WO2022258040A1 - Heterocyclic compound for tead inhibitor - Google Patents

Heterocyclic compound for tead inhibitor Download PDF

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WO2022258040A1
WO2022258040A1 PCT/CN2022/098060 CN2022098060W WO2022258040A1 WO 2022258040 A1 WO2022258040 A1 WO 2022258040A1 CN 2022098060 W CN2022098060 W CN 2022098060W WO 2022258040 A1 WO2022258040 A1 WO 2022258040A1
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methyl
membered
alkyl
ring
hydrogen
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Chinese (zh)
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张学军
常少华
李学强
王洪强
李金平
刘礼飞
刘勇
李莉娥
杨俊�
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武汉人福创新药物研发中心有限公司
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the field of medicine, in particular, the invention relates to a heterocyclic compound used as a TEAD inhibitor and its application.
  • the Hippo signaling pathway is a highly conserved signaling pathway composed of a series of kinase cascades, involved in the regulation of physiological processes such as cell proliferation, cell differentiation, cell stemness, extracellular matrix deposition, damage repair, and organ development.
  • NF2 neurofibromatosis type 2, neurofibromin 2
  • MST1/2 Mesmalian sterile 20-like kinase 1/2
  • LAST1/2 large tumor suppressor kinase 1/2
  • phosphorylated YAP/TAZ is localized in the cytoplasm and degraded in a ubiquitin-dependent manner, while unphosphorylated YAP/TAZ translocates to the nucleus
  • TEADs/TEADs Transcriptional Enhanced Associate Domains, Transcriptional Enhanced Associate Domains
  • TEADs/TEADs are the final effectors of the Hippo signaling pathway.
  • the DNA-binding TEA domain has a YAP/TAZ-binding domain at the C-terminus.
  • the DNA-binding domain and the YAP/TAZ-binding domain are highly conserved in mammals, but the link between the TEA domain and the transactivation domain
  • linkers of the four TEADs subtypes and the overall homology of the four TEADs subtypes ranges from 61% to 73%.
  • the function of TEADs is mediated by their interaction with nuclear coactivators, and YAP is the main nuclear coactivator interacting with TEADs.
  • YAP/TAZ-TEADs The activation of YAP/TAZ-TEADs promotes tumor development, and inhibiting the interaction between YAP/TAZ and TEADs has the potential to treat tumors.
  • some cancers such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma
  • the YAP/TAZ-TEADs complex is frequently overactivated or overexpressed, leading to cancer progression.
  • This hyperactivation is usually caused by changes in genes upstream of the Hippo signaling pathway, especially in patients with malignant mesothelioma, 40%-50% of tumors have NF2 mutations or deletions, ⁇ 25% of tumors have MST1 or LAST1/2 mutations or Deletion, 70% of YAP overexpression, and overactivation of YAP/TAZ-TEADs complex contribute to the promotion of tumor cell proliferation, metastasis, epithelial-to-mesenchymal transition (EMT) and maintenance of tumor stem cells.
  • EMT epithelial-to-mesenchymal transition
  • YAP/TAZ and TEADs interaction inhibitors (VT-01, IK-930) have entered the clinical stage, and the inhibition of YAP/TAZ and TEADs interaction may be a promising new anti-tumor chemotherapy.
  • the invention provides a heterocyclic compound used as a TEAD inhibitor, the heterocyclic compound can obviously inhibit the activity of TEAD transcription, and can be used for preventing and/or treating diseases related to the increased expression of TEAD.
  • Ring A is a benzene ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring;
  • Ring B is a benzene ring or a 5-6 membered heteroaromatic ring
  • Z is -O-, -NH- or -CH 2 -; the hydrogen atoms in the -NH- or -CH 2 - are optionally substituted by one or two Ra; each Ra is independently selected from methyl, ethyl or propyl;
  • L is absent or is C 1 -C 3 alkylene
  • Said L is optionally substituted by one or more of halogen or C 1 -C 3 alkyl, each independently;
  • Ring E is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; n is selected from 0, 1, 2, 3, 4 or 5;
  • Each R 0 is the same or different, independently hydrogen, oxo C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
  • R 1 is selected from the following substituents:
  • R 11 , R 12 , R 13 , R 14 are each independently hydrogen or the following groups optionally substituted by 1, 2 or more Rb: C 1 -C 6 alkyl, C 1 -C 6 haloalkane Base, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 4-6 membered heterocycloalkyl; each Rb is the same or different, each independently selected from deuterium, phenyl or 5-6 membered Heteroaryl;
  • R is hydrogen or a substituent selected from the following: Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
  • R 3 is -SF 5 or -CF 2 -OR 31 ;
  • R 31 is C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
  • R 31 is optionally substituted by a substituent selected from the group consisting of halogen, hydroxyl, -SF 5 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl;
  • R 4 is hydrogen or a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl.
  • the compound shown in formula I has the structure shown in formula II:
  • A, B, Z, L, R 1 , R 2 , R 3 , R 4 each independently have the definitions described herein;
  • R 5 and R 6 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 3-6 membered cycloalkane Base, 3-6 membered halogenated cycloalkyl group.
  • Ring A is a benzene ring or a 5-6 membered heteroaromatic ring
  • Ring B is a benzene ring or a 5-6 membered heteroaromatic ring
  • Z is -NH- or -CH 2 -; the hydrogen atom in the -NH- or -CH 2 - is optionally substituted by Ra; Ra is methyl, ethyl or propyl;
  • L is absent or is C 1 -C 3 alkylene
  • Said L is optionally substituted by halogen or C 1 -C 3 alkyl
  • R 1 is selected from the following substituents:
  • R 11 , R 12 , R 13 , and R 14 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3- 6-membered halocycloalkyl, 4-6-membered heterocycloalkyl;
  • R is hydrogen or a substituent selected from the following: Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
  • R 3 is -SF 5 or -CF 2 -OR 31 ;
  • R 31 is C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
  • R 31 is optionally substituted by a substituent selected from the group consisting of halogen, hydroxyl, -SF 5 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl;
  • R 4 is hydrogen or a substituent selected from the following: halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
  • R 5 and R 6 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkane base.
  • the ring A is selected from: benzene ring, pyridine, pyrimidine, Preferably, ring A is a benzene ring or pyridine.
  • R is hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl.
  • R 2 is hydrogen or Preferably, R 2 is hydrogen or And ring A is pyridine.
  • Z is -O-, -NH- or -CH 2 -;
  • L does not exist or is -CH 2 -, -CH(CH 3 )-;
  • the group -ZL - is -O-, -ZL- is -NH-, -CH 2 - or -NH-CH 2 -;
  • Z is -NH- or -CH 2 -; L does not exist or is -CH 2 -, -CH(CH 3 )-; preferably, the group -ZL- is -NH -, -CH2- or -NH - CH2-.
  • ring B is selected from: benzene ring, pyridine, pyrimidine; preferably, ring B is benzene ring or pyridine.
  • ring E is selected from: Preferably, ring E is selected from:
  • each R 0 is independently selected from methyl, oxo, and trideuteromethyl.
  • n is selected from 0, 1, 2 or 3.
  • the heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has formula Ia or Ib Structure shown:
  • W represents CRw, N;
  • Rw is hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 haloalkyl, 3-6 membered halogenated cycloalkyl;
  • Y 1 and Y 2 are each independently selected from CR 4 or N;
  • Y 3 , Y 4 , Y 5 are each independently selected from CR 3 or N;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 have at most two Ns;
  • R 1 , R 3 , R 4 , R 5 are as defined herein.
  • Rw is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; preferably, Rw is hydrogen.
  • R is R 11 , R 12 are each independently hydrogen or the following groups optionally substituted by 1, 2 or more Rb: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; each Rb is the same or different, each independently selected from deuterium or 5-6 membered heteroaryl.
  • R is R 11 and R 12 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, pyridyl-C 1 - C 6 alkyl;
  • R 11 and R 12 are each independently hydrogen, methyl, ethyl, propyl, trideuteromethyl, pyridylmethyl;
  • R 11 is hydrogen and R 12 is methyl.
  • R 5 is hydrogen or a substituent selected from the following groups: methyl, ethyl, cyclopropyl, cyclobutyl; preferably, R 5 is methyl.
  • L is -CH 2 - or -CH(CH 3 )-.
  • R 3 is -SF 5 or -CF 2 -OR 31 ;
  • R 31 is selected from methyl, ethyl, propyl, butyl, cyclopropane, cyclobutane, cyclopentane, Cyclohexane; preferably, R 31 is methyl or cyclopropane.
  • R 3 is -SF 5 , -CF 2 -O-CH 3 or
  • R 4 is hydrogen or a substituent selected from the following: halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; preferably, R 4 is hydrogen.
  • heterocyclic compounds their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs include:
  • a pharmaceutical composition which includes: the heterocyclic compound as a TEAD inhibitor as described in the first aspect of the present invention, its tautomer, stereo isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and pharmaceutically acceptable carriers.
  • a heterocyclic compound as described in the first aspect of the present invention its tautomers, stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts
  • the purposes of prodrug, or the purposes of pharmaceutical composition as described in the second aspect of the present invention described purposes comprises:
  • the TEADs include: TEAD1, TEAD2, TEAD3 and TEAD4.
  • the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
  • the present invention also provides a method for treating diseases, comprising administering to patients a therapeutically effective amount of the compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable At least one of a salt, a prodrug, or the pharmaceutical composition.
  • the disease is a disease associated with increased expression of TEAD.
  • the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
  • the patient is a mammal, preferably a human.
  • the inventors unexpectedly developed a heterocyclic compound for TEAD inhibitors, which can significantly inhibit the activity of TEAD transcription, and can significantly inhibit NCI-H226 (ATCC, cat#CRL5826) has a significant effect on inhibiting the growth of NCI-H226 mesothelioma, and exhibits excellent pharmacokinetic properties and good druggability.
  • the heterocyclic compound can be used to prepare drugs, pharmaceutical compositions or preparations for preventing and/or treating diseases related to increased expression of TEAD; and/or, to prepare drugs for reducing/inhibiting TEAD expression and increasing TEAD activity, A pharmaceutical composition or preparation; and/or, preparation of a drug, pharmaceutical composition or preparation for reducing/inhibiting the Hippo signaling pathway.
  • the TEAD includes: TEAD1, TEAD2, TEAD3 and TEAD4; the disease is preferably a cell proliferative disorder; the cell proliferative disorder is preferably cancer.
  • reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein.
  • the techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
  • R 1 ", “R1” and “R 1 " have the same meaning and can be substituted for each other. For other symbols such as R 2 , similar definitions have the same meanings.
  • halogen means fluorine, chlorine, bromine, iodine alone or as part of another substituent.
  • amino alone or as part of another substituent means -NH2 .
  • nitro alone or as part of another substituent means -NO2 .
