WO2023016562A1 - 多环类化合物及其用途 - Google Patents

多环类化合物及其用途 Download PDF

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WO2023016562A1
WO2023016562A1 PCT/CN2022/112259 CN2022112259W WO2023016562A1 WO 2023016562 A1 WO2023016562 A1 WO 2023016562A1 CN 2022112259 W CN2022112259 W CN 2022112259W WO 2023016562 A1 WO2023016562 A1 WO 2023016562A1
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group
alkyl
compound
aryl
cycloalkyl
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PCT/CN2022/112259
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English (en)
French (fr)
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梁阿朋
李钧
吴豫生
陈少卿
刘广斌
尹洲
董胜利
李美华
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浙江同源康医药股份有限公司
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Priority to KR1020247008000A priority Critical patent/KR20240046891A/ko
Priority to CA3228542A priority patent/CA3228542A1/en
Priority to EP22855542.1A priority patent/EP4385978A1/en
Priority to AU2022326724A priority patent/AU2022326724A1/en
Priority to CN202280047848.2A priority patent/CN117677608A/zh
Priority to JP2024508668A priority patent/JP2024530956A/ja
Publication of WO2023016562A1 publication Critical patent/WO2023016562A1/zh

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Definitions

  • the present invention relates to the technical field of medicine, in particular to a polycyclic compound used for regulating the Hippo pathway and its preparation method and use, mainly used for the treatment or prevention of proliferative diseases (such as cancer), especially for the regulation and treatment of YAP/ Related diseases caused by abnormal activity of TEAD.
  • proliferative diseases such as cancer
  • the Hippo pathway essentially consists of a core kinase cascade comprising the Ste-20 family of protein kinases MST1-2, the scaffolding protein Salvador and the large tumor suppressor kinase LATS1-2, and the repressive transcriptional coactivator YAP (Yes1 associated protein) and TAZ (transcriptional coactivator with PDZ binding motif).
  • YAP and TAZ are the main effectors of the Hippo signaling pathway, and together with TEAD (transcriptional enhancer association domain) in the nucleus, they act as transcription factors to increase the expression of target genes such as CTGF (connective tissue growth factor), CYR61, etc.
  • CTGF connective tissue growth factor
  • CYR61 CYR61
  • TEAD transcription factors lie at the heart of the Hippo pathway and are critical for regulating organ growth and wound repair.
  • Dysregulation of TEAD and its regulatory cofactor Yes-associated protein (YAP) have been implicated in many human cancers and hyperproliferative pathological processes, and dysregulation of this pathway is frequently detected in human cancers.
  • YAP and TAZ activation have been identified in many human tumors and are critical for tumor initiation, progression, and metastasis, as seen in patients with breast, ovarian, colon, liver, and pancreatic cancers. There was elevated expression of YAP and it was associated with reduced survival.
  • YAP or TAZ enhanced TEAD-dependent gene expression (eg, CCN1, CTGF, ITGB2 and Birc5/survivin) and promoted cell proliferation and migration in many cell types.
  • blocking signaling or interfering with YAP/TAZ-TEAD complex formation to prevent the expression of many mitogenic TEAD target genes significantly reduced cell proliferation and oncogenic transformation activity.
  • the Hippo pathway also cross-talks with other signaling pathways such as Wnt, Notch, Hedgehog, and MAPK, thereby affecting a variety of biological functions, and its dysfunction may not only be involved in cancer, but also be involved in in many human diseases. Therefore, the YAP-TEAD complex is a promising therapeutic target.
  • the object of the present invention is to provide a compound represented by formula I and its preparation method and application.
  • the first aspect of the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof,
  • L 1 is selected from the absence or CR 3 R 4 ;
  • B is selected from C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, and C5-C10 cycloalkyl;
  • X is selected from O, NH, CR 3 R 4 or S;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are each independently selected from CR 3 , (CR 3 ) 2 , N, O, S, SR 3 , SR 3 R 4 , NR 4 , CR 3 R 4 , (CR 3 R 4 ) 2 ;
  • Each R 1 is independently selected from H, D, halogen, CN, NH 2 , ureido, carboxyl, carbamate, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkane group, C 3-6 cycloalkoxy group, C6-C10 aryl group, 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, Among them, NH 2 , ester group, urea group, carbamate group, amido group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group Base, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S are optionally substituted by 1, 2 or 3 R;
  • R 6 and R 7 are each independently selected from hydrogen, D, C 1-6 alkyl, C 3-6 cycloalkyl, C6-C10 aryl, NH 2 , NH(C 1-6 alkyl), N( C 1-6 alkyl) 2 , 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, 5-membered heteroaryl containing 1-3 heteroatoms selected from N, O or S -10-membered heterocyclic group, -S(O) 2 -(C 1-6 alkyl), -S(O) 2 -(C 2-6 alkenyl), wherein, C 1-6 alkyl, C 3 -6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S are optionally substituted by 1, 2 or 3 R, or R 6 and R 7 form a 3-7 membered carbocycle, or R 6 and R 7 form a 3-7 membered hetero
  • R 8 is selected from
  • Each R is independently selected from halogen, CN, OH, -(C 1-6 alkylene)-N(C 1-6 alkyl) 2 , NH 2 , NH(C 1-6 alkyl), ester, Urea group, carbamate group, amido group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group , C 2-6 alkenyl group , C 2-6 alkynyl, C6-C10 aryl, 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or R'substituted or unsubstituted containing 1-3 A 5-10 membered heteroaryl group selected from heteroatoms of N, O or S; R' is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, NH 2 , NH(C 1-6 alkyl), N(
  • each m and n is independently selected from 1, 2, 3 or 4;
  • p is selected from 0, 1 or 2.
  • L 1 is selected from the absence or CR 3 R 4 ;
  • B is selected from C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, and C5-C10 cycloalkyl;
  • X is selected from O, NH or S
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CR 3 , (CR 3 ) 2 , N, O, S, NR 4 , CR 3 R 4 , (CR 3 R 4 ) 2 ;
  • R 1 is selected from H, halogen, CN, NH 2 , ureido, carboxyl, carbamate, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3- 6 cycloalkoxy, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, Among them, NH 2 , ester group, urea group, carbamate group, amido group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group Base, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S are optionally substituted by 1, 2 or 3 R;
  • Each of R 2 , R 3 , R 4 and R 5 is independently selected from H, halogen, CN, NH 2 , -CO-(C 1-6 alkyl), ester group, urea group, carbamate group, Amide, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C6-C10 aryl, containing 1-3 selected from N, 5-10 membered heteroaryl group with O or S heteroatom, SF 5 , among them, NH 2 , ester group, urea group, carbamate group, amide group, C 1-6 alkyl, C 1-6 alkane Oxygen, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S optionally substituted by 1, 2 or 3 R;
  • R 6 and R 7 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C6-C10 aryl, NH 2 , NH(C 1-6 alkyl), N(C 1 -6 alkyl) 2 , 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S Heterocyclic group, -S(O) 2 -(C 1-6 alkyl), -S(O) 2 -(C 2-6 alkenyl), wherein, C 1-6 alkyl, C 3-6 Cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S are optionally substituted by 1, 2 or 3 R, or R 6 and R 7 forms a 3-7 membered carbocycle, or R 6 and R 7 form a 3-7 membered heterocyclic ring containing
  • Each R is independently selected from halogen, CN, OH, -(C 1-6 alkylene)-N(C 1-6 alkyl) 2 , NH 2 , NH(C 1-6 alkyl), ester, Urea group, carbamate group, amido group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group , C 2-6 alkenyl group , C 2-6 alkynyl, C6-C10 aryl, 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or R'substituted or unsubstituted containing 1-3 A 5-10 membered heteroaryl group selected from heteroatoms of N, O or S; R' is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, NH 2 , NH(C 1-6 alkyl), N(
  • each m and n is independently selected from 1, 2, 3 or 4;
  • p is selected from 0, 1 or 2.
  • L 1 is selected from the absence or CR 3 R 4 ;
  • 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
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CR 3 , N, O, S or NR 4 ;
  • R 1 is selected from H, halogen, CN, NH 2 , ureido, carboxyl, carbamate, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3- 6 cycloalkoxy, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, Among them, NH 2 , ester group, urea group, carbamate group, amido group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group Base, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S are optionally substituted by 1, 2 or 3 R;
  • Each of R 2 , R 3 , R 4 and R 5 is independently selected from H, halogen, CN, NH 2 , -CO-(C 1-6 alkyl), ester group, urea group, carbamate group, Amide, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C6-C10 aryl, containing 1-3 selected from N, A 5-10-membered heteroaryl group with a heteroatom of O or S, wherein, NH 2 , ester group, urea group, carbamate group, amido group, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 6-C 10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S are optionally 1, 2 or 3 R substitutions;
  • R 6 and R 7 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C6-C10 aryl, 5 containing 1-3 heteroatoms selected from N, O or S -10-membered heteroaryl, -S(O) 2 -(C 1-6 alkyl), -S(O) 2 -(C 2-6 alkenyl), wherein, C 1-6 alkyl, C 3 -6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S are optionally substituted by 1, 2 or 3 R, or R 6 and R 7 form a 3-7 membered carbocycle, or R 6 and R 7 form a 3-7 membered heterocyclic ring containing N, O or S;
  • Each R is independently selected from halogen, CN, OH, NH 2 , ester group, urea group, carbamate group, amide group, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 ring Alkyl, C 3-6 cycloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C6-C10 aryl, or 5 heteroatoms containing 1-3 selected from N, O or S -10 membered heteroaryl;
  • each m and n is independently selected from 1, 2, 3 or 4;
  • p is selected from 0, 1 or 2.
  • L 1 is selected from the absence or CR 3 R 4 ;
  • B is a C6-C10 aryl group
  • X is O
  • X 1 , X 2 , X 3 , X 4 , X 6 and X 7 are each independently selected from CR 3 , N, CR 3 R 4 , or NR 4 ;
  • R 1 is selected from
  • Each of R 2 , R 3 , R 4 and R 5 is independently selected from H, halogen, CN, NH 2 , -CO-(C 1-6 alkyl), C 1-6 alkyl, C 1-6 alkane Oxygen, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, Among them, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C6-C10 aryl, containing 1-3 selected from A 5-10 membered heteroaryl group of heteroatoms of N, O or S is optionally substituted by 1, 2 or 3 R;
  • R 6 and R 7 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C6-C10 aryl, 5 containing 1-3 heteroatoms selected from N, O or S -10-membered heteroaryl, -S(O) 2 -(C 1-6 alkyl), -S(O) 2 -(C 2-6 alkenyl), wherein, C 1-6 alkyl, C 3 -6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S are optionally substituted by 1, 2 or 3 R, or R 6 and R 7 form a 3-7 membered carbocycle, or R 6 and R 7 form a 3-7 membered heterocyclic ring containing N, O or S;
  • R 8 is selected from
  • Each R is independently selected from halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 2- 6 alkenyl, C2-6 alkynyl, C6-C10 aryl, or 5-10 membered heteroaryl 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.
  • L 1 is selected from the absence or CR 3 R 4 ;
  • B is a C6-C10 aryl group
  • X is O
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CR 3 , N, or NR 4 ;
  • R 1 is selected from
  • Each of R 2 , R 3 , R 4 and R 5 is independently selected from H, halogen, CN, NH 2 , -CO-(C 1-6 alkyl), C 1-6 alkyl, C 1-6 alkane Oxygen, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, Among them, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C6-C10 aryl, containing 1-3 selected from A 5-10 membered heteroaryl group of heteroatoms of N, O or S is optionally substituted by 1, 2 or 3 R;
  • R 6 and R 7 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C6-C10 aryl, 5 containing 1-3 heteroatoms selected from N, O or S -10-membered heteroaryl, -S(O) 2 -(C 1-6 alkyl), -S(O) 2 -(C 2-6 alkenyl), wherein, C 1-6 alkyl, C 3 -6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S are optionally substituted by 1, 2 or 3 R, or R 6 and R 7 form a 3-7 membered carbocycle, or R 6 and R 7 form a 3-7 membered heterocyclic ring containing N, O or S;
  • Each R is independently selected from halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 2- 6 alkenyl, C2-6 alkynyl, C6-C10 aryl, or 5-10 membered heteroaryl 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.
  • L 1 is selected from the absence or CR 3 R 4 ;
  • B is a C6-C10 aryl group
  • X is O
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CR 3 , N, or NR 4 ;
  • R 1 is selected from
  • Each of R 2 , R 3 , R 4 and R 5 is independently selected from H, halogen, CN, NH 2 , -CO-(C 1-6 alkyl), C 1-6 alkyl, C 1-6 alkane Oxygen, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, Among them, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C6-C10 aryl, containing 1-3 selected from A 5-10 membered heteroaryl group of heteroatoms of N, O or S is optionally substituted by 1, 2 or 3 R;
  • R 6 and R 7 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C6-C10 aryl, 5 containing 1-3 heteroatoms selected from N, O or S -10-membered heteroaryl, -S(O) 2 -(C 1-6 alkyl), -S(O) 2 -(C 2-6 alkenyl), wherein, C 1-6 alkyl, C 3 -6 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S are optionally substituted by 1, 2 or 3 R, or R 6 and R 7 form a 3-7 membered carbocycle, or R 6 and R 7 form a 3-7 membered heterocyclic ring containing N, O or S;
  • Each R is independently selected from halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 2- 6 alkenyl, C2-6 alkynyl, C6-C10 aryl, or 5-10 membered heteroaryl 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.
  • the compound is selected from the following group:
  • each group is as defined above.
  • the compound is selected from the following group:
  • each group is as defined above.
  • the compound is selected from the following group:
  • each group is as defined above.
  • Said compounds are selected from the group consisting of:
  • R 1 is selected from CN, ureido, carbamate,
  • each group is as defined above.
  • R 1 is selected from CN, urea group, carbamate group,
  • R 2 is selected from trifluoromethyl, fluorine, chlorine, bromine, iodine, methyl, cyclopentyl, or cyclohexyl or 5-sulfuryl fluoride.
  • R 2 is selected from trifluoromethyl, fluorine, chlorine, bromine, iodine, methyl, cyclopentyl, or cyclohexyl.
  • It is an aromatic group or an unsaturated group.
  • It is a non-aromatic group or a saturated group. Similar format groups have similar meanings.
  • the compound is selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof, Solvates or Prodrugs.
  • the third aspect of the present invention provides a use of the pharmaceutical composition described in the second aspect of the present invention for the preparation of drugs for preventing and/or treating related diseases caused by Hippo pathway disorders.
  • the fourth aspect of the present invention provides a use of the pharmaceutical composition described in the second aspect of the present invention for the preparation of prevention and/or treatment of YAP or TAZ or YAP/TAZ or YAP/TEAD or YAP/TAZ/ Drugs for diseases associated with TEAD dysregulation.
  • 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, pleural mesothelioma.
  • the fifth aspect of the present invention provides a combination of the compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, solvate or prodrug and a second drug for the preparation of prevention and/or treatment medicines for 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.
  • the present inventors unexpectedly prepared a class of compounds with excellent YAP/TEAD inhibitory activity. On this basis, the inventors have completed the present invention.
  • halogen refers to F, Cl, Br or I.
