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WO2024088400A1 - 含磷化合物、药物组合物及其应用 - Google Patents

含磷化合物、药物组合物及其应用 Download PDF

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Publication number
WO2024088400A1
WO2024088400A1 PCT/CN2023/127207 CN2023127207W WO2024088400A1 WO 2024088400 A1 WO2024088400 A1 WO 2024088400A1 CN 2023127207 W CN2023127207 W CN 2023127207W WO 2024088400 A1 WO2024088400 A1 WO 2024088400A1
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Prior art keywords
independently
ring
alkyl
compound
heteroatoms selected
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PCT/CN2023/127207
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English (en)
French (fr)
Inventor
张贵平
李家鹏
王奎锋
段霜霜
郑计岳
童晨骅
王翔
谢胜武
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勤浩医药（苏州）有限公司
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Publication of WO2024088400A1 publication Critical patent/WO2024088400A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom

Definitions

  • the invention relates to a phosphorus-containing compound, a pharmaceutical composition and applications thereof.
  • the Hippo signaling pathway is a highly conserved cell signaling pathway from fruit flies to mammals.
  • the main functions of this pathway include regulating the normal development of the body, determining the size ratio of tissues and organs, maintaining the balance of cell proliferation and death, and maintaining the stemness of stem cells.
  • the core components of this signaling pathway are mainly composed of 1 upstream signaling factors; 2 core kinase cascade reaction chain; 3 downstream effector molecules. Once activated by upstream stimuli (such as cell contact inhibition), MST1/2 kinases and SAV1 interact with upstream regulatory factors and become phosphorylated and activated, thereby phosphorylating MOB1A/B and LATS1/2, resulting in the complete activation of the LSTS1/2 kinase complex.
  • the complex further phosphorylates the transcriptional coactivator YAP/TAZ, and the phosphorylated YAP/TAZ is blocked in the cytoplasm by the 14-3-3 protein and induced to be polyubiquitinated by the E3 ligase ⁇ -TrCP, thereby being recognized and degraded by the proteasome.
  • the Hippo pathway is inhibited (e.g., stimulated by serum factors)
  • unphosphorylated YAP/TAZ enters the nucleus and forms a transcription complex mainly with the transcription factor TEAD protein family, thereby activating the transcription of downstream target genes (e.g., CTGF, FGF1, AMOTL2, and CYR61), promoting cell survival and proliferation.
  • downstream target genes e.g., CTGF, FGF1, AMOTL2, and CYR61
  • this pathway can also regulate the self-renewal and differentiation of stem cells, thereby participating in tissue regeneration and wound healing. Therefore, under some conditions, the YAP/TAZ-TEAD transcription complex acts as an oncogene, while the Hippo pathway acts as a tumor suppressor.
  • inactivation or loss of upstream inhibitors of the Hippo signaling pathway can be found in a variety of tumors, including but not limited to liver cancer, lung cancer, ovarian cancer, brain cancer, malignant mesothelioma, breast cancer, head and neck cancer, colorectal cancer, prostate cancer and leukemia.
  • abnormal amplification of YAP/TAZ and TEAD family proteins has been found in a variety of tumors, and a large number of reports have identified TEAD family proteins as key mediators of YAP/TAZ's ability to promote cancer.
  • Clinical studies suggest that the amplification of YAP/TAZ can be used as a biomarker for the prognosis and diagnosis of a variety of tumors.
  • YAP and TAZ can regulate cell proliferation, migration and apoptosis, participate in the self-renewal and EMT (epithelial-mesenchymal transition) characteristics of tumor stem cells, and promote the maintenance of the immunosuppressive effect of the tumor microenvironment, thereby mediating the resistance of tumor cells to conventional chemotherapy, targeted therapy and immunotherapy. Therefore, targeting the YAP/TAZ-TEAD protein complex will be a very promising method for treating a variety of cancers with functional changes in this pathway.
  • the transcriptional complex formed by YAP/TAZ and TEAD is mainly maintained by three protein-protein interaction interfaces, among which interface two and interface three are both crucial for the formation of this protein complex.
  • both interfaces lack the geometric characteristics and electrostatically enriched pockets required for small molecules to bind to proteins.
  • researchers have found that the YAP binding domain of TEAD protein contains a pocket for binding palmitic acid/myristic acid, and palmitic acid molecules reversibly palmitoylate TEAD proteins at this site.
  • the palmitoylation modification of TEAD protein is crucial for its protein stability, the formation and transcriptional activity of the YAP/TAZ-TEAD transcriptional complex, and the inhibition of TEAD family proteins has no significant effect on the homeostasis of adult tissues and organs. Therefore, the oncogenic activity of YAP/TAZ can be effectively blocked by directly inhibiting the palmitoylation modification of TEAD family proteins, especially for the treatment of various tumors with inactivated Hippo upstream genes.
  • the present invention provides inhibitors associated with one or more members of the Hippo pathway network, in particular novel compounds that inhibit the transcriptional activity of the YAP/TAZ-TEAD protein complex.
  • novel compounds that inhibit the transcriptional activity of the YAP/TAZ-TEAD protein complex.
  • the compounds of the present invention also have better physicochemical properties (such as solubility, physical and/or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (such as reduced cardiac toxicity) and/or fewer side effects) and other more excellent properties.
  • the present invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, a solvate thereof, a metabolite thereof, an isotopic derivative thereof or a prodrug thereof,
  • R1 and R2 are independently C1 - C6 alkyl, C3 - C6 cycloalkyl or C6 - C10 aryl;
  • R 1 , R 2 and the atoms to which they are attached together form a 3-12-membered heterocycloalkyl group or a 3-12-membered heterocycloalkyl group substituted by one or more R 1-1 , wherein the 3-12-membered heterocycloalkyl group, in addition to the P atom to which it is attached, further contains 0, 1, 2 or 3 heteroatoms selected from 1, 2 or 3 of the group consisting of N, O and S;
  • R 1-1 is independently C 1 -C 6 alkyl
  • Each R X1 is independently H, C 1 -C 6 alkyl, halogen or CN;
  • RX4 is H, "a 5-12-membered saturated or unsaturated heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", "a 5-12-membered saturated or unsaturated heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", substituted by one or more RX4-1 , C6 - C10 aryl, or C6 - C10 aryl substituted by one or more RX4-5 ;
  • RL1 , RL2 and RL3 are independently H, C1 - C6 alkyl or C3 - C6 cycloalkyl;
  • RL4 and RL5 are independently H or C1 - C6 alkyl
  • L 1 and L 2 are independently -CH 2 -, -O-, -S- or -NH-;
  • Ring A is a C 3 -C 12 saturated or unsaturated carbocyclic ring, "a 5-12 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S";
  • n3 0, 1, 2 or 3;
  • R 5 is independently SF 5 , halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 5-1 , SR 5-2 , OR 5-3 , CN, S( ⁇ O) 2 R 5-4 , C( ⁇ O)R 5-5 , S( ⁇ O) 2 NR d R 5-6 , NR d R 5-6 , C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted by one or more R 5-7 ;
  • R 5-1 is independently hydroxy, CN or halogen
  • R 5-2 , R 5-3 , R 5-4 , and R 5-6 are independently H, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted by one or more R 5-8 ;
  • R 5-5 is independently C 1 -C 6 haloalkyl, H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted by one or more R 5-8 , NR d R 5-6 ;
  • R 5-7 and R 5-8 are independently halogen or C 1 -C 6 haloalkyl
  • Ra , Rb , Rc and Rd are independently H or C1 - C6 alkyl.
  • the compound as shown in Formula I or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopic derivative or prodrug thereof Some groups are defined as follows, and the groups not mentioned are the same as those described in any embodiment of the present invention (referred to as "in some embodiments"), and R 5 is independently C 3 -C 6 cycloalkyl.
  • R 1 and R 2 are independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 6 -C 10 aryl;
  • R 1 , R 2 and the atoms to which they are attached together form a 3-12-membered heterocycloalkyl group or a 3-12-membered heterocycloalkyl group substituted by one or more R 1-1 , wherein the 3-12-membered heterocycloalkyl group, in addition to the P atom to which it is attached, further contains 0, 1, 2 or 3 heteroatoms selected from 1, 2 or 3 of the group consisting of N, O and S;
  • R 1-1 is independently C 1 -C 6 alkyl
  • Each R X1 is independently H, C 1 -C 6 alkyl, halogen or CN;
  • RX4 is H, "a 5-12-membered saturated or unsaturated heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", "a 5-12-membered saturated or unsaturated heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", substituted by one or more RX4-1 , C6 - C10 aryl, or C6 - C10 aryl substituted by one or more RX4-5 ;
  • RL1 , RL2 and RL3 are independently H, C1 - C6 alkyl or C3 - C6 cycloalkyl;
  • RL4 and RL5 are independently H or C1 - C6 alkyl
  • L 1 and L 2 are independently -CH 2 -, -O-, -S- or -NH-;
  • Ring A is a C 3 -C 12 saturated or unsaturated carbocyclic ring, "a 5-12 membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms selected from N, O and S";
  • n3 0, 1, 2 or 3;
  • R 5 is independently SF 5 , halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 5-1 , SR 5-2 , OR 5-3 , CN, S( ⁇ O) 2 R 5-4 , C( ⁇ O)R 5-5 , S( ⁇ O) 2 NR d R 5-6 , NR d R 5-6 or C 3 -C 6 cycloalkyl substituted by one or more R 5-7 ;
  • R 5-1 is independently hydroxy, CN or halogen
  • R 5-2 , R 5-3 , R 5-4 , and R 5-6 are independently H, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted by one or more R 5-8 ;
  • R 5-5 is independently C 1 -C 6 haloalkyl, H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substituted by one or more R 5-8 , NR d R 5-6 ;
  • R 5-7 and R 5-8 are independently halogen or C 1 -C 6 haloalkyl
  • Ra , Rb , Rc and Rd are independently H or C1 - C6 alkyl.
  • the "halogen" is independently fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, such as fluorine.
  • the "C 1 -C 6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl, such as methyl.
  • the “C 1 -C 6 alkoxy” is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy or ethoxy.
  • the “C 1 -C 6 haloalkyl” is independently —CHF 2 , —CH 2 F or —CF 3 .
  • the “C 1 -C 6 haloalkoxy” is independently -OCHF 2 , -OCH 2 F or -OCF 3 .
  • the "C 3 -C 6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl, such as cyclopropyl.
  • the “C 6 -C 10 aryl” is independently phenyl or naphthyl, preferably phenyl.
  • the “heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl” are independently “heteroatoms are selected from 1 or 2 of N and O, and the number of heteroatoms is 1 or 2 5-6-membered heterocycloalkyl”.
  • the “heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3, and the 5-12 membered heteroaryl group” is “the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3, and the 5-6 membered heteroaryl group”.
  • the "heteroatoms selected from 1, 2 or 3 of N, O and S, 5-12 membered saturated or unsaturated heterocyclic group having 1, 2 or 3 heteroatoms” is "heteroatoms selected from 1, 2 or 3 of N, O and S, 5-10 membered unsaturated heterocyclic group having 1, 2 or 3 heteroatoms", for example, pyrrolyl (for example ), pyrazolyl (e.g. ), imidazole (e.g. ), triazole (e.g. ), thiazole Base (e.g. ), oxazolyl (e.g. ), isoxazolyl (e.g. ), pyridyl (e.g.
  • pyrimidine radicals e.g.
  • pyrazinyl e.g.
  • pyridazinyl e.g.
  • imidazolyl e.g.
  • pyrazolyl e.g.
  • Pyridyl e.g.
  • pyrimidinyl e.g.
  • the "C 3 -C 12 saturated or unsaturated carbon ring” is a C 4 -C 10 saturated or unsaturated carbon ring, such as a cyclobutane ring (eg ), cyclohexane ring (e.g. ), spiro[2.5]octane (e.g. ), spiro[3.3]heptane ring (e.g. ), benzene ring (e.g. ), naphthalene ring (e.g.
  • indane ring or tetralin ring for example, C 4 -C 10 saturated carbocyclic ring or C 6 -C 10 aromatic ring, preferably C 6 -C 10 aromatic ring, such as cyclobutane ring (for example ), cyclohexane ring (e.g. ), spiro[3.3]heptane ring (e.g. ), benzene ring (e.g. ), naphthalene ring (e.g. ), an indane ring or a tetralin ring, preferably a C 6 -C 10 aromatic ring.
  • cyclobutane ring for example
  • cyclohexane ring e.g.
  • spiro[3.3]heptane ring e.g.
  • benzene ring e.g.
  • naphthalene ring e.g.
  • the “heteroatoms selected from 1, 2 or 3 of N, O and S, 5-12-membered saturated or unsaturated heterocyclic ring having 1, 2 or 3 heteroatoms” is “heteroatoms selected from 1, 2 or 3 of N, O and S, 5-6-membered monocyclic heteroaromatic ring or 9-10-membered bicyclic ring having 1, 2 or 3 heteroatoms Heterocyclic rings", for example, benzoxolane rings (e.g. ), pyridine ring (e.g. ) or thiophene ring (e.g.
  • a 5-6 membered heteroaromatic ring having 1, 2 or 3 heteroatoms selected from N, O and S such as a pyridine ring (e.g. ) or thiophene ring (e.g. ), such as benzoxolane ring (e.g. ).
  • R 1 and R 2 are independently C 1 -C 6 alkyl, or R 1 , R 2 and the atoms to which they are connected together form a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl, in addition to the P atom to which it is connected, further contains 0, 1, 2 or 3 heteroatoms selected from 1, 2 or 3 of the group consisting of N, O and S, for example, C 1 -C 6 alkyl.
  • L is a single bond, -CR L1 R L2 -, -O-, -S- or -NR L3 -; preferably, L is a single bond, -O-, -S- or -NR L3 , for example, L is -O- or -NR L3 -.
  • RL3 is H.
  • ring A is a C 4 -C 10 saturated carbocyclic ring, a C 6 -C 10 aromatic ring, or a "5-9-membered saturated or unsaturated heterocyclic ring whose heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S", for example, ring A is a C 6 -C 10 aromatic ring or a "5-6-membered heteroaromatic ring whose heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S", for example, ring A is a C 6 -C 10 aromatic ring or a "5-9-membered saturated or unsaturated heterocyclic ring whose heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S".
  • m3 is 0, 1 or 2, for example, m3 is 0 or 1, such as 1 or 2, preferably, m3 is 1.
  • R 5 is independently SF 5 , C 3 -C 6 cycloalkyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 5-1 , or OR 5-3 .
  • R 5 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 5-1 , for example, C 1 -C 6 alkyl substituted by one or more R 5-1 .
  • R 5 is independently SF 5 , halogen, C 1 -C 6 alkyl substituted by one or more R 5-1 .
  • R 5 is independently SF 5 , halogen , or C 1 -C 6 alkyl substituted by one or more R 5-1 .
  • R 5-1 is independently halogen.
  • R 5-3 is independently C 1 -C 6 haloalkyl.
  • each RX1 is independently H.
  • RX4 is "a 5-12-membered saturated or unsaturated heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S", or "a 5-12-membered saturated or unsaturated heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S" substituted by one or more RX4-1 .
  • RX4-1 and RX4-5 are independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more RX4-2 , or C 3 -C 6 cycloalkyl.
  • RX4-2 and RX4-3 are independently halogen.
  • RX4-1 and RX4-5 are independently H, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with one or more RX4-2 .
  • RX4 is For example, RX4 is For example, R X4 is
  • L is a single bond, -CR L1 R L2 -, -O-, -S- or -NH-, for example, L is a single bond, -O- or -NH-, for example, L is -O- or -NH-.
  • the compound represented by Formula I is a compound represented by the following Formula I-7:
  • X 13 is N
  • R 1 , R 2 , RX1 , RX4 , R 5 , L, ring A and m3 are as defined in any one of the present invention.
  • the compound as shown in Formula I is any of the following compounds:
  • the present invention provides a pharmaceutical composition, comprising:
  • the present invention also provides the above-mentioned compound as shown in Formula I, its pharmaceutically acceptable salt, its ester, its stereoisomer, its tautomer, its polymorph, its solvate, its metabolite, its isotopic derivative or its prodrug, or the use of the above-mentioned pharmaceutical composition in the preparation of drugs, wherein the drugs are used to treat diseases and conditions mediated by TEAD, such as cancer (such as solid tumors, leukemia, etc.), organ regeneration, wound healing, fibrosis, etc.
  • TEAD diseases and conditions mediated by TEAD
  • cancer such as solid tumors, leukemia, etc.
  • organ regeneration such as wound healing, fibrosis, etc.
  • the term "pharmaceutically acceptable salt” refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • esters includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compound of the invention in the free acid or alcohol form).
  • the compound of the invention itself may also be an ester.
  • stereoisomer refers to cis-trans isomers or optical isomers.
  • Cis-trans isomers are isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely, and optical isomers are stereoisomers with different optical properties caused by the lack of anti-axis symmetry in the molecule.
  • tautomer refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert into each other. If tautomerism is possible (such as in solution), chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions via reorganization of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • polymorph refers to a compound existing in multiple crystalline forms.
  • solvate refers to a substance formed by the combination of a compound and a solvent. Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
  • metabolite refers to a substance formed in vivo following administration of a compound of the present invention.
  • isotopic derivative refers to a compound in which one or more atoms have an isotopic abundance that differs from its natural abundance. For example, one or more atoms in the compound has been replaced by an atom of a lower mass number found in nature - a hydrogen atom in the compound has been replaced by deuterium.
  • prodrug refers to a derivative of a compound that contains a bioreactive functional group, such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide the compound.
  • the prodrug is inactive, or at least less active than the compound itself, such that its activity cannot be exerted until the compound is cleaved from the bioreactive functional group.
  • the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
  • a prodrug may contain a biohydrolyzable group.
  • biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable ureides.
  • a substituent may be preceded by a single dash "-" to indicate that the named substituent is connected to the parent moiety via a single bond.
  • the connecting group listed in the present invention does not specify its connecting direction, its connecting direction is connected in the same direction as the reading order from left to right, as shown below:
  • the connecting group L is -CD-, in which case -CD- connects ring B and ring A in the same direction as the reading order from left to right to form Rather than constitute Specifically in the present invention, when L is "-NR L3 CR L1 R L2 -", it means that N is connected to the ring B in the parent compound via a single bond, rather than the C terminal being connected to the ring B in the parent compound.
  • the structural fragment means that the structural fragment is connected to the rest of the molecule through this bond.
  • It refers to pyridyl.
  • one or more refers to 1, 2, 3, 4 or 5, such as 1, 2 or 3.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 1 -C 6 ).
  • Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.
  • alkoxy refers to the group R Y -O-, where R Y has the same definition as the term "alkyl”.
  • Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • cycloalkyl refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 3 -C 6 ). Cycloalkyl groups include, but are not limited to: wait.
  • heterocycloalkyl refers to a ring having a specified number of ring atoms (e.g., 3-12 members, 5-6 members), a specified number of heteroatoms, (e.g., 1, 2, or 3) of a specified heteroatom type (one or more of N, O, and S), a cyclic, saturated, monovalent group.
  • Heterocycloalkyl is attached to the rest of the molecule via a carbon atom or a heteroatom.
  • Heterocycloalkyl includes, but is not limited to: wait.
  • heteroaryl refers to a cyclic, unsaturated group with a specified number of ring atoms (e.g., 5-12 members, 5-6 members), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified type of heteroatoms (one or more of N, O and S), which is a monocyclic or polycyclic ring.
  • ring atoms e.g., 5-12 members, 5-6 members
  • heteroatoms e.g., 1, 2 or 3
  • a specified type of heteroatoms one or more of N, O and S
  • heteroaryl group is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl group is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms.
  • Heteroaryl includes but is not limited to wait.
  • aryl refers to a cyclic, unsaturated hydrocarbon group with a specified number of carbon atoms (e.g., C 6 -C 10 ), which is monocyclic or polycyclic (e.g., 2 or 3). When it is polycyclic, the monocyclic rings share two atoms and one bond, and each ring has aromaticity.
  • Aryl includes, but is not limited to, phenyl, naphthyl, etc.
  • the term "pharmaceutically acceptable excipients” refers to all substances contained in pharmaceutical preparations except active pharmaceutical ingredients, which are generally divided into two categories: excipients and additives.
  • excipients and additives for details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).
  • the reagents and raw materials used in the present invention are commercially available.
  • Step 1 Compound I-1 and compound I-2 react to obtain compound I-3.
  • W is selected from halogen or alkyl/aryl sulfonate group, wherein halogen is preferably chlorine, bromine and iodine, and alkyl/aryl sulfonate group includes but is not limited to methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate or naphthalenesulfonate, preferably methanesulfonate and p-toluenesulfonate; U is selected from H, OH, SH, NHR L3 , CR L1 R L2 tin reagent, CR L1 R L2 zinc reagent, CR L1 R L2 magnesium reagent, etc.; V is selected from From boronic acid, boronic acid ester, halogen or alkyl/aryl sulfonate group, wherein halogen is preferably chlorine, bromine and io
  • the reaction occurs in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, trisdibenzylideneacetone dipalladium, palladium dichloride, palladium acetate, chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium, etc., preferably 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride;
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylpho
  • reaction occurs in the presence of a suitable base, such as sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., preferably sodium carbonate;
  • a suitable base such as sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., preferably sodium carbonate;
  • the reaction takes place in a suitable solvent, such as 1,4-dioxane, 1,4-dioxane/water, 1,2-dichloroethane, 1,2-dichloroethane/water, N,N-dimethylformamide, N,N-dimethylformamide/water, dimethyl sulfoxide, dimethyl sulfoxide/water, N-methylpyrrolidone, N-methylpyrrolidone/water, etc., preferably 1,4-dioxane/water and N,N-dimethylformamide;
  • a suitable solvent such as 1,4-dioxane, 1,4-dioxane/water, 1,2-dichloroethane, 1,2-dichloroethane/water, N,N-dimethylformamide, N,N-dimethylformamide/water, dimethyl sulfoxide, dimethyl sulfoxide/water, N-methylpyrrolidone, N-methylpyrrolidone/water
  • the reaction takes place at a suitable temperature, such as 25-140°C, preferably 80-110°C.
  • Step 2 Compound I-3 is reacted with phosphine oxide I-4 to obtain compound I.
  • the reaction occurs in the presence of a suitable catalyst, such as: tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, trisdibenzylideneacetone dipalladium, palladium dichloride, palladium acetate, chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium, etc., preferably chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium and trisdibenzylideneacetone dipalla suitable catalyst
  • the reaction occurs in the presence of a suitable base, such as sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., preferably cesium carbonate;
  • a suitable base such as sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., preferably cesium carbonate;
  • the reaction takes place in a suitable solvent, such as 1,4-dioxane, 1,4-dioxane/water, 1,2-dichloroethane, 1,2-dichloroethane/water, N,N-dimethylformamide, N,N-dimethylformamide/water, dimethyl sulfoxide, dimethyl sulfoxide/water, N-methylpyrrolidone, N-methylpyrrolidone/water, etc., preferably 1,4-dioxane and N,N-dimethylformamide;
  • a suitable solvent such as 1,4-dioxane, 1,4-dioxane/water, 1,2-dichloroethane, 1,2-dichloroethane/water, N,N-dimethylformamide, N,N-dimethylformamide/water, dimethyl sulfoxide, dimethyl sulfoxide/water, N-methylpyrrolidone, N-methylpyrrolidone/water, etc
  • the reaction takes place at a suitable temperature, such as 25 to 140°C, preferably 40 to 110°C.
  • Step 1 Compound I-7-1 reacts with compound RX4 -Z to obtain compound I-7-2.
  • Y is selected from halogen or alkyl/aryl sulfonate group, wherein halogen is preferably chlorine, bromine and iodine, and alkyl/aryl sulfonate group includes but is not limited to methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate or naphthalenesulfonate, preferably methanesulfonate and p-toluenesulfonate; Z is selected from boric acid, boric ester, tin reagent, zinc reagent or magnesium reagent, preferably boric acid and boric ester;
  • the reaction occurs in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, tridibenzylideneacetone dipalladium, palladium dichloride, palladium acetate, chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium, etc., preferably tetrakis(triphenylphosphine)palladium and 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride;
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphin
  • reaction occurs in the presence of a suitable base, such as sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., preferably sodium carbonate;
  • a suitable base such as sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., preferably sodium carbonate;
  • the reaction takes place in a suitable solvent such as 1,4-dioxane, 1,4-dioxane/water, 1,2-dichloroethane, 1,2-dichloroethane/water, N,N-dimethylformamide, N,N-dimethylformamide/water, dimethyl sulfoxide, dimethyl sulfoxide/water, N-methylpyrrolidone, N-methylpyrrolidone/water, etc., preferably 1,4-dioxane/water and N,N-dimethylformamide;
  • the reaction takes place at a suitable temperature, such as 25 to 140°C, preferably 40 to 110°C;
  • Step 2 Compound I-7-2 and compound I-7-3 react to obtain compound I-7-4.
  • the reaction occurs in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium dichloride, palladium acetate, chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium, etc., preferably 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride;
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-
  • reaction occurs in the presence of a suitable base, such as sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., preferably sodium carbonate;
  • a suitable base such as sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., preferably sodium carbonate;
  • the reaction takes place in a suitable solvent, such as 1,4-dioxane, 1,4-dioxane/water, 1,2-dichloroethane, 1,2-dichloroethane/water, N,N-dimethylformamide, N,N-dimethylformamide/water, dimethyl sulfoxide, dimethyl sulfoxide/water, N-methylpyrrolidone, N-methylpyrrolidone/water, etc., preferably 1,4-dioxane/water and N,N-dimethylformamide;
  • a suitable solvent such as 1,4-dioxane, 1,4-dioxane/water, 1,2-dichloroethane, 1,2-dichloroethane/water, N,N-dimethylformamide, N,N-dimethylformamide/water, dimethyl sulfoxide, dimethyl sulfoxide/water, N-methylpyrrolidone, N-methylpyrrolidone/water
  • the reaction takes place at a suitable temperature, such as 25-140°C, preferably 80-110°C.
  • Step 3 Compound I-7-4 reacts with phosphine oxide I-7-5 to obtain compound I-7.
  • the reaction occurs in the presence of a suitable catalyst, such as: tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, trisdibenzylideneacetone dipalladium, palladium dichloride, palladium acetate, chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium, etc., preferably chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium and trisdibenzylideneacetone dipalla suitable catalyst
  • the reaction occurs in the presence of a suitable base, such as sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., preferably cesium carbonate;
  • a suitable base such as sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., preferably cesium carbonate;
  • the reaction takes place in a suitable solvent, such as 1,4-dioxane, 1,4-dioxane/water, 1,2-dichloroethane, 1,2-dichloroethane/water, N,N-dimethylformamide, N,N-dimethylformamide/water, dimethyl sulfoxide, dimethyl sulfoxide/water, N-methylpyrrolidone, N-methylpyrrolidone/water, etc., preferably 1,4-dioxane and N,N-dimethylformamide;
  • a suitable solvent such as 1,4-dioxane, 1,4-dioxane/water, 1,2-dichloroethane, 1,2-dichloroethane/water, N,N-dimethylformamide, N,N-dimethylformamide/water, dimethyl sulfoxide, dimethyl sulfoxide/water, N-methylpyrrolidone, N-methylpyrrolidone/water, etc
  • the reaction takes place at a suitable temperature, such as 25 to 140°C, preferably 40 to 110°C.
  • reaction solution was poured into a citric acid aqueous solution, extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography, and then slurried with petroleum ether, filtered, and dried to obtain a white solid 9d (2.3 g, yield: 75%).
  • comparative compound B3 (VT103) is: CAS number: 2290608-13-6, synthesized by referring to the synthetic route in patent WO2019040380A1.
  • the structure of comparative compound B4 (MRK-A) is CAS No.: 2821763-12-4, Purchase source: Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd., Batch number: AK23-1338803-1-1.
  • the YAP-TEAD reporter gene assay was performed as follows. First, the 8xGTIIC promoter sequence (GAGCTCTTACGCGTGCTAGCCCGGCCAGTGCCAAGTTGAGACACATTCCACACATTCCACTGCAAGCTTGAGACACATTCCACACATTCC
  • TTCCCAGACAGCCGCCGGCACCCACCGCTCCGTGGGACGATCCCCCAAGAGCTTGGCATTCCGGTACTGTTGGTAAA was constructed into the pGL4.20 (luc2-Puro) plasmid, and the TK promoter (AAATGAGTCTTCGGACCTCGCGGGGGCCGCTTAAGCGGTGGTTAGGGTTTGTCTGACGCGGGGGGAGGGGGAAGGAACGAAACACTCTCA
  • GAACACCGAGCGACCCTGCAGCGACCCGCTTAA was constructed into the pGL4.78 (hRlucCP/Hygro) plasmid to construct 293T stable transfected cells that can stably and continuously respond to the transcriptional activity of the YAP-TEAD transcription complex. After selecting and identifying a single clone, the clone was grown and maintained in DMEM, 10% fetal bovine serum, penicillin-streptomycin solution, 1ug/mL puromycin and 150ug/ml hygromycin culture medium.
  • the above-mentioned cells with good growth status were taken and plated into a 384-well plate at a cell density of 3000 per well, 90 ⁇ l per well, and the surrounding was sealed with an appropriate amount of PBS to prevent water evaporation in the edge wells.
  • the drug was administered the next day after cell plating, and compounds with different concentration gradients were added to each well. Three replicates were set for each concentration point. The compound concentration was 5 ⁇ M as the starting concentration and was diluted seven times with a 5-fold gradient. In addition, a corresponding DMSO negative treatment control group was set.
  • Dual-Lumi TM Firefly Luciferase Detection Reagent and Dual-Lumi TM Renilla Luciferase 1.
  • Add 100 ⁇ l of Dual-Lumi TM Renilla Luciferase Assay Buffer to the 96-well plate and allow it to reach room temperature.
  • Dual-Lumi TM Renilla Luciferase Assay Working Solution Prepares an appropriate amount of Dual-Lumi TM Renilla Luciferase Assay Working Solution according to the amount of 100 ⁇ l Dual-Lumi TM Renilla Luciferase Assay Working Solution required for each sample. 4. Mix an appropriate amount of Dual-Lumi TM Renilla Luciferase Assay Substrate (100X) and Dual-Lumi TM Renilla Luciferase Assay Buffer in a ratio of 1:100 to prepare the Dual-Lumi TM Renilla Luciferase Assay Working Solution. 5. Take out the cell culture plate and equilibrate it at room temperature for 10 minutes (usually not more than 30 minutes). 6.
  • Dual-Lumi TM Firefly Luciferase Assay Reagent 100 ⁇ l of Dual-Lumi TM Firefly Luciferase Assay Reagent to each well of the 96-well plate (25 ⁇ l per well of the 384-well plate) and mix well. Incubate at room temperature (about 25°C) for 10 minutes to stabilize the luminescent signal, and then use a multifunctional microplate reader with a chemiluminescence detection function for chemiluminescence detection. After that, start the detection of Renilla luciferase. First, add 100 ⁇ l Dual-Lumi TM Renilla luciferase detection working solution to each well of the 6-well plate (25 ⁇ l per well of the 384-well plate) and mix well.
  • NCI-H2052 (NF2 mutant), NCI-H226 (NF2 mutant), NCI-H2452 (NF2 wide-type), NCI-H28 (NF2 wide-type) and MSTO-211H (NF2 wide-type) cells were cultured with RPMI 1640 complete medium.
  • the above-mentioned cells with normal growth were digested with trypsin cell digestion solution, centrifuged, counted, and plated into 96-well plates at a density of 1000 cells per well.
  • Drugs were administered 24 hours after cell plating, and 10 ⁇ L of inhibitors with different concentration gradients were added to each well. Three replicates were set for each concentration point, with a starting concentration of 20 ⁇ M, and then diluted 8 times with a 4-fold gradient. In addition, a corresponding 1/1000 DMSO negative treatment control group was set.
  • the cell culture plate to be tested was taken out of the incubator, the culture medium in the 96-well plate was aspirated, 190 ⁇ L RPMI 1640 complete medium was added again, and the cells were cultured again for 72 hours.
  • the 96-well plate was taken out and placed at room temperature for 10 minutes, the culture medium in the 96-well plate was aspirated, 200 ⁇ L CellTiter-Lumi TM luminescent cell viability detection solution (mixed with the culture medium 1:1) was added, and the reaction was allowed to react at room temperature for 10 minutes after shaking for two minutes. 150 ⁇ L of liquid was aspirated from the transparent 96-well plate and transferred to a 96-well white plate for chemiluminescence reading.
  • the first-phase metabolic stability of the test compounds was assessed in liver microsomes of CD-1 mice, Sprague-Dawley rats, and humans.
  • the animal and human liver microsomes used in this test system were purchased from Xenotech, Corning or other qualified suppliers and stored in a refrigerator below -60°C before use.
  • the information of the animal and human liver microsomes used is as follows:
  • test sample and the control compound were incubated with animal and human liver microsomes at 37 ⁇ 1°C for a certain period of time, with the longest incubation time being 60 minutes. Samples were taken out at the specified time point and the reaction was terminated with acetonitrile or other organic solvents containing internal standards. After centrifugation, the resulting supernatant was detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • test sample powder is prepared into a stock solution of a certain concentration using DMSO or other organic solvents, and then further diluted with a suitable organic solvent.
  • control compounds testosterone, diclofenac and propafenone were prepared as 10 mM stock solutions in DMSO and then further diluted in appropriate organic solvents.
  • NADP nicotinamide adenine dinucleotide phosphate
  • ISO isocitrate
  • the stop solution is prepared with acetonitrile or other organic solvents containing an internal standard (tolbutamide or other suitable compounds).
  • the prepared stop solution is stored in a refrigerator at 2-8°C.
  • Incubations will be done in 96-well plates. Prepare 8 incubation plates, named T0, T5, T15, T30, T45, T60, Blank60, and NCF60. The first 6 plates correspond to reaction time points of 0, 5, 15, 30, 45, and 60 minutes, respectively. No test or control compound is added to the Blank60 plate, and samples are taken after 60 minutes of incubation. In the NCF60 plate, potassium phosphate buffer is used instead of NADPH regeneration system solution for incubation for 60 minutes. All condition samples are three parallels.
  • the reaction temperature is 37 ⁇ 1°C
  • the final reaction volume is 200 ⁇ L
  • the reaction system includes 0.5mg/mL microsomes, 1.0 ⁇ M substrate, 1mM NADP, 6mM ISO and 1unit/mL IDH.
  • the CV of the internal standard peak area in each matrix should be within 20% for each analytical run.
  • the in vitro elimination rate constant ke of the compound was obtained by converting the ratio of the peak area of the compound to the internal standard into the residual rate in the following formula:
  • CL int(mic) 0.693/T 1/2 /microsomal protein content (microsomal concentration during incubation mg/mL)
  • CL int(liver) CL int(mic) ⁇ amount of microsomal protein in liver (mg/g) ⁇ liver weight to body weight ratio
  • the hepatic intrinsic clearance and hepatic clearance can be converted by the following formula.
  • HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8mg/mL G418 at 37°C and 5% CO2 .
  • the cells were digested with TrypLE TM Express and centrifuged to adjust the cell density to 2 ⁇ 10 6 cells/mL.
  • the cells were then gently mixed on a room temperature balanced shaker for 15-20min and then put on the machine for patch clamp detection.
  • the culture medium of the prepared cells was replaced with extracellular fluid.
  • the intracellular and extracellular fluids were drawn from the liquid pool and added to the intracellular fluid pool, cell and test substance pool of the QPlate chip respectively.
  • the whole-cell patch clamp recorded the voltage stimulation of the whole-cell hERG potassium current, and the experimental data were collected and stored by Qpatch.
  • the compound started at 30 ⁇ M, diluted 3 times, and 6 concentration points were set. Each drug concentration was set to be administered twice for at least 5 minutes. The current detected in the external solution without the compound for each cell was used as its own control group. At least two cells were used for each concentration and the detection was repeated twice independently. All electrophysiological experiments were performed at room temperature.
  • 100mM K-Buffer Mix 9.5mL of stock solution A into 40.5mL of stock solution B, adjust the total volume to 500mL with ultrapure water, and titrate the buffer to pH 7.4 with KOH or H 3 PO 4 .
  • Raw material A (1M potassium dihydrogen phosphate): 136.5 g potassium dihydrogen phosphate in 1 L water;
  • test substance powder is prepared into a stock solution of a certain concentration using DMSO or other organic solvents, and then further diluted with a suitable organic solvent.
  • the in vitro incubation system of liver microsomes for the study of CYP450 enzyme metabolic phenotype is a biochemical reaction carried out under conditions simulating physiological temperature and physiological environment, with the prepared liver microsomes supplemented with redox coenzymes and enzyme-specific selective inhibitors.
  • the compound of the present invention was administered to Balb/c mice by single intravenous injection and oral gavage, and the mouse plasma was collected at each time point.
  • the drug concentration of the test compound in BALB/c plasma tissue was detected by LC-MS/MS analysis method, and pharmacokinetic analysis was performed.
  • IV preparation vials are sterilized in an infrared sterilizer one day in advance.
  • Intravenous injection The drug is administered through the tail vein. After the needle is inserted, slowly withdraw the syringe. If blood returns, it means that the needle has entered the vein and the drug solution can be injected.
  • Gavage choose appropriate gavage needle and syringe, insert the gavage needle from the root of the tongue into the esophagus until it approaches the cardia of the stomach, then push the drug preparation and pull out the gavage needle.
  • gavage needles When using disposable plastic gavage needles, use one for each group.
  • Preparation concentration detection is determined by HPLC or LCMS/MS method.
  • Plasma concentration detection This experiment uses the developed LC-MS/MS method to detect the compounds in plasma.
  • the compounds of the present invention have high oral exposure and good bioavailability.
  • High-dose (100mpk or 200mpk) pharmacokinetic test of the compound in mice Oral administration preparation solvent: 10% hydroxypropyl ⁇ -cyclodextrin solution of 5% dimethyl sulfoxide and 15% polyethylene glycol-15 hydroxystearate
  • Preparation steps Weigh an appropriate amount of compound, calculate the total volume of the solution according to the dosage (such as the dosage is 200mg/kg, the fixed dosage volume of mice is 10ml/kg, and the concentration is 20mg/ml), add 5% DMSO and vortex, then add 15% HS15 and vortex, and finally add 10% cyclodextrin aqueous solution, vortex, and prepare a final concentration solution or suspension.
  • the rest of the operations refer to the pharmacokinetic operation of mice at a dosage of 10mpk.
  • the test results are shown in Table 7.
  • the compounds of the present invention still have very high oral exposure at high doses (100 mpk or 200 mpk). Compared with the 10 mpk PO results in Table 6, the exposure is linearly dependent on the dose.
  • Plasma concentrations were determined using LC-MS/MS methods. WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma drug concentration data of the compounds using a non-compartmental model. The linear logarithmic trapezoidal method was used to calculate the relevant pharmacokinetic parameters.
  • the sample doses of the compounds in Table 8 were IV: 2 mg/kg, PO: 10 mg/kg, and the test results are shown in Table 8:
  • the compounds of the present invention have high oral exposure and good bioavailability.
  • Healthy female nude mice (BALB/c nu/nu) aged 6-8 weeks were used and maintained in an SPF environment in accordance with animal ethics guidelines. 10 7 H226 cells in good growth condition were obtained by trypsinization, washed in phosphate-buffered saline (PBS), and then resuspended in PBS with 50% Matrigel (BD Biosciences).
  • PBS phosphate-buffered saline
  • mice were randomly assigned to different treatment groups, and then any of the compounds described in the present invention were formulated accordingly and then administered at a suitable dose. Finally, the tumor growth of nude mice was analyzed after 4 to 6 weeks according to the growth of the tumor. The test results are shown in Table 9:
  • mice were randomly assigned to different treatment groups, and then any of the compounds described in the present invention were formulated accordingly and then administered at a suitable dose. Finally, the tumor growth of nude mice was analyzed after 4 to 6 weeks according to the growth of the tumor. The test results are shown in Table 10:
  • FaSSIF solid was added into a 50 mL volumetric flask, add the above buffer to dissolve, dilute to the scale, shake well, and let stand at room temperature for more than 2 h.
  • Test sample Take about 1 mg of the test sample, add 1 ml of FaSSIF solution, stir at room temperature overnight, centrifuge, and take the supernatant for analysis.
  • Reference solution Accurately weigh about 1.5 mg of the test sample into a 50 mL volumetric flask, add DMF to dissolve and dilute to the scale, mix well, and obtain.
  • Mobile phase A Accurately measure 1000 mL of purified water, add 1 mL of formic acid, mix well, and degas by ultrasonication.