  • alkyl alone or as part of another substituent, means consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and is bonded to the molecule by a single bond. The rest are connected straight or branched hydrocarbon chain groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.
  • An alkyl group can be unsubstituted or substituted with one or more suitable substituents.
  • alkyl groups may also be isotopomers of naturally abundant alkyl groups that are rich in carbon and/or hydrogen isotopes (ie, deuterium or tritium).
  • alkenyl means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds.
  • alkynyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
  • C 1 -C 6 alkyl alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3
  • C 1 -C 5 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4 or 5 carbon atoms.
  • said groups have 1, 2 or 3 carbon atoms (“C 1 -C 3 alkyl”), for example methyl, ethyl, n-propyl or isopropyl.
  • C 1 -C 6 alkoxy alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms Composed of and oxygen atom, or expressed as C 1 -C 6 alkyl-OC 1 -C 6 alkyl definition As described in this specification, the oxygen atom can be attached to a straight or straight chain of C 1 -C 6 alkyl on any carbon atom. Including but not limited to: methoxy (CH 3 -O-), ethoxy (C 2 H 5 -O-), propoxy (C 3 H 7 -O-), butoxy (C 4 H 9 -O-).
  • cycloalkyl or “carbocyclyl” by themselves or as part of another substituent refer to a cyclic alkyl group.
  • mn-membered cycloalkyl or “ Cm - Cncycloalkyl” is understood to mean a saturated, unsaturated or partially saturated carbocycle having m to n atoms.
  • 3-10 membered cycloalkyl or “C 3 -C 10 cycloalkyl” refers to a cyclic alkyl group containing 3 to 10 carbon atoms, which may contain 1 to 3 rings.
  • the cyclic alkyl group includes monocyclic, bicyclic, tricyclic, spiro or bridged rings.
  • unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decahydronaphthalene rings.
  • Cycloalkyl groups may be substituted with one or more substituents.
  • a cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl group.
  • heterocycle or “heterocycloalkyl” or “heterocyclyl” by itself or as part of another substituent means a group in which one or more (in some embodiments 1 to 3) carbon atoms are replaced by Cycloalkyl (eg, cycloalkyl, cycloalkenyl, cycloalkynyl) substituted by heteroatoms such as, but not limited to, N, O, S, and P.
  • heterocycloalkyl is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 10 atoms.
  • a heterocycloalkyl group can be a heterocycloalkyl group fused to an aryl or heteroaryl group.
  • a prefix such as 3-8 membered is used to denote heterocycloalkyl, the number of carbons is also meant to include heteroatoms. Including monocyclic, bicyclic, tricyclic, spiro or bridged rings.
  • heterocycles include, but are not limited to, dihydropyridine, dihydropyridazine, dihydropyrazine, including substituted forms thereof, such as heterocyclyl including, but not limited to, 1-methyl-6-oxo- 1,6-dihydropyridazin-3-yl, 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl, 2-oxo-1,2-dihydropyridyl, etc. .
  • heteroaryl/heteroaromatic ring refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. Heteroaryl is preferably 5- or 6-membered.
  • heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, tri Azolyl, thiadiazolyl, thia-4H-pyrazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzo Imidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives , such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • Haloalkyl or halogen-substituted alkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl.
  • the compounds provided herein, including intermediates useful in the preparation of the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof.
  • "Protected derivatives” are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also known as protecting groups).
  • Suitable protecting groups for the carboxyl moiety include benzyl, tert-butyl, etc., and isotopes, etc.
  • Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable hydroxy protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
  • the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
  • the prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or D are dextrorotatory.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
  • solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent force, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
  • Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • excipient means a pharmaceutically acceptable inert ingredient.
  • categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
  • treatment and other similar synonyms include the following meanings:
  • the reaction temperature can be appropriately selected according to the solvent, starting material, reagent, etc.
  • the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc.
  • the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next step reaction, the target compound can also directly enter the next step reaction without separation and purification.
  • each step reaction of the present invention is preferably carried out in an inert solvent
  • the inert solvent includes but not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethylmethylene Sulfone, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof things.
  • Fig. 1 is a graph showing compound I-2 inhibiting the growth of NCI-H226 mesothelioma.
  • the synthetic route is as follows:
  • reaction system was slowly raised to room temperature at 20° C. and stirred for 1 hour. After the reaction was completed, the reaction solution was poured into a mixed aqueous solution (1000 mL) of potassium ferricyanide (46.8 g, 142 mmol) and potassium hydroxide (15.9 g, 284 mmol) under nitrogen protection and stirred overnight at room temperature.
  • Extract with ethyl acetate 500mL ⁇ 3
  • the second step the synthesis of 5-(chloro(tetrafluoro)- ⁇ 6 -sulfanyl)-2-fluoropyridine (A1-3)
  • the third step the synthesis of 2-fluoro-5-(pentafluoro- ⁇ 6 -sulfanyl)pyridine (A1-4)
  • reaction solution containing 2-fluoro-5-(pentafluoro- ⁇ 6 -sulfanyl)pyridine (A1-4), which was directly used in the next step.
  • Step 4 Synthesis of -5-(pentafluoro- ⁇ 6 -sulfanyl)-2-aminopyridine (A1)
  • the synthetic route is as follows:
  • reaction solution was diluted with 100mL dichloromethane, the organic phase was washed with aqueous hydrochloric acid (0.5M, 50mL x 3), the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product, which was washed with petroleum Ether/methyl tert-butyl ether (10/1, v/v) (100mL) was beaten to obtain 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide ( A2) (12g, yield 84.5%).
  • A2 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide
  • the synthetic route is as follows:
  • reaction solution was diluted with 100mL dichloromethane, the organic phase was washed with aqueous hydrochloric acid (0.5M, 50mL x 3), the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product, which was washed with petroleum Ether/methyl tert-butyl ether (10:1, v/v) (100mL) was beaten to obtain 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3- Sulfonamide (A3) (10 g, yield 67.5%).
  • A3 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3- Sulfonamide
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • intermediate A3-2 refers to the patent publication WO2018130563A1, under the protection of nitrogen at 0°C, to 1-(4-methoxyphenyl)-N-deuteromethylmethylamine (A3-2) (3.3g, 22mmol ) and diisopropylethylamine (4.8ml, 27.4mmol) in dichloromethane (100ml) solution was added dropwise 5-bromo-6-chloropyridine-3-sulfonyl chloride (A3-1) (5.3g, 18.3mmol ). The reaction mixture was stirred at 0°C under nitrogen for 0.5 hours. Then the temperature was raised to 25° C. and stirred for 2 hours under the protection of nitrogen.
  • reaction solution was diluted with 100mL dichloromethane, the organic phase was washed with aqueous hydrochloric acid (0.5M, 50mL x 3), the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product, which was washed with petroleum Ether/methyl tert-butyl ether (10:1, v/v) (100mL) was beaten to obtain 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3- Sulfonamide (A5) (4.8 g, yield 66%).
  • A5 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3- Sulfonamide
  • Embodiment 1 the preparation of target compound I-1
  • the synthetic route is as follows:
  • the N,N- NaH (0.124g, 3.09mmol, 60%) was added in portions to a solution of dimethylformamide (10mL), and then 5-(pentafluoro- ⁇ 6 -sulfanyl)pyridin-2-amine (0.408g, 1.854 mmol) was slowly added to the reaction solution.
  • the reaction solution was stirred at 25° C. for 18 hours under nitrogen protection.
  • the reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine.
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((5-( Pentafluoro- ⁇ 6 -sulfanyl)pyridin-2-yl)amino)benzenesulfonamide (I-1) (0.185g, yield 53%).
  • a preparative silica gel plate ethyl acetate
  • Embodiment 2 the preparation of compound 1-2
  • the synthetic route is as follows:
  • reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), and the organic phase was collected and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-( Pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (I-2) (0.21 g, yield 70%).
  • a preparative silica gel plate ethyl acetate
  • Embodiment 3 the preparation of target compound 1-3
  • the synthetic route is as follows:
  • reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain a crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((3-( Pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (I-3) (0.25g, yield 80%).
  • a preparative silica gel plate ethyl acetate
  • Embodiment 4 the preparation of target compound 1-4
  • the synthetic route is as follows:
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), and the organic phase was collected and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-( Pentafluoro- ⁇ 6 -sulfanyl)benzyl)amino)benzenesulfonamide (I-4) (0.2 g, yield 60.9%).
  • Embodiment 5 the preparation of target compound 1-5
  • the synthetic route is as follows:
  • the first step 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)pyridine-3 -Synthesis of sulfonamide (B5-1)
  • reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-( Pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (I-5) (0.2 g, yield 63%).
  • a preparative silica gel plate ethyl acetate
  • Embodiment 6 the preparation of target compound 1-6
  • the synthetic route is as follows:
  • the first step 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((3-(pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)pyridine-3 -Synthesis of sulfonamide (B6-1)
  • reaction solution was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((3-( Pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (I-6) (0.25g, yield 78%).
  • a preparative silica gel plate ethyl acetate
  • Embodiment 7 the preparation of target compound 1-7
  • the synthetic route is as follows:
  • the first step 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(pentafluoro- ⁇ 6 -sulfanyl)benzyl)amino)pyridine-3 -Synthesis of sulfonamide (B7-1)
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-( Pentafluoro- ⁇ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (I-7) (0.2 g, yield 61%).
  • Embodiment 8 the preparation of target compound 1-8
  • the synthetic route is as follows:
  • the first step the synthesis of 2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridin-4-amine (B8-2)
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the second step the synthesis of 4-bromo-2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridine (B8-3)
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the third step the synthesis of 4-(benzylthio)-2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridine (B8-4)
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the dichloro Add N,N-diisopropylethylamine (1.07g, 8.34mmol) and 1-(4-methoxyphenyl)-N-methylmethylamine (453mg, 3mmol) to the methane (10mL) solution.
  • the reaction mixture was stirred at 0°C for 2 hours.
  • the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine.
  • the seventh step N-(4-methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)-2-oxo-1-(4-(five Synthesis of Fluoro- ⁇ 6 -sulfanyl)benzyl)-1,2-dihydropyridine-4-sulfonamide (B8-8)
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-6-(1-methyl-1H-imidazol-4-yl)-2-oxo-1- (4-(Pentafluoro- ⁇ 6 -sulfanyl)benzyl)-1,2-dihydropyridine-4-sulfonamide (I-8) (100 mg, yield 42%).
  • a preparative silica gel plate ethyl acetate
  • Embodiment 9 the preparation of target compound 1-9
  • Compound I-9 was synthesized with reference to the synthetic method of compound I-2, replacing 4-(pentafluoro- ⁇ 6 -sulfanyl)aniline with 4-(difluoro(methoxy)methyl)aniline to obtain the target compound 4-((4-(difluoro(methoxy)methyl)phenyl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzenesulfonamide (I- 9).