  • C1-C6 alkyl refers to a linear or branched alkyl group including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl group, neopentyl group, tertyl group, or similar groups.
  • C 1-6 alkyl has a similar meaning.
  • C2-C6 alkenyl refers to a straight chain or branched alkenyl group with 2-6 carbon atoms containing a double bond, including non-limiting ethenyl, propenyl, butenyl , Isobutenyl, Pentenyl and Hexenyl etc.
  • C 2-6 alkenyl has a similar meaning.
  • C2-C6 alkynyl refers to a straight-chain or branched-chain alkynyl group with 2-6 carbon atoms containing a triple bond, including without limitation ethynyl, propynyl, butynyl, group, isobutynyl, pentynyl and hexynyl, etc.
  • C2-6alkynyl has a similar meaning.
  • C3-C8 cycloalkyl refers to a cyclic alkyl group having 3-8 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cycloheptyl, cyclooctyl, etc.
  • the terms “C 3-8 cycloalkyl”, “C 3-6 cycloalkyl”, “C 5-10 cycloalkyl” have similar meanings.
  • C1-C6 alkoxy refers to a straight-chain or branched alkoxy group with 1-6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, Isopropoxy and butoxy, etc. Preference is given to C1-C4 alkoxy.
  • C 1-6 alkoxy has a similar meaning.
  • heterocyclic group is a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, S, including (but not limited to) the following groups:
  • aromatic ring or “aryl” has the same meaning, preferably “C6-C10 aryl”.
  • C6-C10 aryl refers to an aromatic ring group having 6-10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl and the like.
  • heteroaryl has the same meaning and refers to a heteroaromatic group containing one to more heteroatoms.
  • C3-C10 heteroaryl refers to an aromatic heterocyclic ring containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen and 3-10 carbon atoms.
  • Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • halo refers to substitution by halogen.
  • deuterated refers to substitution by deuterium.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • the substituents are for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
  • the term 1-6 means 1, 2, 3, 4, 5 or 6. Other similar terms each independently have a similar meaning.
  • ester group has the structure -C(O)-O-R' or R'-C(O)-O-, wherein R' independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl , C6-C10 aryl, heteroaryl, heterocyclyl, as defined above.
  • ureido has Structure, wherein Ra, Rb are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C6-C10 aryl.
  • urethane group has Structure, wherein Ra, Rb are each independently selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C6-C10 aryl.
  • Amido refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or Substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • aralkyl means an aryl or heteroaryl substituted alkyl group, wherein aryl, heteroaryl and alkyl are as defined herein.
  • the aryl group can have 6-14 carbon atoms
  • the heteroaryl group can have 5-14 ring atoms
  • the alkyl group can have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof,
  • each group is as defined above.
  • A, L 1 , B, R 1 , R 2 , m, and n are each independently a group corresponding to each specific compound in the present invention.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid
  • salts of the compounds of the invention with bases such as alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), ammonium salts (e.g.
  • lower alkanolammonium salts and other pharmaceutically acceptable amine salts such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butyl amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • methylamine salts such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butyl amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salt
  • solvate refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • “Hydrate” refers to a complex formed by coordination between the compound of the present invention and water.
  • the compounds of the present invention also include prodrugs of the compounds represented by formula I.
  • prodrug includes itself may be biologically active or inactive, when administered in an appropriate manner, it undergoes metabolism or chemical reactions in the human body to convert into a class of compounds of formula I, or formula I A salt or solution of a compound.
  • the prodrugs include (but are not limited to) carboxylates, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxides, amino compounds, carbamates, azo compounds of the compounds , phosphoramide, glucoside, ether, acetal and other forms.
  • compositions and methods of administration are provided.
  • the present invention also provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and one or more safe and effective doses of the compound or its pharmaceutically acceptable salt, solvate or prodrug.
  • the compound of the present invention has excellent antitumor activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and drugs containing the compound of the present invention as the main active ingredient
  • the composition can be used for the treatment, prevention and alleviation of tumor-related diseases.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • calcium sulfate such
  • the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antineoplastic drugs).
  • other pharmaceutically acceptable compounds such as antineoplastic drugs.
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 50-1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the present invention has the following main advantages:
  • the compound has excellent YAP, TAZ and/or TEAD inhibitory activity
  • the compound has excellent pharmacokinetic properties.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the raw material compound SM4 (5g, 1.0eq), palladium acetate (0.3g, 0.1eq), dppf (1.5g, 0.2eq), triethylamine (9ml, 5eq), solvent ethanol (10ml), DMF (15ml) were mixed Evenly, replace with nitrogen three times, then replace with CO three times, and protect with positive pressure of CO balloon, react at 40°C for 18h. TLC showed that there was no remaining raw material.
  • the reaction solution was directly concentrated and then extracted with water and EA for liquid separation. After the EA phase was concentrated, it was purified by column to obtain 2.5 g of compound SM6. HPLC purity: 97.16%.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • SM2 169mg, 0.73mmol, 1.0eq
  • SM3 400mg, 0.87mmol, 1.2eq
  • Pd(PPh 3 ) 4 84mg, 0.073mol, 0.1eq
  • potassium carbonate 201.4mg, 1.46mmol, 2.0eq
  • the reaction solution 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 synthetic route is as follows:
  • SM1 (5.7g, 29mmol, 1.0eq) was dissolved in methanol (100mL), cooled to 0°C, concentrated sulfuric acid (3.5g, 1.9mL, 1.2eq) was added dropwise and heated to 70°C under reflux overnight.
  • LCMS showed complete reaction of starting material. Cool to room temperature and concentrate to remove methanol. Add saturated sodium bicarbonate and extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain the product (5.6 g) as a white solid.
  • SM4 169mg, 0.73mmol, 1.0eq
  • SM3 400mg, 0.87mmol, 1.2eq
  • Pd(PPh 3 ) 4 84mg, 0.073mol, 0.1eq
  • potassium carbonate 201.4mg, 1.46mmol, 2.0eq
  • the reaction solution 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 synthetic route is as follows:
  • SM2 (5g, 122mmol, 1.0eq), B 2 Pin 2 (34.1g, 134.2mmol, 1.1eq), Pd(dppf)Cl 2 (4.46g, 6.1mmol, 0.05eq), KOAc (35.9g, 366mmol, 3eq), added into 1,4-dioxane (764ml), protected by nitrogen, then heated to 105°C, and reacted for 1.5h. LCMS showed that the product had been obtained and was relatively pure.
  • reaction solution was diluted with 1L of EA, filtered through 100g of diatomaceous earth, spin-dried, added 250ml of toluene, 400ml of ethanol, spin-dried, added 250ml of toluene, 400ml of ethanol, spin-dried, and washed with PE to obtain 48g of SM3.
  • SM5 100mg, 0.2424mmol, 1eq
  • phenylboronic acid 60.1mg, 0.4848mmol, 2eq
  • Cu(OAc) 2 4.4mg, 0.02424mmol, 0.1eq
  • TEA 49mg, 0.4848mmol, 2eq
  • the reaction solution was diluted with DCM and water, filtered with Celite, extracted with DCM, washed with saturated NaCl, dried over anhydrous sodium sulfate, mixed, and passed through the column to obtain 25 mg of SM6 .
  • the synthetic route is as follows:
  • T-110 (387mg, 1eq), DIPEA (258mg, 2eq) and HATU (380mg, 1eq) in DCM, stir at room temperature for 10min, then add isopropylamine (71mg, 1.2eq), and continue the reaction for 12h. After the reaction was completed, TLC (pure EA) was monitored, and the reaction of T-110 was complete. Add about ten times of DCM to dilute, wash with 0.05% citric acid to remove DIPEA, then wash with saturated NaCl solution, and then dry, after spin-drying, add DCM and methanol to dissolve the crude product and then use PTLC or column chromatography to obtain 302mg T-86.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • TLC pure EA
  • SM2 13.2g (1eq), biboronic acid pinacol ester 14.5g (2eq) and Pd(dppf)Cl 2 1.04g (0.05eq) were dissolved in 1,4-dioxane solution (132ml) successively, placed in Stir in the round bottom flask, then add KOAc 5.6g (2eq), replace with nitrogen 2-3 times, heat the oil bath to 105°C for 3h.
  • the synthetic route is as follows:
  • the 50ml round bottom flask was first protected with nitrogen, and SM2 (2g, 5.362mmol, 1eq), crotonic acid (1.154g, 13.4mmol, 2.5eq), DIEA (6.92g, 53.62mmol, 10eq), THF (10ml) were put into In the original round bottom flask, pump nitrogen, then continue to add Pd(PHCN)3Cl2 (102.8mg, 0.268mmol, 0.05eq), Tri(o-tolyl)phosphine (81.6g, 0.26mmol, 0.05eq), acetic anhydride (1.68 ml) under nitrogen protection, heated to 70°C, refluxed, and reacted overnight.
  • the synthetic route is as follows:
  • the reaction solution was cooled, rotary evaporated, water and 2N HCl were added, a large amount of white solids were precipitated, and 85 mg of SM6 was obtained by filtration.
  • the synthetic route is as follows:
  • SM2 (2.8g, 0.009mol, 1.0eq) and cuprous bromide (2.68g, 0.0186mol, 2.0eq) acetonitrile (50ml) were added in a 100ml reaction flask, and isoamyl nitrite (2.87g, 3.3 ml, 0.0243mol, 2.7eq), and then heated to 50 degrees for 16h. TLC showed a little SM2 remaining.
  • reaction system was cooled to room temperature, diluted by adding EA (200ml), and filtered using a Buchner funnel with diatomaceous earth. Water (200ml) was added to the filtrate, and the EA layer was separated. The aqueous layer was extracted with EA (200ml*2), and the organic layers were combined and dried by adding saturated sodium sulfate. Then concentrated through the column to obtain 2.2g product SM3
  • SM3 (2.0g, 5.5mmol, 1.0eq), pinacol borate (1.7g, 6.6mmol, 1.2eq), anhydrous potassium acetate (1.6g, 16.5mmol, 3.0eq), Pd(dppf)Cl2 (0.201g, 0.28mmol, 5%) and ultra-dry dioxane (20ml) were added to the reaction flask, then vacuumed and replaced with nitrogen and heated to 100°C for 16h. After cooling to room temperature, add ethyl acetate to dilute, add diatomaceous earth for suction filtration, and after the filtrate is concentrated, add toluene:ethanol (6:1) successively to concentrate, and finally obtain 2.2g SM4
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • SM2 Synthesis of SM2: compound SM1 (1g, 1.0eq), p-trifluoroaniline (728mg, 1.28eq), Cs 2 CO 3 (1.71g, 1.5eq), Pd(OAc) 2 (39mg, 0.05eq), Xantphos (506mg, 0.25eq) was dissolved in dioxane (20mL), stirred under N 2 protection at 105°C for 14h, and the basic reaction of the raw materials was completed.
  • reaction solution was diluted with EA, added a small amount of water, extracted with EA to obtain an organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness to obtain crude SM3 (1.02 g).
  • reaction solution was diluted with EA, added a small amount of water, extracted with EA to obtain an organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness to obtain crude SM3 (126 mg).
  • the synthetic route is as follows:
  • Tumor cells were cultured in RPMI-1640 (containing 10% FBS and 100 U/mL penicillin-G/streptomycin) at 37°C, 5% CO2 and saturated humidity to a density of 80-90%.
  • the cell suspension was added to a 96-well plate with a volume of 100 ⁇ L per well, and cultured overnight in a 37° C., 5% CO2 incubator.
  • test compound gradient dilution solution the test compound was prepared as 1 mM stock solution. Then, 1.5 ⁇ l of the stock solution was dissolved in 1.5 ml of DMSO-free culture solution, and then 3-fold serial dilution was performed with 0.1% DMSO culture solution, with a total of 9 concentrations.
  • concentration of the compound after dilution was as follows:
  • Cell viability The cell proliferation activity or cytotoxicity activity is obtained by curve fitting with GraphPad Prism 8 software to obtain the IC50 value.
  • 293T cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • DMEM medium high sugar, no phenol red, Bio-Channel
  • DMSO dimethyl sulfoxide
  • Lipo6000 transfection reagent Beiyuntian
  • pGL3B-8xGTiiC-nLuc-CMV-fLuc plasmid Lipo6000 transfection reagent
  • pGL3B-8xGTiiC-nLuc-CMV-fLuc plasmid Lipo6000 transfection reagent
  • pGL3B-8xGTiiC-nLuc-CMV-fLuc plasmid Lipo6000 transfection reagent
  • pGL3B-8xGTiiC-nLuc-CMV-fLuc plasmid Lipo6000 transfection reagent
  • pGL3B-8xGTiiC-nLuc-CMV-fLuc plasmid Lipo6000 transfection reagent
  • Vi-cell to measure the cell concentration and dilute to a suspension of 5*10 ⁇ 5 cells per ml. After the cell suspension is prepared, mix gently and add 10ml of liquid to a 10cm culture dish. In this way, the number of cells in each 10cm dish is 5*10 ⁇ 6. Incubate at 37°C for 1 day in a 5% CO2 incubator.
  • the above mixture was evenly added dropwise to a 10 cm Petri dish, and replaced with fresh complete medium after 6 hours of cultivation.
  • Vi-cell to measure the cell concentration and dilute to a suspension of 20,000 cells per milliliter.
  • the 10 mM compound stock solution was diluted to 50 ⁇ M with culture medium, and 50 ⁇ M compound solution was added to the third column of the deep well plate in turn, and 216 ⁇ L of medium containing 0.5% DMSO was added to the fourth to eleventh columns.
  • the 96-well plate was incubated in a 5% CO2 incubator at 37° C. for 48 hours, then taken out and equilibrated at room temperature for 10 minutes.
  • Animals were kept in rat cages, and were fasted (not less than 10 h) without water from the day before the test; on the day of the test, they were weighed and marked at the tail. Blank blood was collected before administration.
  • the blood collection method adopts the tail vein to draw blood.
  • Administration route intragastric administration (p.o.); administration dose: 10 mg/kg; administration volume: 10 mL/kg.