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Abstract

本发明提供了一种含磷化合物、药物组合物及其应用。具体提供了如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药。本发明含磷化合物能有效治疗由TEAD介导的疾病和病症，例如癌症。

Description

含磷化合物、药物组合物及其应用
本申请要求申请日为2022/10/27的中国专利申请202211328612.4的优先权，本申请引用上述中国专利申请的全文。
本申请要求申请日为2023/03/30的中国专利申请202310331481.3的优先权，本申请引用上述中国专利申请的全文。
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技术领域
本发明涉及一种含磷化合物、药物组合物及其应用。
背景技术
Hippo信号通路是一条从果蝇到哺乳动物高度保守的细胞信号通路，该通路主要功能包括调控机体正常发育、决定组织器官大小比例、维持细胞增殖死亡平衡与干细胞的干性维持。该信号通路的核心元件主要由①上游信号因子；②核心激酶级联反应链；③下游效应分子组成。一旦被上游刺激因子激活(例如细胞接触抑制)，MST1/2激酶和SAV1与上游调节因子相互作用并产生磷酸化而被激活，从而磷酸化MOB1A/B与LATS1/2，致使LSTS1/2激酶复合体完全活化。该复合物进一步磷酸化转录共激活因子YAP/TAZ，磷酸化的YAP/TAZ被14-3-3蛋白阻滞在细胞质中，并被E3连接酶β-TrCP诱导多聚泛素化，从而被蛋白酶体识别并降解。而当Hippo通路被抑制时(例如血清因子刺激)，未被磷酸化的YAP/TAZ进入细胞核并主要和转录因子TEAD蛋白家族形成转录复合体，从而激活下游靶基因的转录(例如CTGF、FGF1、AMOTL2和CYR61)，促进细胞存活与增殖。与此同时，该通路还可调控干细胞的自我更新和分化，从而参与组织再生和伤口愈合。因此，在一些条件下，YAP/TAZ-TEAD转录复合体发挥致癌基因的作用，而Hippo通路则发挥肿瘤抑制的作用。
目前，在多种肿瘤中包括但不限于肝癌、肺癌、卵巢癌、脑癌、恶性间皮瘤、乳腺癌、头颈癌、结直肠癌、前列腺癌和白血病中均可发现Hippo信号通路上游抑制因子例如NF2、MST1/2与LATS1/2的失活或者丢失。同时，在多种肿瘤中YAP/TAZ与TEAD家族蛋白被发现存在异常扩增，并且大量报道鉴定TEAD家族蛋白为YAP/TAZ促癌能力的关键介导因子。临床研宄则提示YAP/TAZ的扩增可作为多种肿瘤的预后与诊断的生物标志物。
一般认为YAP和TAZ的过度活化可调控细胞增殖、迁移和凋亡，参与肿瘤干细胞相关的自我更新和EMT(上皮-间质转化)特性，并且促进维持肿瘤微环境的免疫抑制效果，从而介导肿瘤细胞对于常规化疗，靶向治疗与免疫疗法的耐药。因此，靶向YAP/TAZ-TEAD蛋白复合体将会是治疗具备这一通路功能改变的多种癌症的极具潜力的方法。
YAP/TAZ与TEAD形成的转录复合体主要由三个蛋白-蛋白相互作用界面维持，其中界面二与界面三均对此蛋白复合体的形成至关重要，然而这两个界面均缺乏小分子结合蛋白质所需要的具有几何学特性且含有静电富集的口袋。近年来研究者发现在TEAD蛋白质的YAP结合结构域的中含有一个结合棕榈酸/豆蔻酸的口袋，且棕榈酸分子在该位点对TEAD蛋白质进行可逆的棕榈酰修饰。而TEAD蛋白的棕榈酰化修饰对于其蛋白稳定性，以及YAP/TAZ-TEAD转录复合体的形成与转录活性至关重要，并且抑制TEAD家族蛋白对成体组织器官的稳态无显著影响。因此通过直接通过抑制TEAD家族蛋白棕榈酰化修饰可有效阻碍YAP/TAZ的致癌活性，特别是可用于治疗Hippo上游基因失活的多种肿瘤。
发明内容
本发明提供了与Hippo途径网络的一个或多个成员相关的抑制剂，尤其是抑制YAP/TAZ-TEAD蛋白复合体转录活性的新的化合物。本发明的化合物还具有较好的物理化学性质(例如溶解度、物理和/或化学稳定性)、改善的药物代谢动力学性质(例如改善的生物利用度、改善的代谢稳定性、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性(例如降低的心脏毒性)和/或较少的副作用)等更优异的性质。
本发明提供了如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，
其中，
R1和R2独立地为C1-C6烷基、C3-C6环烷基或C6-C10芳基；
或者，R1、R2和与其相连的原子一起形成3-12元杂环烷基或被一个或多个R1-1取代的3-12元杂环烷基，其中，所述3-12元杂环烷基中，除了所连接的P原子外，还额外含有0个、1个、2个或3个选自N、O和S中的1种、2种或3种的杂原子；
R1-1独立地为C1-C6烷基；
为
其中，
各RX1独立地为H、C1-C6烷基、卤素或CN；
RX4为H、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”、被一个或多个RX4-1取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”、C6-C10芳基或被一个或多个RX4- 5取代的C6-C10芳基；
RX4-1和RX4-5独立地为H、氘、卤素、C1-C6烷基、C1-C6烷氧基、CN、被一个或多个RX4-2取代的C1-C6烷基、被一个或多个RX4-3取代的C1-C6烷氧基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-12元杂环烷基”、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元杂芳基”、C(＝O)NRcRd、C3-C6环烷基、被一个或多个RX4- 4取代的C3-C6环烷基；
RX4-2和RX4-3独立地为氘、卤素、OH、CN、C1-C6烷氧基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-12元杂环烷基”、C(＝O)NRcRd或NRbC(＝O)Ra；
RX4-4独立地为CN、C(＝O)NRcRd或C(＝O)ORa；
L为单键、-CRL1RL2-、-O-、-S-、-NRL3-、-NRL3CRL1RL2-、-CRL4＝CRL5-、
RL1、RL2和RL3独立地为H、C1-C6烷基或C3-C6环烷基；
RL4和RL5独立地为H或C1-C6烷基；
L1和L2独立地为-CH2-、-O-、-S-或-NH-；
环A为C3-C12饱和或不饱和的碳环、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环”；
m3为0、1、2或3；
R5独立地为SF5、卤素、C1-C6烷基、被一个或多个R5-1取代的C1-C6烷基、SR5-2、OR5-3、CN、S(＝O)2R5-4、C(＝O)R5-5、S(＝O)2NRdR5-6、NRdR5-6、C3-C6环烷基或被一个或多个R5-7取代的C3-C6环烷基；
R5-1独立地为羟基、CN或卤素；
R5-2、R5-3、R5-4、R5-6独立地为H、C1-C6卤代烷基、C1-C6烷基、C3-C6环烷基或被一个或多个R5- 8取代的C3-C6环烷基；
R5-5独立地为C1-C6卤代烷基、H、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C6环烷基或被一个或多个R5-8取代的C3-C6环烷基、NRdR5-6；
R5-7和R5-8独立地为卤素或C1-C6卤代烷基；
Ra、Rb、Rc和Rd独立地为H或C1-C6烷基。
在本发明某些优选实施方案中，所述的如式I所示的化合物或、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药中的某 些基团如下定义，未提及的基团同本发明任一方案所述(简称“在一些实施方式中”)，R5独立地为C3-C6环烷基。
在一些实施方式中，R1和R2独立地为C1-C6烷基、C3-C6环烷基或C6-C10芳基；
或者，R1、R2和与其相连的原子一起形成3-12元杂环烷基或被一个或多个R1-1取代的3-12元杂环烷基，其中，所述3-12元杂环烷基中，除了所连接的P原子外，还额外含有0个、1个、2个或3个选自N、O和S中的1种、2种或3种的杂原子；
R1-1独立地为C1-C6烷基；
为
其中，
各RX1独立地为H、C1-C6烷基、卤素或CN；
RX4为H、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”、被一个或多个RX4-1取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”、C6-C10芳基或被一个或多个RX4- 5取代的C6-C10芳基；
RX4-1和RX4-5独立地为H、氘、卤素、C1-C6烷基、C1-C6烷氧基、CN、被一个或多个RX4-2取代的C1-C6烷基、被一个或多个RX4-3取代的C1-C6烷氧基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-12元杂环烷基”、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元杂芳基”、C(＝O)NRcRd、C3-C6环烷基、被一个或多个RX4- 4取代的C3-C6环烷基；
RX4-2和RX4-3独立地为氘、卤素、OH、CN、C1-C6烷氧基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-12元杂环烷基”、C(＝O)NRcRd或NRbC(＝O)Ra；
RX4-4独立地为CN、C(＝O)NRcRd或C(＝O)ORa；
L为单键、-CRL1RL2-、-O-、-S-、-NRL3-、-NRL3CRL1RL2-、-CRL4＝CRL5-、
RL1、RL2和RL3独立地为H、C1-C6烷基或C3-C6环烷基；
RL4和RL5独立地为H或C1-C6烷基；
L1和L2独立地为-CH2-、-O-、-S-或-NH-；
环A为C3-C12饱和或不饱和的碳环、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环”；
m3为0、1、2或3；
R5独立地为SF5、卤素、C1-C6烷基、被一个或多个R5-1取代的C1-C6烷基、SR5-2、OR5-3、CN、S(＝O)2R5-4、C(＝O)R5-5、S(＝O)2NRdR5-6、NRdR5-6或被一个或多个R5-7取代的C3-C6环烷基；
R5-1独立地为羟基、CN或卤素；
R5-2、R5-3、R5-4、R5-6独立地为H、C1-C6卤代烷基、C1-C6烷基、C3-C6环烷基或被一个或多个R5- 8取代的C3-C6环烷基；
R5-5独立地为C1-C6卤代烷基、H、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C6环烷基或被一个或多个R5-8取代的C3-C6环烷基、NRdR5-6；
R5-7和R5-8独立地为卤素或C1-C6卤代烷基；
Ra、Rb、Rc和Rd独立地为H或C1-C6烷基。
在一些实施方式中，所述“卤素”分别独立地为氟、氯、溴或碘，优选氟或氯，例如氟。
在一些实施方式中，所述“C1-C6烷基”分别独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选甲基或乙基，例如甲基。
在一些实施方式中，所述“C1-C6烷氧基”分别独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基，优选甲氧基或乙氧基。
在一些实施方式中，所述“C1-C6卤代烷基”分别独立地为-CHF2、-CH2F或-CF3。
在一些实施方式中，所述“C1-C6卤代烷氧基”分别独立地为-OCHF2、-OCH2F或-OCF3。
在一些实施方式中，所述“C3-C6环烷基”分别独立地为环丙基、环丁基、环戊基或环己基，优选环丙基或环丁基，例如环丙基。
在一些实施方式中，所述“C6-C10芳基”分别独立地为苯基或萘基，优选苯基。
在一些实施方式中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-12元杂环烷基”分别独立地为“杂原子选自N和O中的1种或2种，杂原子数为1个或2个的5-6元杂环烷基”。
在一些实施方式中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元杂芳基”为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-6元杂芳基”。
在一些实施方式中，RX4中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-10元不饱和的杂环基”，例如为吡咯基(例如)、吡唑基(例如)、咪唑基(例如)、三唑基(例如)、噻唑 基(例如)、恶唑基(例如)、异恶唑基(例如)、吡啶基(例如)、嘧啶基(例如)、吡嗪基(例如)、哒嗪基(例如)、 又如为咪唑基(例如)、吡唑基(例如)、吡啶基(例如)或嘧啶基(例如)。
在一些实施方式中，环A中，所述“C3-C12饱和或不饱和的碳环”为C4-C10饱和或不饱和的碳环，例如环丁烷环(例如)、环己烷环(例如)、螺[2.5]辛烷(例如)、螺[3.3]庚烷环(例如)、苯环(例如)、萘环(例如)、二氢化茚环或四氢化萘环，例如C4-C10饱和的碳环或C6-C10芳环，优选为C6-C10芳环，又如环丁烷环(例如)、环己烷环(例如)、螺[3.3]庚烷环(例如)、苯环(例如)、萘环(例如)、二氢化茚环或四氢化萘环，优选为C6-C10芳环。
在一些实施方式中，环A中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环”(例如为5-10元饱和或不饱和杂环)为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-6元单环杂芳环或9-10元双环 杂环”，例如，苯并氧杂戊烷环(例如)，吡啶环(例如)或噻吩环(例如)，又如为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-6元杂芳环”，例如吡啶环(例如)或噻吩环(例如)，例如苯并氧杂戊烷环(例如)。
在一些实施方式中，R1和R2独立地为C1-C6烷基，或者，R1、R2和与其相连的原子一起形成3-12元杂环烷基，其中，所述3-12元杂环烷基中，除了所连接的P原子外，还额外含有0个、1个、2个或3个选自N、O和S中的1种、2种或3种的杂原子，例如C1-C6烷基。
在一些实施方式中，L为单键、-CRL1RL2-、-O-、-S-或-NRL3-；较佳地，L为单键、-O-、-S-或-NRL3，例如L为-O-或-NRL3-。
在一些实施方式中，RL3为H。
在一些实施方式中，环A为C4-C10饱和碳环、C6-C10芳环或“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-9元饱和或不饱和杂环”，例如，环A为C6-C10芳环或“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-6元杂芳环”，例如，环A为C6-C10芳环或“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-9元饱和或不饱和杂环”。
在一些实施方式中，m3为0、1或2，例如，m3为0或1，又如1或2，优选地，m3为1。
在一些实施方式中，R5独立地为SF5、C3-C6环烷基、卤素、C1-C6烷基、被一个或多个R5-1取代的C1-C6烷基或OR5-3，例如，R5独立地为卤素、C1-C6烷基、被一个或多个R5-1取代的C1-C6烷基，例如被一个或多个R5-1取代的C1-C6烷基，又如R5独立地为SF5、卤素、被一个或多个R5-1取代的C1-C6烷基，优选地，R5独立地为SF5、卤素或被一个或多个R5-1取代的C1-C6烷基。
在一些实施方式中，R5-1独立地为卤素。
在一些实施方式中，R5-3独立地为C1-C6卤代烷基。
在一些实施方式中，各RX1独立地为H。
在一些实施方式中，RX4为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”、被一个或多个RX4-1取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”。
在一些实施方式中，RX4-1和RX4-5独立地为H、卤素、C1-C6烷基、被一个或多个RX4-2取代的C1-C6烷基或C3-C6环烷基。
在一些实施方式中，RX4-2和RX4-3独立地为卤素。
在一些实施方式中，RX4-1和RX4-5独立地为H、C1-C6烷基、被一个或多个RX4-2取代的C1-C6烷基。
在一些实施方式中，为
在一些实施方式中，RX4为 例如，RX4为 又如，RX4为
在一些实施方式中，为
在一些实施方式中，为
例如，为
在一些实施方式中，L为单键、-CRL1RL2-、-O-、-S-或-NH-，例如，L为单键、-O-或-NH-，又如L为-O-或-NH-。
在一些实施方式中，为 例如， 例如，为
在一些实施方式中，所述如式I所示的化合物为如下式I-7所示的化合物：
X13为N；
其中，R1、R2、RX1、RX4、R5、L、环A和m3的定义如本发明任一项所述。
在一些实施方式中，所述如式I所示的化合物为如下任一化合物：





