Polycyclic compounds and their uses

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, and more specifically to polycyclic compounds used to modulate the Hippo pathway, which are mainly used for the treatment or prevention of proliferative disorders (e.g., cancer), and in particular for the regulation and treatment of related diseases due to abnormal activity of YAP / TEAD, as well as methods for their preparation and use. [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 scaffold protein Salvador, and the large tumor inhibitor kinases LATS1-2, as well as the inhibitory transcriptional coactivators YAP (Yes1-related protein) and TAZ (transcriptional coactivator with a PDZ-binding motif). YAP and TAZ are major effectors of the Hippo signaling pathway, and together with the nuclear TEAD (transcriptionally enhanced binding domain), they act as transcription factors, thereby increasing the expression of target genes such as CTGF (connective tissue growth factor) and CYR61. The Hippo pathway is a crucial regulator of cell growth, proliferation, and migration. The TEAD transcription factor is located at the core of the Hippo pathway and is critical to the regulation of organ growth and wound repair. Dysregulation of TEAD and its regulatory cofactor Yes-related protein (YAP) are involved in the pathological processes of many human cancers and hyperproliferations, and dysregulation of this pathway is frequently detected in human cancers. Similar to the TEAD protein, activation of YAP and TAZ has been observed in many human tumors and is important for tumor development, progression, and metastasis. For example, elevated YAP expression is observed in patients with breast, ovarian, colon, liver, and pancreatic cancers and is associated with decreased survival rates. Consistently, 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 signaling for YAP / TAZ-TEAD complex formation or intervening to inhibit the expression of many mitotic TEAD target genes can significantly reduce cell proliferation and oncogenic transformation activity. Furthermore, the Hippo pathway crosstalks with other signaling pathways such as Wnt, Notch, Hedgehog, and MAPK, thereby influencing various biological functions, and its dysfunction may be involved in many diseases in addition to cancer. Therefore, the YAP-TEAD complex is a promising therapeutic target. [Overview of the project] [Problems that the invention aims to solve]

[0003] The object of the present invention is to provide a compound represented by formula I, as well as a method for preparing and using the same. [Means for solving the problem]

[0004] A first aspect of the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [ka] Here, A is [ka] Selected from, L1 is either absent or selected from 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, and (CR3R4)2. R1 independently consists of H, D, halogen, CN, NH2, urea group, carboxyl group, urethane group, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, C6-C10 aryl group, 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S, [ka] Selected from, where NH2, ester group, urea group, urethane group, amide group, C1-6 An alkyl group, C 1-6 An alkoxy group, C 3-6 A cycloalkyl group, C 3-6 A cycloalkoxy group, a C6-C10 aryl group, a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S is 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,

Chemical formula

[0005] In another preferred example, A is [ka] Selected from, L1 is either absent or selected from 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, carboxyl group, urethane group, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, C6-C10 aryl group, 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S, [ka] Selected from, where NH2, ester group, urea group, urethane group, amide group, C 1-6 Alkyl alkyl group, C 1-6An alkoxy group, C 3-6 A cycloalkyl group, C 3-6 A cycloalkoxy group, a C6-C10 aryl group, or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, or S is optionally substituted by 1, 2, or 3 Rs, Each of R2, R3, R4, and R5 is independently H, halogen, CN, NH2, -CO-(C 1-6 Alkyl), an ester group, a urea group, a urethane group, an amide group, C 1-6 An alkyl group, C 1-6 An alkoxy group, C 3-6 A cycloalkyl group, C 3-6 A cycloalkoxy group, a C6-C10 aryl group, or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, or S, where the NH2, ester group, urea group, urethane group, amide group, C 1-6 An alkyl group, C 1-6 An alkoxy group, C 3-6 A cycloalkyl group, C 3-6 A cycloalkoxy group, a C6-C10 aryl group, or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, or S is optionally substituted by 1, 2, or 3 Rs, R6 and R7 are each independently hydrogen, C 1-6 An alkyl group, C 3-6 A cycloalkyl group, a C6-C10 aryl group, a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, or S, -S(O)2-(C 1-6 Alkyl), -S(O)2-(C 2-6 Alkenyl), where the C 1-6 An alkyl group, C 3-6 A cycloalkyl group, a C6-C10 aryl group, or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, or S is optionally substituted by 1, 2, or 3 Rs, or R6 and R7 form a 3- to 7-membered carbocyclic ring, or R6 and R7 form a 3- to 7-membered heterocyclic ring containing N, O, or S, Each R represents a halogen, CN, OH, NH2, ester group, urea group, urethane group, amide group, C 1-6 Alkyl 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 example, A is [ka] Selected from, L1 is either absent or selected from 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] Selected from, Each of R2, R3, R4, and R5 independently contains H, halogen, CN, NH2, -CO-(C) 1-6 Alkyl), C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Selected from a cycloalkoxy group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S, where NH2, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6A cycloalkoxy group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S may be optionally substituted with 1, 2, or 3 R atoms. R6 and R7 are independently hydrogen and C 1-6 Alkyl 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 Selected from Alkenil, where C 1-6 Alkyl 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, may be optionally substituted with 1, 2, or 3 R atoms, or R6 and R7 may form a 3-7 membered carbon ring, or R6 and R7 may form a 3-7 membered heterocycle containing N, O, or S. The R8 is [ka] Selected from, Each R represents halogen, CN, OH, NH2, and C. 1-6 Alkyl 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 example, A is [ka] Selected from, L1 is either absent or selected from 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] Selected from, Each of R2, R3, R4, and R5 independently contains H, halogen, CN, NH2, -CO-(C) 1-6 Alkyl), C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Selected from a cycloalkoxy group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S, where NH2, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 A cycloalkoxy group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S may be optionally substituted with 1, 2, or 3 R atoms. R6 and R7 are independently hydrogen and C 1-6 Alkyl 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 Selected from Alkenil, where C 1-6 Alkyl 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, may be optionally substituted with 1, 2, or 3 R atoms, or R6 and R7 may form a 3-7 membered carbon ring, or R6 and R7 may form a 3-7 membered heterocycle containing N, O, or S. Each R represents halogen, CN, OH, NH2, and C. 1-6 Alkyl 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 example, A is [ka] Selected from, L1 is either absent or selected from 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] Selected from, Each of R2, R3, R4, and R5 independently contains H, halogen, CN, NH2, -CO-(C) 1-6 Alkyl), C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6Selected from a cycloalkoxy group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S, where NH2, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 A cycloalkoxy group, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S may be optionally substituted with 1, 2, or 3 R atoms. R6 and R7 are independently hydrogen and C 1-6 Alkyl 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 Selected from Alkenil, where C 1-6 Alkyl 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, may be optionally substituted with 1, 2, or 3 R atoms, or R6 and R7 may form a 3-7 membered carbon ring, or R6 and R7 may form a 3-7 membered heterocycle containing N, O, or S. Each R represents halogen, CN, OH, NH2, and C. 1-6 Alkyl 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 example, the compound is [ka] [ka] Selected from the group consisting of, Here, each group is as defined above.

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

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

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

[0013] In another preferred example, R1 is CN, urea group, urethane group, [ka] Selected from.

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

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

[0016] In another preferred example, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is selected from the group consisting of the following.

[0017] A second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of a compound described in the first aspect of the present invention or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0018] A third aspect of the present invention provides the use of the pharmaceutical composition described in the second aspect of the present invention for use in the preparation of drugs for preventing and / or treating related diseases caused by dysregulation of the Hippo pathway.

[0019] A fourth aspect of the present invention provides the use of the pharmaceutical composition described in the second aspect of the present invention for use in the preparation of drugs for preventing and / or treating related diseases caused by YAP or TAZ or YAP / TAZ or YAP / TEAD or YAP / TAZ / TEAD dysregulation. In another preferred example, the disease is lung cancer, breast cancer, pre- stand The patient is selected from the group consisting of adenocarcinoma, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, uterine cancer, and pleural mesothelioma.

[0020] A fifth aspect of the present invention provides a combination of a compound described in the first aspect of the present invention or a pharmaceutically acceptable salt, solvate, or prodrug thereof with a second drug, used in the preparation of a drug for the prevention and / or treatment of cancer. The second drug is selected from the group consisting of ERK inhibitors, MEK inhibitors, KRAS inhibitors, BRAF inhibitors, EGFR inhibitors, Wnt inhibitors, PD-1 inhibitors, or combinations thereof. [Effects of the Invention]

[0021] It should be understood that, within the scope of the present invention, new or preferred technical solutions can be constructed by combining the above-described technical features of the present invention with the technical features specifically described below (e.g., in the examples). Due to space limitations, this will not be repeated here. [Modes for carrying out the invention]

[0022] After extensive and detailed research, the inventors unexpectedly prepared a compound with excellent YAP / TEAD inhibitory activity. Based on this, the counterinventors completed the present invention.

[0023] term In this invention, unless otherwise specified, terms used have the ordinary meanings known to those skilled in the art. In this 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 a linear or branched chain of 1 to 6 carbon atoms, such as a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, neopentyl group, t-pentyl group, or similar groups. 1-6 The term "alkyl group" has a similar meaning.

[0025] In the present invention, the term "C2-C6 alkenyl group" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms containing one double bond, including butenyl, isobutenyl, pentenyl, and hexenyl groups, without limitation. 2-6 The term "alkenyl group" has a similar meaning.

[0026] In the present invention, the term "C2-C6 alkynyl group" refers non-limited to a linear or branched alkynyl group having 2 to 6 carbon atoms including one triple key, such as an ethynyl group, propynyl group, butynyl group, isobutynyl group, pentynyl group, and hexynyl group.2-6 The term "alkynyl group" has a similar meaning.