  • reference compound 1 is a compound with the best properties disclosed in the patent WO2020097389A1, and its compound structural formula is shown in the figure below:

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Abstract

本发明涉及多环类化合物及其用途。具体地，本发明化合物具有式I所示结构，其中各基团和取代基的定义如说明书中所述；本发明还公开了所述化合物的制备方法及其在调节和治疗与YAP/TEAD的异常活性所导致的相关疾病方面的用途。

Description

多环类化合物及其用途 技术领域
本发明涉及医药技术领域，具体涉及用作调节Hippo通路的多环化合物及其制备方法和用途，主要用于增殖性疾病(如癌症)的治疗或预防，尤其是用于调节和治疗与YAP/TEAD的异常活性所导致的相关疾病。
背景技术
Hippo通路基本上由一个核心激酶级联反应组成，该级联反应包含蛋白激酶MST1-2的Ste-20家族，支架蛋白Salvador和大肿瘤抑制激酶LATS1-2，以及抑制转录共激活因子YAP(Yes1相关蛋白)和TAZ(具有PDZ结合基序的转录共激活子)。YAP和TAZ是Hippo信号通路的主要效应因子，它们与核内的TEAD(转录增强的缔合结构域)一起充当转录因子，从而增加诸如CTGF(结缔组织生长因子)、CYR61等靶基因的表达。Hippo途径是细胞生长、增殖和迁移的重要调节因子。TEAD转录因子位于Hippo途径的核心，对于调节器官生长和伤口修复至关重要。TEAD的失调和其调节辅因子Yes-相关蛋白(YAP)已涉及许多人类癌症和过度增殖病理过程，在人类癌症中经常检测到该通路的失调。与TEAD蛋白一样，YAP和TAZ激活已在许多人类肿瘤中被鉴定，并且对肿瘤的起始、进展和转移至关重要，如在乳腺癌、卵巢癌、结肠癌、肝癌和胰腺癌患者中均存在YAP表达升高，且与生存率降低有关。与此一致，YAP或TAZ的激活或过表达增强TEAD依赖性基因表达(例如，CCN1，CTGF，ITGB2和Birc5/存活蛋白)并促进许多细胞类型中的细胞增殖和迁移。相反，阻断YAP/TAZ-TEAD复合物形成的信号或干预阻止许多促有丝分裂TEAD靶基因的表达，能显著降低细胞增殖和致癌转化活性。此外，Hippo通路还与其他信号传导通路诸如Wnt、Notch、Hedgehog和MAPK等通路发生串扰(cross-talk)，从而影响多种生物功能，其功能失调可能除了参与到癌症中之外，还参与到很多人类疾病中。因此YAP-TEAD复合物是一种很有前景的治疗靶点。
发明内容
本发明的目的在于提供一种式I所示化合物及其制备方法和用途。
本发明的第一方面，提供了一种式I所示化合物或其药学上可以接受的盐、溶剂化物或前药，
Figure PCTCN2022112259-appb-000001
其中，
A选自
Figure PCTCN2022112259-appb-000002
Figure PCTCN2022112259-appb-000003
L 1选自不存在或者CR 3R 4；
B选自C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、C5-C10的环烷基；
X选自O、NH、CR 3R 4或者S；
X 1、X 2、X 3、X 4、X 5、X 6和X 7各自独立地选自CR 3、(CR 3) 2、N、O、S、SR 3、SR 3R 4、NR 4、CR 3R 4、(CR 3R 4) 2；
R 1各自独立地选自H、D、卤素、CN、NH 2、脲基、羧基、氨基甲酸酯基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、
Figure PCTCN2022112259-appb-000004
Figure PCTCN2022112259-appb-000005
Figure PCTCN2022112259-appb-000006
其中，NH 2、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；
各R 2、R 3、R 4和R 5各自独立地选自H、D、卤素、CN、NH 2、-CO-(C 1-6烷基)、＝O、-C(＝O)-O-(C1-C6烷基)、-C(＝O)-O-OBi、-S(＝O) 2-NR 6R 7、
Figure PCTCN2022112259-appb-000007
酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、SF 5，其中，NH 2、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；或者，X 1和X 7分别独立地为CR 3R 4，且X 1和X 7共用1个R 3，且R 3为C1-C6亚烷基；
R 6和R 7各自独立地选自氢、D、C 1-6烷基、C 3-6环烷基、C6-C10芳基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、含1-3个选自N、O或S的杂原子的5-10元杂芳基、含1-3个选自N、O或S的杂原子的5-10元杂环基、-S(O) 2-(C 1-6烷基)、-S(O) 2-(C 2-6烯基)，其中，C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代，或者R 6和R 7形成3-7元的碳环，或者R 6和R 7形成含有N、O或S的3-7元的杂环；
R 8选自
Figure PCTCN2022112259-appb-000008
Figure PCTCN2022112259-appb-000009
各R独立地选自卤素、CN、OH、-(C 1-6亚烷基)-N(C 1-6烷基) 2、NH 2、NH(C 1-6烷基)、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-6烯基、C 2-6炔基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂环基或R’取代或未取代的含1-3个选自N、O或S的杂原子的5-10元杂芳基；R’选自下组：C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、CN、卤素、＝O；
各m和n各自独立地选自1、2、3或4；
p选自0、1或2。
在另一优选例中，
A选自
Figure PCTCN2022112259-appb-000010
Figure PCTCN2022112259-appb-000011
L 1选自不存在或者CR 3R 4；
B选自C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、C5-C10的环烷基；
X选自O、NH或者S；
X 1、X 2、X 3、X 4和X 5各自独立地选自CR 3、(CR 3) 2、N、O、S、NR 4、CR 3R 4、(CR 3R 4) 2；
R 1选自H、卤素、CN、NH 2、脲基、羧基、氨基甲酸酯基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、
Figure PCTCN2022112259-appb-000012
Figure PCTCN2022112259-appb-000013
其中，NH 2、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；
各R 2、R 3、R 4和R 5各自独立地选自H、卤素、CN、NH 2、-CO-(C 1-6烷基)、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、SF 5，其中，NH 2、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；
R 6和R 7各自独立地选自氢、C 1-6烷基、C 3-6环烷基、C6-C10芳基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、含1-3个选自N、O或S的杂原子的5-10元杂芳基、含1-3个选自N、O或S的杂原子的5-10元杂环基、-S(O) 2-(C 1-6烷基)、-S(O) 2-(C 2-6烯基)，其中，C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代，或者R 6和R 7形成3-7元的碳环，或者R 6和R 7形成含有N、O或S的3-7元的杂环；
各R独立地选自卤素、CN、OH、-(C 1-6亚烷基)-N(C 1-6烷基) 2、NH 2、NH(C 1-6烷基)、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-6烯基、C 2-6炔基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂环基或R’取代或未取代的含1-3个选自N、O或S的杂原子的5-10元杂芳基；R’选自下组：C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、CN、卤素；
各m和n各自独立地选自1、2、3或4；
p选自0、1或2。
在另一优选例中，
A选自
Figure PCTCN2022112259-appb-000014
L 1选自不存在或者CR 3R 4；
B选自C6-C10芳基或含1-3个选自N、O或S的杂原子的5-10元杂芳基；
X选自O、NH或者S；
X 1、X 2、X 3和X 4各自独立地选自CR 3、N、O、S或NR 4；
R 1选自H、卤素、CN、NH 2、脲基、羧基、氨基甲酸酯基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、
Figure PCTCN2022112259-appb-000015
Figure PCTCN2022112259-appb-000016
其中，NH 2、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；
各R 2、R 3、R 4和R 5各自独立地选自H、卤素、CN、NH 2、-CO-(C 1-6烷基)、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基，其中，NH 2、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；
R 6和R 7各自独立地选自氢、C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、-S(O) 2-(C 1-6烷基)、-S(O) 2-(C 2-6烯基)，其中，C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代，或者R 6和R 7形成3-7元的碳环，或者R 6和R 7形成含有N、O或S的3-7元的杂环；
各R独立地选自卤素、CN、OH、NH 2、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-6烯基、C 2-6炔基、C6-C10芳基、或含1-3个选自N、O或S的杂原子的5-10元杂芳基；
各m和n各自独立地选自1、2、3或4；
p选自0、1或2。
在另一优选例中，
A选自
Figure PCTCN2022112259-appb-000017
Figure PCTCN2022112259-appb-000018
L 1选自不存在或者CR 3R 4；
B为C6-C10芳基；
X为O；
X 1、X 2、X 3、X 4、X 6和X 7各自独立地选自CR 3、N、CR 3R 4、或NR 4；
R 1选自
Figure PCTCN2022112259-appb-000019
Figure PCTCN2022112259-appb-000020
各R 2、R 3、R 4和R 5各自独立地选自H、卤素、CN、NH 2、-CO-(C 1-6烷基)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基，其中，NH 2、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；
R 6和R 7各自独立地选自氢、C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、-S(O) 2-(C 1-6烷基)、-S(O) 2-(C 2-6烯基)，其中，C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代，或者R 6和R 7形成3-7元的碳环，或者R 6和R 7形成含有N、O或S的3-7元的杂环；
R 8选自
Figure PCTCN2022112259-appb-000021
各R独立地选自卤素、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-6烯基、C 2-6炔基、C6-C10芳基、或含1-3个选自N、O或S的杂原子的5-10元杂芳基；
各m和n各自独立地选自1、2、3或4；
p选自0、1或2。
在另一优选例中，
A选自
Figure PCTCN2022112259-appb-000022
Figure PCTCN2022112259-appb-000023
L 1选自不存在或者CR 3R 4；
B为C6-C10芳基；
X为O；
X 1、X 2、X 3和X 4各自独立地选自CR 3、N、或NR 4；
R 1选自
Figure PCTCN2022112259-appb-000024
Figure PCTCN2022112259-appb-000025
各R 2、R 3、R 4和R 5各自独立地选自H、卤素、CN、NH 2、-CO-(C 1-6烷基)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基，其中，NH 2、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；
R 6和R 7各自独立地选自氢、C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、-S(O) 2-(C 1-6烷基)、-S(O) 2-(C 2-6烯基)，其中，C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代，或者R 6和R 7形成3-7元的碳环，或者R 6和R 7形成含有N、O或S的3-7元的杂环；
各R独立地选自卤素、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-6烯基、C 2-6炔基、C6-C10芳基、或含1-3个选自N、O或S的杂原子的5-10元杂芳基；
各m和n各自独立地选自1、2、3或4；
p选自0、1或2。
在另一优选例中，
A选自
Figure PCTCN2022112259-appb-000026
L 1选自不存在或者CR 3R 4；
B为C6-C10芳基；
X为O；
X 1、X 2、X 3和X 4各自独立地选自CR 3、N、或NR 4；
R 1选自
Figure PCTCN2022112259-appb-000027
Figure PCTCN2022112259-appb-000028
各R 2、R 3、R 4和R 5各自独立地选自H、卤素、CN、NH 2、-CO-(C 1-6烷基)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基，其中，NH 2、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；
R 6和R 7各自独立地选自氢、C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、-S(O) 2-(C 1-6烷基)、-S(O) 2-(C 2-6烯基)，其中，C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代，或者R 6和R 7形成3-7元的碳环，或者R 6和R 7形成含有N、O或S的3-7元的杂环；
各R独立地选自卤素、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-6烯基、C 2-6炔基、C6-C10芳基、或含1-3个选自N、O或S的杂原子的5-10元杂芳基；
各m和n各自独立地选自1、2、3或4；
p选自0、1或2。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2022112259-appb-000029
Figure PCTCN2022112259-appb-000030
其中，各基团如上文所定义。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2022112259-appb-000031
其中，各基团如上文所定义。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2022112259-appb-000032
其中，各基团如上文所定义。
在另一优选例中，
所述化合物选自下组：
Figure PCTCN2022112259-appb-000033
Figure PCTCN2022112259-appb-000034
R 1选自CN、脲基、氨基甲酸酯基、
Figure PCTCN2022112259-appb-000035
Figure PCTCN2022112259-appb-000036
其中，各基团如上文所定义。
在另一优选例中，R 1选自CN、脲基、氨基甲酸酯基、
Figure PCTCN2022112259-appb-000037
Figure PCTCN2022112259-appb-000038
在另一优选例中，R 2选自三氟甲基、氟、氯、溴、碘、甲基、环戊基、或环己基或5氟 化硫基。
在另一优选例中，R 2选自三氟甲基、氟、氯、溴、碘、甲基、环戊基、或环己基。
在另一优选例中，
Figure PCTCN2022112259-appb-000039
为芳香性基团或不饱和基团。
在另一优选例中，
Figure PCTCN2022112259-appb-000040
为非芳香性基团或饱和基团。类似格式基团具有类似含义。
在另一优选例中，
Figure PCTCN2022112259-appb-000041
表示含其结构为芳香性基团或不饱和基团。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2022112259-appb-000042
Figure PCTCN2022112259-appb-000043
Figure PCTCN2022112259-appb-000044
Figure PCTCN2022112259-appb-000045
Figure PCTCN2022112259-appb-000046
Figure PCTCN2022112259-appb-000047
Figure PCTCN2022112259-appb-000048