  • Embodiment 10 the preparation of target compound I-10
  • Compound 1-10 was synthesized with reference to the synthetic method of compound 1-2, and 4-(pentafluoro- ⁇ 6 -sulfanyl)aniline was replaced with 4-(cyclopropoxydifluoromethyl)aniline to obtain target compound 4 -((4-(cyclopropoxydifluoromethyl)phenyl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzenesulfonamide (I-10) .
  • Embodiment 11 Preparation of target compound I-11
  • Compound I-11 was synthesized with reference to the synthetic method of compound I-2, replacing 4-(pentafluoro- ⁇ 6 -sulfanyl)aniline with 5-(difluoro(methoxy)methyl)pyridin-2-amine , to obtain the target compound 4-((5-(difluoro(methoxy)methyl)pyridin-2-yl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl ) Benzenesulfonamide (I-11).
  • Embodiment 12 Preparation of target compound 1-12
  • compound I-12 refers to the synthetic method of compound I-2, and 4-(pentafluoro- ⁇ 6 -sulfanyl)aniline is replaced by 5-(cyclopropoxydifluoromethyl)pyridin-2-amine, To obtain the target compound 4-((5-(cyclopropoxydifluoromethyl)pyridin-2-yl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzene Sulfonamide (I-12).
  • Embodiment 13 Preparation of target compound 1-13
  • the synthetic route is as follows:
  • reaction solution was diluted with water (40.0 mL), then extracted with ethyl acetate (30.0 mL*4), the organic phases were combined, washed with water (30.0 mL*3), dried over sodium sulfate, and concentrated to obtain a crude product.
  • N-(4-methoxybenzyl)-N-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-4-((4-(pentafluoro - ⁇ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B13-2, 500 mg, 847 ⁇ mol) was dissolved in trifluoroacetic acid (10.0 mL), and reacted at 70°C for 2 hours.
  • Embodiment 14 Preparation of Target Compound I-14
  • the synthetic route is as follows:
  • Embodiment 15 Preparation of target compound I-15
  • the synthetic route is as follows:
  • the third step N-(4-methoxybenzyl)-N-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-4-((4- Preparation of (pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B15-4)
  • N-(4-methoxybenzyl)-N-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-4-((4-(pentafluoro - ⁇ 6-sulfanyl)phenyl)amino)benzenesulfonamide was dissolved in trifluoroacetic acid (10.0 mL), and reacted at 70°C for 1 hour.
  • the reaction solution was added to water (50.0 mL), then extracted with ethyl acetate (50.0 mL*3), the organic phase was washed with saturated brine (50.0 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
  • Embodiment 16 Preparation of Target Compound I-16
  • the synthetic route is as follows:
  • the first step 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl) Preparation of Benzenesulfonamide (B16-1)
  • 6-Bromo-2-methylpyridazin-3(2H)-one (1.24g, 6.55mmol) and 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A4, 3.00 g, 6.89 mmol) was dissolved in acetonitrile (30.0 mL) and water (30.0mL), add potassium carbonate (2.86g, 20.7mmol) and 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (504mg, 689 ⁇ mol), then stir the reaction at 95°C under nitrogen protection for 10 Hour.
  • reaction solution was added dropwise to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
  • N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4-((4- (Pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B16-2, 900mg, 1.46mmol) was dissolved in trifluoroacetic acid (20.0mL), and reacted at 70°C for 1 hour.
  • reaction solution was added to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
  • Embodiment 17 Preparation of target compound I-17
  • the synthetic route is as follows:
  • reaction solution was added dropwise to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
  • N-(4-methoxybenzyl)-N-methyl-3-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-4-((4- (Pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B17-2, 300 mg, 487 ⁇ mol) was dissolved in trifluoroacetic acid (20.0 mL), and reacted at 70°C for 1 hour.
  • reaction solution was added to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
  • Embodiment 18 Preparation of target compound I-18
  • the synthetic route is as follows:
  • the first step 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzenesulfonate Preparation of Amide (B18-1)
  • reaction liquid was added into water (10ml), extracted with ethyl acetate (10mL X 3), and the organic phase was collected and washed with 10mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)-4-((4-(five Fluoro- ⁇ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B18-2, 180mg, 0.305mmol) was dissolved in dichloromethane (5ml), added trifluoroacetic acid (1ml), and stirred for 12h.
  • Embodiment 19 Preparation of Compound I-19
  • the synthetic route is as follows:
  • Step 1 Preparation of methyl 3-bromo-4-((4-(pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)benzoate (B19-2)
  • reaction liquid was cooled to room temperature, concentrated by distillation under reduced pressure, the mixture was added with water (30 mL), extracted with ethyl acetate (30 mL x 3), and the organic phase was collected and washed with 30 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • reaction solution was concentrated to remove methanol and tetrahydrofuran to obtain a crude product, which was diluted with water (15 mL), adjusted to pH 5 with dilute hydrochloric acid (2M), and extracted with ethyl acetate ( 20mL ⁇ 3), the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product that was directly used in the next step to obtain 3-(1-methyl-1H-imidazol-4-yl)-4- ((4-(Pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)benzoic acid (B19-4, 285 mg, yield 89%).
  • reaction mixture was stirred at 25°C for 0.5 hours, and then pyridin-2-ylmethylamine (76 mg, 0.70 mmol) was added.
  • the reaction mixture was stirred at 25°C for 2 hours.
  • Embodiment 20 Preparation of Compound I-20
  • the synthetic route is as follows:
  • the first step the synthesis of 2-(4-bromo-1-methyl-1H-imidazol-2-yl)propan-2-ol (B20-2)
  • Nitrogen replacement was performed 3 times, and the reaction was carried out at 100° C. for 21 hours under nitrogen protection. Cool to room temperature, remove the reaction solvent by subtractive evaporation, add water (40 mL), extract with ethyl acetate (50 mL ⁇ 3), combine the organic phases, and dry over anhydrous sodium sulfate.
  • the third step 3-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-N-(4-methoxybenzyl)-N-methyl -Synthesis of 4-(4-(pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B20-4)
  • reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • Embodiment 21 Preparation of Compound I-21
  • the synthetic route is as follows:
  • reaction solution was diluted with 100 mL of dichloromethane, the organic phase was washed with aqueous hydrochloric acid (0.5M, 50 mL x 3), the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product, which was washed with silica gel Purified by column chromatography to obtain 3-bromo-4-fluoro-N-(2-hydroxyethyl)benzenesulfonamide (B21-1) (2.2g, yield 80.1%).
  • reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the crude product was purified by silica gel column chromatography to obtain 3-bromo-N-(2-hydroxyethyl)-4-((4-(pentafluoro- ⁇ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B21-2 ) (172mg, yield 30%).
  • Embodiment 22 Preparation of compound 1-22
  • the synthetic route is as follows:
  • the third step is to synthesize N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-(4-(pentafluoro- ⁇ 6 - Preparation of sulfanyl)phenoxy)pyridine-3-sulfonamide
  • N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-(4-(pentafluoro- ⁇ 6 -sulfanyl )phenoxy)pyridine-3-sulfonamide (1.20g, 2.03mmol) was dissolved in dichloromethane (10.0mL), trifluoroacetic acid (10.0mL) was added thereto, and stirred at room temperature for 2h.
  • Embodiment 23 Preparation of compound 1-23
  • the synthetic route of I-23 refers to I-22, and the raw material 1-methyl-4-(tributylstannyl)-1H-imidazole of the third step is replaced by 1-deuteromethyl-4-(tributylstannyl Alkyl)-1H-imidazole, LC-MS, M/Z (ESI): 474.1[M+H] + .
  • Test Example 1 TEADs-mediated transcriptional inhibition IC 50 evaluation test
  • HEK293T-TEAD Reporter Assay was used to detect the inhibitory effect of small molecule compounds on TEADs-mediated transcription.
  • HEK293T-TEAD-LUC reporter cell line is prepared with DMEM (Dulbecco's modified Eagle's medium) + 10% FBS (fetal bovine serum) + 1% PS (penicillin-streptomycin) + 200 ⁇ g/ ml Hygromycin (hygromycin) is used as a complete medium for culture, cells in the logarithmic phase are seeded in a 384-well plate, 2500cell/well/35 ⁇ L, 37°C, 5% CO 2 Incubate overnight, add to each well the next day 5 ⁇ L of the diluted compound (the final concentration of DMSO is 0.1%), set up a positive control group with only DMSO added at the same time, and use the signal value of 2 ⁇ M Okacid acid as the signal of the negative control group, then incubate at 37°C, 5% CO 2 for 48 hours, and incubate when done use luciferase assay system (Promega, E2550) and measure the fluorescence signal value
  • Inhibition rate% (signal of positive control group - signal of test well) / (signal of positive control group - signal of negative control group) * 100
  • test compound IC 50 (nM) Control compound 70 I-1 16 I-2 14 I-3 8 I-14 27.5 I-18 76.9
  • HEK293T-TEAD Reporter Assay show that the compounds of the present invention can significantly inhibit the transcriptional activity of TEADs on HEK293T-TEAD-LUC reporter cell line cells, and show a better inhibitory effect than the control compound.
  • Test Example 2 Inhibition of malignant mesothelioma cell proliferation test
  • the NCI-H226 cell proliferation assay with NF2 mutation was used to detect the inhibitory effect of small molecule compounds on the proliferation of malignant mesothelioma cells.
  • NCI-H226 (ATCC, cat#CRL5826) is cultured with RPMI1640 (RPMI 1640 medium) + 10% FBS (fetal bovine serum) + 1% PS (penicillin-streptomycin) as a complete medium, and will be in logarithmic phase Seed the cells in a 96-well plate, 800cell/well/195uL, incubate overnight at 37°C, 5% CO 2 , add 5 ⁇ L of the diluted compound to each well the next day (the final concentration of DMSO is 0.1%), and set only DMSO to be added positive control group, and the signal value of Staurosporine at 1 ⁇ M was used as the signal value of the negative control group, and then incubated at 37°C, 5% CO 2 for 6 days.
  • RPMI1640 RPMI 1640 medium
  • FBS fetal bovine serum
  • PS penicillin-streptomycin
  • Fluorescent signal values were measured on Envision 2104 Multilabel Reader according to the instructions provided by the supplier.
  • the inhibition rate was calculated by the following formula, and then the log value of the concentration of the inhibitor was plotted on the X-axis, and the inhibition rate was drawn on the Y-axis, and the IC 50 was calculated with Graphpad 7.0.
  • Inhibition rate% (signal of positive control group - signal of test well) / (signal of positive control group - signal of negative control group) * 100
  • NCI-H226 cell proliferation test show that the compound of the present invention can obviously inhibit the proliferation of NCI-H226 (ATCC, cat#CRL5826).