[0027] In the present invention, the term "C3-C8 cycloalkyl group" refers non-limitingly to a cyclic alkyl group having 3 to 8 carbon atoms on the ring, including cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc. 3-8 Cycloalkyl group, C 3-6 Cycloalkyl group, C 5-10 The term "cycloalkyl group" has a similar meaning.

[0028] In the present invention, the term "C1-C6 alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, including butoxy, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups, without limitation. Preferably, it is a C1-C4 alkoxy group. 1-6 The term "alkoxy group" has a similar meaning.

[0029] In the present invention, the term "heterocyclic group" is defined as follows: [ka] It is a 4- to 8-membered heterocyclic group containing (but not limited to) 1, 2, or 3 heteroatoms selected from N, O, and S.

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

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

[0032] In this invention, the term "halogenation" refers to substitution with a halogen. In this invention, the term "deuterated" refers to substitution with deuterium.

[0033] In the present invention, the term “substitution” refers to the substitution of one or more hydrogen atoms on a particular group with a particular substituent. The particular substituent is one of the substituents described herein as appropriate, or one of the substituents described in each example. Unless otherwise specified, a substituted group may have a substituent selected from the particular groups at any of its substitutable sites, and such substituents may be the same or different at each position. Those skilled in the art will understand that the substituent combinations envisioned by the present invention are stable or chemically achievable. Examples of such substituents include (but are not limited to) halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3-12 membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, and C1-C10 sulfonyl groups.

[0034] In this invention, the terms 1 to 6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms have independent and similar meanings. The term "ester group" refers to a group having a -C(O)-O-R' or R'-C(O)-O- structure, where R' independently represents 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" is, [ka] The structure is such that Ra and Rb are each independently selected from H, C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, and C6-C10 aryl groups.

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

[0037] The term "amide group" refers to a group having the structure -CONRR', where R and R' can 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' may be the same or different in the 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 may have 6 to 14 carbon atoms, the heteroaryl group may have 5 to 14 ring atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, the benzyl group, phenylethyl group, phenylpropyl group, and phenylbutyl group.

[0039] When a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent of the others and may be identical or different. That is, the phrase "selected from the group consisting of:" has the same meaning as the phrase "each independently selected from the group consisting of:".

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

[0041] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is suitable as a drug when formed with an acid or base of the compound of the present invention. pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is one formed with an acid of the compound of the present invention. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; 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, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0042] Other preferred salts are salts formed with the compound of the present invention and a base, 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 alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, t-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0043] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with a solvent molecule to form a specific ratio. The term "hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0044] Furthermore, the compounds of the present invention further include prodrugs of the compounds represented by Formula I. The term "prodrug" includes being biologically active or inactive in itself, and being metabolized or chemically reacted in the human body after being administered in an appropriate manner to be converted into the compound of Formula I, or a salt or solution comprising the compound of Formula I. The prodrug includes (but is not limited to) forms of the compound such as carboxylic acid esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, and acetals.

[0045] Pharmaceutical composition and method of administration The present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0046] Because the compounds of the present invention possess excellent antitumor activity, the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvents, and pharmaceutical compositions containing the compounds of the present invention as a principal active ingredient can be used to treat, prevent, and alleviate tumor-related diseases.

[0047] The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier in a safe and effective amount. Here, “safe and effective amount” means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg of the compound / agent of the present invention, more preferably 10 to 1000 mg of the compound / agent of the present invention. Preferably, “one agent” is one capsule or tablet.

[0048] "Pharmacochemically acceptable carrier" means one or more compatible solid or liquid fillers or gels that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that each component of the composition can be blended with each other in relation to the compounds of the present invention and among them without significantly reducing the potency 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®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0049] The aforementioned pharmaceutical composition is in the form of an injection, capsule, tablet, pill, powder, or granule. The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and typical methods 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 inactive excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or compatibilizers such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants such as glycerin; (d) agar, calcium carbonate, potato tempura It is mixed with components such as (e) potato starch or tapioca starch, tapioca starch, alginic acid, certain complex silicates, and disintegrants such as sodium carbonate, (e) delaying solvents such as paraffin, (f) absorption enhancers 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 glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include a buffer.

[0051] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coating and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compound from such compositions can be delayed in specific parts of the digestive tract. Examples of usable embedding components are polymers and waxes. If necessary, the active compound can form microcapsules with one or more of the above excipients.

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

[0053] In addition to these inert diluents, the composition may also include auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances. In addition to the active compound, the suspension may include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof.

[0054] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or aqueous 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 as needed.

[0056] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., antitumor drugs). The therapeutic method of the present invention can be used alone or in combination with other therapeutic means or therapeutic agents.

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

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

[0059] The present invention will be further described below in conjunction with specific examples. These examples are used solely to illustrate the present invention and should not be used to limit its scope. In the following examples, experimental methods that do not specify conditions typically follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: Experimental Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or conditions proposed by the manufacturer. Unless otherwise specified, percentages and quantities are calculated by weight.

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

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

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

[0063] The experimental process is as follows: (1) Synthesis of compound 2 50 mg (1.0 eq) of compound 1, 150 mg (3.0 eq) of 4-trifluoromethylbenzeneboronic acid, 60 mg (2.4 eq) of copper acetate anhydrous, 64 mg (2.0 eq) of DIPEA, 10 ml of solvent 1,6-dioxane, and 1 g of 4A molecular sieve were homogeneously mixed, purged three times with nitrogen gas, protected with oxygen gas, and reacted at room temperature for 18 hours. TLC and LC-MS showed that the reaction consisted mainly of the product with only a small amount of starting material remaining. The reaction mixture was quenched with water and extracted with EA. The organic phase was dried, spin-dried, and separated and purified by preparative plate to obtain 1.91 mg of compound 2. HPLC purity: 98.01%.

[0064] (2) Synthesis of compound T-1 30 mg (1.0 eq) of compound 2 and 12 mg (3.0 eq) of anhydrous lithium hydroxide were added to 10 ml of solvent (tetrahydrofuran / methanol / water = 6:3:1) and mixed homogeneously. After three purgings with nitrogen gas, the mixture was reacted overnight at room temperature. TLC showed that the starting materials had disappeared, and LC-MS detected mainly the product. The reaction mixture was quenched with 2N hydrochloric acid and the pH was adjusted to 4, followed by extraction with EA. The organic phase was dried, spin-dried, separated and purified by preparative plate separation to obtain 1.87 mg of compound T-1. HPLC purity: 97.20%.

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

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

[0067] The experimental process is as follows: Synthesis of compound T-3 100 mg (1.0 eq) of T-1, 53 mg (3.0 eq) of isopropylamine, 343 mg (3.0 eq) of HATU, 388 mg (10.0 eq) of DIPEA, and 5 ml of solvent DMF were homogeneously mixed. After purging three times with nitrogen gas, the mixture was reacted at room temperature for 18 hours under nitrogen gas protection. Water was added to the reaction mixture to quench it, and then it was extracted with EA. The organic phases were combined, washed with saturated brine, dried, and separated and purified by preparative plate to obtain 15 mg of compound T-3. HPLC purity: 95.80%.

[0068] Refer to the synthesis methods of Examples T-1 and T-3 to synthesize the following compounds. [Table 1-1] [Table 1-2] [Table 1-3]

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

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

[0071] The experimental process is as follows: (1) Synthesis of compound SM2 1.0 g (1.0 eq) of the starting compound SM1, 5 ml (8.2 eq) of DMF-DMA, 0.13 g (0.1 eq) of p-toluenesulfonic acid monohydrate, and 5 ml of the solvent toluene were homogeneously mixed. After submerging the mixture three times with nitrogen gas, the mixture was protected with nitrogen gas, and the oil bath was heated to reflux for 18 hours. TLC showed that no starting materials remained, and the reaction mixture was directly spin-evaporated to dryness to obtain 1.3 g of the crude product compound SM2.

[0072] (2) Synthesis of compound SM3 1.2 g (1.0 eq) of SM2, 0.85 g (1.2 eq) of p-trifluoromethylaniline, and 12 ml (10 times the volume) of toluene solvent were homogeneously mixed. The mixture was then purged three times with nitrogen gas, protected with nitrogen gas, and the oil bath was heated to reflux for 18 hours. TLC showed that the starting materials remained, and LCMS confirmed its accuracy. The reaction mixture was stirred directly and passed through a column to obtain 70 mg of SM3.

[0073] (3) Synthesis of compound SM4 Homogeneously mix 70 mg (1.0 eq) of SM3 with 2 ml of solvent DMF, purge three times with nitrogen gas, protect with nitrogen gas, cool the ice bath to 0°C, add 10 mg of NaH in batches, allow to rise naturally to room temperature after addition, stir for 15 minutes, raise the oil bath to 100°C and react for 18 hours. Show that no starting materials remain by TLC and show accuracy by LC-MS, cool the reaction mixture, quench with water, extract with EA, separate and purify the EA phase by preparative plate to obtain 15 mg of SM4.

[0074] (4) Synthesis of compound SM5 500 mg (1.0 eq) of SM4, 518 mg (1.5 eq) of pinacol diborate, 400 mg (3.0 eq) of potassium acetate, 100 mg (0.1 eq) of Pd(dppf)Cl2, and 5 ml (10 times the volume) of dioxane solvent were homogeneously mixed. The mixture was then purged three times with nitrogen gas, the temperature was raised to 90°C, and the mixture was reacted for 18 hours. Complete reaction of the starting materials was detected by TLC. Purification by PE:EA=1:1 column chromatography yielded 200 mg of SM5.