Figure PCTCN2022112259-appb-000049
Figure PCTCN2022112259-appb-000050
本发明的第二方面，提供了一种药物组合物，包含药学上可接受的载体和一种或多种安全有效量的本发明第一方面所述的化合物或其药学上可以接受的盐、溶剂化物或前药。
本发明的第三方面，提供了一种本发明第二方面所述的药物组合物的用途，用于制备预防和/或治疗由Hippo通路失调导致的相关疾病的药物。
本发明的第四方面，提供了一种本发明第二方面所述的药物组合物的用途，用于制备预防和/或治疗由YAP或TAZ或YAP/TAZ或YAP/TEAD或YAP/TAZ/TEAD失调导致的相关疾病的药物。
在另一优选例中，所述疾病选自下组：肺癌、乳腺癌、前列腺癌、结直肠癌、肝癌、胰腺癌、卵巢癌、白血病、神经母细胞瘤、胃癌、肾癌、食管癌、子宫癌、胸膜间皮瘤。
本发明的第五方面，提供了一种本发明第一方面所述的化合物或其药学上可以接受的盐、溶剂化物或前药和第二药物的联用，用于制备预防和/或治疗癌症的药物；
所述第二药物选自下组：ERK抑制剂、MEK抑制剂、KRAS抑制剂、BRAF抑制剂、EGFR 抑制剂、Wnt抑制剂、PD-1抑制剂、或其组合。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一类具有优异YAP/TEAD抑制活性的化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。术语“C 1-6烷基”具有类似含义。
在本发明中，术语“C2-C6烯基”是指具有2-6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。术语“C 2-6烯基”具有类似含义。
在本发明中，术语“C2-C6炔基”是指具有2-6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。术语“C 2-6炔基”具有类似含义。
在本发明中，术语“C3-C8环烷基”是指在环上具有3-8个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。术语“C 3-8环烷基”、“C 3-6环烷基”、“C 5-10环烷基”具有类似含义。
在本发明中，术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。术语“C 1-6烷氧基”具有类似含义。
在本发明中，术语“杂环基”为含1、2或3个选自N、O、S的杂原子的4-8元杂环基，包括(但并不限于)如下基团：
Figure PCTCN2022112259-appb-000051
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选为“C6-C10芳基”。术语“C6-C10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基，如苯基、萘基等。
在本发明中，术语“芳香杂环”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。例如“C3-C10杂芳基”是指含有1～4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括：呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中，术语“卤代”是指被卤素取代。
在本发明中，术语“氘代”是指被氘取代。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本 发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中，术语1-6个指1、2、3、4、5或6个。其他类似术语各自独立地具有类似含义。
术语“酯基”具有-C(O)-O-R’或R’-C(O)-O-结构，其中，R’独立地代表氢、C1-C6烷基、C3-C6环烷基、C6-C10芳基、杂芳基、杂环基，如上文所定义。
术语“脲基”具有
Figure PCTCN2022112259-appb-000052
结构，其中Ra、Rb各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C6-C10芳基。
术语“氨基甲酸酯基”具有
Figure PCTCN2022112259-appb-000053
结构，其中Ra、Rb各自独立地选自H、C1-C6烷基、卤代C1-C6烷基、C6-C10芳基。
术语“酰胺基”是指带有结构-CONRR'的基团，其中，R和R'可以独立地代表氢、烷基或取代的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
术语“芳烷基”表示芳基或杂芳基取代的烷基，其中所述芳基、杂芳基和烷基如文中所定义。通常，所述芳基可具有6-14个碳原子，所述杂芳基可具有5-14个环原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
应理解，当某一基团同时存在于化合物的多个不同位置时，其在各位置的定义是相互独立地，可以相同也可以不同。亦即，术语“选自下组：”与术语“各独立地选自下组：”具有相同含义。
化合物
本发明提供了式I所示化合物或其药学上可以接受的盐、溶剂化物或前药，
Figure PCTCN2022112259-appb-000054
其中，各基团如上文所定义。
在另一优选例中，A、L 1、B、R 1、R 2、m、n各自独立地为本发明中各具体化合物对应的基团。
如本文所用，术语“药学上可以接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、 叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂化物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外，本发明化合物还包括式I所示化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式I的一类化合物，或式I的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
药物组合物和施用方法
本发明还提供了一种药物组合物，包含药学上可接受的载体和一种或多种安全有效量的所述的化合物或其药学上可以接受的盐、溶剂化物或前药。
由于本发明化合物具有优异的抗肿瘤活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与肿瘤相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2022112259-appb-000055
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明具有以下主要优点：
(1)所述化合物具有优异的YAP、TAZ和/或TEAD抑制活性；
(2)所述化合物具有优异的药代动力学性质。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例T-1
本发明合成的化合物：
Figure PCTCN2022112259-appb-000056
合成路线如下：
Figure PCTCN2022112259-appb-000057
实验过程如下：
(1)化合物2的合成
将50mg(1.0eq)化合物1、4-三氟甲基苯硼酸150mg(3.0eq)、无水醋酸铜60mg(2.4eq)、DIPEA 64mg(2.0eq)，溶剂1,6-二氧六环10ml和1g 4A分子筛混合均匀，用氮气置换三次后，氧气保护，室温下反应18小时。TLC和LC-MS显示主要都是产物，有少许原料剩余，反应液加水淬灭后用EA萃取。有机相干燥旋干，用制备板分离纯化，得到1.91mg的化合物2。HPLC纯度：98.01％。
(2)化合物T-1的合成
将30mg(1.0eq)化合物2、无水氢氧化锂12mg(3.0eq)加入到溶剂中(四氢呋喃/甲醇/水＝6：3:1)(10ml)混合均匀，用氮气置换三次后，室温，反应过夜。TLC显示原料消失，LC-MS检测主要为产物。将反应液用2N盐酸淬灭并调pH到4，然后用EA萃取。有机相干燥，旋干，用制备板分离纯化得到1.87mg的化合物T-1。HPLC纯度：97.20％。
实施例T-3
本发明合成的化合物：
Figure PCTCN2022112259-appb-000058
合成路线如下：
Figure PCTCN2022112259-appb-000059
实验过程如下：
化合物T-3的合成
将T-1 100mg(1.0eq)、异丙胺53mg(3.0eq)、HATU 343mg(3.0eq)、DIPEA 388mg(10.0eq)，溶剂DMF 5ml混合均匀，用氮气置换三次后，氮气保护下，室温反应18 小时。反应液加水淬灭后用EA萃取。合并有机相，然后用饱和食盐水洗涤，然后有机相干燥旋干，用制备板分离纯化得到15mg化合物T-3。HPLC纯度：95.80％。
参照实施例T-1和T-3的合成方法，合成如下化合物：
Figure PCTCN2022112259-appb-000060
Figure PCTCN2022112259-appb-000061
Figure PCTCN2022112259-appb-000062
实施例T-4
本发明合成的化合物：
Figure PCTCN2022112259-appb-000063
合成路线如下：
Figure PCTCN2022112259-appb-000064
实验过程如下：
(1)化合物SM2的合成
将原料化合物SM1 1.0g(1.0eq)、DMF-DMA 5ml(8.2eq)、一水合对甲基苯磺酸0.13g(0.1eq)，溶剂甲苯5ml混合均匀，用氮气置换三次后，氮气保护，油浴升温至回流，反应18h。TLC显示无原料剩余，反应液直接旋蒸至干燥得到粗品化合物SM2 1.3g。
(2)化合物SM3的合成
将SM2 1.2g(1.0eq)、对三氟甲基苯胺0.85g(1.2eq)，溶剂甲苯12ml(10倍体积)混合均匀，用氮气置换三次后，氮气保护，油浴升温至回流，反应18h。TLC显示部分原料剩余，LCMS正确，反应液直接拌样过柱得到SM3 70mg。
(3)化合物SM4的合成
将SM3 70mg(1.0eq)，溶剂DMF2ml混合均匀，用氮气置换三次后，氮气保护，冰水浴降温至0℃，分批次加入NaH 10mg，加完后自然升至室温后搅拌15min，油浴升温至100℃，反应18h。TLC显示无原料剩余，LCMS正确，反应液降温用水淬灭后用EA萃取，EA相用制备板分离纯化得到15mg的SM4。
(4)化合物SM5的合成
将SM4 500mg(1.0eq)、频哪醇联硼酸酯518mg(1.5eq)、醋酸钾400mg(3.0eq)、Pd(dppf)Cl 2100mg(0.1eq)，溶剂二氧六环5ml(10倍体积)混合均匀，后氮气置换三次，升温至90℃，反应18h。TLC检测原料反应完全。PE:EA＝1:1柱层析纯化得到200mg的SM5。
(5)化合物T-4的合成
200mgSM5(1.0eq)、5mg醋酸钯(0.05eq)、19mg三苯基膦(0.15eq)、二碳酸二叔丁酯210mg(2.0eq)，1ml二氧六环加入至反应体系中，后氮气置换三次100℃反应18h后TLC检测反应结束，由制备液相纯化得到T-4 30mg，纯度99.9％。
1H NMR(400MHz,Chloroform-d)δ9.04(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).
实施例T-5
本发明合成的化合物：
Figure PCTCN2022112259-appb-000065
合成路线如下：
Figure PCTCN2022112259-appb-000066
实验过程如下：
(1)化合物SM6的合成
将原料化合物SM4(5g，1.0eq)、醋酸钯(0.3g，0.1eq)、dppf(1.5g，0.2eq)、三乙胺(9ml，5eq)，溶剂乙醇(10ml)、DMF(15ml)混合均匀，用氮气置换三次后，再用CO置换三次，并用CO气球正压保护，40℃反应，反应18h。TLC显示无原料剩余，反应液直接浓缩后用水和EA萃取分液，EA相浓缩后过柱纯化得到2.5g化合物SM6。HPLC纯度：97.16％。
1H NMR(400MHz,Chloroform-d)δ9.12(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).
(2)化合物T-5的合成
将原料化合物SM6(2.4g，1.0eq)、氢氧化锂(0.84g，3.0eq)，溶剂四氢呋喃(29ml)、甲醇(14ml)、水(5ml)混合均匀，用氮气置换三次后，室温反应18h。TLC显示无原料剩余，反应液直接浓缩后加水50ml，滴加2N盐酸约10ml后大量固体析出，抽滤，滤饼用乙酸乙酯溶解后浓缩得到2.3g的化合物T-5。HPLC纯度：98.10％。
1H NMR(400MHz,DMSO-d6)δ8.80(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)。
实施例T-6
本发明合成的化合物：
Figure PCTCN2022112259-appb-000067
合成路线如下：
Figure PCTCN2022112259-appb-000068
实验过程如下：
化合物T-6的合成
将T-5(30mg，1.0eq)、异丙胺(22mg，2.0eq)、HATU(52mg，1.5eq)、DIPEA(46.5mg，4.0eq)，溶剂DMF(1ml)混合均匀，用氮气置换三次后，氮气保护，室温反应18h。TLC显示无原料剩余，LCMS正确，反应液加水淬灭后用EA萃取。EA相用制备板分离纯化，得到12mg的化合物T-6。HPLC纯度：99.3％。
1H NMR(400MHz,Chloroform-d)δ8.67(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).
参照实施例T-6的合成方法，合成如下化合物：
Figure PCTCN2022112259-appb-000069
Figure PCTCN2022112259-appb-000070
实施例T-7&T-15
本发明合成的化合物：
Figure PCTCN2022112259-appb-000071
合成路线如下：
Figure PCTCN2022112259-appb-000072
实验过程如下：
(1)化合物2的合成：
取5.0g(1.0eq)化合物1于250mL烧瓶中，加入60mL DCM和2.85g(1.03eq)4-甲氧基-N-甲基苄胺，随后缓慢滴加11.5g(5eq)DIPEA，并于室温下反应2h。待反应结束后，加入60mL水，DCM萃取，合并有机相，蒸干过柱得6.8g化合物2。HPLC纯度：95.3％。
(2)化合物3的合成：
取3.33g(1.0eq)对三氟甲基苯胺于烧瓶中，加入80mL DMF，并在冰浴条件下，加入2.48g(3.0eq)NaH，反应10min。随后加入8.0g(1.0eq)的化合物2，并缓慢升至室温反应。反应结束后，加水淬灭反应，EA萃取，蒸干，过柱得5.3g的化合物2。
(3)化合物4的合成：
取1.0g化合物3于烧瓶中，加入4.0mL TFA和12mL DCM，在rt下反应。反应结束后，加水，DCM萃取，蒸干过柱，得化合物0.65g的化合物2。
(4)化合物5的合成：
取430mg(1.0eq)化合物4于烧瓶中，加入6mL二氧六环、402mg(1.5eq)联硼酸频那醇酯、206mg(2.0eq)KOAc和39mg(0.05eq)Pd(dppf)Cl 2，N 2保护下，100℃反应。反应结束后，加水EA萃取，蒸干过柱，得化合物3粗品直接用于下一步。
(5)化合物T-15的合成：
取200mg(1.2eq)化合物5于烧瓶内，加入4mL二氧六环、0.4mL水、85mg(1.0eq)4-溴-1-甲基-5-乙氧羰基咪唑、21mg(0.05eq)Pd(PPh 3) 4和100mg(2.0eq)K 2CO 3，N 2保护下，100℃反应。反应结束后，加水EA萃取，蒸干过柱，得120mg化合物T-15。HPLC：97.7％。
1H NMR(400MHz,DMSO-d6)δ8.57(d,J＝2.4Hz,1H),8.43(s,1H),8.06(d,J＝8.4Hz,2H),7.79–7.65(m,3H),7.60(m,1H),6.78(d,J＝8.8Hz,1H),4.06(s,3H),2.41(d,J＝5.2Hz,3H)。
(6)化合物T-7的合成：
取100mg(1.0eq)T-15于烧瓶中，加入3mL超干THF，在冰浴下，加入46mg(5.0eq)LiAlH 4，并缓慢升至室温反应。反应结束后，加水，EA萃取，制备得到36mg的化合物T-7。HPLC：95.1％。
1H NMR(400MHz,DMSO-d6)δ7.86(d,J＝2.4Hz,1H),7.82(d,J＝8.4Hz,2H),7.74(s,1H),7.57(d,J＝8.4Hz,2H),7.29(m,1H),6.82(d,J＝8.8Hz,1H),5.17(s,2H),3.63(s,3H),2.39(s,3H)。
参照实施例T-7&T-15的合成方法，合成如下化合物：
Figure PCTCN2022112259-appb-000073
Figure PCTCN2022112259-appb-000074
Figure PCTCN2022112259-appb-000075
实施例T-18&T-31
本发明合成的化合物：
Figure PCTCN2022112259-appb-000076
合成路线如下：
Figure PCTCN2022112259-appb-000077
实验过程如下：
(1)化合物SM2的合成：
将SM1(6.57g,39mmol,1.0eq)、CuBr(11.12g,78mmol,2.0eq)加入到乙腈(245mL)中,氮气保护，然后冷却到零度，加入亚硝酸异戊酯(13.39g，105mmol,2.7eq)。 升温到50度，反应过夜。TLC(PE:EA＝5:1)显示原料反应完毕。浓缩反应液然后加入300mL水以及300mL乙酸乙酯。硅藻土过滤，分出有机层，水层使用300mL乙酸乙酯萃取两次。合并有机层，300mL水洗两次，300mL盐水洗2次，无水硫酸钠干燥过滤浓缩得到粗品然后过硅胶柱得到产品5.5g。
1HNMR(400MHz,MeOD)δ8.13(s,1H),4.27(q,2H),3.88(s,3H),1.33(t,3H)。
(2)化合物T-31的合成：
将SM2(169mg,0.73mmol,1.0eq)、SM3(400mg，0.87mmol,1.2eq)、Pd(PPh 3) 4(84mg,0.073mol,0.1eq)、碳酸钾(201.4mg，1.46mmol，2.0eq)加入到1,4-二氧六环(5mL)和水(0.5mL)中，氮气保护。然后105度反应过夜，LCMS显示产品峰。将反应液冷却到室温，减压去除溶剂加入水30mL以及乙酸乙酯50mL。分出有机层，水层使用50mL乙酸乙酯萃取两次，合并有机层20mL水洗一次，饱和食盐水20mL洗涤两次。无水硫酸钠干燥，浓缩过柱得到产品100mg
1HNMR(400MHz,CDCl3)δ8.70(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).