  • test compound IC 50 (nM) Control compound 32.6 I-1 19.0 I-2 22.9
  • mice For the mouse pharmacokinetics test, three male ICR mice, 20-25g in weight, were fasted overnight and administered orally (10 mg/kg) by gavage. Blood was collected before administration and 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes to collect plasma and stored at -80°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.
  • mice pharmacokinetic test results show that the compound of the present invention exhibits excellent pharmacokinetic properties and good druggability.
  • mice After one week of adaptive feeding of Nu/Nu nude mice (CRL), resuspend the NCI-H226 cells in logarithmic phase in PBS, and inoculate 5 ⁇ 10 6 NCI-H226 cells on the right rear of the mice at 100 ⁇ L/mouse Subcutaneously, observe the tumor growth regularly. When the tumor grows to an average volume of 80-100mm3 , the mice are randomly divided into the model group and the administration group according to the tumor size and body weight, and the tumor is measured and recorded before and during the administration. Volume and animal weight. After the treatment, the model group was used as the control group, and the growth inhibitory effect of the administration group on the tumor was counted, and TGI was calculated.

Abstract

Provided is a heterocyclic compound for a TEAD inhibitor. The heterocyclic compound has the structure shown in formula I, and the groups in formula I are defined as described herein. The heterocyclic compound is used for preventing and/or treating diseases associated with increased TEAD expression, such as cell proliferation disorders.

Description

用于TEAD抑制剂的杂环化合物Heterocyclic Compounds for TEAD Inhibitors
本申请要求享有于2021年6月11日向中国国家知识产权局提交的，专利申请号为202110655338.0，名称为“用于TEAD抑制剂的咪唑类化合物”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。This application claims the priority of the previous application filed with the State Intellectual Property Office of China on June 11, 2021, with the patent application number 202110655338.0, entitled "Imidazole Compounds for TEAD Inhibitors". The entirety of this prior application is incorporated by reference into the present application.
技术领域technical field
本发明属于医药领域，具体地，本发明涉及到一种用于TEAD抑制剂的杂环化合物及用途。The invention belongs to the field of medicine, in particular, the invention relates to a heterocyclic compound used as a TEAD inhibitor and its application.
背景技术Background technique
Hippo信号通路是由一系列激酶级联组成的高度保守的信号通路，参与调节细胞增殖、细胞分化、细胞干性、细胞外间质沉积、损伤修复、器官发育等生理过程。Hippo信号通路被上游的GPCR、机械应力等信号激活后，导致NF2(neurofibromatosis type 2，神经纤维蛋白2)激活MST1/2(Mammalian sterile 20-like kinase 1/2)，MST1/2激活LAST1/2(large tumor suppressor kinase 1/2)，激活的LATS1/2磷酸化YAP(Yes Associated Protein，Yes相关蛋白)/TAZ(Transcriptional coactivator with PDZ-binding motif，带有PDZ结合基序的转录辅助激活因子)，磷酸化的YAP/TAZ定位于细胞质并以泛素依赖的方式降解，而未磷酸化的YAP/TAZ转移到细胞核并与包括TEADs在内的几个核转录因子结合，形成转录复合物，诱导包括CTGF(Connective tissue growth factor，结缔组织生长因子)、Cyr61(Mysteine rich angiogenic inducer 61，富含半胱氨酸的血管生成诱导剂61)和AXL(AXL receptor tyrosine kinase，受体酪氨酸激酶AXL)在内的几个下游靶基因的表达，进而促进了机体的生理病理过程。The Hippo signaling pathway is a highly conserved signaling pathway composed of a series of kinase cascades, involved in the regulation of physiological processes such as cell proliferation, cell differentiation, cell stemness, extracellular matrix deposition, damage repair, and organ development. After the Hippo signaling pathway is activated by upstream GPCR, mechanical stress and other signals, NF2 (neurofibromatosis type 2, neurofibromin 2) activates MST1/2 (Mammalian sterile 20-like kinase 1/2), and MST1/2 activates LAST1/2 (large tumor suppressor kinase 1/2), activated LATS1/2 phosphorylated YAP (Yes Associated Protein, Yes related protein)/TAZ (Transcriptional coactivator with PDZ-binding motif, transcriptional coactivator with PDZ binding motif) , phosphorylated YAP/TAZ is localized in the cytoplasm and degraded in a ubiquitin-dependent manner, while unphosphorylated YAP/TAZ translocates to the nucleus and binds to several nuclear transcription factors including TEADs to form transcription complexes that induce Including CTGF (Connective tissue growth factor, connective tissue growth factor), Cyr61 (Mysteine rich angiogenic inducer 61, cysteine-rich angiogenesis inducer 61) and AXL (AXL receptor tyrosine kinase, receptor tyrosine kinase AXL ), including the expression of several downstream target genes, which in turn promote the physiological and pathological processes of the body.
TEADs/TEAD(Transcriptional Enhanced Associate Domains，转录增强相关结构域)是Hippo信号通路的最终效应器，有四个家族成员，分别为TEAD1、TEAD2、TEAD3和TEAD4，所有TEADs亚型N端都有一个与DNA结合的TEA结构域，在C末端都有一个与YAP/TAZ结合的结构域，DNA结合域和YAP/TAZ结合域在哺乳动物中高度保守，但在连接TEA结构域和反式激活结构域的连接子上有很大的不同，四个TEADs亚型的总体同源性介于61％至73％之间。TEADs的功能由其与核辅助激活因子的相互作用介导，YAP是与TEADs相互作用的主要核辅助激活因子。TEADs/TEADs (Transcriptional Enhanced Associate Domains, Transcriptional Enhanced Associate Domains) are the final effectors of the Hippo signaling pathway. There are four family members, namely TEAD1, TEAD2, TEAD3, and TEAD4. All TEADs subtypes have a N-terminal with The DNA-binding TEA domain has a YAP/TAZ-binding domain at the C-terminus. The DNA-binding domain and the YAP/TAZ-binding domain are highly conserved in mammals, but the link between the TEA domain and the transactivation domain There are substantial differences in the linkers of the four TEADs subtypes, and the overall homology of the four TEADs subtypes ranges from 61% to 73%. The function of TEADs is mediated by their interaction with nuclear coactivators, and YAP is the main nuclear coactivator interacting with TEADs.
YAP/TAZ-TEADs激活促进肿瘤发展，抑制YAP/TAZ与TEADs的相互作用具有治疗肿瘤的潜力。在一些癌症中，如恶性间皮瘤、卵巢癌和胆管癌，YAP/TAZ-TEADs复合物经常过度激活或过度表达，导致癌症进展。这种过度激活通常是由Hippo信号通路上游基因的改变引起的，尤其在恶性间皮瘤患者中，40％-50％的肿瘤NF2突变或缺失，<25％的肿瘤MST1或LAST1/2突变或缺失，70％的YAP高表达，YAP/TAZ-TEADs复合物的过度激活有助于促进肿瘤细胞的增殖、转移、上皮向间充质转化(EMT)和肿瘤干细胞的维持。YAP和TEADs的相互作用对于启动转录程序以驱动肿瘤发生和增殖至关重要，DNA结合域缺陷的TEADs能够阻断Hippo信号通路上游基因突变介导的肿瘤形成，这表明抑制YAP/TAZ与TEADs的相互作用具有抗肿瘤作用。Invenva Pharma公开的专利表明，抑制YAP/TAZ与TEADs的相互作用后能明显抑制肿瘤细胞的增殖(WO 2017064277)。其他的研究还表明YAP/TAZ-TEADs的下游蛋白CTGF和CYR61能够诱导肿瘤细胞对紫杉醇等化疗药物产生耐药性，YAP/TAZ-TEADs已成为耐药癌细胞的替代生存途径。这些都表明抑制YAP/TAZ与TEADs的相互作用具有治疗肿瘤的潜力，特别是Hippo信号通路上游过度激活或突变的肿瘤。The activation of YAP/TAZ-TEADs promotes tumor development, and inhibiting the interaction between YAP/TAZ and TEADs has the potential to treat tumors. In some cancers, such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma, the YAP/TAZ-TEADs complex is frequently overactivated or overexpressed, leading to cancer progression. This hyperactivation is usually caused by changes in genes upstream of the Hippo signaling pathway, especially in patients with malignant mesothelioma, 40%-50% of tumors have NF2 mutations or deletions, <25% of tumors have MST1 or LAST1/2 mutations or Deletion, 70% of YAP overexpression, and overactivation of YAP/TAZ-TEADs complex contribute to the promotion of tumor cell proliferation, metastasis, epithelial-to-mesenchymal transition (EMT) and maintenance of tumor stem cells. The interaction between YAP and TEADs is critical for initiating transcriptional programs to drive tumorigenesis and proliferation, and DNA-binding domain-deficient TEADs can block tumorigenesis mediated by mutations in genes upstream of the Hippo signaling pathway, suggesting that inhibiting the interaction of YAP/TAZ with TEADs The interaction has an antitumor effect. The patent published by Invenva Pharma shows that inhibiting the interaction between YAP/TAZ and TEADs can significantly inhibit the proliferation of tumor cells (WO 2017064277). Other studies have also shown that the downstream proteins of YAP/TAZ-TEADs, CTGF and CYR61, can induce tumor cell resistance to chemotherapy drugs such as paclitaxel, and YAP/TAZ-TEADs have become an alternative survival pathway for drug-resistant cancer cells. These all indicate that inhibiting the interaction between YAP/TAZ and TEADs has the potential to treat tumors, especially those with overactivation or mutation upstream of the Hippo signaling pathway.
目前一些YAP/TAZ与TEADs相互作用抑制剂(VT-01、IK-930)已进入临床阶段，YAP/TAZ与TEADs相互作用抑制可能是有希望的新型抗肿瘤化疗法。At present, some YAP/TAZ and TEADs interaction inhibitors (VT-01, IK-930) have entered the clinical stage, and the inhibition of YAP/TAZ and TEADs interaction may be a promising new anti-tumor chemotherapy.
发明内容Contents of the invention
本发明提供了一种用于TEAD抑制剂的杂环化合物，所述杂环化合物能明显抑制TEAD转录的活性，可以用于预防和/或治疗与TEAD表达增加相关的疾病。The invention provides a heterocyclic compound used as a TEAD inhibitor, the heterocyclic compound can obviously inhibit the activity of TEAD transcription, and can be used for preventing and/or treating diseases related to the increased expression of TEAD.