[0075] (5) Synthesis of compound T-4 200 mg of SM5 (1.0 eq), 5 mg of palladium acetate (0.05 eq), 19 mg of triphenylphosphine (0.15 eq), 210 mg (2.0 eq) of di-t-butyl dicarbonate, and 1 ml of dioxane were added to the reaction system. The system was then purged three times with nitrogen gas and reacted at 100°C for 18 hours. The completion of the reaction was detected by TLC, and the solution was purified by preparative liquid phase to obtain 30 mg 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 by the present invention: [ka]

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

[0078] The experimental process is as follows: (1) Synthesis of compound SM6 The starting compound SM4 (5 g, 1.0 eq), palladium acetate (0.3 g, 0.1 eq), dppf (1.5 g, 0.2 eq), triethylamine (9 ml, 5 eq), solvent ethanol (10 ml), and DMF (15 ml) were homogeneously mixed. The mixture was purged three times with nitrogen gas, then three times with CO, and protected under positive pressure using a CO balloon. The mixture was reacted at 40°C for 18 hours. After confirming that no starting materials remained by TLC, the reaction mixture was directly concentrated, extracted with water and EA, separated, and the EA phase was concentrated and purified by column chromatography to obtain 2.5 g 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 starting compound SM6 (2.4 g, 1.0 eq), lithium hydroxide (0.84 g, 3.0 eq), solvent tetrahydrofuran (29 ml), methanol (14 ml), and water (5 ml) were homogeneously mixed, and after submerging three times with nitrogen gas, the mixture was reacted at room temperature for 18 hours. After confirming that no starting materials remained by TLC, the reaction solution was directly concentrated, 50 ml of water was added, and approximately 10 ml of 2N hydrochloric acid was added dropwise, resulting in the precipitation of a large amount of solid. The mixture was filtered by suction, the filter cake was dissolved in ethyl acetate, and then concentrated to obtain 2.3 g 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 by the present invention: [ka]

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

[0082] The experimental process is as follows: Synthesis of compound T-6 T-5 (30 mg, 1.0 eq), isopropylamine (22 mg, 2.0 eq), HATU (52 mg, 1.5 eq), DIPEA (46.5 mg, 4.0 eq), and solvent DMF (1 ml) were homogeneously mixed, purged three times with nitrogen gas, protected with nitrogen gas, and reacted at room temperature for 18 hours. TLC confirmed that no starting materials remained, LCMS confirmed accuracy, and the reaction mixture was quenched with water and extracted with EA. The EA phase was separated and purified by preparative plate to obtain 12 mg 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] Refer to the synthesis method of Example T-6 to synthesize the following compound. [Table 2-1] [Table 2-2]

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

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

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

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

[0088] (3) Synthesis of compound 4: Place 1.0 g of compound 3 in a flask, add 4.0 mL of TFA and 12 mL of DCM, and allow to react at room temperature. After the reaction is complete, add water, extract with DCM, evaporate to dryness, and pass through a column to obtain 0.65 g of compound 2.

[0089] (4) Synthesis of compound 5: 430 mg (1.0 eq) of compound 4 is placed in a flask, and 6 mL of dioxane, 402 mg (1.5 eq) of pinacol diborate, 206 mg (2.0 eq) of KOAc, and 39 mg (0.05 eq) of Pd(dppf)Cl2 are added. The mixture is reacted at 100°C 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 compound 3. The crude product is used directly in the next step.

[0090] (5) Synthesis of compound T-15: 200 mg (1.2 eq) of compound 5 is placed in a flask, and 4 mL of dioxane, 0.4 mL of water, 85 mg (1.0 eq) of 4-bromo-1-methyl-5-ethoxycarbonylimidazole, 21 mg (0.05 eq) of Pd(PPh3)4, and 100 mg (2.0 eq) of K2CO3 are added. The mixture is reacted at 100°C 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 120 mg 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: Place 100 mg (1.0 eq) of T-15 in a flask, add 3 mL of ultra-dried THF, and under an ice bath, add 46 mg (5.0 eq) of LiAlH4. Allow to react by slowly raising the temperature to room temperature. After the reaction is complete, add water and extract with EA to obtain 36 mg of compound T-7. HPLC: 95.1%. 11H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.74 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.29 (m, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.17 (s, 2H), 3.63 (s, 3H), 2.39 (s, 3H).

[0092] Referring to the synthesis methods of Examples T-7 & T-15, the following compounds are synthesized.

Table 3-1

Table 3-2

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

Chemical formula

[0094] The synthetic route is as follows.

Chemical formula

[0095] The experimental process is as follows. (1) Synthesis of Compound SM2: SM1 (6.57 g, 39 mmol, 1.0 eq) and CuBr (11.12 g, 78 mmol, 2.0 eq) are added to acetonitrile (245 mL), protected with nitrogen gas, then cooled to 0°C, and isoamyl nitrite (13.39 g, 105 mmol, 2.7 eq) is added. The temperature is raised to 50°C and the mixture is reacted overnight. TLC (PE:EA = 5:1) is used to indicate that the starting materials have reacted completely. The reaction mixture is concentrated, and then 300 mL of water and 300 mL of ethyl acetate are added. The mixture is filtered through diatomaceous earth to separate the organic layer, and the aqueous layer is extracted twice with 300 mL of ethyl acetate. The organic layers are combined, washed twice with 300 mL of water, washed twice with 300 mL of brine, dried over anhydrous sodium sulfate, filtered, concentrated to obtain the crude product, which is passed through a silica gel column to obtain 5.5 g of the 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), and potassium carbonate (201.4 mg, 1.46 mmol, 2.0 eq) were added to 1,4-dioxane (5 mL) and water (0.5 mL), and the mixture was protected with nitrogen gas. The reaction was then allowed to proceed overnight at 105 °C, and the product peak was shown by LC-MS. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and 30 mL of water and 50 mL of ethyl acetate were added. The organic layer was separated, the aqueous layer was extracted twice with 50 mL of ethyl acetate, the organic layers were combined, washed once with 20 mL of water, and washed twice with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate and passed through a concentration column to obtain 100 mg of the 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: 100 mg (1.0 eq) of T-31 is placed in a flask, 5 mL of ultra-dried THF is added, and 46 mg (5.0 eq) of LiAlH4 is added under an ice bath. The mixture is slowly heated to room temperature and then refluxed. After the reaction is complete, water is added, and the mixture is extracted with EA to obtain 16 mg of compound T-18. HPLC: 95.1%.

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

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

[0100] The experimental process is as follows: (1) Synthesis of compound SM2: SM1 (5.7 g, 29 mmol, 1.0 eq) is dissolved in methanol (100 mL), cooled to 0°C, concentrated sulfuric acid (3.5 g, 1.9 mL, 1.2 eq) is added dropwise, then the temperature is raised to 70°C and refluxed overnight. LC-MS confirms that the starting materials have reacted completely. The mixture is cooled to room temperature, and methanol is removed by concentration. Saturated sodium bicarbonate is added, then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid product (5.6 g). 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 minutes. Then add iodomethane (0.9 g, 0.4 ml, 6.4 mmol, 1.3 eq) dropwise. Allow to slowly return to room temperature and stir overnight. Pour the reaction mixture into ice water (100 ml), extract three times with 50 mL of ethyl acetate, and wash with saturated saline solution. Dry over anhydrous sodium sulfate, filter, and concentrate to obtain 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), and potassium carbonate (201.4 mg, 1.46 mmol, 2.0 eq) were added to 1,4-dioxane (5 mL) and water (0.5 mL), and the mixture was protected with nitrogen gas. The reaction was then carried out overnight at 105 °C, and the product peak was shown by LC-MS. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and 30 mL of water and 50 mL of ethyl acetate were added. The organic layer was separated, the aqueous layer was extracted twice with 50 mL of ethyl acetate, the organic layers were combined, washed once with 20 mL of water, and washed twice with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate and passed through a concentration column to obtain 80 mg of the 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: 50 mg (1.0 eq) of T-32 was placed in a flask, 3 mL of ultra-dry THF was added, and under an ice bath, 25 mg (5.0 eq) of LiAlH4 was added. The temperature was slowly raised to room temperature and then refluxed. After the reaction was completed, water was added and extracted with EA to obtain 12 mg of compound T-19. HPLC: 97.2%.

[0104] Refer to the synthesis methods of Examples T-18, T-19, T-31 & T-32 to synthesize the following compounds.

Table 4-1

Table 4-2

Table 4-3

Table 4-4

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

Chemical formula

[0106] The synthesis route is as follows.

Chemical formula

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

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

[0109] (3) Synthesis of SM4: SM3 (4.93g, 11.33 mmol, 1.2eq), 3-bromo-1-methyl-1H-pyrazole-4-carboxylate ethyl (2.2g, 9.44 mmol, 1.0eq), K2CO3 (2.61g, 18.88 mmol, 2.0eq), Pd(dppf)Cl2 (0.345g, 0.47 mmol, 0.05eq), and a mixed solvent (ethanol, 1,4-dioxane, water 5:2:1, total 35.2mL) were added to the reaction flask. The flask was evacuated and replaced with nitrogen gas three times, then the temperature was raised to 95°C and the reaction was allowed to proceed for 3 hours. TLC (PE:EA=2:1) ​​was used to indicate that the starting materials had reacted completely. The mixture is cooled to room temperature, 200 mL of  and 30 mL of water are added, diatomaceous earth is added, and the mixture is filtered to separate the EA layer. The mixture is then washed with saturated brine (30 mL*1), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This product is then passed through a column to obtain 2 g of oily product.

[0110] (4) Synthesis of SM5: SM4 (2g), dioxane (20mL), and aqueous ammonia (15mL) are added to an autoclave, and the mixture is evacuated and replaced with nitrogen gas three times. The temperature is then raised to 100°C and the mixture is reacted for 24 hours. TLC is used to confirm that the starting materials have reacted completely. The mixture is cooled to room temperature, filtered by suction, and the filter cake is washed with water, methanol, and petroleum ether. The mixture is then vacuum dried to obtain 0.8g of the 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), and 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. TLC (PE:EA = 1:2) showed that the starting materials were almost complete. The reaction mixture was diluted with DCM and water, filtered through diatomaceous earth, extracted with DCM, washed with saturated NaCl, dried over anhydrous sodium sulfate, the sample was stirred, and passed through a column to obtain 25 mg of SM6.