(3)化合物T-18的合成：
取100mg(1.0eq)T-31于烧瓶中，加入5mL超干THF，在冰浴下，加入46mg(5.0eq)LiAlH 4，并缓慢升至室温，然后回流反应。反应结束后，加水，EA萃取，制备得到16mg的化合物T-18。HPLC：95.1％。
实施例T-19&T-32
本发明合成的化合物：
Figure PCTCN2022112259-appb-000078
合成路线如下：
Figure PCTCN2022112259-appb-000079
实验过程如下：
(1)化合物SM2的合成：
将SM1(5.7g，29mmol,1.0eq)溶于甲醇(100mL)中，冷却到0度，滴加浓硫酸(3.5g,1.9mL,1.2eq)然后升温到70度回流过夜。LCMS显示原料反应完毕。冷却到室温，浓缩除去甲醇。加入饱和碳酸氢钠然后使用乙酸乙酯萃取，饱和食盐水洗涤无水硫酸钠干燥，过滤浓缩得到产品(5.6g)白色固体。
1HNMR(400MHz,MeOD)δ7.79(s,1H),3.91(s,3H)。
(2)化合物SM4的合成：
将NaH(0.39g,9.8mmol,2.0eq)加入到THF(20mL)中，冷却到零度，加入SM2(1g，4.9mmol，1.0eq)，搅拌20分钟。然后滴加碘甲烷(0.9g，0.4ml，6.4mmol，1.3eq)。缓慢恢复到室温，搅拌过夜。将反应液倒入冰水中(100ml)，使用50mL乙 酸乙酯萃取三次，饱和食盐水洗涤。无水硫酸钠干燥，过滤浓缩得到产品(1.0g，白色固体)
1HNMR(400MHz,MeOD)δ8.13(s,1H),4.8(s,3H),3.88(s,3H)。
(3)化合物T-32的合成：
将SM4(169mg,0.73mmol,1.0eq)、SM3(400mg，0.87mmol,1.2eq)、Pd(PPh 3) 4(84mg,0.073mol,0.1eq)、碳酸钾(201.4mg，1.46mmol，2.0eq)加入到1,4-二氧六环(5mL)和水(0.5mL)中，氮气保护。然后105度反应过夜，LC-MS显示产品峰。将反应液冷却到室温，减压去除溶剂加入水30mL以及乙酸乙酯50mL。分出有机层，水层使用50mL乙酸乙酯萃取两次，合并有机层20mL水洗一次，饱和食盐水20mL洗涤两次。无水硫酸钠干燥，浓缩过柱得到产品80mg
1HNMR(400MHz,CDCl 3)δ8.70(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)。
(4)化合物T-19的合成：
取50mg(1.0eq)T-32于烧瓶中，加入3mL超干THF，在冰浴下，加入25mg(5.0eq)LiAlH 4，并缓慢升至室温，然后回流反应。反应结束后，加水，EA萃取，制备得到12mg的化合物T-19。HPLC：97.2％。
参照实施例T-18、T-19、T-31&T-32的合成方法，合成如下化合物：
Figure PCTCN2022112259-appb-000080
Figure PCTCN2022112259-appb-000081
Figure PCTCN2022112259-appb-000082
Figure PCTCN2022112259-appb-000083
实施例T-61
本发明合成的化合物：
Figure PCTCN2022112259-appb-000084
合成路线如下：
Figure PCTCN2022112259-appb-000085
实验过程如下：
(1)SM2的合成:
将SM1(50g,183mmol,1.0eq)、N-(4-甲氧基苄基)-N-甲胺(28g,185mmol,1.01eq)、加入到DCM(500ml)中，滴加DIEA(28.33g，219.6mmol,1.2eq)，氮气保护，然后保持温度在30℃，LC(PE:EA＝2:1)显示原料反应完毕。反应液用NaCl清洗(300ml)，加70g硅胶拌，过柱，得74.2g产品。
(2)SM3的合成：
将SM2(5g,122mmol,1.0eq)、B 2Pin 2(34.1g,134.2mmol,1.1eq)、Pd(dppf)Cl 2(4.46g,6.1mmol,0.05eq)、KOAc(35.9g,366mmol,3eq)、加入到1,4-二氧六环(764ml)中，氮气保护，然后升温到105℃，反应1.5h。LCMS显示产物已经得到，并且较纯。反应液加1L EA稀释，100g硅藻土过滤，旋干，加250ml甲苯，400ml乙醇，旋干，加250ml甲苯，400ml乙醇，旋干，加PE洗涤，得48g SM3。
(3)SM4的合成：
将SM3(4.93g,11.33mmol,1.2eq)、3-溴-1-甲基-1H-吡唑-4-羧酸乙酯(2.2g,9.44mmol,1.0eq)、K 2CO 3(2.61g,18.88mmol,2.0eq)、Pd(dppf)Cl 2(0.345g,0.47mmol,0.05eq)以及混合溶剂(乙醇、1，4-二氧六环、水5：2：1，共35.2mL)加入到反应瓶中，抽真空换氮气3次，然后升温至95度，反应3个小时。TLC(PE:EA＝2：1)显示原料反应完毕。冷却到室温，加入200mL EtOAc以及30mL水，加硅藻土过滤，分出EA层，然后使用饱和食盐水洗涤(30mL*1)，使用无水硫酸钠干燥，浓缩得到粗品，然后过柱子得到2g油状物产品
(4)SM5的合成：
将SM4(2g)、dioxane(20mL)、氨水(15mL)加入到高压釜中，抽真空换氮气三次，然后升温至100度，反应24h。TLC显示原料反应完毕。冷却到室温，抽滤，滤饼使用水洗，甲醇洗涤，石油醚洗涤，真空干燥得到0.8g产品。
(5)SM6的合成：
将SM5(100mg,0.2424mmol,1eq)、苯硼酸(59.1mg,0.4848mmol,2eq)、Cu(OAc) 2(4.4mg,0.02424mmol,0.1eq)、TEA(49mg,0.4848mmol,2eq)、加入到DCM(3ml)中，3g分子筛，氧气保护，反应过夜。TLC(PE:EA＝1:2)显示原料基本反应完毕，反应液加DCM和水稀释，硅藻土过滤，DCM萃取，饱和NaCl清洗，无水硫酸钠干燥，拌样，过柱得25mg SM6。
(6)T-61的合成：
将SM6(25mg,0.051mmol,1eq)、0.83ml TFA加入到4.2ml DCM中，氮气保护，反应过夜。TLC(PE:EA＝1:3)显示原料基本反应完毕，反应液加饱和NaHCO 3溶液，直至溶液呈碱性，DCM萃取，饱和NaCl清洗，无水硫酸钠干燥，拌样，过柱得20mg T-61。
1H NMR(400MHz,DMSO-d 6)δ8.82–8.77(m,1H),8.56(d,J＝2.2Hz,1H),7.76(m,J＝8.9,2.3Hz,1H),7.74–7.66(m,2H),7.70–7.56(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).
参照实施例T-61的合成方法，合成如下化合物：
Figure PCTCN2022112259-appb-000086
Figure PCTCN2022112259-appb-000087
Figure PCTCN2022112259-appb-000088
Figure PCTCN2022112259-appb-000089
Figure PCTCN2022112259-appb-000090
Figure PCTCN2022112259-appb-000091
实施例T-86、T-100&T-110
本发明合成的化合物：
Figure PCTCN2022112259-appb-000092
合成路线如下：
Figure PCTCN2022112259-appb-000093
Figure PCTCN2022112259-appb-000094
实验过程如下：
(1)SM2的合成
将SM1 50g(1.0eq)、碳酸铯72g(1.5eq)、Xantphos 22g(0.25eq)、醋酸钯1.64g(0.05eq)和1L 1,4-二氧六元环混合均匀，将4-(trifluoromethyl)aniline 31g缓慢加入，抽真空换氮气，105度回流反应16小时，TLC显示原料反应完毕。用1L EA稀释，然后用硅藻土抽滤，滤液加入硅胶拌样，柱层析得到38g SM2。
1H NMR(400MHz,Chloroform-d)δ8.25(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).
(2)SM3的合成
将SM2 24g(1.0eq)、B 2Pin 2 21.5g(1.3eq)、KOAc 12.6g(2.0eq)、Pd(dppf)d 22.4g(0.05eq)和1,4-二氧六环300ml混合均匀，氮气保护，105℃回流反应1.5h。冷却到室温，加500mL EA，然后用硅藻土抽滤。然后用甲苯：无水乙醇＝5:8超声混匀，搅拌5min，旋蒸。重复此过程，直到旋蒸状态成固体，然后用适量PE将固体混匀，发现有固体析出。抽滤，收集固体，晾干得SM3 20g。
1H NMR(400MHz,DMSO-d 6)δ8.47(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).
(3)T-100的合成
将SM3 18g(1.2eq)、3-溴-1-甲基-1H-吡唑-4-羧酸乙酯21.5g(1.3eq)、K 2CO 315.0g(2.0eq)、Pd(dppf)d 2 1.3g(0.05eq)和1,4-二氧六环/水/无水甲醇＝5:2:1 250ml混合均匀，氮气保护，105℃回流反应1.5h，后TLC显示有产物形成。冷却到室温，然后用硅藻土抽滤，旋干，水淬灭，EA萃取。用柱层析得9.5g T-100。
1H NMR(400MHz,DMSO-d 6)δ8.73(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).
(4)T-110的合成
将T-100 4.5g(1.0eq)、一水LiOH 1.42g(3.0eq)和THF/水/无水甲醇＝2:1:4 50ml混合均匀，氮气保护，50℃反应2-5h，后TLC显示有产物形成。冷却到室温，旋干，水淬灭，EA萃取去除有机杂质,水相调pH＝2,EA萃取，得3.6g T-110。
1H NMR(400MHz,Methanol-d 4)δ8.90(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).
(5)T-86的合成：
将T-110(387mg,1eq)、DIPEA(258mg，2eq)和HATU(380mg,1eq)溶于DCM中，室温搅拌10min,再投入异丙胺(71mg,1.2eq)，继续反应12h。反应结束后，TLC(纯EA)进行监测，T-110反应完全。加入约十倍的DCM进行稀释，用0.05％柠檬酸洗去DIPEA，然后使用饱和NaCl溶液洗涤，然后进行干燥，旋干后，粗产品加入DCM和甲醇溶解然后使用PTLC或者柱层析纯化得到302mg T-86。 1H NMR(400MHz,Chloroform-d)δ8.49(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).
参照实施例T-86、T-100&T-110的合成方法，合成如下表所示的化合物：
Figure PCTCN2022112259-appb-000095
Figure PCTCN2022112259-appb-000096
Figure PCTCN2022112259-appb-000097
Figure PCTCN2022112259-appb-000098
Figure PCTCN2022112259-appb-000099
Figure PCTCN2022112259-appb-000100
Figure PCTCN2022112259-appb-000101
Figure PCTCN2022112259-appb-000102
Figure PCTCN2022112259-appb-000103
Figure PCTCN2022112259-appb-000104
Figure PCTCN2022112259-appb-000105
Figure PCTCN2022112259-appb-000106
Figure PCTCN2022112259-appb-000107
Figure PCTCN2022112259-appb-000108
Figure PCTCN2022112259-appb-000109
Figure PCTCN2022112259-appb-000110
Figure PCTCN2022112259-appb-000111
Figure PCTCN2022112259-appb-000112
Figure PCTCN2022112259-appb-000113
Figure PCTCN2022112259-appb-000114
Figure PCTCN2022112259-appb-000115
Figure PCTCN2022112259-appb-000116
Figure PCTCN2022112259-appb-000117
Figure PCTCN2022112259-appb-000118
Figure PCTCN2022112259-appb-000119
Figure PCTCN2022112259-appb-000120
Figure PCTCN2022112259-appb-000121
Figure PCTCN2022112259-appb-000122
Figure PCTCN2022112259-appb-000123
实施例T-170
本发明合成的化合物：
Figure PCTCN2022112259-appb-000124
合成路线如下：
Figure PCTCN2022112259-appb-000125
实验过程如下：
(1)SM2的合成：
将SM1 50g(1.0eq)、碳酸铯72g(1.5eq)、Xantphos 22g(0.25eq)、醋酸钯1.64g(0.05eq)和1L 1,4-二氧六元环混合均匀，将4-(trifluoromethyl)aniline 31g缓慢加入，抽真空换氮气，105度回流反应16小时，TLC显示原料反应完毕。用1L EA稀释，然后用硅藻土抽滤，滤液加入硅胶拌样，柱层析得到38g SM2。
1H NMR(400MHz,Chloroform-d)δ8.25(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).
(2)SM3的合成：
将SM2 24g(1.0eq)、B 2Pin 2 21.5g(1.3eq)、KOAc 12.6g(2.0eq)、Pd(dppf)d 2 2.4g(0.05eq)和1,4-二氧六环300ml混合均匀，氮气保护，105℃回流反应1.5h。冷却到室温，加500mL EA，然后用硅藻土抽滤。然后用甲苯：无水乙醇＝5:8超声混匀，搅拌5min，旋蒸。重复此过程，直到旋蒸状态成固体，然后用适量PE将固体混匀，发现有固体析出。抽滤，收集固体，晾干得SM3 20g。
1H NMR(400MHz,DMSO-d 6)δ8.47(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).
(3)SM4的合成：
将SM3 18g(1.2eq)、3-溴-1-甲基-1H-吡唑-4-羧酸乙酯21.5g(1.3eq)、K 2CO 315.0g(2.0eq)、Pd(dppf)d 2 1.3g(0.05eq)和1,4-二氧六环/水/无水甲醇＝5:2:1 250ml混合均匀，氮气保护，105℃回流反应1.5h，后TLC显示有产物形成。冷却到室温，然后用硅藻土抽滤，旋干，水淬灭，EA萃取。用柱层析得9.5g SM4。
1H NMR(400MHz,DMSO-d 6)δ8.73(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).
(4)SM5的合成：
将SM4 4.5g(1.0eq)、一水LiOH 1.42g(3.0eq)和THF/水/无水甲醇＝2:1:4 50ml混合均匀，氮气保护，50℃反应2-5h，后TLC显示有产物形成。冷却到室温，旋干，水淬灭，EA萃取去除有机杂质,水相调pH＝2,EA萃取，得3.6gSM5。
1H NMR(400MHz,Methanol-d 4)δ8.90(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).
(5)SM6的合成：
将SM5 1.0g(1.0eq)、TEA 0.4g(1.5eq)和t-BuOH 20ml混合均匀，氮气保护，80℃回流，滴加DPPA 0.85g(1.2eq)，反应2h，TLC显示有产物形成。冷却到室温，旋干，水淬灭，EA萃取，柱层析得2.3g SM6。
(6)SM7的合成：
将SM6 2.3g、TEA 23ml和DCM 30ml混合均匀，氮气保护，过夜常温反应，旋干，水淬灭，DCM萃取，柱层析得280m g SM7。
1H NMR(400MHz,Methanol-d 4)δ8.40(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).
(7)T-170的合成：
将2-吡啶羧酸(147.6mg,1.2eq)、HATU(465.6mg,1.2eq)、DIPEA(490mg,4.0eq)和2ml无水二氯甲烷混匀常温反应20min，然后将化合物SM7(394mg,1.0eq)加入到反应液中，常温反应18h。TLC显示原料消失，LCMS正确，反应液旋干后加水淬灭，用EA萃取，EA相用0.5％柠檬酸洗一遍，无水硫酸钠干燥。EA相用制备板分离纯化，得到产品T-170。
1H NMR(400MHz,Methanol-d 4)δ8.96(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).
实施例T-172
本发明合成的化合物：
Figure PCTCN2022112259-appb-000126
合成路线如下：
Figure PCTCN2022112259-appb-000127
实验过程如下：
T-172的合成：
将SM7(394mg,1.0eq)、DIPEA(490mg,4.0eq)和2ml无水二氯甲烷混匀常温反应20min，然后将化合物丙烯酰氯(108mg,1.2eq)加入到反应液中，常温反应18h。TLC显示原料消失，LCMS正确，反应液旋干后加水淬灭，用EA萃取，EA相用0.5％柠檬酸洗一遍，无水硫酸钠干燥。EA相用制备液相分离纯化，得到产品T-172。
1H NMR(400MHz,DMSO-d6)δ10.35(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).
实施例T-186
本发明合成的化合物：
Figure PCTCN2022112259-appb-000128
合成路线如下：
Figure PCTCN2022112259-appb-000129
实验过程如下：
T-186的合成：
将SM7(394mg，1.0eq)、吡啶(237mg，3.0eq)、苯磺酰氯(352mg，2.0eq)和溶剂无水二氯甲烷2ml混合均匀，常温反应18h。TLC显示原料消失，LCMS正确，反应液旋干后加水淬灭，用EA萃取，EA相用0.5％柠檬酸洗一遍，无水硫酸钠干燥。EA相用制备板分离纯化，得到产品T-186。
1H NMR(400MHz,Methanol-d 4)δ8.39(s,1H),8.00–7.87(m,5H),7.87–7.69(m,3H),7.60–7.36(m,1H),7.08(dd,J＝9.1,2.6Hz,1H),6.44(d,J＝9.1Hz,1H),5.50(s,1H),4.15(s,3H).