本发明提供了一种药物组合物，所述药物组合物包括：
(1)上述如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，和
(2)药学上可接受的辅料。
本发明还提供了上述如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，或上述药物组合物在制备药物中的应用，所述的药物用于治疗由TEAD介导的疾病和病症，例如癌症(例如实体瘤、白血病等)、器官再生、伤口愈合、纤维化等。
术语说明
本发明中，术语“药学上可接受的盐”是指化合物与药学上可接受的酸或碱反应得到的盐。当化合物中含有相对酸性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的碱与化合物接触的方式获得碱加成盐。当化合物中含有相对碱性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的酸与化合物接触的方式获得酸加成盐。具体可参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl,Camille G.Wermuth,2011,2nd Revised Edition)。
术语“酯”包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。除此以外，本发明的化合物本身也可以是酯。
术语“立体异构体”是指顺反异构体或旋光异构体，顺反异构体是因双键或成环碳原子的单键不能自由旋转而引起的异构体，旋光异构体是因分子中没有反轴对称性而引起的具有不同旋光性能的立体异构体。
术语“互变异构体”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
术语“多晶型物”是指化合物以多种晶型的形式存在。
术语“溶剂合物”是指化合物与溶剂结合形成的物质。溶剂合物分为化学计量类溶剂合物和非化学计量类溶剂合物。
术语“代谢物”在施用本发明的化合物后体内形成的物质。
术语“同位素衍生物”是指其中的一个或多个原子的同位素丰度与其自然丰度不同的化合物。例如，化合物中的一个或多个原子被在自然界中占比较低的质量数的原子替代——化合物中的一个氢原子被氘替代。
术语“前药”是指包含生物反应官能团的化合物的衍生物，使得在生物条件下(体外或体内)，生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常，前药无活性，或者至少比化合物本身活性低，使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如，前药可包含可生物水解的基团。可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。
本发明中，所用的取代基前面可以加单破折号“-”，表明被命名取代基与母体部分之间通过单键相连。本发明所列举的连接基团没有指明其连接方向时，其连接方向是按与从左往右的读取顺序相同的方向进行连接的，举例说明如下，中连接基团L为-C-D-，此时-C-D-按与从左往右的读取顺序相同的方向连接环B和环A构成而不构成具体到本发明中，L为“-NRL3CRL1RL2-”时表示N与母体中的环B通过单键相连，而不是C端与母体中的环B相连。
本发明中，结构片段中的是指该结构片段通过该键与分子其余部分相连。例如，是指吡啶基。
本发明中，术语“一个或多个”是指1个、2个、3个、4个或5个，例如1个、2个或3个。
本发明中，术语“卤素”是指氟、氯、溴或碘。
术语“氧代”是指＝O，氧原子替代同一碳原子上的两个氢，也即，以羰基替代亚甲基。
本发明中，术语“烷基”是指具有指定碳原子数(例如，C1-C6)的、直链或支链的、饱和的一价烃基。烷基包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
本发明中，术语“烷氧基”是指基团RY-O-，RY的定义同术语“烷基”。烷氧基包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基等。
本发明中，术语“环烷基”是指具有指定碳原子数(例如，C3-C6)的、环状的、饱和的一价烃基。环烷基包括但不限于：等。
本发明中，术语“杂环烷基”是指具有指定环原子数(例如，3-12元、5-6元)的、指定杂原子数 (例如，1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、饱和的一价基团。杂环烷基通过碳原子或杂原子与分子其余部分相连。杂环烷基包括但不限于： 等。
本发明中，术语“杂芳基”是指具有指定环原子数(例如，5-12元、5-6元)的、指定杂原子数(例如，1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、不饱和的基团，其为单环或多环，为多环时，单环之间共用两个原子和一根键，且每一个环都具有芳香性。杂芳基通过碳原子或杂原子与分子其余部分相连；杂芳基通过具有杂原子的环或不具有杂原子的环与分子其余部分相连。杂芳基包括但不限于等。
本发明中，术语“芳基”是指具有指定碳原子数(例如，C6-C10)的、环状的、不饱和的烃基，其为单环或多环(例如，2个或3个)，为多环时，单环之间共用两个原子和一根键，且每一个环都具有芳香性。芳基包括但不限于：苯基、萘基等。
本发明中，术语“药学上可接受辅料”是指除活性药物成分以外，包含在药物制剂中的所有物质，一般分为赋形剂和附加剂两大类。具体可参见《中华人民共和国药典(2020年版)》、Handbook of Pharmaceutical Excipients(Paul J Sheskey,Bruno C Hancock,Gary P Moss,David J Goldfarb,2020,9th Edition)。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明如式I所示的化合物可以通过以下路线得到：
路线1：
步骤一：化合物I-1和化合物I-2反应得到化合物I-3。
其中，W选自卤素或烷基/芳基磺酸酯基团，其中，卤素优选氯、溴和碘，烷基/芳基磺酸酯基团包括但不限于甲磺酸酯、三氟甲磺酸酯、苯磺酸酯、对甲苯磺酸酯或萘磺酸酯，优选甲磺酸酯和对甲苯磺酸酯；U选自H、OH、SH、NHRL3、CRL1RL2锡试剂、CRL1RL2锌试剂、CRL1RL2镁试剂等；V选 自硼酸、硼酸酯、卤素或烷基/芳基磺酸酯基团，其中，卤素优选氯、溴和碘，烷基/芳基磺酸酯基团包括但不限于甲磺酸酯、三氟甲磺酸酯、苯磺酸酯、对甲苯磺酸酯或萘磺酸酯，优选甲磺酸酯和对甲苯磺酸酯；
该反应在合适的催化剂存在下发生，如：四(三苯基膦)钯、双(三苯基膦)二氯化钯、1,1'-双二苯基膦二茂铁二氯化钯、三二亚苄基丙酮二钯、二氯化钯、醋酸钯、氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯等，优选1,1'-双二苯基膦二茂铁二氯化钯；
该反应在合适的碱存在下发生，如：碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠等，优选碳酸钠；
该反应在合适的溶剂中发生，如1,4-二氧六环、1,4-二氧六环/水、1,2-二氯乙烷、1,2-二氯乙烷/水、N,N-二甲基甲酰胺、N,N-二甲基甲酰胺/水、二甲基亚砜、二甲基亚砜/水、N-甲基吡咯烷酮、N-甲基吡咯烷酮/水等，优选1,4-二氧六环/水和N,N-二甲基甲酰胺；
该反应在合适的温度下发生，如25～140℃，优选80～110℃。
步骤二：化合物I-3和氧化膦I-4反应得到化合物I。
其中，该反应在合适的催化剂存在下发生，如：四(三苯基膦)钯、双(三苯基膦)二氯化钯、1,1'-双二苯基膦二茂铁二氯化钯、三二亚苄基丙酮二钯、二氯化钯、醋酸钯、氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯等，优选氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯和三二亚苄基丙酮二钯；
该反应在合适的碱存在下发生，如：碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠等，优选碳酸铯；
该反应在合适的溶剂中发生，如1,4-二氧六环、1,4-二氧六环/水、1,2-二氯乙烷、1,2-二氯乙烷/水、N,N-二甲基甲酰胺、N,N-二甲基甲酰胺/水、二甲基亚砜、二甲基亚砜/水、N-甲基吡咯烷酮、N-甲基吡咯烷酮/水等，优选1,4-二氧六环和N,N-二甲基甲酰胺；
该反应在合适的温度下发生，如25～140℃，优选40～110℃。
路线2：
步骤一：化合物I-7-1和化合物RX4-Z反应得到化合物I-7-2。
其中，Y选自卤素或烷基/芳基磺酸酯基团，其中，卤素优选氯、溴和碘，烷基/芳基磺酸酯基团包括但不限于甲磺酸酯、三氟甲磺酸酯、苯磺酸酯、对甲苯磺酸酯或萘磺酸酯，优选甲磺酸酯和对甲苯磺酸酯；Z选自硼酸、硼酸酯、锡试剂、锌试剂或镁试剂，优选硼酸和硼酸酯；
该反应在合适的催化剂存在下发生，如：四(三苯基膦)钯、双(三苯基膦)二氯化钯、1,1'-双二苯基膦二茂铁二氯化钯、三二亚苄基丙酮二钯、二氯化钯、醋酸钯、氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯等，优选四(三苯基膦)钯和1,1'-双二苯基膦二茂铁二氯化钯；
该反应在合适的碱存在下发生，如：碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠等，优选碳酸钠；
该反应在合适的溶剂中发生，如1,4-二氧六环、1,4-二氧六环/水、1,2-二氯乙烷、1,2-二氯乙烷/水、 N,N-二甲基甲酰胺、N,N-二甲基甲酰胺/水、二甲基亚砜、二甲基亚砜/水、N-甲基吡咯烷酮、N-甲基吡咯烷酮/水等，优选1,4-二氧六环/水和N,N-二甲基甲酰胺；
该反应在合适的温度下发生，如25～140℃，优选40～110℃；
步骤二：化合物I-7-2和化合物I-7-3反应得到化合物I-7-4。
其中，该反应在合适的催化剂存在下发生，如：四(三苯基膦)钯、双(三苯基膦)二氯化钯、1,1'-双二苯基膦二茂铁二氯化钯、三二亚苄基丙酮二钯、二氯化钯、醋酸钯、氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯等，优选1,1'-双二苯基膦二茂铁二氯化钯；
该反应在合适的碱存在下发生，如：碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠等，优选碳酸钠；
该反应在合适的溶剂中发生，如1,4-二氧六环、1,4-二氧六环/水、1,2-二氯乙烷、1,2-二氯乙烷/水、N,N-二甲基甲酰胺、N,N-二甲基甲酰胺/水、二甲基亚砜、二甲基亚砜/水、N-甲基吡咯烷酮、N-甲基吡咯烷酮/水等，优选1,4-二氧六环/水和N,N-二甲基甲酰胺；
该反应在合适的温度下发生，如25～140℃，优选80～110℃。
步骤三：化合物I-7-4和氧化膦I-7-5反应得到化合物I-7。
其中，该反应在合适的催化剂存在下发生，如：四(三苯基膦)钯、双(三苯基膦)二氯化钯、1,1'-双二苯基膦二茂铁二氯化钯、三二亚苄基丙酮二钯、二氯化钯、醋酸钯、氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯等，优选氯(2-二环己基膦基-2',6'-二-异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯和三二亚苄基丙酮二钯；
该反应在合适的碱存在下发生，如：碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠等，优选碳酸铯；
该反应在合适的溶剂中发生，如1,4-二氧六环、1,4-二氧六环/水、1,2-二氯乙烷、1,2-二氯乙烷/水、N,N-二甲基甲酰胺、N,N-二甲基甲酰胺/水、二甲基亚砜、二甲基亚砜/水、N-甲基吡咯烷酮、N-甲基吡咯烷酮/水等，优选1,4-二氧六环和N,N-二甲基甲酰胺；
该反应在合适的温度下发生，如25～140℃，优选40～110℃。
实施例1：(化合物8)
第一步：(化合物8b)
化合物8a(330mg,1.1mmol)，1-甲基-4-三正丁基锡基咪唑(408mg,1.1mmol)，四(三苯基膦)钯(127mg,0.1mmol)加入到1.4-二氧六环(10mL)中，置换氮气三次，升温至60℃搅拌14小时，LCMS显示反应完全，反应液降温至室温，垫硅藻土过滤，柱层析得亮蓝色固体8b(263.0mg,产率：94.1％)。
LCMS m/z[M+H]+:253.1.
1HNMR(400MHz,DMSO-d6)δ7.88(q,J＝2.4Hz,2H),7.79-7.73(m,2H),7.19(s,2H),3.71(s,3H).
第二步：(化合物8c)
8b(260mg,1.0mmol)溶于1.2-二氯乙烷(5mL)中，加入对三氟甲基苯硼酸(300mg,1.6mmol)，醋酸铜(920mg,0.1mmol)，加毕，反应液空气氛下搅拌4天，LCMS显示大部分产物生成，反应液垫硅藻土过滤，二氯甲烷淋洗，浓缩，柱层析(得到棕色固体8c(80mg,产率：19.6％)。
LCMS m/z[M+H]+:397.2.
1HNMR(400MHz,DMSO-d6)δ12.06(s,1H),8.24-8.19(m,2H),8.03(d,J＝1.2Hz,1H),7.96(d,J＝1.2Hz,1H),7.92(d,J＝8.4Hz,2H),7.64(d,J＝8.4Hz,2H),3.77(s,3H).
第三步：(化合物8)
化合物8c(70mg,0.2mmol)，二甲基氧化磷(29mg,0.4mmol)，碳酸铯(65mg,0.2mmol)溶于1.4-二氧六环(7mL)中，置换氮气三次，氮气保护下加入醋酸钯(9mg,0.04mmol)，4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(46mg,0.08mmol)，加毕，升温至110℃，搅拌12小时，LCMS显示原料反应完全，反应液倒入水中，乙酸乙酯萃取，有机相盐水洗一次，无水硫酸钠干燥，浓缩，柱层析得到棕色粘稠固体8(20mg,产率：28.8％)。
LCMS m/z[M+H]+:395.2.
1HNMR(400MHz,DMSO-d6)δ12.27(s,1H),8.43(dd,J＝6.0,2.0Hz,1H),8.25(dd,J＝11.2,2.0Hz,1H),8.06-7.94(m,4H),7.67(d,J＝8.8Hz,2H),3.79(s,3H),1.72(s,3H),1.69(s,3H).
实施例2：(化合物9)
第一步：(化合物9b)
化合物9a(4g,28mmol)加入到三溴氧磷(20mL)中，置换氮气三次，升温至70℃，搅拌14小时，LCMS显示反应完全，反应液倒入冰水中，加入碳酸氢钠水溶液和碳酸钾水溶液调节pH＝9～10，二氯甲烷萃取，有机相盐水洗，无水硫酸钠干燥，浓缩得棕色固体9b(4.8g,产率：91％)。
LCMS m/z[M+H]+:186.9.
1HNMR(400MHz,CDCl3)δ6.85(d,J＝1.2Hz,1H),4.04-3.92(m,2H),2.86(t,J＝7.6Hz,2H),2.56 (q,J＝7.6Hz,2H).
第二步：(化合物9d)
9c(2.0g,10mmol)加入到四氢呋喃(15mL)中，氮气保护下加入DMAP(3.84g,31mmol),二碳酸二叔丁酯(5.71g,26mmol)。加毕，升温至45℃搅拌2小时，LCMS显示无原料剩余，反应液倒入柠檬酸水溶液中，乙酸乙酯萃取，有机相盐水洗，无水硫酸钠干燥，浓缩，柱层析纯化，然后在经过石油醚打浆，过滤，干燥得白色固体9d(2.3g,产率：75％)。
LCMS m/z[M+H]+:291.0.
第三步：(化合物9e)
化合物9d(2.6g,7mmol)加入到DMSO(20mL)中，置换氮气三次，加入对三氟甲基苯酚(1.3g,8mmol),碳酸铯(4.34g,13mmol)，加毕，升温至110℃搅拌1小时，LCMS显示反应完全，反应液降温至室温，乙酸乙酯稀释，加入少量水，分液，乙酸乙酯萃取，有机相盐水洗一次，无水硫酸钠干燥，浓缩，粗品柱层析纯化得黄色固体9e(1.8g,产率：81.31％)。
LCMS m/z[M+H]+:333.1.
1HNMR(400MHz,DMSO-d6)δ7.70(d,J＝8.8Hz,2H),7.60(d,J＝2.4Hz,1H),7.40(d,J＝2.4Hz,1H),7.10(d,J＝8.8Hz,2H),5.52(s,2H).
第四步：(化合物9f)
化合物9e(1.8g,5mmol)加入到四氢呋喃(20mL)中，氮气保护下加入DMAP(2.0g,16mmol),二碳酸二叔丁酯(3.6g,16mmol)加毕，室温搅拌2小时，LCMS显示反应完全，反应液倒入柠檬酸水溶液中，乙酸乙酯萃取，有机相盐水洗，无水硫酸钠干燥，浓缩，粗品经过石油醚打浆，过滤，干燥得白色固体9f(1.2g,产率：41％)。
1HNMR(400MHz,DMSO-d6)δ8.34(d,J＝2.4Hz,1H),8.08(d,J＝2.4Hz,1H),7.82(d,J＝8.4Hz,2H),7.38(d,J＝8.4Hz,2H),1.40(s,18H).
第五步：(化合物9g)
9f(1.4g,3mmol)，联硼酸频那醇酯(1.38g,5mmol)，醋酸钾(645mg,7mmol)加入到1，4-二氧六环(28mL)中，置换氮气三次，氮气保护下加入Pd(dppf)Cl2(190mg,0.3mmol)，加毕升温至100℃，搅拌2小时，LCMS显示反应完全，反应液降温至室温，乙酸乙酯稀释，垫硅藻土过滤，乙酸乙酯淋洗两次，滤液浓缩，粗品柱层析得黄色固体9g(1.2g,产率：92％)。
LCMS m/z[M+H]+:499.3.
1HNMR(400MHz,DMSO-d6)δ8.17(d,J＝2.8Hz,1H),7.89(d,J＝2.8Hz,1H),7.77(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,2H),1.41(s,18H),1.27(s,12H).
第六步：(化合物9h)
9g(500mg,1mmol)，9b(225mg,1mmol)，碳酸钾(280mg,2mmol)加入1，4-二氧六环(10mL)和水(1mL)中，置换氮气三次，氮气保护下加入Pd(dppf)Cl2(74mg,0.1mmol,加毕，升温至80℃搅拌3小时，LCMS显示反应完全，反应液降温至室温，垫硅藻土过滤，滤液浓缩得粗品，粗品柱层析纯化得类白色固体9h(400mg,产率：71％)。
LCMS m/z[M+H]+:561.3.
1HNMR(400MHz,DMSO-d6)δ8.22(d,J＝2.8Hz,1H),7.86(d,J＝2.8Hz,1H),7.81(d,J＝8.4Hz,2H),7.67(s,1H),7.37(d,J＝8.4Hz,2H),4.00(t,J＝7.2Hz,2H),2.79(t,J＝7.6Hz,2H),2.53(d,J＝7.2Hz,2H),1.41(s,18H).
第七步：(化合物9i)
9h(350mg,0.6mmol)加入到氯化氢二氧六环溶液(4M，15mL)中，加毕，室温搅拌2小时，LCMS显示反应完全，反应液浓缩，倒入碳酸氢钠水溶液中，乙酸乙酯萃取，有机相盐水洗，无水硫酸钠干燥，过滤，浓缩得类白色固体9i(225mg,产率：100％)。
LCMS m/z[M+H]+:361.2.
1H NMR(400MHz,DMSO-d6)δ7.80(d,J＝2.8Hz,1H),7.68(d,J＝8.4Hz,2H),7.42(d,J＝2.8Hz,1H),7.36(s,1H),7.11(d,J＝8.4Hz,2H),5.23(s,2H),3.92(t,J＝7.2Hz,2H),2.74(t,J＝7.6Hz,2H),2.47(d,J＝7.2Hz,2H).
第八步：(化合物9j)
9i(350mg,0.6mmol)和溴化亚铜(320mg,2mmol)溶于氢溴酸(560mg,7mmol)水(3mL)溶液中，0～5℃下滴加亚硝酸钠(80mg,1mmol)水(1mL)溶液，滴毕，缓慢回温至室温，搅拌5小时。LCMS显示产物生成，反应液倒入亚硫酸氢钠水溶液中，氢氧化钠水溶液调节pH＝10，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得到白色固体9j(100mg,产率：42％)。
LCMS m/z[M+H]+:424.1.
1HNMR(400MHz,DMSO-d6)δ8.54(d,J＝2.4Hz,1H),8.08(d,J＝2.4Hz,1H),7.80(d,J＝8.4Hz,2H),7.69(s,1H),7.40(d,J＝8.4Hz,2H),4.00(t,J＝7.2Hz,2H),2.80(t,J＝7.6Hz,2H),2.54(t,J＝7.2Hz,2H).
第九步：(化合物9)
9j(80mg,0.2mmol)，二甲基氧化磷(30mg,2mmol)，磷酸钾(80mg,0.4mmol)溶于1，4-二氧六环(2mL)中，置换氮气三次，氮气保护下加入醋酸钯(10mg,0.05mmol)，4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(51mg,0.09mmol)，加毕，升温至110℃，搅拌1小时，LCMS显示原料反应完全，反应液倒入水中，乙酸乙酯萃取，有机相盐水洗一次，无水硫酸钠干燥，浓缩，粗品经过反相制备得到类白色固体9(25mg,产率：31％)。
LCMS m/z[M+H]+:422.2.
1HNMR(400MHz,DMSO-d6)δ8.77(dd,J＝10.8,2.4Hz,1H),8.26(dd,J＝6.0,2.4Hz,1H),7.82(d,J＝8.4Hz,2H),7.71(s,1H),7.43(d,J＝8.4Hz,2H),4.01(t,J＝7.2Hz,2H),2.81(t,J＝7.6Hz,2H),2.54(q,J＝7.2Hz,2H),1.73(s,3H),1.70(s,3H).
实施例3：(化合物11)
第一步：(化合物11a)
9g(550mg,1mmol)，1-甲基-4-溴咪唑(200mg,1mmol)，碳酸钾(265mg,2mmol),加入1，4-二氧六环(20mL)和水(2mL)中，置换氮气三次，氮气保护下加入Pd(dppf)Cl2(76mg,0.1mmol)，加毕，升温至80℃搅拌3小时，LCMS显示反应完全，反应液降温至室温，垫硅藻土过滤，滤液浓缩,柱层析纯化得棕色固体11a(300mg,产率：59％)。
LCMS m/z[M+H]+:535.2.
1HNMR(400MHz,DMSO-d6)δ8.25(d,J＝2.8Hz,1H),7.87(d,J＝2.8Hz,1H),7.82(d,J＝8.4Hz,2H),7.77(d,J＝1.2Hz,1H),7.73(d,J＝1.2Hz,1H),7.40(d,J＝8.4Hz,2H),3.71(s,3H),1.41(s,18H).
第二步：(化合物11b)
11a(270mg,0.51mmol)加入到氯化氢二氧六环溶液(4M，5mL)中，加毕，室温搅拌2小时，LCMS显示反应完全，反应液浓缩，倒入碳酸氢钠水溶液中(pH＝9)，乙酸乙酯萃取，有机相盐水洗，无水硫酸钠干燥，过滤，浓缩得棕色固体11b(200mg,产率：100％)。
LCMS m/z[M+H]+:335.1.
1HNMR(400MHz,DMSO-d6)δ7.82(d,J＝2.8Hz,1H),7.72-7.65(m,3H),7.43(dd,J＝4.4,2.0Hz,2H),7.19-7.12(m,2H),5.25(s,2H),3.64(s,3H).
第三步：(化合物11c)
化合物11b(180mg,0.5mmol)和溴化亚铜(306mg,2mmol)溶于氢溴酸(530mg,7mmol)水(4mL)溶液中，0～5℃下滴加亚硝酸钠(72mg,1mmol)水(1mL)溶液，滴毕，缓慢回温至室温，搅拌5小时。LCMS显示产物生成，反应液倒入亚硫酸氢钠水溶液中，氢氧化钠水溶液调节pH＝10，乙酸乙酯萃取，有机相盐水洗一次，无水硫酸钠干燥，浓缩，柱层析纯化得到黄色固体11c(40mg,产率：18％)。
LCMS m/z[M+H]+:398.0.
1HNMR(400MHz,DMSO-d6)δ8.57(d,J＝2.4Hz,1H),8.10(d,J＝2.4Hz,1H),7.84-7.78(m,3H),7.75(d,J＝1.2Hz,1H),7.43(d,J＝8.4Hz,2H),3.71(s,3H).
第四步：(化合物11)
11c(30mg,0.08mmol)，二甲基氧化磷(12mg,0.2mmol)，碳酸铯(29mg,0.09mmol)溶于1，4-二氧六环(3mL)中，置换氮气三次，氮气保护下加入醋酸钯(12mg,0.05mmol)，4,5-双(二苯基膦基)- 9,9-二甲基氧杂蒽(65mg,0.1mmol)，加毕，升温至110℃，搅拌4小时，LCMS显示原料反应完全，反应液倒入水中，乙酸乙酯萃取，有机相盐水洗一次，无水硫酸钠干燥，浓缩，粗品反相制备得到白色固体11(3mg,产率：10％)。
LCMS m/z[M+H]+:396.2.
1HNMR(400MHz,DMSO-d6)δ8.80(dd,J＝10.8,2.4Hz,1H),8.28(dd,J＝5.6,2.4Hz,1H),7.83(d,J＝8.4Hz,2H),7.79(d,J＝1.2Hz,1H),7.76(d,J＝1.2Hz,1H),7.46(d,J＝8.4Hz,2H),3.72(s,3H),1.73(s,3H),1.70(s,3H).
实施例4：(化合物17)
第一步：(化合物17b)
将17a(3.0g，10mmol)溶于二氧六环(50mL)，加入二甲基氧化膦(0.86g，11mmol)，磷酸钾(2.33g，11mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.35g，0.6mmol)和三(二亚苄基丙酮)二钯(0.27g，0.3mmol)，氮气置换三次，升温至100℃搅拌3小时。将反应液浓缩得粗品用柱层析分离得到棕色固体17b(2g，产率：80％)。
LCMS m/z[M+H]+:249.0
第二步：(化合物17c)
将17b(500mg，2.01mmol)溶于乙腈(10mL)，加入4-三氟甲基苯硼酸(766.7mg，4.02mmol)，2,6-二甲基吡啶(430mg，4.02mmol)，醋酸铜(547mg，3.01mmol)和三乙胺(406.3mg，4.02mmol)，氧气置换三次，升温至80℃搅拌反应24小时。将反应液浓缩，粗品用柱层析分离得到棕色固体17c(200mg，产率：25％)。
LCMS m/z[M+H]+:393.0
第三步：(化合物17)
将17c(90mg,0.23mmol)溶于二氧六环(3mL)和水(1mL)中，加入1-甲基吡唑-3-硼酸(43.2mg,0.34mmol)，碳酸钾(63.3mg,0.46mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(16.8mg,0.023mmol)，氮气置换三次，然后升温到100℃反应16小时。将反应液浓缩。粗品用柱层析分离，再经高效液相色谱分离得到白色固体17(50.8mg，产率：56％)。
LCMS m/z[M+H]+:395.1
1HNMR(400MHz,MeOD)δ8.53(dd,J＝6.0,2.1Hz,1H),8.36(dd,J＝11.4,2.2Hz,1H),8.06(d,J＝8.5Hz,2H),7.76(d,J＝2.4Hz,1H),7.63(d,J＝8.6Hz,2H),6.97(d,J＝2.4Hz,1H),4.09(s,3H),1.89(s,3H),1.86(s,3H).
实施例5：(化合物18)
将17c(200mg,0.51mmol)溶于二氧六环(10mL)中，加入吡唑(173.2mg，2.55mmol)，氧化亚铜(36.4mg,0.25mmol)，碳酸铯(331.5mg,1.02mmol)，水杨酸肟(69.8mg,0.51mmol)，然后氮气保护下120℃反应60小时。将反应液浓缩，用柱层析分离，粗品再经高效液相色谱分离得到白色固体(53.3mg，产率：28％)。