[0112] (6) Synthesis of the T-61: SM6 (25 mg, 0.051 mmol, 1 eq) and 0.83 ml of TFA were added to 4.2 ml of DCM, protected with nitrogen gas, and allowed to react overnight. TLC (PE:EA = 1:3) showed that the starting material was almost complete. Saturated NaHCO3 solution was added to the reaction mixture until the solution became basic, extracted with DCM, washed with saturated NaCl, dried over anhydrous sodium sulfate, the sample was stirred, and passed 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] Refer to the synthesis method of Example T-61 to synthesize the following compound. [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 by the present invention: [ka]

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

[0116] The experimental process is as follows: (1) Synthesis of SM2 50 g (1.0 eq) of SM1, 72 g (1.5 eq) of cesium carbonate, 22 g (0.25 eq) of xanthophos, 1.64 g (0.05 eq) of palladium acetate, and 1 L of 1,4-dioxane were homogeneously mixed. 31 g of 4-(trifluoromethyl)aniline was slowly added, the mixture was evacuated, nitrogen gas was purged, and the mixture was refluxed at 105°C for 16 hours. TLC was used to indicate that the starting materials had reacted completely. The mixture was diluted with 1 L of EA, then filtered by suction through diatomaceous earth, silica gel was added to the filtrate, the sample was stirred, and 38 g of SM2 was obtained 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 Homogeneously mix 24 g (1.0 eq) of SM2, 21.5 g (1.3 eq) of B2Pin2, 12.6 g (2.0 eq) of KOAc, 2.4 g (0.05 eq) of Pd(dppf)d2, and 300 ml of 1,4-dioxane, protect with nitrogen gas, and reflux at 105°C for 1.5 hours. Cool to room temperature, add 500 ml of EA, and then filter by suction through diatomaceous earth. Next, sonicate mix with toluene:anhydrous ethanol = 5:8, stir for 5 minutes, and spin evaporate. Repeat this process until the solid is in a spin evaporate state, then mix the solid with an appropriate amount of PE until the solid precipitates. Filter by suction, collect the solid, and dry to obtain 20 g 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 the T-100 18 g (1.2 eq) of SM3, 21.5 g (1.3 eq) of 3-bromo-1-methyl-1H-pyrazole-4-carboxylate ethyl, 15.0 g (2.0 eq) of K2CO3, 1.3 g (0.05 eq) of Pd(dppf)d2, and 250 ml of 1,4-dioxane / water / anhydrous methanol = 5:2:1 were homogeneously mixed, protected with nitrogen gas, and refluxed at 105°C for 1.5 hours. TLC showed that the product had formed. The mixture was cooled to room temperature, then filtered by suction through diatomaceous earth, spin-dried, quenched with water, and extracted with EA. Column chromatography yielded 9.5 g of T-100. 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 4.5 g (1.0 eq) of T-100, 1.42 g (3.0 eq) of LiOH monohydrate, and 50 ml of THF / water / anhydrous methanol = 2:1:4 were homogeneously mixed, protected with nitrogen gas, and reacted at 50°C for 2-5 hours. The formation of the product was then shown by TLC. The mixture was cooled to room temperature, spin-dried, quenched with water, extracted with EA to remove organic impurities, the aqueous phase was adjusted to pH=2, and extracted with EA to obtain 3.6 g of 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 the T-86: T-110 (387 mg, 1 eq), DIPEA (258 mg, 2 eq), and HATU (380 mg, 1 eq) were dissolved in DCM, stirred at room temperature for 10 minutes, and isopropylamine (71 mg, 1.2 eq) was added, followed by a reaction for 12 hours. After the reaction was complete, the completion of the T-110 reaction was monitored by TLC (pure EA). The mixture was diluted with approximately 10-fold DCM, DIPEA was washed off with 0.05% citric acid, then washed with saturated NaCl solution, dried, and spin-dried. The crude product was then dissolved in DCM and methanol, and 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] Refer to the synthesis methods of Examples T-86, T-100 & T-110 to synthesize the compounds shown in the following table. [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 by the present invention: [ka]

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

[0124] The experimental process is as follows: (1) Synthesis of SM2: 50 g (1.0 eq) of SM1, 72 g (1.5 eq) of cesium carbonate, 22 g (0.25 eq) of xanthophos, 1.64 g (0.05 eq) of palladium acetate, and 1 L of 1,4-dioxane were homogeneously mixed. 31 g of 4-(trifluoromethyl)aniline was slowly added, the mixture was evacuated, nitrogen gas was purged, and the mixture was refluxed at 105°C for 16 hours. TLC was used to indicate that the starting materials had reacted completely. The mixture was diluted with 1 L of EA, then filtered by suction through diatomaceous earth, silica gel was added to the filtrate, the sample was stirred, and 38 g of SM2 was obtained 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: Homogeneously mix 24 g (1.0 eq) of SM2, 21.5 g (1.3 eq) of B2Pin2, 12.6 g (2.0 eq) of KOAc, 2.4 g (0.05 eq) of Pd(dppf)d2, and 300 ml of 1,4-dioxane, protect with nitrogen gas, and reflux at 105°C for 1.5 hours. Cool to room temperature, add 500 ml of EA, and then filter by suction through diatomaceous earth. Next, sonicate mix with toluene:anhydrous ethanol = 5:8, stir for 5 minutes, and spin evaporate. Repeat this process until the solid is in a spin evaporate state, then mix the solid with an appropriate amount of PE until the solid precipitates. Filter by suction, collect the solid, and dry to obtain 20 g 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: 18 g (1.2 eq) of SM3, 21.5 g (1.3 eq) of ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate, 15.0 g (2.0 eq) of K2CO3, 1.3 g (0.05 eq) of Pd(dppf)d2, and 250 ml of 1,4-dioxane / water / anhydrous methanol = 5:2:1 were homogeneously mixed, protected with nitrogen gas, and refluxed at 105°C for 1.5 hours. TLC showed that the product had formed. The mixture was cooled to room temperature, then filtered by suction through diatomaceous earth, spin-dried, quenched with water, and extracted with EA. Column chromatography yielded 9.5 g of SM4. 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: 4.5 g (1.0 eq) of SM4, 1.42 g (3.0 eq) of LiOH monohydrate, and 50 ml of THF / water / anhydrous methanol = 2:1:4 were homogeneously mixed, protected with nitrogen gas, and reacted at 50°C for 2-5 hours. The formation of the product was then shown by TLC. The mixture was cooled to room temperature, spin-dried, quenched with water, extracted with EA to remove organic impurities, the aqueous phase was adjusted to pH=2, and extracted with EA to obtain 3.6 g of 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: 1.0 g (1.0 eq) of SM5, 0.4 g (1.5 eq) of TEA, and 20 ml of t-BuOH were homogeneously mixed, protected with nitrogen gas, refluxed at 80°C, and 0.85 g (1.2 eq) of DPPA was added dropwise. The mixture was allowed to react for 2 hours, and TLC indicated that a product had formed. The mixture was cooled to room temperature, spin-dried, quenched with water, extracted with EA, and 2.3 g of SM6 was obtained by column chromatography.

[0129] (6) Synthesis of SM7: 2.3 g of SM6, 23 ml of TEA, and 30 ml of DCM were homogeneously mixed, protected with nitrogen gas, reacted overnight at room temperature, spin-dried, quenched with water, extracted with DCM, and obtained 280 mg of SM7 by column chromatography. 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 the 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 mixture and react at room temperature for 18 hours. TLC shows that the starting materials have disappeared, LCMS shows accuracy, the reaction mixture is spin-dried, water is added to quench, and the mixture is extracted with EA. The EA phase is washed once with 0.5% citric acid and dried over anhydrous sodium sulfate. The EA phase is separated and purified by preparative 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 by the present invention: [ka]

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

[0133] The experimental process is as follows: T-172 synthesis: SM7 (394 mg, 1.0 eq), DIPEA (490 mg, 4.0 eq), and 2 ml of anhydrous dichloromethane were mixed and reacted at room temperature for 20 minutes. Then, compound acryloyl chloride (108 mg, 1.2 eq) was added to the reaction mixture and reacted at room temperature for 18 hours. TLC showed that the starting materials had disappeared, LCMS confirmed accuracy, and after spin-drying the reaction mixture, water was added to quench it. Extraction was performed with EA, the EA phase was washed once with 0.5% citric acid, and dried over anhydrous sodium sulfate. The EA phase was separated and purified 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 by the present invention: [ka]

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

[0136] The experimental process is as follows: T-186 synthesis: SM7 (394 mg, 1.0 eq), pyridine (237 mg, 3.0 eq), benzenesulfonyl chloride (352 mg, 2.0 eq), and 2 ml of anhydrous dichloromethane solvent were homogeneously mixed and reacted at room temperature for 18 hours. TLC showed that the starting materials had disappeared, LC-MS confirmed accuracy, the reaction mixture was spin-dried, water was added to quench, and the mixture was extracted with EA. The EA phase was washed once with 0.5% citric acid and dried over anhydrous sodium sulfate. The EA phase was separated and purified by preparative plate to obtain 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] Referencing the synthesis methods of Examples T-170, T-172 & T-186, the following compounds were synthesized. [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 by the present invention: [ka]

[0139] The synthesis 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, 3 eq if d is the hydrochloride salt) of DIPEA and 34.083 g (1 eq) of HATU in 250 ml of DCM, stir at room temperature for 10 minutes, add 13.14 g (1.2 eq) of the compound pyridineethylamine, and continue to react for 1.5 hours. After the reaction is complete, monitor for complete reaction of 5,6-dibromonicotinic acid by TLC (pure EA), dilute with 5-fold DCM, wash off DIPEA with 0.1 mol hydrochloric acid, dry with saturated NaCl solution, stir the sample with 2-2.5-fold silica gel, and pass through a PE:EA=3:1 column to obtain 30.7 g of yellow viscous liquid SM1.