参照实施例T-170、T-172&T-186的合成方法，合成如下化合物：
Figure PCTCN2022112259-appb-000130
Figure PCTCN2022112259-appb-000131
Figure PCTCN2022112259-appb-000132
Figure PCTCN2022112259-appb-000133
Figure PCTCN2022112259-appb-000134
Figure PCTCN2022112259-appb-000135
Figure PCTCN2022112259-appb-000136
Figure PCTCN2022112259-appb-000137
实施例T-243
本发明合成的化合物：
Figure PCTCN2022112259-appb-000138
合成路线如下：
Figure PCTCN2022112259-appb-000139
(1)SM1的合成
将5,6-二溴烟酸25g(1eq)、DIPEA 23.13g(2eq,d为盐酸盐时,3eq)和HATU 34.083g(1eq)溶于DCM(250ml)中rt搅拌10min,再投入化合物吡啶乙胺13.14g(1.2eq)，继续反应1.5h。反应结束后，TLC(纯EA)进行监测，5,6-二溴烟酸反应完全，加五倍的DCM进行稀释，用0.1mol盐酸洗去DIPEA，饱和NaCl溶液进行干燥，2～2.5倍硅胶进行拌样过柱PE:EA＝3:1过出黄色黏状液体30.7g SM1。
(2)SM2的合成
依次将SM1 30.7g(1eq)、Cs 2CO 3 52.2g(2eq)、xantphos 4.6g(0.1eq)和对氟苯胺12.9g(1eq)溶于超干1，4-二氧六环溶液(300ml)中，置于圆底烧瓶中。再加入Pd(OAc) 20.9g(0.05eq),氮气置换2～3次,升温至105℃,反应1.5h。反应结束后，TLC(PE:EA＝1:1)进行监测，原料反应完全。用溶剂的十倍EA进行稀释，硅藻土进行抽滤，拌样，用层析柱进行分离，PE:EA＝2:1过出产物，黄色固体15.2g SM2。
(3)SM3的合成
依次将SM2 13.2g(1eq)、联硼酸频哪醇酯14.5g(2eq)和Pd(dppf)Cl 2 1.04g(0.05eq)溶于1，4-二氧六环溶液(132ml)，置于圆底烧瓶中搅拌，再加入KOAc 5.6g(2eq),氮气置换2～3次，油浴锅升温至105℃反应3h。反应结束后，TLC(PE:EA＝1:1.5)进行监测，原料反应完全，用显色剂茜素熏，SM3显黄色。用溶剂的十倍EA进行稀释，硅藻土进行抽滤，旋干溶剂。加入5：8的甲苯和乙醇溶液搅拌5min,旋干溶剂。再重复上一步，旋干溶剂。再加入少量PE，充分晃动震荡，抽滤得到灰棕色固体13.1g SM3。
(4)TM的合成
将SM3(1eq)溶于1，4-dioxane溶液中，再依次加入K 2CO 3(3eq),
Pd(dppf)Cl 2(0.16eq)和4-溴-1-甲基吡唑-3-甲酸乙酯(1eq)于圆底烧瓶中，氮气置换2～3次，升温至105℃，反应1h。反应结束后，TLC(PE:EA＝3：1)进行监测，SM3完全反应，产物极性较大。TLC(PE:EA＝1：1)进行监测，SM4完全爬离远点。抽滤，加EA进行拌样，用层析柱进行分离(PE:EA＝1:1)过处产物点，米棕色固体24mg。
参照实施例T-243的合成方法，合成如下化合物：
Figure PCTCN2022112259-appb-000140
Figure PCTCN2022112259-appb-000141
Figure PCTCN2022112259-appb-000142
Figure PCTCN2022112259-appb-000143
Figure PCTCN2022112259-appb-000144
Figure PCTCN2022112259-appb-000145
Figure PCTCN2022112259-appb-000146
Figure PCTCN2022112259-appb-000147
Figure PCTCN2022112259-appb-000148
Figure PCTCN2022112259-appb-000149
Figure PCTCN2022112259-appb-000150
Figure PCTCN2022112259-appb-000151
Figure PCTCN2022112259-appb-000152
Figure PCTCN2022112259-appb-000153
Figure PCTCN2022112259-appb-000154
Figure PCTCN2022112259-appb-000155
实施例T-276
本发明合成的化合物：
Figure PCTCN2022112259-appb-000156
合成路线如下：
Figure PCTCN2022112259-appb-000157
实验过程如下：
SM3的合成：
50ml的圆底烧瓶先用氮气保护，将SM2(2g,5.362mmol,1eq)、巴豆酸(1.154g,13.4mmol,2.5eq)、DIEA(6.92g,53.62mmol,10eq)、THF(10ml)投入原圆底烧瓶内，抽氮气，再继续加Pd(PHCN)3Cl2(102.8mg,0.268mmol,0.05eq)、Tri(o-tolyl)phosphine(81.6g,0.26mmol,0.05eq)、乙酸酐(1.68ml)氮气保护，加热到70℃，回流，反应过夜。TLC(PE:EA＝10:1)显示原料全部反应完。冷却，加20ml 2N HCl，10ml水，50mlEA萃取，再用NaHCO3洗，EA萃取(20ml×3)，饱和氯化钠清洗(20ml×2)，无水硫酸钠干燥，拌样，过柱，共得到892mg SM5。
SM4的合成：
将SM3(85mg,0.235mmol,1eq)、LiOH(16.9mg,0.705mmol,3eq)、MeOH(1.2ml)、H2O(0.3ml)、THF(0.6ml)，氮气保护，反应4.5h，LC-MS显示反应为完全。反应液冷却，旋蒸，加DCM旋干，得到80mg产品。
SM5的合成：
将SM4(640mg,1.458mmol,1eq)、三丁基(1-乙氧基乙烯)锡(789.8mg,52.187mmol,1.5eq)、Pd(PPh3)Cl2(102.3mg,0.1458mmol,0.1eq)、DMF(13ml)投入圆底烧瓶内，氮气保护，加热到120℃，回流，0.5h。TLC(PE:EA＝3:1)显示原料已反应完。冷却，加15ml水，硅藻土过滤，EA萃取(30ml×3)，饱和氯化钠清洗(40ml×2)，无水硫酸钠干燥，拌样，过柱，共得到363mg SM4。
SM6的合成：
将SM5(363mg,0.842mmol,1eq)、甲醇(10ml)、HCl.1,4-二氧六环(10ml)投入圆底烧瓶内，氮气保护，25℃，2.5h。TLC(PE:EA＝3:1)显示原料已反应完。旋干得到312mg SM6。
SM7的合成：
将SM6(312mg,0.774mmol,1eq)、LiOH(55.6mg,2.322mmol,3eq)、MeOH(6ml)、H2O(1.5ml)、THF(3ml)，25℃，氮气保护，反应过夜，TLC(DCM:MeOH＝10:1)显示已完全反应。反应液冷却，旋蒸，加5ml水，2ml 2N HCl，有大量白色固体析出，过滤，滤液用EA萃取，饱和NaCl洗，无水硫酸钠干燥，旋干，共得280mg SM7。
T-276的合成：
将SM7(280mg,0.72mmol,1eq)、吡啶乙胺(105.4mg,0.864mmol,1.2eq)、HATu(237.8mg,0.72mmol,1eq)、DIEA(185.8mg,1.44mmol,2eq)加入到5ml DCM中，氮气保护，常温，反应过夜，TLC(EA)显示原料反应完毕，产物已生成。反应液加水和EA萃取，再用0.5％柠檬酸清洗，饱和氯化钠清洗，无水硫酸钠干燥，过柱得到335mg产品。HPLC:97％
1H NMR(400MHz,Methanol-d4)δ8.55(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).
参照实施例T-276的合成方法，合成如下化合物：
Figure PCTCN2022112259-appb-000158
Figure PCTCN2022112259-appb-000159
实施例T-281
本发明合成的化合物：
Figure PCTCN2022112259-appb-000160
合成路线如下：
Figure PCTCN2022112259-appb-000161
实验过程如下：
SM4的合成：
将SM3(2.54g,6.02mmol,1.2eq)、邻溴苯乙酮(1g,5.02mmol,1eq)、Pd(dppf)Cl2(183.7mg,0.251mmol,0.05eq)、K2CO3(1.385mg,10.04mmol,2eq)、甲醇(10ml)、水(5ml)、1,4-二氧六环(25ml)投入圆底烧瓶内，氮气保护，加热到90℃，回流，反应过夜。TLC(PE:EA＝3:1)显示原料大部分已反应。冷却，加15ml水，硅藻土过滤，EA萃取(50ml×3)，饱和氯化钠清洗(50ml×2)，无水硫酸钠干燥，拌样，过柱，共得到161mg SM4。
SM5的合成：
将SM4(161mg,0.393mmol,1eq)、Pd(OH)2(20mg,0.142mmol,0.36eq)、乙醇(3ml)投入圆底烧瓶内，氮气保护，常温反应，反应过夜。TLC(PE:EA＝5:1)显示原料已反应完。硅藻土过滤，拌样，过柱，共得到100mg SM5。
SM6的合成：
将SM5(100mg,0.252mmol,1eq)、LiOH(18.1mg,0.756mmol,3eq)、MeOH(2ml)、H 2O(0.5ml)、THF(1ml)，25℃，氮气保护，过夜，TLC(DCM:MeOH＝10:1)显示已完全反应。反应液冷却，旋蒸，加水，2N HCl，有大量白色固体析出，过滤得85mg SM6。
T-281的合成
将SM6(85mg,0.222mmol,1eq)、吡啶乙胺(32.5mg,0.2664mmol,1.2eq)、HATu(84.4mg,0.222mmol,1eq)、DIEA(57.3mg,0.444mmol,2eq)加入到2ml DCM中，氮气保护，常温，反应过夜，TLC(PE:EA＝1:3)显示原料反应完毕，产物已生成。反应液加水和EA萃取，再用0.5％柠檬酸清洗，饱和氯化钠清洗，无水硫酸钠干燥，爬板得到62mg产品。HPLC:99.03％
1H NMR(400MHz,Chloroform-d)δ8.59(t,J＝5.3Hz,1H),8.42(s,1H),7.93(d,J＝7.8Hz,1H),7.78(d,J＝7.2Hz,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).
实施例T-282
本发明合成的化合物：
Figure PCTCN2022112259-appb-000162
合成路线如下：
Figure PCTCN2022112259-appb-000163
实验过程如下：
Sm2的合成：
将SM1(15g，59.18mmol，1.0eq),对三氟甲基苯硼酸(16.86g,88.77mmol,1.5eq),Mo(CO) 6(15.62g,39.18mmol,1.0eq),碳酸钾(24.54g，177.54mmol，3.0eq)，醋酸钯(398.59mg，1.78mmol，0.03eq)苯甲醚(150ml)依次加入500ml三口瓶中，抽真空换氮气，然后升温至105度反应16h。TLC(PE:EA＝10:1，UV)显示原料消耗完毕。
冷却至室温，加入300ml甲醇稀释反应体系，然后使用布氏漏斗加硅藻土抽滤，滤饼使用甲醇洗涤。滤液在45度进行浓缩后加入300ml EA以及300ml水，分出有机层，水层使用EA(300ml*2)进行萃取，合并有机层，使用饱和氯化钠洗涤硫酸钠干燥。浓缩后加入40g硅胶拌样过柱子得到2.8g SM2(黄色油状物)
SM3的合成
SM2(2.8g，0.009mol，1.0eq)以及溴化亚铜(2.68g，0.0186mol，2.0eq)乙腈(50ml)加入100ml反应瓶中，0度滴加亚硝酸异戊酯(2.87g，3.3ml，0.0243mol，2.7eq)，然后升温至50度反应16h。TLC显示有一点点SM2剩余。
将反应体系冷却到室温，加入EA(200ml)稀释，使用布氏漏斗加硅藻土过滤。滤液中加入水(200ml)，分出EA层，水层使用EA(200ml*2)萃取，合并有机层加入饱和硫酸钠干燥。然后浓缩过柱子得到2.2g产品SM3
Sm4的合成
将SM3(2.0g，5.5mmol，1.0eq)，频哪醇硼酸酯(1.7g，6.6mmol，1.2eq)，无水醋酸钾(1.6g，16.5mmol,3.0eq),Pd(dppf)Cl2(0.201g,0.28mmol,5％),超干二氧六环(20ml)加入反应瓶中，然后抽真空换氮气升温至100度反应16h。冷却到室温后加入乙酸乙酯稀释，加硅藻土抽滤，滤液浓缩后依次加入甲苯：乙醇(6：1)进行浓缩，最后得到2.2g SM4
SM5的合成
将SM4(1.38g，4.8mmol，1.0eq)，tert-butyl(2-bromobenzyl)carbamate(2.8g，6.8mmol，1.4eq)、碳酸钾(1.33g，9.7mmol，2.0eq)、Pd(dppf)Cl2(0.177g,0.24mmol,5％eq)以及二氧六环/水(50ml：5ml)加入反应瓶中，抽真空换氮气反应过夜。LCMS显示原料反应完毕。冷却到室温，加入EA(100ml)以及水(50ml)分出有机层，水层使用EA(100ml*2)萃取，合并有机层使用饱和食盐水洗涤，干燥后浓缩过柱得到800mg产品