在本发明第一方面，提供了一种式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：In the first aspect of the present invention, there is provided a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
Figure PCTCN2022098060-appb-000001
Figure PCTCN2022098060-appb-000001
其中，环A为苯环、5-6元杂环或5-6元杂芳环；Wherein, Ring A is a benzene ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring;
环B为苯环或5-6元杂芳环；Ring B is a benzene ring or a 5-6 membered heteroaromatic ring;
Z为-O-、-NH-或-CH 2-；所述-NH-或-CH 2-中的氢原子任选地被一个或两个Ra取代；各个Ra各自独立地选自甲基、乙基或丙基； Z is -O-, -NH- or -CH 2 -; the hydrogen atoms in the -NH- or -CH 2 - are optionally substituted by one or two Ra; each Ra is independently selected from methyl, ethyl or propyl;
L不存在或为C 1-C 3亚烷基； L is absent or is C 1 -C 3 alkylene;
所述L任选地被卤素或C 1-C 3烷基中的一个或更多个各自独立地取代； Said L is optionally substituted by one or more of halogen or C 1 -C 3 alkyl, each independently;
环E为5-6元杂环或5-6元杂芳环；n选自0、1、2、3、4或5；Ring E is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; n is selected from 0, 1, 2, 3, 4 or 5;
每个R 0相同或不同，各自独立地为氢、氧代
Figure PCTCN2022098060-appb-000002
C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6氘代烷基、3-6元环烷基、3-6元卤代环烷基； Each R 0 is the same or different, independently hydrogen, oxo
Figure PCTCN2022098060-appb-000002
C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
R 1选自下列的取代基：
Figure PCTCN2022098060-appb-000003
R 1 is selected from the following substituents:
Figure PCTCN2022098060-appb-000003
R 11、R 12、R 13、R 14各自独立地为氢或任选被1个、2个或更多个Rb取代的下列基团：C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基、4-6元杂环烷基；每个Rb相同或不同，各自独立地选自氘、苯基或5-6元杂芳基； R 11 , R 12 , R 13 , R 14 are each independently hydrogen or the following groups optionally substituted by 1, 2 or more Rb: C 1 -C 6 alkyl, C 1 -C 6 haloalkane Base, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 4-6 membered heterocycloalkyl; each Rb is the same or different, each independently selected from deuterium, phenyl or 5-6 membered Heteroaryl;
R 2为氢或选自下列的取代基：
Figure PCTCN2022098060-appb-000004
卤素、C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基； R is hydrogen or a substituent selected from the following:
Figure PCTCN2022098060-appb-000004
Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
R 3为-SF 5或-CF 2-O-R 31； R 3 is -SF 5 or -CF 2 -OR 31 ;
R 31为C 1-C 6烷基、3-6元环烷基、3-6元杂环烷基； R 31 is C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
R 31任选地被选自下组的取代基取代：卤素、羟基、-SF 5、C 1-C 6烷基、C 1-C 6烷氧基、3-6元环烷基、3-6元杂环烷基； R 31 is optionally substituted by a substituent selected from the group consisting of halogen, hydroxyl, -SF 5 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl;
R 4为氢或选自下列的取代基：卤素、C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基。 R 4 is hydrogen or a substituent selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl.
根据本发明的实施方案，式I所示化合物具有式II所示的结构：According to an embodiment of the present invention, the compound shown in formula I has the structure shown in formula II:
Figure PCTCN2022098060-appb-000005
Figure PCTCN2022098060-appb-000005
其中，A、B、Z、L、R 1、R 2、R 3、R 4各自独立地具有本文中所述的定义； Wherein, A, B, Z, L, R 1 , R 2 , R 3 , R 4 each independently have the definitions described herein;
R 5、R 6各自独立地为氢或选自下列的取代基：C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6氘代烷基、3-6元环烷基、3-6元卤代环烷基。 R 5 and R 6 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 3-6 membered cycloalkane Base, 3-6 membered halogenated cycloalkyl group.
根据本发明的实施方案，环A为苯环或5-6元杂芳环；According to an embodiment of the present invention, Ring A is a benzene ring or a 5-6 membered heteroaromatic ring;
环B为苯环或5-6元杂芳环；Ring B is a benzene ring or a 5-6 membered heteroaromatic ring;
Z为-NH-或-CH 2-；所述-NH-或-CH 2-中的氢原子任选地被Ra取代；Ra为甲基、乙基或丙基； Z is -NH- or -CH 2 -; the hydrogen atom in the -NH- or -CH 2 - is optionally substituted by Ra; Ra is methyl, ethyl or propyl;
L不存在或为C 1-C 3亚烷基； L is absent or is C 1 -C 3 alkylene;
所述L任选地被卤素或C 1-C 3烷基取代； Said L is optionally substituted by halogen or C 1 -C 3 alkyl;
R 1选自下列的取代基：
Figure PCTCN2022098060-appb-000006
R 1 is selected from the following substituents:
Figure PCTCN2022098060-appb-000006
R 11、R 12、R 13、R 14各自独立地为氢或选自下列的取代基：C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基、4-6元杂环烷基； R 11 , R 12 , R 13 , and R 14 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3- 6-membered halocycloalkyl, 4-6-membered heterocycloalkyl;
R 2为氢或选自下列的取代基：
Figure PCTCN2022098060-appb-000007
卤素、C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基； R is hydrogen or a substituent selected from the following:
Figure PCTCN2022098060-appb-000007
Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
R 3为-SF 5或-CF 2-O-R 31； R 3 is -SF 5 or -CF 2 -OR 31 ;
R 31为C 1-C 6烷基、3-6元环烷基、3-6元杂环烷基； R 31 is C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
R 31任选地被选自下组的取代基取代：卤素、羟基、-SF 5、C 1-C 6烷基、C 1-C 6烷氧基、3-6元环烷基、3-6元杂环烷基； R 31 is optionally substituted by a substituent selected from the group consisting of halogen, hydroxyl, -SF 5 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl;
R 4为氢或选自下列的取代基：卤素、C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基； R 4 is hydrogen or a substituent selected from the following: halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
R 5、R 6各自独立地为氢或选自下列的取代基：C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基。 R 5 and R 6 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkane base.
在本发明一优选实施方式中，所述环A选自：苯环、吡啶、嘧啶、
Figure PCTCN2022098060-appb-000008
较佳地，环A为苯环或吡啶。 In a preferred embodiment of the present invention, the ring A is selected from: benzene ring, pyridine, pyrimidine,
Figure PCTCN2022098060-appb-000008
Preferably, ring A is a benzene ring or pyridine.
在本发明一优选实施方式中，R 2为氢或选自下列的取代基：
Figure PCTCN2022098060-appb-000009
C 1-C 6烷基、C 1-C 6卤代烷基。 In a preferred embodiment of the present invention, R is hydrogen or a substituent selected from the following:
Figure PCTCN2022098060-appb-000009
C 1 -C 6 alkyl, C 1 -C 6 haloalkyl.
在本发明一优选实施方式中，R 2为氢或
Figure PCTCN2022098060-appb-000010
较佳地，R 2为氢或
Figure PCTCN2022098060-appb-000011
且环A为吡啶。 In a preferred embodiment of the present invention, R 2 is hydrogen or
Figure PCTCN2022098060-appb-000010
Preferably, R 2 is hydrogen or
Figure PCTCN2022098060-appb-000011
And ring A is pyridine.
在本发明一优选实施方式中，Z为-O-、-NH-或-CH 2-；L不存在或为-CH 2-、-CH(CH 3)-；较佳地，基团-Z-L-为-O-、-Z-L-为-NH-、-CH 2-或-NH-CH 2-； In a preferred embodiment of the present invention, Z is -O-, -NH- or -CH 2 -; L does not exist or is -CH 2 -, -CH(CH 3 )-; preferably, the group -ZL - is -O-, -ZL- is -NH-, -CH 2 - or -NH-CH 2 -;
在本发明一优选实施方式中，Z为-NH-或-CH 2-；L不存在或为-CH 2-、-CH(CH 3)-；较佳地，基团-Z-L-为-NH-、-CH 2-或-NH-CH 2-。 In a preferred embodiment of the present invention, Z is -NH- or -CH 2 -; L does not exist or is -CH 2 -, -CH(CH 3 )-; preferably, the group -ZL- is -NH -, -CH2- or -NH - CH2-.
在本发明一优选实施方式中，环B选自：苯环、吡啶、嘧啶；较佳地，环B为苯环或吡啶。In a preferred embodiment of the present invention, ring B is selected from: benzene ring, pyridine, pyrimidine; preferably, ring B is benzene ring or pyridine.
在本发明一优选实施方式中，环E选自：
Figure PCTCN2022098060-appb-000012
Figure PCTCN2022098060-appb-000013
较佳地，环E选自
Figure PCTCN2022098060-appb-000014
Figure PCTCN2022098060-appb-000015
In a preferred embodiment of the present invention, ring E is selected from:
Figure PCTCN2022098060-appb-000012
Figure PCTCN2022098060-appb-000013
Preferably, ring E is selected from
Figure PCTCN2022098060-appb-000014
Figure PCTCN2022098060-appb-000015
在本发明一优选实施方式中，各个R 0各自独立地选自甲基、氧代、三氘代甲基。 In a preferred embodiment of the present invention, each R 0 is independently selected from methyl, oxo, and trideuteromethyl.
在本发明一优选实施方式中，n选自0、1、2或3。In a preferred embodiment of the present invention, n is selected from 0, 1, 2 or 3.
在本发明一优选实施方式中，
Figure PCTCN2022098060-appb-000016
选自
Figure PCTCN2022098060-appb-000017
Figure PCTCN2022098060-appb-000018
In a preferred embodiment of the present invention,
Figure PCTCN2022098060-appb-000016
selected from
Figure PCTCN2022098060-appb-000017
Figure PCTCN2022098060-appb-000018
在本发明一优选实施方式中，所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有式Ia或Ib所示结构：In a preferred embodiment of the present invention, the heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has formula Ia or Ib Structure shown:
Figure PCTCN2022098060-appb-000019
Figure PCTCN2022098060-appb-000019
Figure PCTCN2022098060-appb-000020
Figure PCTCN2022098060-appb-000020
其中，W表示CRw、N；Among them, W represents CRw, N;
Rw为氢、卤素、C 1-C 6烷基、3-6元环烷基、C 1-C 6卤代烷基、3-6元卤代环烷基； Rw is hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 haloalkyl, 3-6 membered halogenated cycloalkyl;
Y 1、Y 2各自独立地选自CR 4或N； Y 1 and Y 2 are each independently selected from CR 4 or N;
Y 3、Y 4、Y 5各自独立地选自CR 3或N； Y 3 , Y 4 , Y 5 are each independently selected from CR 3 or N;
且Y 1、Y 2、Y 3、Y 4、Y 5中至多有两个N； And Y 1 , Y 2 , Y 3 , Y 4 , Y 5 have at most two Ns;
L、R 1、R 3、R 4、R 5的定义如本文中所述。 L, R 1 , R 3 , R 4 , R 5 are as defined herein.
在本发明一优选实施方式中，Rw为氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基；较佳地，Rw为氢。 In a preferred embodiment of the present invention, Rw is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; preferably, Rw is hydrogen.