[0141] (2) Synthesis of SM2 30.7 g (1 eq) of SM1, 52.2 g (2 eq) of Cs2CO3, 4.6 g (0.1 eq) of xanthophos, and 12.9 g (1 eq) of p-fluoroaniline were sequentially dissolved in 300 ml of ultra-dried 1,4-dioxane solution and placed in a round-bottom flask. 0.9 g (0.05 eq) of Pd(OAc)2 was added, the flask was purged with nitrogen gas 2-3 times, and the temperature was raised to 105°C for 1.5 hours. After the reaction was complete, the reaction of the starting materials was monitored by TLC (PE:EA=1:1). The mixture was diluted 10 times with solvent EA, filtered by suction through diatomaceous earth, the sample was stirred, separated by chromatography, and passed through PE:EA=2:1 to obtain 15.2 g of the yellow solid product SM2.

[0142] (3) Synthesis of SM3 Dissolve 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 sequentially in 132 ml of 1,4-dioxane solution, place in a round-bottom flask, stir, add 5.6 g (2 eq) of KOAc, purge with nitrogen gas 2-3 times, and heat the oil bath to 105°C and react for 3 hours. After the reaction is complete, monitor that the starting materials have reacted completely by TLC (PE:EA = 1:1.5), and fumigate with the colorant alizarin; SM3 will appear yellow. Dilute 10 times with solvent EA, filter by suction through diatomaceous earth, and spin dry the solvent. Add a 5:8 toluene-ethanol solution and stir for 5 minutes, then spin dry the solvent. Repeat the above steps and spin dry the solvent. A small amount of PE is added, shaken thoroughly, and filtered by suction to obtain 13.1 g of grayish-brown solid SM3.

[0143] (4) Synthesis of TM SM3 (1 eq) is dissolved in 1,4-dioxane solution, and K2CO3 (3 eq), Pd (dppf)Cl2 (0.16 eq), and 4-bromo-1-methylpyrazole-3-carboxylate ethyl (1 eq) are sequentially added to a round-bottom flask. The flask is purged with nitrogen gas 2-3 times, the temperature is raised to 105°C, and the reaction is allowed to proceed for 1 hour. After the reaction is complete, the complete reaction of SM3 is monitored by TLC (PE:EA=3:1), and the polarity of the product is relatively high. The complete elimination of SM4 from a distance is monitored by TLC (PE:EA=1:1). The sample is filtered by suction, EA is added and the sample is stirred, and chromatography (PE:EA=1:1) is performed to obtain a 24 mg beige-brown solid formation site.

[0144] Refer to the synthesis method of Example T-243 to synthesize the following compound. [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 by the present invention: [ka]

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

[0147] The experimental process is as follows: SM3 synthesis: Protect a 50 ml round-bottom flask with nitrogen gas. Add SM2 (2 g, 5.362 mmol, 1 eq), crotonic acid (1.154 g, 13.4 mmol, 2.5 eq), DIEA (6.92 g, 53.62 mmol, 10 eq), and THF (10 ml) to the original round-bottom flask. Evaporate the nitrogen gas, then add Pd(PHCN)3Cl2 (102.8 mg, 0.268 mmol, 0.05 eq), tri(o-tolyl)phosphine (81.6 g, 0.26 mmol, 0.05 eq), and acetic anhydride (1.68 ml). Protect with nitrogen gas, heat to 70°C, reflux, and allow to react overnight. TLC (PE:EA = 10:1) shows that all starting materials have reacted completely. The sample was cooled, extracted with 20 ml of 2N HCl, 10 ml of water, and 50 ml of EA, washed with NaHCO3, extracted with EA (20 ml x 3), washed with saturated sodium chloride (20 ml x 2), dried over anhydrous sodium sulfate, stirred, and passed through a column to obtain 892 mg of SM5.

[0148] SM4 synthesis: SM3 (85 mg, 0.235 mmol, 1 eq), LiOH (16.9 mg, 0.705 mmol, 3 eq), MeOH (1.2 ml), H2O (0.3 ml), and THF (0.6 ml) were protected with nitrogen gas and reacted for 4.5 hours. Complete reaction was confirmed by LC-MS. The reaction mixture was cooled, evaporated by spin evaporation, and DCM was added and the mixture was spin-dried to obtain 80 mg of product.

[0149] SM5 synthesis: 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), and DMF (13 ml) were placed in a round-bottom flask, protected with nitrogen gas, heated to 120°C, and refluxed for 30 minutes. TLC (PE:EA = 3:1) was used to confirm that the starting materials had reacted completely. After cooling, 15 ml of water was added, filtered through diatomaceous earth, extracted with EA (30 ml x 3), washed with saturated sodium chloride (40 ml x 2), dried over anhydrous sodium sulfate, the sample was stirred, and passed through a column to obtain 363 mg of SM4.

[0150] SM6 synthesis: SM5 (363 mg, 0.842 mmol, 1 eq), methanol (10 ml), and 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) was performed to confirm that the starting materials had reacted completely. Spin drying was performed to obtain 312 mg of SM6.

[0151] SM7 synthesis: SM6 (312 mg, 0.774 mmol, 1 eq), LiOH (55.6 mg, 2.322 mmol, 3 eq), MeOH (6 ml), H2O (1.5 ml), and THF (3 ml) were protected with nitrogen gas at 25°C and allowed to react overnight. Complete reaction was indicated by TLC (DCM:MeOH = 10:1). The reaction mixture was cooled, spun evaporated, and 5 ml of water and 2 ml of 2N HCl were added. A large amount of white solid precipitated, which was filtered, the filtrate was extracted with EA, washed with saturated NaCl, dried over anhydrous sodium sulfate, and spun dried to obtain 280 mg of SM7.

[0152] T-276 synthesis: SM7 (280 mg, 0.72 mmol, 1 eq), pyridineethylamine (105.4 mg, 0.864 mmol, 1.2 eq), HATu (237.8 mg, 0.72 mmol, 1 eq), and DIEA (185.8 mg, 1.44 mmol, 2 eq) were added to 5 ml of DCM, protected with nitrogen gas, and allowed to react overnight at room temperature. TLC(EA) was used to indicate that the starting materials had reacted completely and the product had been formed. The reaction mixture was extracted with water and EA, washed with 0.5% citrate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and passed through a column to obtain 335 mg 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] Referencing the synthesis method of Example T-276, the following compounds are synthesized. [Table 9]

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

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

[0156] The experimental process is as follows: SM4 synthesis: 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 allowed to react overnight. TLC (PE:EA = 3:1) showed that most of the starting materials had reacted. After cooling, 15 ml of water was added, filtered through diatomaceous earth, extracted with EA (50 ml x 3), washed with saturated sodium chloride (50 ml x 2), dried over anhydrous sodium sulfate, the sample was stirred, and passed through a column to obtain 161 mg of SM4.

[0157] SM5 synthesis: 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. Complete reaction of the starting materials was confirmed by TLC (PE:EA = 5:1). The mixture was filtered through diatomaceous earth, the sample was stirred, and passed through a column to obtain 100 mg of SM5.

[0158] SM6 synthesis: SM5 (100 mg, 0.252 mmol, 1 eq), LiOH (18.1 mg, 0.756 mmol, 3 eq), MeOH (2 ml), H2O (0.5 ml), and THF (1 ml) were protected with nitrogen gas at 25°C and left overnight. Complete reaction was indicated by TLC (DCM:MeOH = 10:1). The reaction mixture was cooled, spun evaporated, and water and 2N HCl were added. A large amount of white solid precipitated, which was filtered to obtain 85 mg of SM6.

[0159] T-281 synthesis SM6 (85 mg, 0.222 mmol, 1 eq), pyridineethylamine (32.5 mg, 0.2664 mmol, 1.2 eq), HATu (84.4 mg, 0.222 mmol, 1 eq), and DIEA (57.3 mg, 0.444 mmol, 2 eq) were added to 2 ml of DCM, protected with nitrogen gas, and allowed to react overnight at room temperature. TLC (PE:EA = 1:3) was used to indicate that the starting materials had reacted completely and that a product had been formed. The reaction mixture was extracted with water and EA, washed with 0.5% citrate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and TLC was performed to obtain 62 mg of product. 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 by the present invention: [ka]

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

[0162] The experimental process is as follows: Sm2 synthesis: SM1 (15g, 59.18 mmol, 1.0eq), p-trifluoromethylbenzeneboronic acid (16.86g, 88.77 mmol, 1.5eq), Mo(CO)6 (15.62g, 39.18 mmol, 1.0eq), potassium carbonate (24.54g, 177.54 mmol, 3.0eq), palladium acetate (398.59mg, 1.78 mmol, 0.03eq), and anisole (150ml) were sequentially added to a 500ml three-necked flask. The flask was then evacuated, replaced with nitrogen gas, and the temperature was raised to 105°C for 16 hours. TLC (PE:EA=10:1, UV) showed that the starting materials had been consumed.

[0163] The reaction system is cooled to room temperature, diluted with 300 ml of methanol, then filtered by suction using a Buchner funnel and diatomaceous earth, and the filter cake is washed with methanol. The filtrate is concentrated at 45°C, then 300 ml of EA and 300 ml of water are added to separate the organic layer, the aqueous layer is extracted with EA (300 ml x 2), the organic layers are combined, washed with saturated sodium chloride, and dried with sodium sulfate. After concentration, 40 g of silica gel is added, the sample is stirred, and passed through a column to obtain 2.8 g of SM2 (yellow oily substance).