LCMS m/z[M+H]+:381.2
1HNMR(400MHz,DMSO-d6)δ8.53(dd,J＝6.0,2.0Hz,1H),8.33–8.28(m,1H),8.09(dd,J＝11.2,2.0Hz,1H),7.91(dd,J＝12.1,5.2Hz,3H),7.58(d,J＝8.6Hz,2H),6.66–6.61(m,1H),1.86(s,3H),1.82(s,3H).
实施例6：(化合物20)
将17c(200mg,0.51mmol)溶于1,4-二氧六环(10mL)中，加入4-(三氟甲基)-1H-吡唑(348.7mg,2.54mmol)，氧化亚铜(36.4mg,0.25mmol)，碳酸铯(331.5mg,1.02mmol)，水杨酸肟(69.8mg,0.51mmol)，然后在氮气保护下120℃反应72小时。将反应液浓缩，剩余物用柱层析分离，粗品再经高效液相色谱分离得到白色固体20(28.8mg，产率：13％)。
LCMS m/z[M+H]+:449.1
1HNMR(400MHz,DMSO-d6)δ8.82(d,J＝0.7Hz,1H),8.60(dd,J＝5.9,2.0Hz,1H),8.20(s,1H),8.14(dd,J＝11.1,2.0Hz,1H),7.86(d,J＝8.5Hz,2H),7.58(d,J＝8.6Hz,2H),1.86(s,3H),1.82(s,3H).
实施例7：(化合物22)
第一步：(化合物22a)
化合物8a(980mg,3.28mmol)，21b(1200mg,2.72mmol)，四(三苯基膦)钯(314mg,0.27mmol)，碘化亚铜(52mg,0.27mmol)加入到1,4-二氧六环(10mL)中，置换氩气三次，升温至80℃搅拌26小时，反应液浓缩，柱层析分离得到棕色固体22a(450mg，产率：59％)。
LCMS m/z[M+H]+:279.1
第二步：(化合物22b)
化合物22a(330mg,1.18mmol)溶于1,2-二氯乙烷(10mL)中，加入4-三氟甲基苯硼酸(240mg,1.26mmol)，醋酸铜(200mg,1.1mmol)，加毕，反应液暴露在空气环境下搅拌3小时，反应液乙酸乙酯稀释，浓缩，柱层析分离得到黄色固体22b(250mg，产率：50％)。
LCMS m/z[M+H]+:423.1
第三步：(化合物22)
化合物22b(170mg,0.40mmol)，二甲基氧化磷(51mg,0.65mmol)，磷酸钾(170mg,0.80mmol)溶于1,4-二氧六环(10mL)中，置换氩气三次，氩气保护下加入三二亚苄基丙酮二钯(44mg,0.048mmol)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(54mg,0.093mmol)，加毕，升温至110℃，搅拌12小时，反应液合并，垫硅藻土过滤，乙酸乙酯淋洗，有机相盐水洗一次，无水硫酸钠干燥，浓缩，柱层析分离得到白色固体，再经过石油醚/乙酸乙酯＝5/1(5mL)打浆，过滤，滤饼真空干燥得黄色固体22(120mg，产率：71％)。
LCMS m/z[M+H]+:421.2
1HNMR(400MHz,DMSO-d6)δ12.35(d,J＝3.5Hz,1H),8.41(dq,J＝4.4,2.1Hz,1H),8.22(dq,J＝11.1,2.1Hz,1H),7.99(dt,J＝8.7,3.5Hz,3H),7.70–7.61(m,2H),4.09(q,J＝6.0,3.7Hz,2H),2.98–2.88(m,2H),2.60(d,J＝10.0Hz,2H),1.72(d,J＝3.8Hz,3H),1.69(d,J＝3.6Hz,3H).
实施例8：(化合物34)
第一步：(化合物34b)
将化合物8a(1.0g,3.34mmol)，化合物34a(1.23g,3.34mmol)和四(三苯基膦)钯(0.37g,0.03mmol)加入到1,4-二氧六环(40mL)中，氮气置换三次，氮气保护下加热至100℃搅拌过夜，LC-MS显示有部分原料未反应完全，反应液降至室温，减压浓缩，剩余物经柱层析(PE/EA＝5:1-3:1)纯化得到黄色固体34b(250mg，收率30％)。LCMS(ESI)m/z＝252.0[M+H]+.
第二步：(化合物34c)
将化合物34b(250mg,1.0mmol)，4-三氟甲基苯硼酸(303.84mg,1.6mmol)，三乙胺(101.19mg,1.0mmol)和醋酸铜(18.2mg,0.1mmol)加入到1,2-二氯乙烷(10mL)中，氧气置换三次，氧气氛围下加热至70℃搅拌16小时，反应液减压浓缩，剩余物经柱层析纯化得到黄色固体34c(180 mg，收率4.7％)。LCMS(ESI)m/z＝394.0[M+H]+.
第三步：(化合物34)
将化合物34c(100mg,0.25mmol)，二甲基氧化磷(49.5mg,0.63mmol)，碳酸铯(121.87mg,0.38mmol)，Xantphos(57.86mg,0.1mmol)和醋酸钯(11.2mg,0.05mol)加入到1,4-二氧六环(10mL)中，氮气置换三次，氮气保护下加热至110℃搅拌过夜，反应液降至室温，减压浓缩，剩余物经柱层析纯化得到白色固体34(45mg，收率45.35％)。LCMS(ESI)m/z＝392.1[M+H]+.1H NMR(400MHz,DMSO-d6):δ12.68(s,1H),8.86-8.85(m,1H),8.63-8.62(s,1H),8.56-8.52(s,1H),8.26(d,J＝8.0Hz,1H),8.10-8.04(m,3H),7.68(d,J＝8.4Hz,2H),7.55-7.52(m,1H),1.78(s,3H),1.74(s,3H).
实施例9：(化合物35)
第一步：(化合物35a)
将化合物8b(300mg,1.18mmol)，化合物30a(238mg,1.18mmol)，三乙胺(120mg,1.18mmol)和醋酸铜(22mg,0.12mol)加入到1,2-二氯乙烷(20mL)中，氧气置换三次，氧气氛围下室温搅拌8小时，反应液减压浓缩，剩余物经柱层析纯化得到黄色固体35a(185mg，收率38.5％)。LCMS(ESI)m/z＝409.1[M+H]+.
第二步：(化合物35)
将化合物35a(143mg,0.35mmol)，二甲基氧化磷(56mg,0.71mmol)，碳酸铯(117mg,0.35mmol)，Xantphos(83mg,0.14mmol)和醋酸钯(16mg,0.07mol)加入到1,4-二氧六环(10mL)中，氮气置换三次，氮气保护下加热至110℃搅拌过夜，反应液降至室温，减压浓缩，剩余物经柱层析纯化得到白色固体35(92.5mg，收率65.1％)。LCMS(ESI)m/z＝407.1[M+H]+.1H NMR(400MHz,DMSO-d6):δ12.00(s,1H),8.39-8.36(m,1H),8.22-8.19(m,1H),8.15(d,J＝2.4Hz,1H),8.01(d,J＝1.2Hz,1H),7.93(d,J＝0.8Hz,1H),7.35-7.25(m,2H),3.78(s,3H),1.71(s,3H),1.67(s,3H).
实施例10：(化合物36)
第一步：(化合物36a)
将化合物8b(225mg,0.89mmol)，4-氯苯硼酸(223mg,1.42mmol)，三乙胺(90mg,0.89mmol)和醋酸铜(16mg,0.09mol)加入到1,2-二氯乙烷(40mL)中，氧气置换三次，氧气氛围下室温搅拌8小时，LC-MS显示原料反应完全，反应液减压浓缩，剩余物经柱层析纯化得到黄色固体36a(180mg，收率55.5％)。LCMS(ESI)m/z＝363.0[M+H]+.
第二步：(化合物36)
将化合物36a(100mg,0.27mmol)，二甲基氧化磷(43mg,0.55mmol)，碳酸铯(90mg,0.27mmol)，Xantphos(64mg,0.11mmol)和醋酸钯(11mg,0.05mol)加入到1,4-二氧六环(5mL)中，氮气置换三次，氮气保护下加热至110℃搅拌过夜，LC-MS显示原料反应完全，反应液降至室温，减压浓缩，剩余物经柱层析纯化得到白色固体36(48mg，收率48.4％)。LCMS(ESI)m/z＝361.0[M+H]+.1H NMR(400MHz,DMSO-d6):δ11.97(s,1H),8.38-8.36(m,1H),8.21-8.18(m,1H),8.00(d,J＝1.2Hz,1H),7.94(d,J＝0.8Hz,1H),7.82-7.80(m,2H),7.37-7.35(m,2H),3.78(s,3H),1.70(s,3H),1.67(s,3H).
实施例11：(化合物37)
第一步：(化合物37b)
将化合物37a(4.0g，12.6mmol)溶于1，4-二氧六环(40mL)中，加入二甲基氧化膦(1.5g，18.9mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(1.5g，2.52mmol)，三乙胺(3.8g，37.8mmol)和三(二亚苄基丙酮)二钯(2.3g，2.52mmol)，然后氮气保护下50℃搅拌16小时。TLC显示反应结束后，反应液冷却至室温，过滤，滤液用水(100mL)稀释，用含有10％甲醇的乙酸乙酯混合液(100mL×6)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压脱溶，残余物用硅胶柱层析纯化得到粗品6g，用反向制备得到化合物37b(1g，黄色固体，产率29.64％)。MS(ESI):m/z＝267.8[M+1]+。
第二步：(化合物37c)
将化合物37b(500mg，1.86mmol)溶于二甲基亚砜(10mL)中，加入五氟化(4-氨苯基)硫(490mg，2.23mmol)和碳酸铯(1.2g，3.72mmol)，然后在氮气保护下110℃搅拌16小时。TLC显示反应结束后，用水(100mL)稀释，乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，减压脱溶，残余物用硅胶柱层析纯化得到化合物37c(450mg，黄色 油状，产率53.55％)。MS(ESI):m/z＝450.9[M+1]+。
第三步：(化合物37)
将化合物37c(50mg，0.11mmol)溶于1,4-二氧六环(2mL)中，加入N-甲基-4-(三正丁基锡)咪唑(41mg，0.11mmol)，碘化亚铜(3mg，0.02mmol)和四三苯基膦钯(12.8mg，0.01mmol)，然后在氮气保护下80℃搅拌16小时。TLC显示反应结束后，反应液冷却至室温，用水(10mL)稀释，乙酸乙酯(8mL×3)萃取。合并有机相，用饱和食盐水(5mL×2)洗涤，减压脱溶，残余物用prep-TLC分离得到37(5mg，绿色固体)。MS(ESI):m/z＝452.9[M+1]+.1H NMR(400MHz,Chloroform-d)δ(ppm)11.96(s,1H),8.29(d,J＝5.5Hz,1H),8.24–8.16(m,1H),7.89(d,J＝8.7Hz,2H),7.68(d,J＝8.8Hz,2H),7.57(s,1H),7.46(s,1H),3.80(s,3H),1.79(s,3H),1.76(s,3H).
实施例12：(化合物38)
将化合物37c(100mg，0.22mmol)溶于1,4-二氧六环(5mL)中，加入化合物21b(146mg，0.22mmol，60％)，碘化亚铜(6mg，0.03mmol)和四三苯基膦钯(25.6mg，0.02mmol)，然后在氮气保护下80℃搅拌16小时。TLC显示反应结束后，反应液冷却至室温，用水(15mL)稀释，乙酸乙酯(10mL×3)萃取。合并的有机相用饱和食盐水(8mL×2)洗涤，减压脱溶，残余物用prep-TLC分离得到粗品(100mg)，粗品化合物再通过HPLC纯化得到化合物38(20mg，类白色固体)。MS(ESI):m/z＝479.1[M+1]+。1H NMR(300MHz,DMSO-d6)δ(ppm)12.42(s,1H),8.50–8.35(m,1H),8.24(d,J＝11.1Hz,1H),8.07-7.91(m,3H),7.83(d,J＝8.9Hz,2H),4.09(t,J＝7.2Hz,2H),2.94(t,J＝7.4Hz,2H),2.59(t,J＝7.5Hz,2H),1.73(s,3H)1.68(s,3H).
实施例13：(化合物39)
第一步：(化合物39a)
将化合物22a(182mg,0.64mmol)，4-氯苯硼酸(164mg,1.04mmol)，三乙胺(68mg,0.64mmol)和醋酸铜(24mg,0.02mol)加入到1,2-二氯乙烷(10mL)中，氧气置换三次，氧气氛围下室温搅拌8小时，LC-MS显示原料反应完全，反应液减压浓缩，剩余物经柱层析纯化得到黄色固体39a(130mg，收率51.1％)。LCMS(ESI)m/z＝389.1[M+H]+
第二步：(化合物39)
将化合物39a(130mg,0.33mmol)，二甲基氧化磷(53mg,0.67mmol)，碳酸铯(109mg,0.33mmol)，Xantphos(78mg,0.13mmol)和醋酸钯(15mg,0.06mol)加入到1,4-二氧六环(15mL)中，氮气置换三次，氮气保护下加热至110℃搅拌过夜，LC-MS显示原料反应完全，反应液降至室温，减压浓缩，剩余物经柱层析纯化得到棕色固体39(80mg，收率62.0％)。LCMS(ESI)m/z＝387.0[M+H]+.1H NMR(400MHz,DMSO-d6):δ12.04(s,1H),7.35(d,J＝4.4Hz,1H),8.18-8.15(m,1H),7.94(s,1H),7.81(d,J＝8.8Hz,2H),7.36(d,J＝8.4Hz,2H),4.10-4.06(m,2H),2.94-2.90(m,2H),2.60-2.56(m,2H),1.70(s,3H),1.66(s,3H).
实施例14：(化合物40)
第一步：(化合物40a)
将化合物22a(182mg,0.64mmol)，化合物30a(210.1mg,1.04mmol)，三乙胺(68mg,0.64mmol)和醋酸铜(24mg,0.02mol)加入到1,2-二氯乙烷(10mL)中，氧气置换三次，氧气氛围下室温搅拌8小时，反应液减压浓缩，剩余物经柱层析纯化得到黄色固体40a(130mg，收率46.9％)。LCMS(ESI)m/z＝435.1[M+H]+
第二步：(化合物40)
将化合物40a(130mg,0.33mmol)，二甲基氧化磷(53mg,0.67mmol)，碳酸铯(109mg,0.33mmol)，Xantphos(78mg,0.13mmol)和醋酸钯(15mg,0.06mol)加入到1,4-二氧六环(15mL)中，氮气置换三次，氮气保护下加热至110℃搅拌过夜，反应液降至室温，减压浓缩，剩余物经柱层析纯化得到棕色固体40(65mg，收率45.8％)。LCMS(ESI)m/z＝433.1[M+H]+.1H NMR(400MHz,DMSO-d6):δ12.09(s,1H),8.37-8.35(m,1H),8.19-8.16(m,2H),7.94(s,1H),7.34(d,J＝8.8Hz,1H),7.26-7.23(m,1H),4.10-4.06(m,2H),2.94-2.90(m,2H),2.60-2.56(m,2H),1.70(s,3H),1.67(s,3H).
实施例15：(化合物41)
第一步：(化合物41b)
将化合物41a(1g，3.14mmol),二甲基氧化磷(245mg，3.14mmol),碳酸铯(2g,6.28mmol)，醋酸钯(78g,0.35mmol)，XantPHos(382g,0.66mmol)加入DMF(5mL)溶液中。置换氩气三次,升温至100℃搅拌16小时。LCMS显示反应完全，反应液加水(50mL),乙酸乙酯(20mL*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，得到棕色油状产物41b(0.3g,收率：51％)。
第二步：(化合物41d)
将化合物41b(300mg，2.64mmol),化合物41c(0.36g,2.64mmol),碳酸铯(1.7g,5.28mmol)加入DMSO(3mL)溶液中,氩气鼓泡1min,升温至100℃搅拌16小时。LCMS显示反应完全，反应液浓缩，柱层析纯化得到类白色固体产物41d(0.5g，纯度：78％)。LCMS(ESI)m/z＝367.1[M+H]+
第三步：(化合物41)
将化合物41d(150mg，0.45mmol)，N-甲基-4-(三正丁基锡)咪唑(330mg,0.90mmol)，四三苯基膦钯(52mg，0.045mmol)，三乙胺(140mg,1.35mmol))加入DMF(2mL)溶液中，LCMS显示反应完成，真空下除去反应液，柱层析得到白色固体产物41(130mg,收率：86％，纯度：100％)。LCMS(ESI)m/z＝369.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.34(d,J＝7.2Hz,1H),8.24(dd,J＝6.1,2.1Hz,1H),7.99(dd,J＝10.9,2.1Hz,1H),7.85(dd,J＝10.8,1.3Hz,2H),4.24(d,J＝9.0Hz,1H),3.76(s,3H),2.13–1.95(m,8H),1.67(s,3H),1.64(s,3H).
效果实验例
对比化合物B3(VT103)的结构为：CAS号：2290608-13-6，参考专利WO2019040380A1中的合成路线合成得到。对比化合物B4(MRK-A)的结构为CAS号：2821763-12-4，购买来源：江苏艾康生物医药研发有限公司， 批号：AK23-1338803-1-1。
效果实验例一：
YAP-TEAD报告基因
YAP-TEAD报告基因测定如下进行。首先将8xGTIIC启动子序列(GAGCTCTTACGCGTGCTAGCCCGGCCAGTGCCAAGTTGAGACACATTCCACACATTCCACTGCAAGCTTGAGACACATTCCACACATTCC
ACTGCAAGCTTGGCCAGTGCCAAGTTGAGACACATTCCACACATTCCACTGCAAGCTTGAGACACATTCCACACATTCCACTGCAAGCTT
CTAGAGATCTGCAGGTCGAGGTCGACGGTATCGATAAGCTTGGGGGTGGGCGCCGGGGGGACCTTAAAGCCTCTGCCCCCCAAGGAGCCC
TTCCCAGACAGCCGCCGGCACCCACCGCTCCGTGGGACGATCCCCCAAGAGCTTGGCATTCCGGTACTGTTGGTAAA)构建入pGL4.20(luc2-Puro)质粒，并将与hippo通路无关的TK启动子(AAATGAGTCTTCGGACCTCGCGGGGGCCGCTTAAGCGGTGGTTAGGGTTTGTCTGACGCGGGGGGAGGGGGAAGGAACGAAACACTCTCA
TTCGGAGGCGGCTCGGGGTTTGGTCTTGGTGGCCACGGGCACGCAGAAGAGCGCCGCGATCCTCTTAAGCACCCCCCCGCCCTCCGTGGA
GGCGGGGGTTTGGTCGGCGGGTGGTAACTGGCGGGCCGCTGACTCGGGCGGGTCGCGCGCCCCAGAGTGTGACCTTTTCGGTCTGCTCGC
AGACCCCCGGGCGGCGCCGCCGCGGCGGCGACGGGCTCGCTGGGTCCTAGGCTCCATGGGGACCGTATACGTGGACAGGCTCTGGAGCAT
CCGCACGACTGCGGTGATATTACCGGAGACCTTCTGCGGGACGAGCCGGGTCACGCGGCTGACGCGGAGCGTCCGTTGGGCGACAAACAC
CAGGACGGGGCACAGGTACACTATCTTGTCACCCGGAGGCGCGAGGGACTGCAGGAGCTTCAGGGAGTGGCGCAGCTGCTTCATCCCCGT
GGCCCGTTGCTCGCGTTTGCTGGCGGTGTCCCCGGAAGAAATATATTTGCATGTCTTTAGTTCTATGATGACACAAACCCCGCCCAGCGT
CTTGTCATTGGCGAATTCGAACACGCAGATGCAGTCGGGGCGGCGCGGTCCCAGGTCCACTTCGCATATTAAGGTGACGCGTGTGGCCTC
GAACACCGAGCGACCCTGCAGCGACCCGCTTAA)构建入pGL4.78(hRlucCP/Hygro)质粒，从而构建可稳定持续反应YAP-TEAD转录复合体转录活性的293T稳转细胞。选择并鉴定单个克隆后，使克隆生长并保持在DMEM、10％胎牛血清、青霉素链霉素溶液、1ug/mL puromycin与150ug/ml hygromycin培养液中。为了用待测化合物进行报告基因测定，取上述生长状态良好的细胞，以3000每孔的细胞密度铺到384孔板中，每孔90μl，周围用适量PBS进行水封，以防边缘孔内水分蒸发。细胞铺板后第二天进行给药，每孔加不同浓度梯度的化合物，每个浓度点设三个复孔，化合物浓度以5μM浓度为起始浓度,并以5倍梯度向后稀释七次。另外设置相应的DMSO阴性处理对照组。药物处理24h后，首先准备检测试剂，融解Dual-LumiTM萤火虫萤光素酶检测试剂和Dual-LumiTM海肾萤光 素酶检测缓冲液，并达到室温。Dual-LumiTM海肾萤光素酶检测底物(100X)置于冰浴或冰盒上备用。按照检测每个样品需100μl Dual-LumiTM海肾萤光素酶检测工作液的量，配制适量Dual-LumiTM海肾萤光素酶检测工作液。按照1:100的比例混合适量的Dual-LumiTM海肾萤光素酶检测底物(100X)和Dual-LumiTM海肾萤光素酶检测缓冲液，即配制成Dual-LumiTM海肾萤光素酶检测工作液。取出细胞培养板在室温平衡10分钟(通常不宜超过30分钟)。然后96孔板每孔加入100μl Dual-LumiTM萤火虫萤光素酶检测试剂(384孔板每孔25μl)，混匀。室温(约25℃)孵育10分钟，使发光信号趋于稳定，然后使用具有检测化学发光功能的多功能酶标仪进行化学发光检测。之后开始海肾萤光素酶的检测，首先6孔板每孔加入100μl Dual-LumiTM海肾萤光素酶检测工作液(384孔板每孔25μl)并混匀。然后室温(约25℃)孵育10分钟，使发光信号趋于稳定。最后使用具有检测化学发光功能的多功能酶标仪进行化学发光检测。所得数据应用GraphPad Prism 7.0软件,使用非线性回归模型绘制S型剂量-存活率曲线并计算IC50值。测试结果如表1所示：
表1
效果实验例二：细胞增殖抑制
取NCI-H2052(NF2 mutant)，NCI-H226(NF2 mutant)，NCI-H2452(NF2 wide-type)，NCI-H28(NF2 wide-type)和MSTO-211H(NF2 wide-type)细胞用RPMI 1640完全培养基培养。
上述生长正常的细胞，用胰酶细胞消化液进行消化，离心，计数，以每孔1000个细胞的密度铺到96孔板中。细胞铺板24h后进行给药，每孔加10μL不同浓度梯度的抑制剂,每个浓度点设三个复孔，以20μM浓度为起始浓度,并以4倍梯度向后稀释8次，另外设置相应的千分之一的DMSO阴性处理对照组。药物处理72h后，于培养箱中取出待测细胞培养板，吸出96孔板中的培养液，重新加入190μL RPMI 1640完全培养基，并再次给药培养细胞72h。取出96孔板放置室温平衡10min，吸出96孔板中的培养基加入200μL的CellTiter-LumiTM发光法细胞活力检测液(与培养基1：1混合)，震荡两分钟后室温反应10min。从透明的96孔板中吸取150μL液体转移到96孔白板中进行化学发光读数。每孔数值减去本底值后，计算细胞存活率。存活率(％)＝(Sample/Vehicle-1)*100。Sample为药物处理组的化学发光，Vehicle为DMSO对照组的吸光度。应用GraphPad Prism 7.0软件,使用非线性回 归模型绘制S型剂量-存活率曲线并计算IC50或GI50值。测试结果如表2所示：
表2
效果实验例三：肝微粒体稳定性测试
评定受试化合物在CD-1小鼠、Sprague-Dawley大鼠、和人的肝微粒体中的一相代谢稳定性。
实验体系：
该测试体系所用到的动物和人肝微粒体购买自Xenotech、Corning或其他有资质的供应商，在使用前储存在低于-60℃冰箱内。所使用的动物和人肝微粒体信息如下：
实验简介：
供试品和对照化合物在37±1℃条件下，分别与动物和人肝微粒体孵育一定的时间，最长孵育时间为60分钟，在指定的时间点取出样品，用含有内标的乙腈或其他有机溶剂终止反应。离心后，所产生的上清液用液相色谱-串联质谱(LC-MS/MS)方法进行检测。
实验方法：
1.缓冲液的配制
用4000mL的超纯水溶解73.21g三水磷酸氢二钾和10.78g磷酸二氢钾。使用10％磷酸或者1M氢氧化钾调整溶液pH值在7.40±0.10之间，其终浓度为100mM。
2.工作液的配制
供试品粉末用DMSO或其他的有机溶剂配制成一定浓度的储备液，然后用合适的有机溶剂进行进一步的稀释。
对照化合物睾酮、双氯芬酸和普罗帕酮用DMSO配制成10mM的储备液，然后用合适的有机溶剂进行进一步的稀释。
3.肝微粒体溶液的配制
用100mM磷酸钾盐缓冲液将各种属的微粒体稀释成2×的工作液。在反应体系中微粒体的终浓度为0.5mg/mL。
4.还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)再生体系的配制
称量适量的烟酰胺腺嘌呤磷酸二核苷酸(NADP)和异柠檬酸(ISO)粉末，溶于氯化镁溶液中，振荡混匀。加入适量的异柠檬酸脱氢酶(IDH)轻轻的上下颠倒混合均匀。在反应体系中终浓度分别为：1mM NADP、1mM氯化镁、6mM ISO和1unit/mL IDH。
5.终止液的配制
终止液用含有内标(甲苯磺丁脲或其他合适的化合物)的乙腈或其他有机溶剂来配制。配制好的终止液储存于2-8℃冰箱。
6.孵育过程
孵育将在96孔板中完成。准备8块孵育板，分别命名为T0、T5、T15、T30、T45、T60、Blank60和NCF60。前6块板对应反应时间点分别为0、5、15、30、45和60分钟。Blank60板中不加入供试品或对照化合物，并在孵育60分钟后取样。NCF60板中用磷酸钾盐缓冲液代替NADPH再生体系溶液进行孵育60分钟。所有条件样品为三个平行。
将微粒体和供试品或对照化合物混合，然后将除T0和NCF60外的孵育板Blank60、T5、T15、T30、T45和T60放置于37℃水浴锅中预孵育大约10分钟。孵育板T0中先加入终止液后再添加NADPH再生体系工作液，孵育板NCF60每个样品孔内添加98μL磷酸钾盐缓冲液以启动反应。孵育板Blank60、T5、T15、T30、T45和T60预孵育结束后，每个样品孔内添加98μL NADPH再生体系工作液以启动反应。反应的温度为37±1℃，反应的最终体积是200μL，反应体系中包括0.5mg/mL的微粒体、1.0μM的底物、1mM NADP、6mM ISO和1unit/mL IDH。
分别在5、15、30、45和60分钟时，将含有内标的冷的终止液加入到反应板中以终止反应。
将终止后的所有反应板摇匀，并在4℃，3220×g，离心20分钟。将上清液稀释一定比例后进行LC-MS/MS分析。
样品分析
样品分析采用液相色谱-串联质谱(LC-MS/MS)方法进行，不含标准曲线和质控样品。使用分析物峰面积与内标峰面积的比值进行半定量测定。分析物和内标的保留时间、色谱图采集和色谱图的积分采用软件Analyst(Sciex，Framingham，Massachusetts，USA)进行处理。
每个分析批中每种基质中的内标峰面积的CV应在20％之内。
数据分析
通过下面公式中化合物与内标峰面积的比值转化成剩余率求得化合物的体外消除速率常数ke：