在本发明一优选实施方式中，R 1为
Figure PCTCN2022098060-appb-000021
R 11、R 12各自独立地为氢或任选被1个、2个或更多个Rb取代的下列基团：C 1-C 6烷基、C 1-C 6卤代烷基；每个Rb相同或不同，各自独立地选自氘或5-6元杂芳基。 In a preferred embodiment of the present invention, R is
Figure PCTCN2022098060-appb-000021
R 11 , R 12 are each independently hydrogen or the following groups optionally substituted by 1, 2 or more Rb: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; each Rb is the same or different, each independently selected from deuterium or 5-6 membered heteroaryl.
在本发明一优选实施方式中，R 1为
Figure PCTCN2022098060-appb-000022
R 11、R 12各自独立地为氢或选自下列的取代基：C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6氘代烷基、吡啶基-C 1-C 6烷基； In a preferred embodiment of the present invention, R is
Figure PCTCN2022098060-appb-000022
R 11 and R 12 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, pyridyl-C 1 - C 6 alkyl;
较佳地，R 11、R 12各自独立地为氢、甲基、乙基、丙基、三氘代甲基、吡啶基甲基； Preferably, R 11 and R 12 are each independently hydrogen, methyl, ethyl, propyl, trideuteromethyl, pyridylmethyl;
更佳地，R 11为氢，R 12为甲基。 More preferably, R 11 is hydrogen and R 12 is methyl.
在本发明一优选实施方式中，R 5为氢或选自下列的取代基：甲基、乙基、环丙基、环丁基；较佳地，R 5为甲基。 In a preferred embodiment of the present invention, R 5 is hydrogen or a substituent selected from the following groups: methyl, ethyl, cyclopropyl, cyclobutyl; preferably, R 5 is methyl.
在本发明一优选实施方式中，L为-CH 2-或-CH(CH 3)-。 In a preferred embodiment of the present invention, L is -CH 2 - or -CH(CH 3 )-.
在本发明一优选实施方式中，R 3为-SF 5或-CF 2-O-R 31；R 31选自甲基、乙基、丙基、丁基、环丙烷、环丁烷、环戊烷、环己烷；较佳地，R 31为甲基或环丙烷。 In a preferred embodiment of the present invention, R 3 is -SF 5 or -CF 2 -OR 31 ; R 31 is selected from methyl, ethyl, propyl, butyl, cyclopropane, cyclobutane, cyclopentane, Cyclohexane; preferably, R 31 is methyl or cyclopropane.
在本发明一优选实施方式中，R 3为-SF 5、-CF 2-O-CH 3或
Figure PCTCN2022098060-appb-000023
In a preferred embodiment of the present invention, R 3 is -SF 5 , -CF 2 -O-CH 3 or
Figure PCTCN2022098060-appb-000023
在本发明一优选实施方式中，R 4为氢或选自下列的取代基：卤素、C 1-C 6烷基、C 1-C 6卤代烷基；较佳地，R 4为氢。 In a preferred embodiment of the present invention, R 4 is hydrogen or a substituent selected from the following: halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; preferably, R 4 is hydrogen.
在本发明一优选实施方式中，所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，包括：In a preferred embodiment of the present invention, the heterocyclic compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs include:
Figure PCTCN2022098060-appb-000024
Figure PCTCN2022098060-appb-000024
Figure PCTCN2022098060-appb-000025
Figure PCTCN2022098060-appb-000025
在本发明第二方面，提供了一种药物组合物，所述药物组合物包括：如本发明第一方面中所述的作为TEAD抑制剂的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；和药学上可接受的载体。In the second aspect of the present invention, a pharmaceutical composition is provided, which includes: the heterocyclic compound as a TEAD inhibitor as described in the first aspect of the present invention, its tautomer, stereo isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and pharmaceutically acceptable carriers.
在本发明第三方面，提供了一种如本发明第一方面中所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途，或如本发明第二方面中所述的药物组合物的用途，所述用途包括：In the third aspect of the present invention, there is provided a heterocyclic compound as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts Or the purposes of prodrug, or the purposes of pharmaceutical composition as described in the second aspect of the present invention, described purposes comprises:
制备用于预防和/或治疗与TEAD表达增加相关的疾病的药物、药物组合物或制剂；和/或，Preparation of a medicament, pharmaceutical composition or formulation for the prevention and/or treatment of diseases associated with increased expression of TEAD; and/or,
制备用于降低/抑制TEAD表达、TEAD活性增加的药物、药物组合物或制剂；和/或，Preparation of medicaments, pharmaceutical compositions or preparations for reducing/inhibiting TEAD expression, increasing TEAD activity; and/or,
制备用于降低/抑制Hippo信号通路的药物、药物组合物或制剂。Medicines, pharmaceutical compositions or preparations for reducing/inhibiting Hippo signaling pathways are prepared.
在本发明一优选实施方式中，所述TEAD包括：TEAD1、TEAD2、TEAD3和TEAD4。In a preferred embodiment of the present invention, the TEADs include: TEAD1, TEAD2, TEAD3 and TEAD4.
在本发明一优选实施方式中，所述疾病是细胞增殖性病症；较佳地，所述细胞增殖性病症为癌症。In a preferred embodiment of the present invention, the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
本发明还提供一种治疗疾病的方法，包括给与患者治疗有效量的式(I)所示化合物、其互 变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐、前药或所述药物组合物中的至少一种。The present invention also provides a method for treating diseases, comprising administering to patients a therapeutically effective amount of the compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable At least one of a salt, a prodrug, or the pharmaceutical composition.
在本发明一优选实施方式中，所述疾病为与TEAD表达增加相关的疾病。In a preferred embodiment of the present invention, the disease is a disease associated with increased expression of TEAD.
在本发明一优选实施方式中，所述疾病是细胞增殖性病症；较佳地，所述细胞增殖性病症为癌症。In a preferred embodiment of the present invention, the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
在一些实施方案中，所述患者哺乳动物，优选是人。In some embodiments, the patient is a mammal, preferably a human.
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
有益效果Beneficial effect
本发明人经过广泛而深入地研究，意外地开发了一种用于TEAD抑制剂的杂环类化合物，所述杂环类化合物能明显抑制TEAD转录的活性，能明显抑制NCI-H226(ATCC，cat#CRL5826)的增殖，具有显著的抑制NCI-H226间皮瘤生长的作用，表现出优良的药代动力学性质，成药性好。After extensive and in-depth research, the inventors unexpectedly developed a heterocyclic compound for TEAD inhibitors, which can significantly inhibit the activity of TEAD transcription, and can significantly inhibit NCI-H226 (ATCC, cat#CRL5826) has a significant effect on inhibiting the growth of NCI-H226 mesothelioma, and exhibits excellent pharmacokinetic properties and good druggability.
所述杂环类化合物可以制备用于预防和/或治疗与TEAD表达增加相关的疾病的药物、药物组合物或制剂；和/或，制备用于降低/抑制TEAD表达、TEAD活性增加的药物、药物组合物或制剂；和/或，制备用于降低/抑制Hippo信号通路的药物、药物组合物或制剂。其中，所述TEAD包括：TEAD1、TEAD2、TEAD3和TEAD4；所述疾病优选是细胞增殖性病症；所述细胞增殖性病症优选为癌症。The heterocyclic compound can be used to prepare drugs, pharmaceutical compositions or preparations for preventing and/or treating diseases related to increased expression of TEAD; and/or, to prepare drugs for reducing/inhibiting TEAD expression and increasing TEAD activity, A pharmaceutical composition or preparation; and/or, preparation of a drug, pharmaceutical composition or preparation for reducing/inhibiting the Hippo signaling pathway. Wherein, the TEAD includes: TEAD1, TEAD2, TEAD3 and TEAD4; the disease is preferably a cell proliferative disorder; the cell proliferative disorder is preferably cancer.
术语定义与说明Definition and Explanation of Terms
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。Unless otherwise stated, the definitions of groups and terms recorded in the specification and claims of this application include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations and combined group definitions and compound structures should fall within the scope of the description of the present application.
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited in their entirety herein are hereby incorporated by reference in their entirety unless otherwise indicated. If there is more than one definition of a term herein, the definition in this chapter shall prevail.
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, unless the context clearly dictates otherwise, as used in the specification and claims, the singular includes the plural of the referents. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "comprises" as well as other forms, such as "comprises", "comprises" and "comprises" is not limiting.
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。Definitions of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectroscopy, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are set forth, terms employed herein in the relevant descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are those that are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构 式时所得到的在化学上等同的取代基。举例而言，CH 2O等同于OCH 2。如本文所用，
Figure PCTCN2022098060-appb-000026
Figure PCTCN2022098060-appb-000027
表示基团的连接位点。如本文所用，“R 1”、“R1”和“R 1”的含义相同，可相互替换。对于R 2等其它其他符号，类似定义的含义相同。 When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 . As used herein,
Figure PCTCN2022098060-appb-000026
Figure PCTCN2022098060-appb-000027
Indicates the attachment site of the group. As used herein, "R 1 ", "R1" and "R 1 " have the same meaning and can be substituted for each other. For other symbols such as R 2 , similar definitions have the same meanings.
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。The section headings used herein are for the purpose of organizing the article only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings shown below unless otherwise specified.
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～5的整数”应当理解为记载了0、1、2、3、4和5的每一个整数。For the numerical ranges described in the specification and claims of this application, when the numerical range is understood as an "integer", it should be understood as describing the two endpoints of the range and each integer within the range. For example, "an integer of 0 to 5" should be understood as describing every integer of 0, 1, 2, 3, 4, and 5.
在本申请中，在单独或作为其他取代基一部分时，术语“卤素”是指氟、氯、溴、碘。In this application, the term "halogen" means fluorine, chlorine, bromine, iodine alone or as part of another substituent.
如本文所用，在单独或作为其他取代基一部分时，术语"氨基"表示-NH 2。 As used herein, the term "amino" alone or as part of another substituent means -NH2 .
如本文所用，在单独或作为其他取代基一部分时，术语"硝基"表示-NO 2。 As used herein, the term "nitro" alone or as part of another substituent means -NO2 .
如本文所用，在单独或作为其他取代基一部分时，术语"氰基"表示-CN。As used herein, the term "cyano" by itself or as part of another substituent means -CN.
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基，叔丁基，戊基，异戊基，新戊基和己基。烷基可以是未取代的或被一个或多个合适的取代基取代。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。如本文所用，术语“烯基”表示无支链或支链的单价烃链，其含有一个或多个碳-碳双键。如本文所用，术语“炔基”是指无支链或支链的一价烃链，其含有一个或多个碳-碳三键。As used herein, the term "alkyl", alone or as part of another substituent, means consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and is bonded to the molecule by a single bond. The rest are connected straight or branched hydrocarbon chain groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl. An alkyl group can be unsubstituted or substituted with one or more suitable substituents. The alkyl groups may also be isotopomers of naturally abundant alkyl groups that are rich in carbon and/or hydrogen isotopes (ie, deuterium or tritium). As used herein, the term "alkenyl" means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
在单独或作为其他取代基一部分时，术语“C 1-C 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。术语“C 1-C 5烷基”应理解为表示具有1、2、3、4或5个碳原子的直链或支链饱和一价烃基。特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。 The term "C 1 -C 6 alkyl" alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. The term "C 1 -C 5 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4 or 5 carbon atoms. In particular, said groups have 1, 2 or 3 carbon atoms (“C 1 -C 3 alkyl”), for example methyl, ethyl, n-propyl or isopropyl.