[0164] SM3 synthesis SM2 (2.8g, 0.009mol, 1.0eq), cuprous bromide (2.68g, 0.0186mol, 2.0eq), and acetonitrile (50ml) were added to a 100ml reaction flask. Isoamyl nitrite (2.87g, 3.3ml, 0.0243mol, 2.7eq) was added dropwise at 0°C, and the temperature was then raised to 50°C for 16 hours. TLC showed that a small amount of SM2 remained. The reaction system is cooled to room temperature, diluted with EA (200 ml), and filtered using a Buchner funnel with diatomaceous earth added. 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 the mixture is dried over saturated sodium sulfate. The mixture is then concentrated and passed through a column to obtain 2.2 g of product SM3.

[0165] Sm4 synthesis SM3 (2.0 g, 5.5 mmol, 1.0 eq), pinacol borate (1.7 g, 6.6 mmol, 1.2 eq), potassium acetate anhydrous (1.6 g, 16.5 mmol, 3.0 eq), Pd(dppf)Cl2 (0.201 g, 0.28 mmol, 5%), and ultra-dried dioxane (20 ml) were added to a reaction flask. The flask was then evacuated, nitrogen gas was purged, and the temperature was raised to 100°C for 16 hours. After cooling to room temperature, ethyl acetate was added to dilute the mixture, diatomaceous earth was added, and the mixture was filtered by suction. The filtrate was concentrated, and then toluene:ethanol (6:1) was sequentially added to concentrate the mixture to obtain 2.2 g of SM4.

[0166] SM5 synthesis 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) were added to the reaction flask, the flask was evacuated, nitrogen gas was purged, and the mixture was allowed to react overnight. LC-MS was used to confirm that the starting materials had reacted completely. The mixture was cooled to room temperature, EA (100 ml) and water (50 ml) were added, the organic layer was separated, the aqueous layer was extracted with EA (100 ml x 2), the organic layers were combined, washed with saturated brine, dried, concentrated, and passed through a column to obtain 800 mg of product.

[0167] SM6 synthesis: SM5 (540 mg) was dissolved in methanol (2 ml), then hydrochloric acid / dioxane (10 ml) was added, and the mixture was stirred overnight at room temperature. TLC showed that the starting materials had reacted completely (PE:EA = 5:1). The reaction mixture was dried, saturated sodium bicarbonate solution was added, and the mixture was extracted with EA. The organic layer was separated, dried, concentrated, and passed through a column to obtain 300 mg of product SM6.

[0168] SM7 synthesis 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) were added to an autoclave, then evacuated and purged with carbon monoxide. The temperature was raised to 100°C and the mixture was reacted for 24 hours. TLC showed that a small amount of starting material still remained. The mixture was cooled to room temperature, filtered using a Buchner funnel with diatomaceous earth added, diluted with EA, then silica gel (100-200 mesh, 3 g) was added, the sample was stirred, and then separated and purified using a host machine to obtain 200 mg of SM7 and 80 mg of the starting material SM6.

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

[0170] Synthesis of TM: Add SM9 (150 mg, 0.39 mmol, 1.0 eq), HATU (147.38 mg, 0.387 mmol, 1.0 eq), DIEA (100 mg, 141 μL, 0.775 mmol, 2.0 eq), and DCM (2 ml) to a reaction tube and stir at room temperature for 10 minutes. Then add (S)-1-(pyridine-2-yl)ethane-1-amine (56.82 mg, 0.465 mmol, 1.2 eq) and react overnight at room temperature. Lcms indicate that the starting materials have reacted completely. Dilute the reaction mixture with DCM (10 ml), then wash with 0.5% citric acid and saturated brine. Dry, concentrate, and pass through a column to obtain 161 mg of 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 by the present invention: [ka]

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

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

[0174] SM3 synthesis Using an electrically heated mantle, the purchased dicyclopentadiene was distilled at 180°C under atmospheric pressure, and the fraction at 40-42°C was collected to obtain the cyclopentadiene monomer for the synthesis of SM3. At approximately 0°C, 5.5g of SM2, 55ml of methanol, 3.3g of cyclopentadiene, and 2.86g of aqueous formaldehyde solution were added to a 250ml three-necked flask. The mixture was then allowed to react at room temperature for 72 hours. TLC (PE:EA = 10:1) was used to indicate that the starting materials had completely reacted and a white solid precipitated. The mixture was filtered by suction using a sand core funnel, and the filter cake was dried in a vacuum drying oven at 25°C to obtain the target product (approximately 2.6g).

[0175] SM4 synthesis: Two batches were prepared. SM3 (425 mg, 1.25 mmol, 1.0 eq), anhydrous potassium phosphate (1.59 g, 7.49 mmol, 5.0 eq), palladium acetate (20.19 mg, 0.09 mmol, 8%), (S)-1-(pyridine-2-yl)ethane-1-amine (457.79 mg, 3.75 mmol, 3.0 eq), DMAP (302.72 mg, 2.5 mmol, 2.0 eq), Mo(CO)6 (108.16 mg, 0.409 mmol, 0.32 eq), xanthophos (106.96 mg, 0.184 mmol, 14% eq), and dioxane (10 ml) were added to a 30 ml microwave reaction tube and reacted at 120°C for 20 minutes. Complete reaction of the starting materials was then indicated by TLC (PE:EA = 1:1). The mixture is cooled to room temperature, and the two batches of reaction solutions are combined. EA (100 ml) and water (50 ml) are added, the EA layer is separated, the aqueous layer is extracted with EA (50 ml x 2), the organic layers are combined, washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated, and passed through a host machine column to obtain 630 mg of SM4 (yellow solid).

[0176] SM5 synthesis SM4 (200 mg) is added to ethanol (10 ml), then palladium hydroxide (30 mg, w / w 15%) is added, followed by 0.2 ml of 2N HCl. Vacuum evacuation and nitrogen gas purging are repeated three times, followed by vacuum evacuation and hydrogen gas purging (hydrogen balloon) three times. After raising the temperature to 80°C, the mixture is refluxed for 19 hours, and TLC is used to indicate that the starting materials have reacted completely (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 by suction. Silica gel is then added to the filtrate, the sample is stirred, and the mixture is passed through a column using a column passer. SM5 (60 mg, white solid) is obtained.

[0177] T-283 synthesis SM5 (60 mg, 0.186 mmol, 1.0 eq), p-trifluoromethylbromobenzene (50.4 mg, 0.224 mol, 1.2 eq), cesium carbonate (121.64 mg, 0.373 mmol, 2.0 eq), palladium acetate (2.1 mg, 0.01 mmol, 5% eq), xanthophos (10.8 mg, 0.018 mmol, 10% eq), and anhydrous dioxane (1 ml) were added to a reaction tube, and the temperature was raised to 105°C and the reaction was allowed to proceed for 16 hours. TLC was used to indicate that the starting materials had reacted completely. The reaction mixture was cooled to room temperature, 1 ml of water was added, and the mixture was extracted with EA (6 ml x 2). Separation was then performed by PTLC to obtain SM6 (28 mg, 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 by the present invention: [ka]

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

[0180] The experimental process is as follows: SM2 synthesis: Compound SM1 (1 g, 1.0 eq), p-trifluoroaniline (728 mg, 1.28 eq), Cs2CO3 (1.71 g, 1.5 eq), Pd(OAc)2 (39 mg, 0.05 eq), and xanthophos (506 mg, 0.25 eq) were dissolved in dioxane (20 mL), and the mixture was stirred at 105 °C for 14 hours under N2 protection until the starting materials reacted almost completely. Workup: The reaction mixture was diluted with EA, a small amount of water was added, and the mixture was extracted with EA to obtain the organic phase. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness to obtain the crude product SM3 (1.02 g).

[0181] SM3 synthesis Compound SM2 (200 mg, 1.0 eq), crotonic acid (137 mg, 2.5 eq), and DIEA (813 mg, 10 eq) were added to THF, replaced with N2, and then Pd(PhCN)2Cl2 (12 mg, 0.05 eq) and 3(tolyl)phosphorus (10 mg, 0.05 eq) were added. The mixture was reacted overnight at 70°C. The starting materials reacted almost completely, but a large amount of uncyclized product was formed. Therefore, acetic anhydride (0.2 mL) was added to promote the cyclization reaction, and after 1 hour, most of the product was cyclized. This was confirmed by LC-MS. Workup: The reaction mixture was diluted with EA, a small amount of water was added, and the organic phase was extracted with EA. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness to obtain the crude product SM3 (126 mg).

[0182] SM4 synthesis Compounds SM3 (6.0 g, 1.0 eq) and NBS (7.13 g, 2 eq) were added to acetonitrile (60 mL), replaced with N2, and reacted overnight at 90°C. The reactants reacted almost completely, and this was confirmed by LC-MS. Workup: The reaction mixture was diluted with EA, a small amount of water was added, and the organic phase was extracted with EA. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and SM4 (7.42 g) was obtained by column chromatography PE → PE:EA = 50:1 → 20:1 → 10:1.

[0183] SM5 synthesis Compound SM4 (4g, 1.0eq), tributyl(1-ethoxyethylene)tin (5.67g, 1.5eq), and Pd(PPh3)Cl2 (738mg, 0.1eq) were added to DMF (40mL), replaced with N2, and reacted overnight at 120°C. The starting materials reacted almost completely, and accuracy was confirmed by LCMS. Workup: The reaction mixture was diluted with EA, a small amount of water was added, and the organic phase was extracted with EA. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and passed through a column (PE:EA=5:1) to obtain SM5 (970mg). 1 This demonstrates accuracy using HNMR.