CLint(mic)＝0.693/T1/2/微粒体蛋白含量(孵育时微粒体浓度mg/mL)
CLint(liver)＝CLint(mic)×肝脏中微粒体蛋白量(mg/g)×肝重体重比
根据充分搅拌模型(well stir model)，肝固有清除率和肝清除率可以通过如下公式换算。
CL(liver)＝(CLint(liver)*Qh)/(CLint(liver)+Qh)
公式中的参数见下表3。
表3
测试结果如表4所示：
表4
效果实验例四：hERG
将HEK293细胞在含有10％胎牛血清及0.8mg/mL G418的DMEM培养基中培养，培养温度为37℃，CO2浓度为5％。细胞用TrypLETM Express消化后离心，调整细胞密度为2×106cells/mL，然后用室温平衡摇床轻混细胞15-20min，上机进行膜片钳检测。将制备好的细胞的培养基置换为细胞外液。从液体池中吸取细胞内、外液分别加到QPlate芯片的细胞内液池、细胞与受试物池中。全细胞膜片钳记录全细胞hERG钾电流的电压刺激，并将试验数据由Qpatch进行采集并储存。化合物以30μM起始，3倍稀释，设置6个浓度点，每个药物浓度设定为两次给药，时间至少为5分钟。将每一个细胞在不含化合物的外液中检测到的电流作为自己的对照组，每个浓度至少使用两个细胞独立重复检测两次。所有电生理试验在室温下进行。
数据分析，首先将每一个药物浓度作用后的电流和空白对照电流标准化然后计算每一个药物浓度对应的抑制率对每一个浓度计算平均数和标准误，并计算每种化合物的半抑制浓度：
用以上方程对剂量依赖效应进行非线性拟合，其中Y代表抑制率、C代表受试物浓度，IC50为半抑制浓度，HillSlope代表希尔系数。曲线拟合以及IC50的计算利用Graphpad软件完成。
效果实验例五：细胞色素氧化酶P450抑制
1)缓冲液的配制：
100mM K-Buffer：将9.5mL原液A混合到40.5mL原液B中，用超纯水将总体积调至500mL，用KOH或H3PO4滴定缓冲液至pH 7.4。
原料A(1M磷酸二氢钾):136.5g磷酸二氢钾在1L水中；
储备B(1M磷酸二氢钾):174.2g磷酸二氢钾在1L水。
2)受试物的配制
受试物粉末用DMSO或其他的有机溶剂配制成一定浓度的储备液，然后用合适的有机溶剂进行进一步的稀释。
3)体外孵育
CYP450酶代谢表型研究的肝微粒体体外孵育体系，是由制备的肝微粒体辅以氧化还原型辅酶，再加入酶特异的选择性抑制剂，在模拟生理温度及生理环境的条件下进行的生化反应。
4)原型药物或代谢产物的检测
采用LC-MS/MS测定温孵液中原型药物或其代谢产物的浓度。测试结果如表5所示：
表5
效果实验例六：小鼠药代动力学测试
对Balb/c小鼠分别单次静脉注射和口服灌胃给予本发明化合物，采集各时间点的小鼠血浆。利用LC-MS/MS分析方法检测BALB/C血浆组织中待测化合物药物浓度，并进行药动学分析。
1.给药制剂的配制(低剂量)
口服和静脉给药制剂溶媒：3％二甲基亚砜和5％聚乙二醇-15羟基硬脂酸酯的25％的磺丁基β环糊精溶液配制步骤：移取适量的浓度为1mg/ml的待测化合物25％磺丁基β环糊精溶液，加入总体积 3％磺丁基β环糊精溶液，涡旋、振荡、超声，加入剩余体积的25％磺丁基β环糊精(已灭菌)，配制成终浓度溶液或混悬液。
对于静脉注射制剂，将不过滤直接用于动物实验给药。IV配药小瓶提前一天置于红外灭菌柜中消毒。
2.给药
静脉注射：采用尾静脉给药。针头刺入后，慢慢回抽注射器，如有回血，表明针头已进入静脉内，可注入药液。
灌胃：选择适当型号的灌胃针和注射器，将灌胃针从舌根部插入食管，直至接近胃的贲门部，然后推注药物制剂拔出灌胃针使用一次性塑料灌胃针时，每个组别使用一根。
3.血样采集和处理
各时间点颌下静脉或尾静脉(IV组除外)采集全血60μL。置于含抗凝剂EDTA-K2(1μL,15％EDTA-K2溶液)的预冷的抗凝采血管中，湿冰上放置，并于1小时之内完成离心处理(3000g，4℃，离心10分钟)，离心后立即取血浆，转移至EP管中，并保存于-90～-60℃环境中。
4.样本检测
制剂浓度检测:制剂浓度检测采用HPLC或LCMS/MS方法测定。
血浆浓度检测:本实验采用已经开发的LC-MS/MS方法检测血浆中的化合物。
5.数据分析
采用非房室模型，使用(Version 8.2，Pharsight，Mountain View，CA)对血药浓度-时间数据进行分析。表6中的化合物的给样剂量为IV:2mg/kg,PO:10mg/kg，测试结果如表6所示：
表6
由上表可知，本发明的化合物口服暴露量高，生物利用度良好。
化合物高剂量(100mpk或200mpk)小鼠药代动力学测试：口服给药制剂溶媒：5％二甲基亚砜和15％聚乙二醇-15羟基硬脂酸酯的10％的羟丙基β环糊精溶液配制步骤：称取适量化合物，根据给药剂量计算出溶液总体积(如给药剂量是200mg/kg,小鼠固定给药体积为10ml/kg，得出浓度为20mg/ml)，加入5％DMSO后涡旋，再加入15％HS15涡旋，最后加入10％环糊精水溶液，涡旋，配制成终浓度溶液或混悬液。其余操作参考10mpk给药剂量的小鼠药代动力学操作。测试结果见表7。
表7