在单独或作为其他取代基一部分时，术语“C 1-C 6烷氧基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基和氧原子组成，或者表示为C 1-C 6烷基-O-C 1-C 6烷基的定义如本说明书中所述，氧原子可以连接在C 1-C 6烷基的直链或直链的任何一个碳原子上。包括但不限于：甲氧基(CH 3-O-)、乙氧基(C 2H 5-O-)、丙氧基(C 3H 7-O-)、丁氧基(C 4H 9-O-)。 The term "C 1 -C 6 alkoxy" alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms Composed of and oxygen atom, or expressed as C 1 -C 6 alkyl-OC 1 -C 6 alkyl definition As described in this specification, the oxygen atom can be attached to a straight or straight chain of C 1 -C 6 alkyl on any carbon atom. Including but not limited to: methoxy (CH 3 -O-), ethoxy (C 2 H 5 -O-), propoxy (C 3 H 7 -O-), butoxy (C 4 H 9 -O-).
在单独或作为其他取代基一部分时，术语“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“C m-C n环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如，“3-10元环烷基”或者“C 3-C 10环烷基”是指含有3至10个碳原子的环状烷基，它可能包含1至3个环。所述环状烷基包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基，环丁基，环戊基，环己基和金刚烷基，或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。在一些实施方案中，环烷基可以是与芳基或杂芳基稠合的环烷基。 The terms "cycloalkyl" or "carbocyclyl" by themselves or as part of another substituent refer to a cyclic alkyl group. The term "mn-membered cycloalkyl" or " Cm - Cncycloalkyl " is understood to mean a saturated, unsaturated or partially saturated carbocycle having m to n atoms. For example, "3-10 membered cycloalkyl" or "C 3 -C 10 cycloalkyl" refers to a cyclic alkyl group containing 3 to 10 carbon atoms, which may contain 1 to 3 rings. The cyclic alkyl group includes monocyclic, bicyclic, tricyclic, spiro or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decahydronaphthalene rings. Cycloalkyl groups may be substituted with one or more substituents. In some embodiments, a cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl group.
在单独或作为其他取代基一部分时，术语“杂环”或“杂环烷基”或“杂环基”是指其中一个或多个(在一些实施方案中为1至3个)碳原子被杂原子替换的环烃基(如环烷基、环烯基、环炔基)，所述杂原子例如但不限于N、O、S和P。术语“m-n元杂环烷基”或者“C m-C n杂环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的环。例如，术语“4-10元杂环烷基”应理解为表示具有4至10个原子的饱和、不饱和或部分饱和的环。在一些实施方案中，杂环烷基可以是与芳基或杂芳基稠合的杂环烷基。当诸如3-8元的前缀用于表示杂环烷基时，碳的数目也意味着包括杂原子。包括单环、二环、三环、螺环或桥环。杂环的非限制性实例包括但不限于二氢吡啶、二氢哒嗪、二氢吡嗪，包括其被取代的形式，如杂环基包括但不限于1-甲基-6-氧代-1,6-二氢哒嗪-3-基、4-甲基-5-氧代-4,5-二氢吡嗪-2-基、2-氧代-1,2-二氢吡啶基等。 The term "heterocycle" or "heterocycloalkyl" or "heterocyclyl" by itself or as part of another substituent means a group in which one or more (in some embodiments 1 to 3) carbon atoms are replaced by Cycloalkyl (eg, cycloalkyl, cycloalkenyl, cycloalkynyl) substituted by heteroatoms such as, but not limited to, N, O, S, and P. The term "mn-membered heterocycloalkyl" or " Cm - Cnheterocycloalkyl " is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms. For example, the term "4-10 membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 10 atoms. In some embodiments, a heterocycloalkyl group can be a heterocycloalkyl group fused to an aryl or heteroaryl group. When a prefix such as 3-8 membered is used to denote heterocycloalkyl, the number of carbons is also meant to include heteroatoms. Including monocyclic, bicyclic, tricyclic, spiro or bridged rings. Non-limiting examples of heterocycles include, but are not limited to, dihydropyridine, dihydropyridazine, dihydropyrazine, including substituted forms thereof, such as heterocyclyl including, but not limited to, 1-methyl-6-oxo- 1,6-dihydropyridazin-3-yl, 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl, 2-oxo-1,2-dihydropyridyl, etc. .
在单独或作为其他取代基一部分时，术语“杂芳基/杂芳环”指包含1至4个杂原子、5至20个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5元或6元的。杂芳基的非限制性实例包括但不限于噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基和/或吩噁嗪基等。By itself or as part of another substituent, the term "heteroaryl/heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. Heteroaryl is preferably 5- or 6-membered. Non-limiting examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, tri Azolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzo Imidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives , such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazoline quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and/or phenoxazinyl, etc.
在单独或作为其他取代基一部分时，术语“卤代”可与术语“卤素取代”互换使用。“卤代烷基”或“卤素取代的烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基。The term "halo" is used interchangeably with the term "halogen substitution", alone or as part of another substituent. "Haloalkyl" or "halogen-substituted alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl.
本文提供的化合物，包括可用于制备本文提供的化合物的中间体，其含有反应性官能团(例如但不限于羧基，羟基和氨基部分)，还包括其保护的衍生物。“受保护的衍生物”是其中一个或多个反应性位点被一个或多个保护基团(也称为保护基团)封闭的那些化合物。合适的羧基部分保护基包括苄基，叔丁基等，以及同位素等。合适的氨基和酰氨基保护基包括乙酰基，三氟乙酰基，叔丁氧基羰基，苄氧基羰基等。合适的羟基保护基包括苄基等。其他合适的保护基团是本领域普通技术人员所熟知的。The compounds provided herein, including intermediates useful in the preparation of the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof. "Protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also known as protecting groups). Suitable protecting groups for the carboxyl moiety include benzyl, tert-butyl, etc., and isotopes, etc. Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable hydroxy protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or circumstance. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl.
在本申请中，术语“盐”或“药学上可接受的盐”，包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。The term "stereoisomer" refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形 式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。Depending on the choice of starting materials and processes, the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985,62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。When the bond with the chiral carbon in the formula of the present invention is described as a straight line, it should be understood that the (R) and (S) two configurations of the chiral carbon and the resulting enantiomerically pure compounds and Mixtures of both are included within the scope of the general formula. Graphical representations of racemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of a stereocenter is indicated by wedge-shaped bonds and dashed-line bonds.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In this application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
在本申请中，术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。In this application, the term "solvate" means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent force, and when the solvent is water, it is a hydrate.
在本申请中，术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。In the present application, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound. Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)，氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
在本申请中，术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。In this application, the term "excipient" means a pharmaceutically acceptable inert ingredient. Examples of categories of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
本文所用的术语“治疗”和其它类似的同义词包括以下含义：As used herein, the term "treatment" and other similar synonyms include the following meanings:
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；(i) preventing the occurrence of a disease or condition in a mammal, especially when such mammal is susceptible to the disease or condition but has not been diagnosed as having the disease or condition;
(ii)抑制疾病或病症，即遏制其发展；(ii) inhibiting a disease or condition, i.e. arresting its development;
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者(iii) ameliorating a disease or condition, i.e., causing regression of the state of the disease or condition; or
(iv)减轻该疾病或病症所造成的症状。(iv) Alleviating the symptoms caused by the disease or condition.
各步骤的反应，反应温度可因溶剂、起始原料、试剂等适宜选择，反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后，目标化合物可按常用方法自反应体系中进行分离、提纯等步骤，如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响 下一步反应的情况下，目标化合物也可不经过分离、纯化直接进入下一步反应。本发明各步反应优选地在惰性溶剂中进行，所述惰性溶剂包括但不限于：甲苯、苯、水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃二氯甲烷、三氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。In the reaction of each step, the reaction temperature can be appropriately selected according to the solvent, starting material, reagent, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc. After the reaction of each step, the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next step reaction, the target compound can also directly enter the next step reaction without separation and purification. Each step reaction of the present invention is preferably carried out in an inert solvent, and the inert solvent includes but not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethylmethylene Sulfone, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof things.
附图说明Description of drawings
图1为化合物I-2抑制NCI-H226间皮瘤生长曲线图。Fig. 1 is a graph showing compound I-2 inhibiting the growth of NCI-H226 mesothelioma.
具体实施方式Detailed ways
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
中间体A1：中间体A1的制备Intermediate A1: Preparation of Intermediate A1
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000028
Figure PCTCN2022098060-appb-000028
第一步：1,2-二(6-氟吡啶-3-基)二硫化物(A1-2)的合成Step 1: Synthesis of 1,2-bis(6-fluoropyridin-3-yl) disulfide (A1-2)
Figure PCTCN2022098060-appb-000029
Figure PCTCN2022098060-appb-000029
将5-溴-2-氟吡啶(A1-1)(50.0g,284mmol)溶于四氢呋喃(500mL)中，置换氮气，降温至-40℃，缓慢滴加异丙基氯化镁-氯化锂(1.30M,120.2mL)的四氢呋喃溶液，滴加完毕后缓慢升温至室温20℃搅拌2小时。再将反应液降至-40℃，将分散在甲苯(500mL)的硫粉(5.08g,158mmol)缓慢滴加到上述反应液。滴加结束后再将反应体系缓慢升至室温20℃搅拌1小时。反应结束后氮气保护下将反应液倒入铁氰化钾(46.8g,142mmol)和氢氧化钾(15.9g,284mmol)的混合水溶液(1000mL)中室温搅拌过夜。用乙酸乙酯(500mL×3)萃取，合并有机相，然后用饱和食盐水(1000mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品用正相快速硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝0～30％)得到1,2-二(6-氟吡啶-3-基)二硫化物(A1-2)(15g,黄色固体，收率39.14％)。5-Bromo-2-fluoropyridine (A1-1) (50.0g, 284mmol) was dissolved in tetrahydrofuran (500mL), nitrogen was replaced, the temperature was lowered to -40°C, and isopropylmagnesium chloride-lithium chloride (1.30 M, 120.2 mL) in tetrahydrofuran, after the dropwise addition was completed, the temperature was slowly raised to room temperature at 20°C and stirred for 2 hours. Then the reaction liquid was lowered to -40°C, and sulfur powder (5.08 g, 158 mmol) dispersed in toluene (500 mL) was slowly added dropwise to the above reaction liquid. After the dropwise addition, the reaction system was slowly raised to room temperature at 20° C. and stirred for 1 hour. After the reaction was completed, the reaction solution was poured into a mixed aqueous solution (1000 mL) of potassium ferricyanide (46.8 g, 142 mmol) and potassium hydroxide (15.9 g, 284 mmol) under nitrogen protection and stirred overnight at room temperature. Extract with ethyl acetate (500mL×3), combine the organic phases, then wash with saturated brine (1000mL), dry the organic phases with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product, which is separated and purified by normal phase flash silica gel column ( Petroleum ether: ethyl acetate (V/V)=0～30%) to obtain 1,2-bis(6-fluoropyridin-3-yl) disulfide (A1-2) (15g, yellow solid, yield 39.14 %).
