O; each m and n is independently selected from 1, 2, 3, and 4; A compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, characterized in that p is selected from 0, 1 and 2.

2. A has the following formula: 【Chemistry 5】 is selected from L １ is absent, B is a C6-C10 aryl group; X is O; X １ is selected from the group consisting of CR 3 and N; X ２ is selected from the group consisting of CR 3 , N and NR 4 ; X ３ is selected from the group consisting of CR 3 and N; X ４ is selected from the group consisting of CR 3 and N; X ６ is selected from the group consisting of CR 3 and N; X ７ is CR ３ and N, R １ is the following formula: 【Chemistry 6】 is selected from Each R ２ are each independently selected from C 1-6 alkyl; Each R ３ and R4 are each independently H, halogen, CN, NH ２ , -CO-(C １－６ Alkyl), C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ is selected from a cycloalkoxy group, a C6-C10 aryl group, and a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, where NH ２ , C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ Cycloalkoxy groups, C6-C10 aryl groups, and 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O and S are optionally substituted by 1, 2 or 3 R; R ６ and R ７ are each independently hydrogen, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C6-C10 aryl group, -S(O) ２ - (C １－６ alkyl), and -S(O) ２ - (C ２－６ alkenyl), wherein C １－６ Alkyl group, C ３－６ Cycloalkyl groups, and C6-C10 aryl groups are optionally substituted by 1, 2 or 3 R or R ６ and R ７ forms a 3- to 7-membered carbocyclic ring, or R ６ and R ７ forms a 3- to 7-membered heterocyclic ring containing N, O or S, Each R is halogen, CN, OH, NH ２ , C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ Cycloalkoxy group, C ２－６ Alkenyl group, C ２－６ independently selected from alkynyl groups, C6-C10 aryl groups, and 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O and S; each m and n is independently selected from 1, 2, 3, and 4; p is selected from 0, 1 and 2; 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

3. The compound is represented by formula III: 【Chemistry 7】 wherein L 1 , B, X, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , n and p are as defined in claim 1 .

2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

4. The compound has the following formula: 【Chemistry 8】 is selected from the group consisting of R １ is expressed as follows: 【Chemistry 9】 is selected from characterised in that B, X, X1, X2, X3, X4, X6, X7, R6, R7, R2, R3 and n are as defined in claim 1, 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

5. R ２ is selected from the group consisting of a trifluoromethyl group, a methyl group, and a sulfur pentafluoride group; 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

6. A compound comprising: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 or a pharma- ceutically acceptable salt or solvate thereof, selected from the group consisting of:

7. 1. A pharmaceutical composition comprising:

13. A pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a safe and effective amount of one or more compounds according to claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

8. A pharmaceutical composition according to claim 7 for use in the preparation of a medicament for preventing and / or treating an associated disease due to dysregulation of the Hippo pathway, comprising: The pharmaceutical composition, wherein the disease is selected from the group consisting of lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, uterine cancer, and pleural mesothelioma.

9. A pharmaceutical composition according to claim 7 for use in the preparation of a medicament for preventing and / or treating an associated disease due to YAP or TAZ or YAP / TAZ or YAP / TEAD or YAP / TAZ / TEAD dysregulation, comprising: The pharmaceutical composition, wherein the disease is selected from the group consisting of lung cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, uterine cancer, and pleural mesothelioma.

10. Use of a compound according to claim 1, or a pharma- ceutically acceptable salt or solvate thereof, in combination with a second drug for the preparation of a medicament for preventing and / or treating cancer, comprising: The above-mentioned use, wherein the second drug is selected from the group consisting of an ERK inhibitor, a MEK inhibitor, a KRAS inhibitor, a BRAF inhibitor, an EGFR inhibitor, a Wnt inhibitor, a PD-1 inhibitor, and combinations thereof.

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