由上表可知，本发明的化合物在高剂量(100mpk或200mpk)下仍有很高的口服暴露量，与表6中的10mpk PO结果比较，暴露量与剂量呈线性依赖关系。
效果实验例七：大鼠药代动力学测试
本实验例中测试化合物经静脉注射(IV)和灌胃(PO)给药后在SD大鼠体内的药代动力学行为。给药制剂配制参考小鼠低剂量药代动力学测试。
给药当天称量大鼠实际体重并计算给药体积。每组3只大鼠，每个化合物进行两组测试，一组单次静脉注射给药，另一组单次灌胃给药。通过颈静脉采血方式在规定的时间(给药后0.25、0.5、1、2、4、8、24h)采集全血样品。血样采集以后，立即转移至贴有标签的含K2-EDTA(0.85-1.15mg)的商品化样品管中，随后离心处理(3200x g，4℃，10分钟)并取血浆。将血浆转移至预冷的离心管，在干冰中速冻，随后储存在-60℃或更低的超低温冰箱中，直到进行LC-MS/MS分析。
血浆浓度使用LC-MS/MS方法进行测定。使用WinNonlin Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型对化合物的血浆药物浓度数据进行处理。使用线性对数梯形法计算相关药代动力学参数。表8中的化合物的给样剂量为IV:2mg/kg,PO:10mg/kg，测试结果如表8所示：
表8
由上表可知，本发明的化合物口服暴露量高，生物利用度良好。
效果实验例八：药效学测试
在动物伦理准则下使用6-8周大的健康雌性裸鼠(BALB/c nu/nu)在SPF环境下饲养。通过胰蛋白酶消化获取生长状态良好的107H226细胞，然后在磷酸盐缓冲液(PBS)中洗涤，之后重悬于有50％基质胶(BD Biosciences)的PBS中。
然后在小鼠背外侧部位进行皮下注射，此后每三天量一次肿瘤体积。当肿瘤体积在150-200mm3左右时，随机将小鼠分配至不同处理组，然后相应地配制本发明所述的任一种化合物，然后以合适的剂量施用。最后根据肿瘤的生长情况，在4到6周后分析裸鼠肿瘤生长情况。测试结果如表9所示：
表9