SM6的合成：
将SM5(540mg)溶于甲醇(2ml)中然后加入盐酸/二氧六环(10ml)室温搅拌过夜。TLC显示原料反应完毕(PE:EA＝5:1)。拉干反应液加入饱和碳酸氢钠溶液，使用EA进行萃取，分出有机层干燥浓缩过柱得到300mg产品SM6
SM7的合成
将SM6(300mg，0.806mmol，1.0eq)，三乙胺(244mg，334微升，2.4mmol，3.0eq)，Pd(dppf)Cl2(30mg,0.0403mmol,5％),乙醇(35ml)加入高压釜中然后抽真空换一氧化碳。升温至100度反应24h。TLC显示仍有少量原料剩余。冷却到室温，使用布氏漏斗加硅藻土过滤，滤液加EA稀释后加硅胶(100-200目，3g)拌样然后使用过主机分离纯化得到200mgSM7以及80mg原料SM6
SM8的合成
将SM7(200mg，0.)加入到反应瓶中，加入THF/MeOH/H2O(4ml：2ml：1ml)，然后加入氢氧化锂(35.2mg，1.46mmol，3.0eq)然后室温搅拌过夜。TLC显示原料反应完毕。冷却到室温，然后加入5ml水，滴加几滴浓盐酸调节PH为酸性，有白色固体析出，抽滤得到150mg白色固体
TM的合成：
将SM9(150mg，0.39mmol，1.0eq)，HATU(147.38mg，0.387mmol，1.0eq)、DIEA(100mg，141微升，0.775mmol，2.0eq)，DCM(2ml)加入反应管中室温搅拌10min，然后加入(S)-1-(pyridin-2-yl)ethan-1-amine(56.82mg，0.465mmol，1.2eq)，室温反应过夜。Lcms显示原料反应完毕。反应液加入DCM(10ml)进行稀释，然后使用0.5％柠檬酸洗涤、饱和食盐水洗涤。干燥浓缩过柱子得到161mg白色固体。
1HNMR(400MHz,MeOD)δ8.55-8.50(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)
实施例T-283
本发明合成的化合物：
Figure PCTCN2022112259-appb-000164
合成路线如下：
Figure PCTCN2022112259-appb-000165
实验过程如下：
SM2的合成
将SM1(5.3g,0.05mol,1.0eq)、苯甲醛(9.46g，0.055mol，1.1eq)以及乙醇(75ml)加入到反应瓶中，抽真空换氮气然后升温至80度反应3.5h后，冷却至室温，冰浴下分批加入NaBH 4(2.28g，0.06mol，1.2eq)然后室温搅拌过夜。将反应体系倒入1L的三角瓶中，缓慢加入1N HCl(200ml)，使用EA(150ml*3)进行萃取，饱和食盐水洗涤后干燥浓缩得到粗品。然后加入甲醇20ml，HCl/dioxane溶液100ml室温搅拌过夜，水泵除去盐酸气后旋干溶剂得到SM2(11.6g,白色固体SM2)
SM3的合成
使用电加热套将购买的二聚环戊二烯在180度常压蒸馏，收集40-42度的馏分得到环戊二烯单体用于SM3的合成
0度左右向250ml的三口瓶中，加入SM2(5.5g)，甲醇(55ml)以及环戊二烯(3.3g)以及甲醛水溶液(2.86g)，然后室温反应72h，TLC(PE:EA＝10:1)显示原料反应完毕，有白色固体析出。使用砂芯漏斗抽滤，滤饼使用真空干燥箱25度干燥得到目标产品(约2.6g)
SM4的合成：
2批次。将SM3(425mg，1.25mmol，1.0eq)，无水磷酸钾(1.59g，7.49mmol，5.0eq)，醋酸钯(20.19mg，0.09mmol，8％)、(S)-1-(pyridin-2-yl)ethan-1-amine(457.79mg，3.75mmol，3.0eq)、DMAP(302.72mg,2.5mmol,2.0eq)、Mo(CO) 6(108.16mg,0.409mmol,0.32eq)、Xantphos(106.96mg,0.184mmol,14％eq)、二氧六环(10ml)加入30ml微波反应管中，然后120度反应20min，TLC(PE:EA＝1:1)显示原料反应完毕。冷却到室温，将两个批次反应液合并处理。加入EA(100ml)、水(50ml)分出EA层，水层使用EA(50ml*2)
萃取，合并有机层使用饱和氯化钠溶液洗涤，硫酸钠干燥后浓缩后使用过主机过柱得到630mg SM4(黄色固体)
SM5的合成
将SM4(200mg)加入乙醇(10ml)中，然后加入氢氧化钯(30mg，w/w 15％)，加入0.2ml 2N HCl抽真空换氮气3次，然后再抽真空换氢气三次(氢气球)。升温至80度然后回流反应19h，TLC显示原料反应完毕(PE:EA＝1:1)。冷却到室温，加入EA(30ml)，加硅藻土抽滤，然后滤液加硅胶拌样使用过柱机过柱得到SM5(60mg，白 色固体)
T-283的合成
将SM5(60mg，0.186mmol，1.0eq)、对三氟甲基溴苯(50.4mg，0.224mol，1.2eq)、碳酸铯(121.64mg,0.373mmol,2.0eq)、醋酸钯(2.1mg，0.01mmol，5％eq)xantphos(10.8mg,0.018mmol,10％eq)以及无水二氧六环(1ml)加入到反应管中，然后升温到105度反应16h，TLC显示原料反应完毕。将反应液冷却到室温，加入1ml水，使用EA(6ml*2)进行萃取然后使用PTLC进行分离得到SM6(28mg,白色固体)1HNMR(400MHz,CDCl3)δ8.50-8.49(d,1H),8.39-8.35(d,1H),7.71-7.51(m,2H),7.49-7.44(m,3H),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)
实施例T-285
本发明合成的化合物：
Figure PCTCN2022112259-appb-000166
合成路线如下：
Figure PCTCN2022112259-appb-000167
实验过程如下：
SM2的合成:将化合物SM1(1g,1.0eq)、对三氟苯胺(728mg，1.28eq)、Cs 2CO 3(1.71g，1.5eq)、Pd(OAc) 2(39mg，0.05eq)、Xantphos(506mg，0.25eq)溶于二氧六环(20mL)中，N 2下保护105℃下搅拌14h，原料基本反应完成。后处理：反应液加EA稀释，加少量水，EA萃取，得有机相，饱和食盐水洗涤，无水硫酸钠干燥，滤液浓缩至干得到粗品SM3(1.02g)。
SM3的合成
将化合物SM2(200mg,1.0eq)、巴豆酸(137mg，2.5eq)、DIEA(813mg，10eq)加入THF中，置换N 2后加入Pd(PhCN) 2Cl 2(12mg，0.05eq)、3(甲苯基)磷(10mg，0.05eq)，70℃过夜反应，原料基本反应完成，但生成大部分未关环产物，因此补加乙酸酐(0.2mL)促进反应关环，1小时后，大部分已关环。LCMS正确。后处理：反应液加EA稀释，加少量水，EA萃取，得有机相，饱和食盐水洗涤，无水硫酸钠干燥，滤液浓缩至干得到粗品SM3(126mg)。
SM4的合成
将化合物SM3(6.0g,1.0eq)、NBS(7.13g，2eq)加入乙腈(60mL)中，置换N 2后90℃过夜反应，原料基本反应完成，LCMS正确。后处理：反应液加EA稀释，加少量水，EA萃取，得有机相，饱和食盐水洗涤，无水硫酸钠干燥，柱层析PE→PE:EA＝50:1→20:1→10:1),得到SM4(7.42g)。
SM5的合成
将化合物SM4(4g,1.0eq)、三丁基(1-乙氧基乙烯)锡(5.67g，1.5eq)、Pd(PPh 3)Cl 2(738mg，0.1eq)加入DMF(40mL)中，置换N 2后120℃过夜反应，原料基本反应完成，LCMS正确。后处理：反应液加EA稀释，加少量水，EA萃取，得有机相，饱和食盐水洗涤，无水硫酸钠干燥，过柱机(PE:EA＝5:1)，得到SM5(970mg)。1HNMR正确。
SM6的合成
将化合物SM5(970mg,1.0eq)加入MeOH(10mL)中，加入盐酸二氧六环(10mL)，过夜室温反应后原料基本反应完成，LCMS正确。后处理：反应液直接旋干，得到粗产品SM6(728mg)。
SM7的合成
将化合物SM6(728mg,1.0eq)加入MeOH(5mL)中，冰浴下加入硼氢化钠(200mg，2.5eq)，恢复室温反应，后续反应不动，补加硼氢化钠至10倍当量，半个小时后原料基本反应完成，LCMS正确。后处理：反应液加EA稀释，加少量水，EA萃取，得有机相，饱和食盐水洗涤，无水硫酸钠干燥，得到粗产品SM7(734mg)。1HNMR正确。
SM8的合成
将化合物SM7(690mg,1.0eq)、邻苯二甲酰亚胺(438mg,1.5eq)、三苯基膦(1.563g，3eq)加入THF(15mL)中，冰浴下加入DEAD(865mg，2.5eq)，恢复室温反应，过周末后原料基本反应完成，有新点生产。后处理：反应液直接旋干，过柱机(PE:EA＝5:1)得到产品SM8(2.55g)。
SM9的合成
将化合物SM8(2.5g,1.0eq)、水合肼(2.683g,10eq)加入EtOH(25mL)中，过夜回流反应。后处理：反应液直接旋干，柱层析得到粗产品SM9(327mg)。
T-285的合成
将化合物SM9(166mg,1.0eq)、TEA(145mg,3eq)加入DCM(1mL)中，冰浴下滴加丙烯酰氯(50mg，1.15eq)，恢复室温反应，过夜反应原料基本反应完成，LCMS正确。后处理：反应液直接旋干，柱层析(PE→PE:EA＝5:1→PE:EA＝2:1→1:1)得到产品T-285(33mg)。
1H NMR(400MHz,Chloroform-d)δ7.89(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).
实施例T-412
本发明合成的化合物：
Figure PCTCN2022112259-appb-000168
合成路线如下：
Figure PCTCN2022112259-appb-000169
实验过程如下：
T-412-2的合成
将化合物T-412-1(20g,1.0eq)、对三氟苯胺(12.12g，1.28eq)、Cs2CO3(28.75g，1.5eq)、Pd(OAc)2(660mg，0.05eq)、Xantphos(850mg，0.25eq)溶于二氧六环(400mL)中，N2下保护105℃下搅拌14h，原料基本反应完成。后处理：反应液加EA稀释，加少量水，EA萃取，得有机相，饱和食盐水洗涤，无水硫酸钠干燥，滤液浓缩至干，纯化(PE→PE:EA＝50:1)得到粗品T-412-2(20.7g)。注：T-412-2纯度不够可以采取水解在酯化的策略，1HNMR正确。
T-412-3的合成
将化合物T-412-2(10.6g,1.0eq)、巴豆酸(6.11g，2.5eq)、DIEA(36.09g，10eq)加入THF(53mL)中，置换N2后加入Pd(PhCN)2Cl2(545mg，0.05eq)、3(甲苯基)磷(432mg，0.05eq)，70℃过夜反应，原料基本反应完成，但生成大部分未关环产物，因此补加乙酸酐(8.9mL)活化促进反应关环，2小时后，全部生成关环产物。LCMS正确。后处理：加EA稀释，加少量水，EA萃取，得有机相，饱和食盐水洗涤，无水硫酸钠干燥，滤液浓缩至干，过柱机(PE:EA＝5:1)得到粗品T-412-3(4.6g)。
T-412-4的合成
将化合物T-412-3(4.6g,1.0eq)、LiOH(917.5mg，3.0eq)溶于MeOH/THF/H2O(76ml/38mL/19mL)中，N2下保护50室温下搅拌14h，原料基本反应完成，LCMS正确。后处理：反应液加EA稀释，加少量水，分层得水层(此时产物为盐在水相中)，水相加1NHCl调ph＝3左右，EA萃取，得有机相(此时产物在有机相中)，饱和食盐水洗涤，无水硫酸钠干燥，滤液浓缩至干得到粗品T-412-4(3.9g)。LCMS正确。
T-412-5的合成
将化合物T-412-4(3.9g,1.0eq)、DPPA(4.33g，1.4eq)、Et3N(2.04g，1.8eq)加入叔丁醇(80mL)中，90℃过夜反应，原料基本反应完成，LCMS正确。后处理：反应液加EA稀释，加少量水，EA萃取，得有机相，饱和食盐水洗涤，无水硫酸钠干燥，过柱机(PE:EA＝5:1),得到T-412-5(944mg).1HNMR正确。
T-412-6的合成
将化合物T-412-5(944mg,1.0eq)加入MeOH(15mL)中，冰浴下加入4M盐酸二氧六环(15mL)，过夜反应，原料基本反应完成。后处理：直接旋干，得到粗品T-412-6(709mg)。
T-412的合成
将化合物T-412-6(709mg,1.0eq)、TEA(684mg,3eq)加入DCM(15mL)中，冰浴下滴加丙烯酰氯(244mg，1.15eq)，恢复室温反应，过夜反应原料基本反应完成，LCMS正确。后处理：反应液直接旋干，柱层析得到产品T-425(536mg)。继续纯化得到363mg，纯度为93.3％；继续结晶160mg，纯度为97.6％，余混合产物220mg。
1H NMR(400MHz,DMSO-d6)δ10.30(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).