[0184] SM6 synthesis Compound SM5 (970 mg, 1.0 eq) was added to MeOH (10 mL), followed by dioxane hydrochloride (10 mL). The mixture was allowed to react overnight at room temperature, after which the starting materials reacted almost completely, as confirmed by LC-MS. Workup: The reaction mixture was directly spin-dried to obtain the crude product SM6 (728 mg).

[0185] SM7 synthesis 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, and after 30 minutes, the starting materials had reacted almost completely, which was confirmed by LC-MS. Workup: The reaction solution was diluted with EA, a small amount of water was added, and the organic phase was extracted with EA. The solution was washed with saturated brine and dried over anhydrous sodium sulfate to obtain the crude product SM7 (734 mg). This was confirmed by 1H NMR.

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

[0187] SM9 synthesis Compound SM8 (2.5 g, 1.0 eq) and hydrazine hydrate (2.683 g, 10 eq) were added to EtOH (25 mL) and the mixture was refluxed overnight. Workup: The reaction mixture was directly spin-dried, and the crude product SM9 (327 mg) was obtained by column chromatography.

[0188] T-285 synthesis Compounds SM9 (166 mg, 1.0 eq) and TEA (145 mg, 3 eq) were added to DCM (1 mL), acryloyl chloride (50 mg, 1.15 eq) was added dropwise under ice bath, and the mixture was allowed to react at room temperature. After standing overnight, the reaction was confirmed to be almost complete by LC-MS. Workup: The reaction mixture was directly spin-dried, and product T-285 (33 mg) was obtained by column chromatography (PE → PE:EA = 5:1 → PE:EA = 2:1 → 1:1).

[0189] 11H NMR (400 MHz, 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 by the present invention: [ka]

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

[0192] The experimental process is as follows: T-412-2 synthesis 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 xanthophos (850 mg, 0.25 eq) were dissolved in dioxane (400 mL) and stirred at 105 °C for 14 hours under N2 protection until the starting materials reacted almost completely. Workup: The reaction mixture was diluted with EA, a small amount of water was added, and the mixture was extracted with EA to obtain the organic phase. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness. Purification (PE → PE:EA = 50:1) was performed to obtain the crude product T-412-2 (20.7 g). Note: If the purity of T-412-2 is insufficient, hydrolysis and esterification strategies may be employed, and the accuracy can be confirmed by 1H NMR.

[0193] Synthesis of T-412-3 Compound T-412-2 (10.6g, 1.0eq), crotonic acid (6.11g, 2.5eq), and DIEA (36.09g, 10eq) were added to THF (53mL), replaced with N2, and then Pd(PhCN)2Cl2 (545mg, 0.05eq) and 3(tolyl)phosphorus (432mg, 0.05eq) were added. The reaction was allowed to proceed overnight at 70°C. The starting materials reacted almost completely, but a large amount of uncyclized product was produced. Therefore, acetic anhydride (8.9mL) was added to activate the reaction and promote cyclization. After 2 hours, all cyclized products were produced. This was confirmed by LCMS. Workup: Dilution with EA, a small amount of water was added, and the organic phase was extracted with EA. Washed with saturated brine, dried over anhydrous sodium sulfate, the filtrate was concentrated to dryness, and passed through a column (PE:EA=5:1) to obtain the crude product T-412-3 (4.6g).

[0194] Synthesis of T-412-4 Compound T-412-3 (4.6 g, 1.0 eq) and LiOH (917.5 mg, 3.0 eq) were dissolved in MeOH / THF / H2O (76 ml / 38 mL / 19 mL), protected with N2 at 50°C, and stirred at room temperature for 14 hours to confirm that the starting materials had reacted almost completely and that LC-MS was accurate. Workup: The reaction solution was diluted with EA, a small amount of water was added, and the mixture was phased to obtain an aqueous phase (in this case, the product in the aqueous phase is a salt). The aqueous phase was adjusted to approximately pH=3 with 1N HCl, extracted with EA to obtain an organic phase (in this case, the product is in the organic phase), washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness to obtain the crude product T-412-4 (3.9 g). LC-MS was accurate.

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

[0196] T-412-6 synthesis Compound T-412-5 (944 mg, 1.0 eq) was added to MeOH (15 mL), and 4 M dioxane hydrochloride (15 mL) was added under an ice bath. The mixture was allowed to react overnight until the starting materials were almost completely reacted. Workup: Direct spin drying was performed to obtain the crude product T-412-6 (709 mg).

[0197] T-412 synthesis Compound T-412-6 (709 mg, 1.0 eq) and TEA (684 mg, 3 eq) were added to DCM (15 mL), and acryloyl chloride (244 mg, 1.15 eq) was added dropwise under ice bath. The reaction was allowed to proceed at room temperature and overnight. The starting materials reacted almost completely, and this was confirmed by LC-MS. Workup: The reaction mixture was directly spin-dried, and product T-425 (536 mg) was obtained by column chromatography. Further purification yielded 363 mg with a purity of 93.3%, and further crystallization yielded 160 mg with a purity of 97.6%, leaving a remaining mixed product of 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] Referencing the synthesis methods of Examples T-243 and T-412, the following compounds were synthesized. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

[0199] The experimental procedure for the biological activity test is as follows: Experiment Example 1: Cell proliferation inhibition experiment Measurement of YAP-TEAD inhibitor compounds for inhibiting the proliferation of human pleural mesothelioma cells NCI-H226. Experimental materials and equipment: Human pleural mesothelioma cells NCI-H226 were 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 digestate), 1x PBS (phosphate buffer, pH 7.2), 96-well plate (Corning), fetal bovine serum (FBS), 10000 U / mL penicillin-G / streptomycin, high-speed refrigerated centrifuge (EPPENDORF5810R), enzyme-linked immunosorbent detector (Tecan Spark).

[0200] Preparation for the experiment: 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) Remove the culture medium from the 10cm culture dish. C) Rinse the cells once with 10 ml of 1x PBS. D) Add 4 ml of 0.25% EDTA-trypsin, place in a 37°C, 5% CO2 incubator, digest the trypsin for 5 minutes, transfer to a 15 ml centrifuge tube, centrifuge at 200 g for 5 minutes, discard the supernatant, and obtain the cell precipitate. E) Resuspend in 4 ml of DMEM medium, count, and adjust to 10,000 cells / ml. F) Add the cell suspension to a 96-well plate at a volume of 100 μL per well and incubate overnight in a 37°C, 5% CO2 incubator.

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

[0202] 3. Analysis and detection of CCK8 (WST-8) cells A) Remove the cell culture plate and add 10 μL of CCK-8 (WST-8) solution to each well in the biosafety cabinet. B) Return the cell culture plate to the incubator and continue incubation for 3 hours. C) The absorbance value is measured using a TECAN enzyme-linked immunosorbent assay detector with a wavelength of 450 nm selected.

[0203] 4. Data Analysis Use the following formula to calculate cell viability (%Cell Viability). Cell viability (%) = [A (medication) - A (blank)] / [A (no medication) - A (blank)] × 100 A (Medication): Absorbance of wells containing cells, CCK8 solution, and drug solution. A (blank): Absorbance of wells containing culture medium and CCK8 solution but no cells. A(0 dose): Absorbance of wells containing cells and CCK8 solution, but not drug solution. Cell viability: Cell proliferation activity or cytotoxic activity is measured using GraphPad Prism 8 software, and the IC50 value is obtained by curve fitting.

[0204] Experimental Example 2. Nanoluciferase method for detecting YAP-TEAD inhibitor activity (1) Materials and equipment: 293T cells are purchased from Cobioer Biosciences C., LTD. DMEM medium (high sugar, no phenol red, Bio-Channel), DMSO (dimethyl sulfoxide), Lipo6000™ transfection reagent (Beyotime), pGL3B-8xGTiiC-nLuc-CMV-fLuc plasmid, 0.25% EDTA-trypsin (trypsin digestate), 1x PBS (phosphate buffer, pH 7.2), 96-well white cell culture plate (PerkinElmer), fetal bovine serum (FBS), 10000 U / mL penicillin-G / streptomycin, fast refrigerated centrifuge (EPPENDORF5810R), 37°C, CO2 incubator, Vi-cell® cell counter, Envision microplate reader (PerkinElmer).

[0205] reagent [Table 11]

[0206] (2) Transient transfection of 293T cells Recovered 293T cells should be inoculated into a 10 cm culture dish, placed in a 5% CO2 incubator, and cultured at a constant temperature of 37°C. To ensure transfection efficiency, cells in a logarithmic state (cell density of approximately 50% to 70%) should be used.

[0207] The day before transfection, log-phase cells are digested with trypsin-EDTA, the reaction is stopped by adding culture medium, and the mixture is mixed by pipetting to prepare a cell suspension. Using Vi-cell, measure the cell concentration and dilute to a suspension of 5 × 10^5 cells per 1 mL. After preparing the cell suspension, gently mix and add 10 mL of the liquid to a 10 cm culture dish. Thus, the number of cells per 10 cm culture dish is 5 × 10^6. Culture in a 5% CO2 incubator at a constant temperature of 37°C for 1 day.

[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 gently pipette to mix. Add Lipo6000 transfection reagent to the other tube and gently pipette to mix. After standing at room temperature for 5 minutes, gently add the DNA-containing culture medium to the Lipo6000 transfection reagent-containing culture medium, gently invert the centrifuge tubes to mix, and stand at room temperature for 5 minutes. The above mixture is uniformly dropped into a 10 cm culture dish, incubated for 6 hours, and then replaced with fresh complete culture medium.

[0209] (3) Plating of 96-well plates One day after transfection, the cells are digested with trypsin-EDTA, the reaction is stopped by adding culture medium, and the mixture is pipetted to prepare a cell suspension. Cell concentration is measured using Vi-cell and diluted to a suspension of 20,000 cells per 1 mL. After preparing the cell suspension, gently mix it and add 100 μL to each well of a 96-well plate, resulting in a cell density of 2000 cells per well.