在动物伦理准则下使用6-8周大的健康雌性裸鼠(BALB/c nu/nu)在SPF环境下饲养。通过胰蛋白酶消化获取生长状态良好的5M MSTO-211H细胞，然后在磷酸盐缓冲液(PBS)中洗涤，之后重悬于有50％基质胶(BD Biosciences)的PBS中。
然后在小鼠背外侧部位进行皮下注射，此后每三天量一次肿瘤体积。当肿瘤体积在150-200mm3左右时，随机将小鼠分配至不同处理组，然后相应地配制本发明所述的任一种化合物，然后以合适的剂量施用。最后根据肿瘤的生长情况，在4到6周后分析裸鼠肿瘤生长情况。测试结果如表10所示：
表10
效果实验例九：样品在FaSSIF溶液中饱和溶解度的测试
1.实验过程
1.1 FaSSIF溶液配制
缓冲液(pH 6.5)配制：
称取氢氧化钠约0.21g，磷酸二氢钠二水合物约2.24g，氯化钠3.09g，加水500ml，溶解后，用1N氢氧化钠或1N盐酸调节pH至6.5。
称取FaSSIF固体112mg于50mL容量瓶中，加入上述缓冲液溶解，并稀释至刻度，摇匀，室温静置2h以上。
1.2样品配制
供试品：取供试品约1mg，加FaSSIF溶液1ml，室温搅拌过夜，离心，取上清液进样分析。
对照品溶液：精密称取供试品约1.5mg于50mL容量瓶中，加入DMF溶解并稀释至刻度，混匀，即得。
1.3流动相配制
流动相A：准确量取纯化水1000mL，加入甲酸1mL，混匀，超声脱气，即得。
流动相B：乙腈。
1.4色谱条件(表11)
表11