参照实施例T-243、T-412的合成方法，合成如下化合物：
Figure PCTCN2022112259-appb-000170
Figure PCTCN2022112259-appb-000171
Figure PCTCN2022112259-appb-000172
Figure PCTCN2022112259-appb-000173
生物活性测试实验过程如下：
试验例1细胞抗增殖实验
YAP-TEAD抑制剂化合物对人胸膜间皮瘤细胞NCI-H226的增殖抑制测定
实验材料和设备：人胸膜间皮瘤细胞NCI-H226购于南京科佰生物科技有限公司。RPMI-1640培养基(Bio-Channel)，DMSO(二甲基亚砜),CCK8(WST-8)细胞分析试剂盒(碧云天)，0.25％EDTA-Tripsin(胰酶消化液),1xPBS(磷酸盐缓冲液，PH7.2)，96孔板(Corning),胎牛血清(FBS)，10,000U/mL青霉素-G/链霉素,高速冷冻离心机(EPPENDORF 5810R)，酶联免疫检测仪(Tecan Spark)。
实验准备：
1、细胞铺板
A)肿瘤细胞在37℃，5％CO2及饱和湿度的条件下，在RPMI-1640(含10％FBS和100U/mL青霉素-G/链霉素)中培养至80-90％密集度。
B)去除10cm培养皿中的培养基；
C)用10ml 1xPBS润洗细胞一遍；
D)加4ml 0.25％EDTA-Tripsin放入37℃，5％CO2培养箱胰酶消化5分钟，转移到15ml离心管，200g离心5分钟，弃上清得到细胞沉淀；
E)用4ml DMEM培养基重悬，计数并调整到10,000细胞/ml。
F)将细胞悬液加入96孔板每孔体积100μL，在37℃,5％CO2培养箱中培养过夜。
2、化合物处理
化合物稀释
A)配制受测化合物梯度稀释溶液：将测试化合物配置成1mM储液。然后用1.5μl储液溶解于1.5ml无DMSO培养液中，再以0.1％DMSO培养液进行3倍连续梯度稀释，共9个浓度，稀释后化合物浓度如下：
333.33nM，111.11nM，37.03nM，12.35nM，4.15nM，1.37nM，0.46nM，0.15nM
B)充分混匀后分别取100μL培养化合物溶液替代细胞培养板中的培养液，每个浓度4个复孔；
C)将细胞转移至培养箱孵育3天。
3、CCK8(WST-8)细胞分析检测
A)取出细胞培养板，在生物安全柜中每孔加入10微升CCK-8(WST-8)溶液；
B)把细胞培养板放回培养箱继续孵育3小时；
C)在TECAN酶联免疫检测仪上选择450nm波长测定吸光度值。
4、数据分析
使用如下公式计算细胞活力(％Cell Viability):
细胞活力(％)＝[A(加药)－A(空白)]/[A(0加药)－A(空白)]×100
A(加药)：具有细胞、CCK8溶液和药物溶液的孔的吸光度
A(空白)：具有培养基和CCK8溶液而没有细胞的孔的吸光度
A(0加药)：具有细胞、CCK8溶液而没有药物溶液的孔的吸光度
细胞活力：细胞增殖活力或细胞毒性活力通过GraphPad Prism 8软件进行曲线拟合得到IC50数值。
实验例2、Nano Luciferase方法检测YAP-TEAD抑制剂活性
(1)实验材料和设备：293T细胞购于南京科佰生物科技有限公司。DMEM培养基(高糖,无酚红，Bio-Channel)，DMSO(二甲基亚砜),Lipo6000转染试剂(碧云天)，pGL3B-8xGTiiC-nLuc-CMV-fLuc质粒，0.25％EDTA-Tripsin(胰酶消化液),1xPBS(磷酸盐缓冲液，PH7.2)，96孔白色细胞培养板(PerkinElmer),胎牛血清(FBS)，10,000U/mL青霉素-G/链霉素,高速冷冻离心机(EPPENDORF 5810R)，37℃CO2培养箱，
Figure PCTCN2022112259-appb-000174
细胞计数仪，Envision酶标仪(PerkinElmer)。
试剂
Figure PCTCN2022112259-appb-000175
(2)293T细胞瞬时转染
将复苏的293T细胞接种到10cm培养皿，置于5％的CO2培养箱中，37℃恒温培养，为确保转染效率，应当使用处于对数期(细胞密度约50％-70％)的细胞。
在转染前一天，用Trypsin-EDTA消化对数期细胞，加入培养基终止反应，用移液器吹打混匀制成细胞悬液。
使用Vi-cell测定细胞浓度，稀释成每毫升5*10^5个细胞的悬液。细胞悬液制备完成后，轻轻混匀，在10cm培养皿中加入10ml液体。这样每个10cm培养皿中的细胞数量为5*10^6。在5％的CO2培养箱中，37℃恒温培养1天。
取两个洁净无菌离心管，分别加入750μL不含抗生素和血清的opti-MEM Medium，然后于其中一管加入15μg质粒(pGL3B-8xGTiiC-nLuc-CMV-fLuc)，并用移液器轻轻吹打混匀；另一管加入Lipo6000转染试剂，用移液器轻轻吹打混匀。室温静置5分钟后，将含有DNA的培养液轻轻加入含Lipo6000转染试剂的培养液中，轻轻颠倒离心管混匀，室温静置5分钟。
将上述的混合物均匀的滴加到10cm培养皿中，并在培养6小时后更换为新鲜的完全培养基。
(3)96孔板铺板
转染1天后，Trypsin EDTA消化细胞，加入培养基终止反应，用移液器吹打混匀制成细胞悬液。
使用Vi-cell测定细胞浓度，稀释成每毫升20000个细胞的悬液。
细胞悬液制备完成后，轻轻混匀，在96孔板中，每孔加入100μL，这样待测的细胞的密度为2000个每孔。
(4)加入化合物
将接种好的细胞培养板放入培养箱中培养，约24小时后加入浓度梯度的化合物。
将10mM的化合物储液用培养基稀释到50μM，依次在深孔板的第三列加入50μM的化合物溶液，第四到十一列加入216μL含0.5％DMSO的培养基。
梯度稀释：从第三列吸取100μL溶液加入第四列，混匀以后；再从第四列吸取100μL溶液加入第五列，重复该操作直至第十一列。
使用多通道移液器，从深孔板中吸取25μL化合物溶液加入96孔培养板，每个化合物在96孔板上重复四次。最终在96孔板上形成最高浓度为10000nM，1:3.16的浓度梯度。
(5)加入Nano-luciferase检测试剂，读数
96孔板在5％的CO2培养箱中，37℃恒温培养48小时后，取出于室温平衡10分钟。
每孔加入100μL检测试剂，置于水平摇床低速震荡10分钟，充分裂解细胞。使用PerkinElmer Envision酶标仪检测每个孔的荧光值。
(6)结果计算
以0nM作为对照，将每个孔的数值转换成百分比，使用GrahpPad prism软件中的[Inhibitor]vs.response(three parameters)进行非线性拟合计算IC 50。
如表1所示，其中A≤1μM；1μM<B<5μM；C≥5μM
表1
Figure PCTCN2022112259-appb-000176
Figure PCTCN2022112259-appb-000177
Figure PCTCN2022112259-appb-000178
Figure PCTCN2022112259-appb-000179
Figure PCTCN2022112259-appb-000180
Figure PCTCN2022112259-appb-000181
Figure PCTCN2022112259-appb-000182
Figure PCTCN2022112259-appb-000183
Figure PCTCN2022112259-appb-000184
Figure PCTCN2022112259-appb-000185
Figure PCTCN2022112259-appb-000186
Figure PCTCN2022112259-appb-000187
Figure PCTCN2022112259-appb-000188
Figure PCTCN2022112259-appb-000189
Figure PCTCN2022112259-appb-000190
Figure PCTCN2022112259-appb-000191
Figure PCTCN2022112259-appb-000192
Figure PCTCN2022112259-appb-000193
Figure PCTCN2022112259-appb-000194
Figure PCTCN2022112259-appb-000195
Figure PCTCN2022112259-appb-000196
Figure PCTCN2022112259-appb-000197
Figure PCTCN2022112259-appb-000198
Figure PCTCN2022112259-appb-000199
Figure PCTCN2022112259-appb-000200
Figure PCTCN2022112259-appb-000201
Figure PCTCN2022112259-appb-000202
Figure PCTCN2022112259-appb-000203
Figure PCTCN2022112259-appb-000204
Figure PCTCN2022112259-appb-000205
Figure PCTCN2022112259-appb-000206
Figure PCTCN2022112259-appb-000207
Figure PCTCN2022112259-appb-000208
Figure PCTCN2022112259-appb-000209
Figure PCTCN2022112259-appb-000210
Figure PCTCN2022112259-appb-000211
Figure PCTCN2022112259-appb-000212
Figure PCTCN2022112259-appb-000213
Figure PCTCN2022112259-appb-000214
Figure PCTCN2022112259-appb-000215
Figure PCTCN2022112259-appb-000216
Figure PCTCN2022112259-appb-000217
Figure PCTCN2022112259-appb-000218
Figure PCTCN2022112259-appb-000219
Figure PCTCN2022112259-appb-000220
Figure PCTCN2022112259-appb-000221
Figure PCTCN2022112259-appb-000222
Figure PCTCN2022112259-appb-000223
Figure PCTCN2022112259-appb-000224
Figure PCTCN2022112259-appb-000225
Figure PCTCN2022112259-appb-000226
Figure PCTCN2022112259-appb-000227
Figure PCTCN2022112259-appb-000228
Figure PCTCN2022112259-appb-000229
Figure PCTCN2022112259-appb-000230
Figure PCTCN2022112259-appb-000231
Figure PCTCN2022112259-appb-000232
Figure PCTCN2022112259-appb-000233
Figure PCTCN2022112259-appb-000234
Figure PCTCN2022112259-appb-000235
Figure PCTCN2022112259-appb-000236
Figure PCTCN2022112259-appb-000237
Figure PCTCN2022112259-appb-000238
Figure PCTCN2022112259-appb-000239
Figure PCTCN2022112259-appb-000240
Figure PCTCN2022112259-appb-000241
Figure PCTCN2022112259-appb-000242
由表1可以看出，本发明大部分化合物对人胸膜间皮瘤细胞NCI-H226有非常好的抑制作用。
试验例3化合物药代动力学实验
本发明化合物T-32/T-105/T-253/T-272/T-273/T-277的药代动力学测试。
大鼠药代动力学实验方案
(1)所需动物：健康成年SD大鼠，雄性，3只，6-8周龄；体重200-300克。
(2)所需设备：分析天平、动物体重秤、磁力搅拌器、冷冻离心机、单道手动移液器等。
(3)所需试剂：EDTA-Na2抗凝剂等。称取EDTA-Na2 11.2g，置于试剂瓶中，加入生理盐水100mL，振荡使完全溶解。配制完成后分装入1.5mL离心管中，每支20uL，用于全血样品采集。
(3)精密称量约10mg的待测样品，加入换算后5％的DMSO溶解，再加入百分之30的PEG400和65％的(10％Hp-β-CD in PBS)超声，涡旋混匀，获得浓度为1mg/mL的溶液；临用前新鲜配制。
(4)吸取0.1mL样品于1.5mL离心管中，于-80℃保存，用于给药溶液浓度分析。
(5)动物饲养于大鼠笼中，开试验前一天开始禁食(不少于10h)不禁水；试验当天分别称重、并于尾部标记。给药前分别采集空白血。采血方式采用尾静脉取血。
(6)给药途径：灌胃(p.o.)；给药剂量：10mg/kg；给药体积：10mL/kg。
(7)操作流程：用带防咬手套的左手将大鼠捉拿，使其直立，将16号灌胃针从口中喉咙处伸入，试探能感受到无明显阻力的情况下进针，再将药物注射入胃中即可。
(8)受试动物分别于给药前及给药后0.5h,1h,2h,4h,6h,8h，12h，24h采集全血0.2ml于EDTA-Na2抗凝管中，上下颠倒3-4次混匀，于4℃10000g离心5min分离血浆，于-80℃保存待测。采血方式采用尾静脉取血。
(9)建立LC-MS/MS法测定血浆中的原形药物浓度，绘制血药浓度-时间曲线，并采用非房室模型计算主要药动学参数。
(10)T-32/T-105/T-253/T-272/T-273/T-277的药代动力学参数具体如下表2所示。
表2
Figure PCTCN2022112259-appb-000243
其中对照化合物1为专利WO2020097389A1中公开的一个性质最优的化合物，其化合物结构式如下图所示:
Figure PCTCN2022112259-appb-000244
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引 用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I所示化合物或其药学上可以接受的盐、溶剂化物或前药，
    Figure PCTCN2022112259-appb-100001
    其中，
    A选自
    Figure PCTCN2022112259-appb-100002
    Figure PCTCN2022112259-appb-100003
    L 1选自不存在或者CR 3R 4；
    B选自C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、C5-C10的环烷基；
    X选自O、NH、CR 3R 4或者S；
    X 1、X 2、X 3、X 4、X 5、X 6和X 7各自独立地选自CR 3、(CR 3) 2、N、O、S、SR 3、SR 3R 4、NR 4、CR 3R 4、(CR 3R 4) 2；
    R 1各自独立地选自H、D、卤素、CN、NH 2、脲基、羧基、氨基甲酸酯基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子 的5-10元杂芳基、
    Figure PCTCN2022112259-appb-100004
    Figure PCTCN2022112259-appb-100005
    Figure PCTCN2022112259-appb-100006
    其中，NH 2、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；
    各R 2、R 3、R 4和R 5各自独立地选自H、D、卤素、CN、NH 2、-CO-(C 1-6烷基)、＝O、-C(＝O)-O-(C1-C6烷基)、-C(＝O)-O-OBi、-S(＝O) 2-NR 6R 7、
    Figure PCTCN2022112259-appb-100007
    酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、SF 5，其中，NH 2、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；或者，X 1和X 7分别独立地为CR 3R 4，且X 1和X 7共用1个R 3，且R 3为C1-C6亚烷基；
    R 6和R 7各自独立地选自氢、D、C 1-6烷基、C 3-6环烷基、C6-C10芳基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、含1-3个选自N、O或S的杂原子的5-10元杂芳基、含1-3个选自N、O或S的杂原子的5-10元杂环基、-S(O) 2-(C 1-6烷基)、-S(O) 2-(C 2-6烯基)，其中，C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代，或者R 6和R 7形成3-7元的碳环，或者R 6和R 7形成含有N、O或S的3-7元的杂环；
    R 8选自
    Figure PCTCN2022112259-appb-100008
    Figure PCTCN2022112259-appb-100009
    各R独立地选自卤素、CN、OH、-(C 1-6亚烷基)-N(C 1-6烷基) 2、NH 2、NH(C 1-6烷基)、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-6烯基、C 2-6炔基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂环基或R’取代或未取代的含1-3个选自N、O或S的杂原子的5-10元杂芳基；R’选自下组：C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、CN、卤素、＝O；
    各m和n各自独立地选自1、2、3或4；
    p选自0、1或2。
  2. 如权利要求1所述的化合物或其药学上可以接受的盐、溶剂化物或前药，其特征在于，
    A选自
    Figure PCTCN2022112259-appb-100010
    Figure PCTCN2022112259-appb-100011
    L 1选自不存在或者CR 3R 4；
    B为C6-C10芳基；
    X为O；
    X 1、X 2、X 3、X 4、X 6和X 7各自独立地选自CR 3、N、CR 3R 4、或NR 4；
    R 1选自
    Figure PCTCN2022112259-appb-100012
    Figure PCTCN2022112259-appb-100013
    各R 2、R 3、R 4和R 5各自独立地选自H、卤素、CN、NH 2、-CO-(C 1-6烷基)、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基，其中，NH 2、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代；
    R 6和R 7各自独立地选自氢、C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、-S(O) 2-(C 1-6烷基)、-S(O) 2-(C 2-6烯基)，其中，C 1-6烷基、C 3-6环烷基、C6-C10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基任选地被1、2或3个R取代，或者R 6和R 7形成3-7元的碳环，或者R 6和R 7形成含有N、O或S的3-7元的杂环；
    R 8选自
    Figure PCTCN2022112259-appb-100014
    各R独立地选自卤素、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-6烯基、C 2-6炔基、C6-C10芳基、或含1-3个选自N、O或S的杂原子的5-10元杂芳基；
    各m和n各自独立地选自1、2、3或4；
    p选自0、1或2。
  3. 如权利要求1所述的化合物或其药学上可以接受的盐、溶剂化物或前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2022112259-appb-100015
    其中，各基团如权利要求1所定义。
  4. 如权利要求1所述的化合物或其药学上可以接受的盐、溶剂化物或前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2022112259-appb-100016
    Figure PCTCN2022112259-appb-100017
    R 1选自CN、脲基、氨基甲酸酯基、
    Figure PCTCN2022112259-appb-100018
    Figure PCTCN2022112259-appb-100019
    其中，各基团如权利要求1所定义。
  5. 如权利要求1所述的化合物或其药学上可以接受的盐、溶剂化物或前药，其特征在于，
    R 2选自三氟甲基、氟、氯、溴、碘、甲基、环戊基、或环己基或五氟化硫基。
  6. 如权利要求1所述的化合物或其药学上可以接受的盐、溶剂化物或前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2022112259-appb-100020
    Figure PCTCN2022112259-appb-100021
    Figure PCTCN2022112259-appb-100022
    Figure PCTCN2022112259-appb-100023
    Figure PCTCN2022112259-appb-100024
    Figure PCTCN2022112259-appb-100025
    Figure PCTCN2022112259-appb-100026
    Figure PCTCN2022112259-appb-100027
    Figure PCTCN2022112259-appb-100028
    Figure PCTCN2022112259-appb-100029
  7. 一种药物组合物，其特征在于，包含药学上可接受的载体和一种或多种安全有效量的权利要求1所述的化合物或其药学上可以接受的盐、溶剂化物或前药。
  8. 一种权利要求7所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗由Hippo通路失调导致的相关疾病的药物。
  9. 一种权利要求7所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗由YAP或TAZ或YAP/TAZ或YAP/TEAD或YAP/TAZ/TEAD失调导致的相关疾病的药物。
  10. 一种权利要求1所述的化合物或其药学上可以接受的盐、溶剂化物或前药和第二药物的联用，其特征在于，用于制备预防和/或治疗癌症的药物；
    所述第二药物选自下组：ERK抑制剂、MEK抑制剂、KRAS抑制剂、BRAF抑制剂、EGFR抑制剂、Wnt抑制剂、PD-1抑制剂、或其组合。
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CN117327007A (zh) * 2023-09-26 2024-01-02 上海陶术生物科技有限公司 一种vt107的制备方法

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