[0210] (4) Addition of compound The inoculated cell culture plates are placed in an incubator and cultured, and the concentration gradient compound is added after approximately 24 hours. Dilute a 10 mM compound stock solution to 50 μM with culture medium. Add the 50 μM compound solution sequentially to the 3rd row of a deep well plate, and then add 216 μL of 0.5% DMSO-containing medium to rows 4 through 11. Gradient dilution: Take 100 μL of solution from the 3rd column, add it to the 4th column and mix well, then take 100 μL of solution from the 4th column and add it to the 5th column, and repeat this procedure up to the 11th column. Using a multichannel pipette, remove 25 μL of compound solution from a deep-well plate and add it to a 96-well culture plate. Repeat this process four times for each compound in the 96-well plate. Finally, create a 1:3.16 concentration gradient with a maximum concentration of 10,000 nM on the 96-well plate.

[0211] (5) Addition and reading of nanoluciferase detection reagent After culturing the 96-well plate in a 5% CO2 incubator at a constant temperature of 37°C for 48 hours, remove it and allow it to equilibrate at room temperature for 10 minutes. Add 100 μL of detection reagent to each well and shake slowly in a horizontal shaker 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 the result Using 0nM as a control, the values ​​in each well were converted to percentages, and nonlinear fitting was performed using the Inhibitor vs. Response (three parameters) section of the GrahpPad prism software. 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 [Table 12-67]

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

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

[0216] Pharmacokinetic experiment protocol for rats (1) Required animals: 3 healthy adult SD rats, male, 6-8 weeks old, weighing 200-300g. (2) Required equipment: analytical balance, animal scale, magnetic stirrer, refrigerated centrifuge, single-channel manual pipette, etc. (3) Required reagents: EDTA-Na2 anticoagulant, etc. Weigh 11.2 g of EDTA-Na2, place it in a reagent bottle, add 100 mL of physiological saline, and shake until completely dissolved. After preparation, place 20 μL each into 1.5 mL centrifuge tubes to collect whole blood samples.

[0217] (3) Accurately weigh approximately 10 mg of the test sample, dissolve it in the converted 5% DMSO, add 30% PEG400 and 65% (10% Hp-β-CD in PBS), sonicate, vortex and mix to obtain a 1 mg / mL solution, and prepare it fresh before use. (4) Transfer 0.1 mL of the sample to a 1.5 mL centrifuge tube, store at -80°C, and use for concentration analysis of the administered solution.

[0218] (5) The animals are housed in rat cages and fasted from the day before the test (for at least 10 hours), but water is not prohibited. On the day of the test, each animal is weighed and marked on its tail. A blank blood sample is taken from each animal before administration. Tail vein blood collection is used for blood collection. (6) Route of administration: Intragastric administration (po), Dosage: 10 mg / kg, Volume of administration: 10 mL / kg.

[0219] (7) Procedure: With a bite-resistant glove on, grasp the rat with your left hand and hold it upright. Insert a No. 16 gastric tube feeding needle into its mouth and throat. Test the needle when there is no apparent resistance, and then inject the drug into its stomach. (8) 0.2 ml of whole blood was collected from each test animal before administration and at 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration into an EDTA-Na2 anticoagulant tube. The tubes were inverted 3-4 times to mix the blood, and the tubes were centrifuged at 10000 g at 4°C for 5 minutes to separate the plasma. The plasma was then stored at -80°C until the test. Blood collection was performed using the tail vein.

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

[0221] Here, control compound 1 is the compound with the best properties disclosed in patent WO2020097389A1, and its structural formula is as follows. [ka]

[0222] All documents referenced in this invention are cited as references in this application, as if each document were cited individually. Furthermore, after reading the above teachings of this invention, persons skilled in the art can make various changes or modifications to the invention, and these equivalent forms are also included within the scope defined by the claims appended to this application.

Claims

1. A compound represented by formula I, or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 1】 Here, A is the basis of the following equation: 【Chemistry 2】 Selected from, L １ He is absent, B is selected from C6-C10 aryl groups, 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and C5-C10 cycloalkyl groups. X is O, X １ CR ３ and selected from N, X ２ CR ３ , N, O, S, and NR ４ Selected from, X ３ CR ３ and selected from N, X ４ is selected from CR ３ and N, where in X4, R3 is selected from H, D, halogen, CN, NH2, C1-6 haloalkyl group, C1-6 alkoxy group, and C3-6 cycloalkyl group, X ６ CR ３ and selected from N, X ７ CR ３ and selected from N, R １ Each of these is independently the basis of the following equation: 【Transformation 3】 Selected from, Each R ２ These are, independently, C1-C6 alkyl, C1-C6 haloalkyl, and SF ５ Selected from, Unless otherwise specified, each R ３ and R ４ These are H, D, halogen, CN, and NH, respectively, independently. ２ , -CO-(C １－６ Alkyl), =O, -C(=O)-O-(C1-C6 alkyl), -S(=O) ２ -NR ６ R ７ The basis of the following equation: 【Chemistry 4】 Urea group, C １－６ Alkyl alkyl group, C １－６ Alkyl halogenated compounds, 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, and S, and SF ５ Selected from, here, NH ２ , urea group, C １－６ Alkyl alkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyl groups, 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 with 1, 2, or 3 R atoms. R ６ and R ７ These are, independently, hydrogen, D, and C. １－６ Alkyl alkyl group, C ３－６ Cycloalkyl groups, C6-C10 aryl groups, NH ２ NH(C １－６ Alkyl), N (C １－６ Alkyl) ２ , -S(O) ２ - (C １－６ Alkyl), and -S(O) ２ - (C ２－６ Selected from Alkenil, where C １－６ Alkyl alkyl group, C ３－６ The cycloalkyl group and the C6-C10 aryl group may be optionally substituted with 1, 2, or 3 R atoms, or R ６ and R ７ It forms a 3- to 7-membered carbon ring, or R ６ and R ７ It forms a 3- to 7-membered heterocycle containing N, O, or S. Each R is a halogen, CN, OH, -(C １－６ Alkylene)-N(C) １－６ Alkyl) ２ NH ２ NH(C １－６ Alkyl group, urea 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, a 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, and S, and an R'-substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, where R' is independently C １－６ Alkyl alkyl groups, halogenated C １－６ Alkyl alkyl group, C １－６ Alkoxy group, NH ２ NH(C １－６ Alkyl), N (C １－６ Alkyl) ２ Selected from the group consisting of CN, halogens, and =O, Each m and n is independently selected from 1, 2, 3, and 4. The compound represented by formula I, or a pharmaceutically acceptable salt or solvate thereof, characterized in that p is selected from 0, 1, and 2.

2. A is the basis of the following equation: 【Transformation 5】 Selected from, L １ He is absent, B is a C6-C10 aryl group, X is O, X １ CR ３ Selected from the group consisting of and N, X ２ CR ３ , N and NR ４ Selected from the group consisting of, X ３ CR ３ Selected from the group consisting of and N, X ４ CR ３ and selected from the group consisting of N, where in X4, R3 is selected from H, D, halogen, CN, NH2, C1-6 haloalkyl group, C1-6 alkoxy group, and C3-6 cycloalkyl group, X ６ CR ３ Selected from the group consisting of and N, X ７ CR ３ Selected from the group consisting of and N, R １ This is based on the following formula: 【Transformation 6】 Selected from, Each R ２ Each of them is independent of C １－６ Selected from alkyl groups, Unless otherwise specified, each R ３ and R ４ are each independently selected from 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 cycloalkoxy group, a C6-C10 aryl group, and a 5- to 10-member heteroaryl group containing 1 to 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 group, a C6-C10 aryl group, and a 5- to 10-member heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S are optionally substituted by 1, 2, or 3 Rs, R ６ and R ７ These are, independently, hydrogen and C １－６ Alkyl 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 Selected from Alkenil, where C １－６ Alkyl alkyl group, C ３－６ The cycloalkyl group and the C6-C10 aryl group may be optionally substituted with 1, 2, or 3 R atoms, or R ６ and R ７ It forms a 3- to 7-membered carbon ring, or R ６ and R ７ It forms a 3- to 7-membered heterocycle containing N, O, or S. Each R represents halogen, CN, OH, and NH. ２ , C １－６ Alkyl 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, and a 5-10 membered heteroaryl group 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 characterized by being selected from 0, 1, and 2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. The aforementioned compound is the compound shown in formula III, 【Transformation 7】 Here, 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, The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

4. The aforementioned compound has the following formula: 【Transformation 8】 Selected from the group consisting of, R １ This is based on the following formula 【Chemistry 9】 Selected from, Here, B, X, X １ , X ２ , X ３ , X ４ , X ６ , X ７ , R ６ , R ７ , R ２ , R ３ and n are as defined in claim 1, The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

5. R ２ It is characterized by being selected from a trifluoromethyl group, a methyl group, and a sulfur pentafluoride group. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

6. The following compounds: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] A compound or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the following.

7. A pharmaceutical composition, The pharmaceutical composition is characterized by comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound described in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

8. A pharmaceutical composition according to claim 7, for use in the preparation of a drug for preventing and / or treating a related disease caused by a dysregulation of the Hippo pathway, 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 drug for preventing and / or treating related diseases due to YAP or TAZ or YAP / TAZ or YAP / TEAD or YAP / TAZ / TEAD dysregulation, 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 the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, in combination with a second drug, for the preparation of a drug for the prevention and / or treatment of cancer, The use described above is characterized in that the second drug is selected from the group consisting of ERK inhibitors, MEK inhibitors, KRAS inhibitors, BRAF inhibitors, EGFR inhibitors, Wnt inhibitors, PD-1 inhibitors, and combinations thereof.

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