2.结果
将对照品主成份峰和供试品中与其保留时间一致的峰进行积分，按外标法计算其在FaSSIF溶液中的浓度。测试结果如表12所示。
表12

Claims (17)

  1. 如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，
    其中，
    R1和R2独立地为C1-C6烷基、C3-C6环烷基或C6-C10芳基；
    或者，R1、R2和与其相连的原子一起形成3-12元杂环烷基或被一个或多个R1-1取代的3-12元杂环烷基，其中，所述3-12元杂环烷基中，除了所连接的P原子外，还额外含有0个、1个、2个或3个选自N、O和S中的1种、2种或3种的杂原子；
    R1-1独立地为C1-C6烷基；
    为
    其中，
    各RX1独立地为H、C1-C6烷基、卤素或CN；
    RX4为H、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”、被一个或多个RX4-1取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”、C6-C10芳基或被一个或多个RX4- 5取代的C6-C10芳基；
    RX4-1和RX4-5独立地为H、氘、卤素、C1-C6烷基、C1-C6烷氧基、CN、被一个或多个RX4-2取代的C1-C6烷基、被一个或多个RX4-3取代的C1-C6烷氧基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-12元杂环烷基”、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元杂芳基”、C(＝O)NRcRd、C3-C6环烷基、被一个或多个RX4- 4取代的C3-C6环烷基；
    RX4-2和RX4-3独立地为氘、卤素、OH、CN、C1-C6烷氧基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-12元杂环烷基”、C(＝O)NRcRd或NRbC(＝O)Ra；
    RX4-4独立地为CN、C(＝O)NRcRd或C(＝O)ORa；
    L为单键、-CRL1RL2-、-O-、-S-、-NRL3-、-NRL3CRL1RL2-、-CRL4＝CRL5-、
    RL1、RL2和RL3独立地为H、C1-C6烷基或C3-C6环烷基；
    RL4和RL5独立地为H或C1-C6烷基；
    L1和L2独立地为-CH2-、-O-、-S-或-NH-；
    环A为C3-C12饱和或不饱和的碳环、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环”；
    m3为0、1、2或3；
    R5独立地为SF5、卤素、C1-C6烷基、被一个或多个R5-1取代的C1-C6烷基、SR5-2、OR5-3、CN、S(＝O)2R5-4、C(＝O)R5-5、S(＝O)2NRdR5-6、NRdR5-6、C3-C6环烷基或被一个或多个R5-7取代的C3-C6环烷基；
    R5-1独立地为羟基、CN或卤素；
    R5-2、R5-3、R5-4、R5-6独立地为H、C1-C6卤代烷基、C1-C6烷基、C3-C6环烷基或被一个或多个R5- 8取代的C3-C6环烷基；
    R5-5独立地为C1-C6卤代烷基、H、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C6环烷基或被一个或多个R5-8取代的C3-C6环烷基、NRdR5-6；
    R5-7和R5-8独立地为卤素或C1-C6卤代烷基；
    Ra、Rb、Rc和Rd独立地为H或C1-C6烷基。
  2. 如权利要求1所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，
    R1和R2独立地为C1-C6烷基、C3-C6环烷基或C6-C10芳基；
    或者，R1、R2和与其相连的原子一起形成3-12元杂环烷基或被一个或多个R1-1取代的3-12元杂环烷基，其中，所述3-12元杂环烷基中，除了所连接的P原子外，还额外含有0个、1个、2个或3个选自N、O和S中的1种、2种或3种的杂原子；
    R1-1独立地为C1-C6烷基；
    为
    其中，
    各RX1独立地为H、C1-C6烷基、卤素或CN；
    RX4为H、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12 元饱和或不饱和的杂环基”、被一个或多个RX4-1取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”、C6-C10芳基或被一个或多个RX4- 5取代的C6-C10芳基；
    RX4-1和RX4-5独立地为H、氘、卤素、C1-C6烷基、C1-C6烷氧基、CN、被一个或多个RX4-2取代的C1-C6烷基、被一个或多个RX4-3取代的C1-C6烷氧基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-12元杂环烷基”、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元杂芳基”、C(＝O)NRcRd、C3-C6环烷基、被一个或多个RX4- 4取代的C3-C6环烷基；
    RX4-2和RX4-3独立地为氘、卤素、OH、CN、C1-C6烷氧基、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-12元杂环烷基”、C(＝O)NRcRd或NRbC(＝O)Ra；
    RX4-4独立地为CN、C(＝O)NRcRd或C(＝O)ORa；
    L为单键、-CRL1RL2-、-O-、-S-、-NRL3-、-NRL3CRL1RL2-、-CRL4＝CRL5-、
    RL1、RL2和RL3独立地为H、C1-C6烷基或C3-C6环烷基；
    RL4和RL5独立地为H或C1-C6烷基；
    L1和L2独立地为-CH2-、-O-、-S-或-NH-；
    环A为C3-C12饱和或不饱和的碳环、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环”；
    m3为0、1、2或3；
    R5独立地为SF5、卤素、C1-C6烷基、被一个或多个R5-1取代的C1-C6烷基、SR5-2、OR5-3、CN、S(＝O)2R5-4、C(＝O)R5-5、S(＝O)2NRdR5-6、NRdR5-6或被一个或多个R5-7取代的C3-C6环烷基；
    R5-1独立地为羟基、CN或卤素；
    R5-2、R5-3、R5-4、R5-6独立地为H、C1-C6卤代烷基、C1-C6烷基、C3-C6环烷基或被一个或多个R5- 8取代的C3-C6环烷基；
    R5-5独立地为C1-C6卤代烷基、H、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C6环烷基或被一个或多个R5-8取代的C3-C6环烷基、NRdR5-6；
    R5-7和R5-8独立地为卤素或C1-C6卤代烷基；
    Ra、Rb、Rc和Rd独立地为H或C1-C6烷基。
  3. 如权利要求1或2所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，其满足以下条件中的一个或两个以上：
    (1)所述“卤素”分别独立地为氟、氯、溴或碘；
    (2)所述“C1-C6烷基”分别独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    (3)所述“C1-C6烷氧基”分别独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基；
    (4)所述“C1-C6卤代烷基”分别独立地为-CHF2、-CH2F或-CF3；
    (5)所述“C1-C6卤代烷氧基”分别独立地为-OCHF2、-OCH2F或-OCF3；
    (6)所述“C3-C6环烷基”分别独立地为环丙基、环丁基、环戊基或环己基；
    (7)所述“C6-C10芳基”分别独立地为苯基或萘基；
    (8)所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的3-12元杂环烷基”分别独立地为“杂原子选自N和O中的1种或2种，杂原子数为1个或2个的5-6元杂环烷基”；
    (9)所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元杂芳基”为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-6元杂芳基”；
    (10)环A中，所述“C3-C12饱和或不饱和的碳环”为C4-C10饱和或不饱和的碳环，优选为C6-C10芳环；和
    (11)环A中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环”为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-6元杂芳环”。
  4. 如权利要求1或2所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，其满足以下条件中的一个或两个以上：
    (1)所述“卤素”分别独立地为氟或氯，例如氟；
    (2)所述“C1-C6烷基”分别独立地为甲基或乙基，例如甲基；
    (3)所述“C1-C6烷氧基”分别独立地为甲氧基或乙氧基；
    (4)所述“C3-C6环烷基”分别独立地为环丙基或环丁基，例如环丙基；
    (5)所述“C6-C10芳基”分别独立地为苯基；
    (6)RX4中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”为咪唑基(例如)、吡唑基(例如)、吡啶基(例如)或嘧啶基(例如)；
    (7)环A中，所述“C3-C12饱和或不饱和的碳环”为环丁烷环(例如)、环己烷环(例如)、螺[3.3]庚烷环(例如)、苯环(例如)、萘环(例 如)、二氢化茚环或四氢化萘环；和
    (8)环A中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环”为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-6元单环杂芳环或9-10元双环杂环”，例如，苯并氧杂戊烷环(例如)，吡啶环(例如)或噻吩环(例如)，优选地，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环”为吡啶环(例如)或噻吩环(例如)，进一步优选为苯并氧杂戊烷环(例如)。
  5. 如权利要求1所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，其满足以下条件中的一个或两个以上：
    (1)RX4中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”为吡咯基(例如)、吡唑基(例如)、咪唑基(例如)、三唑基(例如)、噻唑基(例如)、恶唑基(例如)、异恶唑基(例如)、吡啶基(例如)、嘧啶基(例如)、吡嗪基(例如)、哒嗪基(例如)、
    (2)环A中，所述“C3-C12饱和或不饱和的碳环”为C4-C10饱和的碳环或C6-C10芳环，例如为环丁烷环(例如)、环己烷环(例如)、螺[2.5]辛烷(例如)、螺[3.3]庚烷环(例如)、苯环(例如)、萘环(例如)、二氢化茚环或四氢化萘环。
  6. 如权利要求1或2所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，其满足以下条件中的一个或两个以上：
    (1)R1和R2独立地为C1-C6烷基；
    (2)L为单键、-CRL1RL2-、-O-、-S-或-NRL3-；较佳地，L为单键、-O-、-S-或-NRL3，例如L为-O-或-NRL3-；
    (3)RL3为H；
    (4)环A为C4-C10饱和碳环、C6-C10芳环或“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-9元饱和或不饱和杂环”，例如，环A为C6-C10芳环或“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-6元杂芳环”，又如环A为C6-C10芳环或“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-9元饱和或不饱和杂环”；
    (5)m3为0、1或2，例如，m3为1；
    (6)R5独立地为SF5、C3-C6环烷基、卤素、C1-C6烷基、被一个或多个R5-1取代的C1-C6烷基或OR5-3，优选地，R5-3独立地为C1-C6卤代烷基；例如，R5独立地为卤素、C1-C6烷基、被一个或多个R5-1取代的C1-C6烷基；又如，R5独立地为SF5、卤素或被一个或多个R5-1取代的C1-C6烷基；和
    (7)R5-1独立地为卤素。
  7. 如权利要求1所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，R5独立地为C3-C6环烷基。
  8. 如权利要求1所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，其满足以下条件中的一个或两个以上：
    (1)R1和R2独立地为C1-C6烷基，或者，R1、R2和与其相连的原子一起形成3-12元杂环烷基，其中，所述3-12元杂环烷基中，除了所连接的P原子外，还额外含有0个、1个、2个或3个选自N、O和S中的1种、2种或3种的杂原子；和
    (2)R5独立地为被一个或多个R5-1取代的C1-C6烷基。
  9. 如权利要求1或2所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，其满足以下条件中的一个或两个以上：
    (1)各RX1独立地为H；
    (2)RX4为“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”、被一个或多个RX4-1取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1个、2个或3个的5-12元饱和或不饱和的杂环基”；
    (3)RX4-1和RX4-5独立地为H、卤素、C1-C6烷基、被一个或多个RX4-2取代的C1-C6烷基或C3-C6环烷基；和
    (4)RX4-2和RX4-3独立地为卤素；
    优选地，其满足如下条件：
    RX4-1和RX4-5独立地为H、C1-C6烷基、被一个或多个RX4-2取代的C1-C6烷基。
  10. 如权利要求1或2所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，其满足以下条件中的一个或两个以上：
    (1)为
    (2)RX4为
  11. 如权利要求1或2所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，
    RX4为 较佳地，RX4为
  12. 如权利要求1或2所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，其满足以下条件中的一个或两个以上：
    (1)为
    (2)为
    (3)L为单键、-O-或-NH-；和
    (4)为
  13. 如权利要求1或2所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，其满足以下条件中的一个或两个以上：
    (1)为
    (2)L为单键、-CRL1RL2-、-O-、-S-或-NH-，例如L为-O-或-NH-；和
    (3)为
  14. 如权利要求1或2所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，所述如式I所示的化合物为如下式I-7所示的化合物：
    其中，
    X13为N；
    R1、R2、L、环A、R5和m3的定义如权利要求1-13任一项所述；
    RX1和RX4的定义如权利要求1-13任一项所述。
  15. 如权利要求1或2所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，其特征在于，所述如式I所示的化合物为如下任一化合物：





  16. 一种药物组合物，其特征在于，所述药物组合物包括：
    (1)如权利要求1-15任一项所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，和
    (2)药学上可接受的辅料。
  17. 如权利要求1-15任一项所述的如式I所示的化合物、其药学上可接受的盐、其酯、其立体异构体、其互变异构体、其多晶型物、其溶剂合物、其代谢物、其同位素衍生物或其前药，或如权利要求16所述的药物组合物在制备药物中的应用，所述的药物用于治疗由TEAD介导的疾病和病症，例如癌症(例如实体瘤、白血病)、器官再生、伤口愈合、纤维化。
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