第二步：5-(氯(四氟)-λ 6-硫烷基)-2-氟吡啶(A1-3)的合成 The second step: the synthesis of 5-(chloro(tetrafluoro)-λ 6 -sulfanyl)-2-fluoropyridine (A1-3)
Figure PCTCN2022098060-appb-000030
Figure PCTCN2022098060-appb-000030
在手套箱内操作，把干燥过的氟化钾(7.25g,125mmol)，三氯异氰脲酸(14.5g,62.4mmol)，1,2-二(6-氟吡啶-3-基)二硫化物(A1-2)(1.00g,3.90mmol)溶于干燥的乙腈(20.0mL)，再加入三氟乙酸(44.5mg,390μmol)，密闭后室温搅拌反应16小时。反应结束后，在氮气氛围中取出反应上清液，氮气吹干乙腈，得到5-(氯(四氟)-λ 6-硫烷基)-2-氟吡啶(A1-3)，粗品立即直接用于下一步。 Operating in a glove box, dry potassium fluoride (7.25g, 125mmol), trichloroisocyanuric acid (14.5g, 62.4mmol), 1,2-bis(6-fluoropyridin-3-yl) di Sulfide (A1-2) (1.00g, 3.90mmol) was dissolved in dry acetonitrile (20.0mL), and trifluoroacetic acid (44.5mg, 390μmol) was added, sealed and stirred at room temperature for 16 hours. After the reaction, the reaction supernatant was taken out in a nitrogen atmosphere, and the acetonitrile was blown dry with nitrogen to obtain 5-(chloro(tetrafluoro)-λ 6 -sulfanyl)-2-fluoropyridine (A1-3), and the crude product was directly for the next step.
第三步：2-氟-5-(五氟-λ 6-硫烷基)吡啶(A1-4)的合成 The third step: the synthesis of 2-fluoro-5-(pentafluoro-λ 6 -sulfanyl)pyridine (A1-4)
Figure PCTCN2022098060-appb-000031
Figure PCTCN2022098060-appb-000031
在手套箱内操作，在聚四氟乙烯闷罐中，把上一步的粗品5-(氯(四氟)-λ 6-硫烷基)-2-氟吡啶(A1-3)(1.00g,4.17mmol)溶于5mL二氯甲烷，加入氟化银(1.06g,8.35mmol)。加完料后密闭，在120℃反应48小时。反应完成后降至室温，滤掉固体，得到含有2-氟-5-(五氟-λ 6-硫烷基)吡啶(A1-4)的反应液，直接用于下一步。 Operate in a glove box, in a polytetrafluoroethylene stuffy tank, put the crude product 5-(chloro(tetrafluoro)-λ 6 -sulfanyl)-2-fluoropyridine (A1-3) (1.00g, 4.17mmol) was dissolved in 5mL of dichloromethane, and silver fluoride (1.06g, 8.35mmol) was added. After the addition of the material, it was sealed and reacted at 120°C for 48 hours. After the reaction was completed, it was lowered to room temperature, and the solid was filtered off to obtain a reaction solution containing 2-fluoro-5-(pentafluoro-λ 6 -sulfanyl)pyridine (A1-4), which was directly used in the next step.
第四步：-5-(五氟-λ 6-硫烷基)-2-氨基吡啶(A1)的合成 Step 4: Synthesis of -5-(pentafluoro-λ 6 -sulfanyl)-2-aminopyridine (A1)
Figure PCTCN2022098060-appb-000032
Figure PCTCN2022098060-appb-000032
把2-氟-5-(五氟-λ 6-硫烷基)吡啶(5.00g,11.2mmol)溶于二氯甲烷(50.0mL)，加入氨水(50.0mL,181mmol)，在聚四氟乙烯闷罐中加热至105℃反应16小时。反应结束后降至室温，加入水(50.0mL),用甲基叔丁基醚萃取(50.0mL×3),盐水(100mL×2)洗涤，干燥浓缩，得到粗品，粗品用正相快速硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝0～50％)得到5-(五氟-λ 6-硫烷基)-2-氨基吡啶(A1)(0.51g,收率21％)。 Dissolve 2-fluoro-5-(pentafluoro-λ 6 -sulfanyl)pyridine (5.00g, 11.2mmol) in dichloromethane (50.0mL), add ammonia (50.0mL, 181mmol), and dissolve in polytetrafluoroethylene Heated to 105°C in a stuffy jar to react for 16 hours. Cool down to room temperature after the reaction, add water (50.0mL), extract with methyl tert-butyl ether (50.0mL × 3), wash with brine (100mL × 2), dry and concentrate to obtain the crude product, which is used on a normal phase flash silica gel column Separation and purification (petroleum ether: ethyl acetate (V/V) = 0-50%) gave 5-(pentafluoro-λ 6 -sulfanyl)-2-aminopyridine (A1) (0.51g, yield 21% ).
1H NMR(400MHz,CDCl 3_d):δ8.44(d,J＝1.6Hz,1H),7.74(dd,J＝2.8,9.2Hz,1H),6.46(d,J＝9.2Hz,1H),4.95(br s,2H)。 1 H NMR (400MHz, CDCl 3 _d): δ8.44 (d, J = 1.6Hz, 1H), 7.74 (dd, J = 2.8, 9.2Hz, 1H), 6.46 (d, J = 9.2Hz, 1H) , 4.95 (br s, 2H).
19F NMR(400MHz,CDCl 3_d):δ85.83(q,J＝158.0Hz,1F),66.25(br d,J＝160.8Hz,4F)。 19 F NMR (400MHz, CDCl 3 _d): δ85.83 (q, J=158.0Hz, 1F), 66.25 (br d, J=160.8Hz, 4F).
LCMS:M/Z(ESI):221.0[M+H] +。 LCMS: M/Z (ESI): 221.0 [M+H] + .
中间体A2：中间体A2的制备Intermediate A2: Preparation of Intermediate A2
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000033
Figure PCTCN2022098060-appb-000033
在0℃氮气保护下，向1-(4-甲氧基苯基)-N-甲基甲胺(6.63g,43.9mmol)和二异丙基乙胺(9.58ml,54.8mmol)的二氯甲烷(100ml)溶液中滴加3-溴-4-氟苯-1-磺酰氯(A2-1)(10g,36.6 mmol)。反应混合物在氮气保护0℃下搅拌0.5小时。然后升温到25℃氮气保护下搅拌2小时。反应结束后，反应液用100mL二氯甲烷稀释，有机相用盐酸水溶液洗(0.5M,50mL x 3)，收集有机相，用无水Na 2SO 4干燥，过滤，浓缩得到粗品，粗品用石油醚/甲基叔丁基醚(10/1,v/v)(100mL)打浆得到3-溴-4-氟-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(A2)(12g,收率84.5％)。 Under the protection of nitrogen at 0°C, the dichloromethane of 1-(4-methoxyphenyl)-N-methylmethylamine (6.63g, 43.9mmol) and diisopropylethylamine (9.58ml, 54.8mmol) 3-Bromo-4-fluorobenzene-1-sulfonyl chloride (A2-1) (10 g, 36.6 mmol) was added dropwise to the methane (100 ml) solution. The reaction mixture was stirred at 0°C under nitrogen for 0.5 hours. Then the temperature was raised to 25° C. and stirred for 2 hours under the protection of nitrogen. After the reaction, the reaction solution was diluted with 100mL dichloromethane, the organic phase was washed with aqueous hydrochloric acid (0.5M, 50mL x 3), the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product, which was washed with petroleum Ether/methyl tert-butyl ether (10/1, v/v) (100mL) was beaten to obtain 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide ( A2) (12g, yield 84.5%).
中间体A3：中间体A3的制备Intermediate A3: Preparation of Intermediate A3
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000034
Figure PCTCN2022098060-appb-000034
在0℃氮气保护下，向1-(4-甲氧基苯基)-N-甲基甲胺(6.63g,43.9mmol)和二异丙基乙胺(9.58ml,54.8mmol)的二氯甲烷(100ml)溶液中滴加5-溴-6-氯吡啶-3-磺酰氯(A3-1)(10.6g,36.6mmol)。反应混合物在氮气保护0℃下搅拌0.5小时。然后升温到25℃氮气保护下搅拌2小时。反应结束后，反应液用100mL二氯甲烷稀释，有机相用盐酸水溶液洗(0.5M,50mL x 3)，收集有机相，用无水Na 2SO 4干燥，过滤，浓缩得到粗品，粗品用石油醚/甲基叔丁基醚(10：1,v/v)(100mL)打浆得到5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(A3)(10g，收率67.5％)。 Under the protection of nitrogen at 0°C, the dichloromethane of 1-(4-methoxyphenyl)-N-methylmethylamine (6.63g, 43.9mmol) and diisopropylethylamine (9.58ml, 54.8mmol) 5-Bromo-6-chloropyridine-3-sulfonyl chloride (A3-1) (10.6g, 36.6mmol) was added dropwise to the methane (100ml) solution. The reaction mixture was stirred at 0°C under nitrogen for 0.5 hours. Then the temperature was raised to 25° C. and stirred for 2 hours under the protection of nitrogen. After the reaction, the reaction solution was diluted with 100mL dichloromethane, the organic phase was washed with aqueous hydrochloric acid (0.5M, 50mL x 3), the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product, which was washed with petroleum Ether/methyl tert-butyl ether (10:1, v/v) (100mL) was beaten to obtain 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3- Sulfonamide (A3) (10 g, yield 67.5%).
中间体A4:中间体A4的制备Intermediate A4: Preparation of Intermediate A4
合成路线如下：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000035
Figure PCTCN2022098060-appb-000035
在25℃和氮气保护下，向3-溴-4-氟-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(A2)(12g,30.9mmol)和双联频哪醇硼酸酯(11.77g,46.4mmol)的1,4-二氧六环(20mL)溶液中加入无水醋酸钾(6.07g,61.8mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(2.262g,3.09mmol)。反应混合物在110℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液用硅藻土过滤，滤液浓缩得到粗品，粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝100:1-1:1)得到4-氟-N-(4-甲氧基苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯磺酰胺(A4)(10.0g，收率74.7％)。Under nitrogen protection at 25°C, to 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (A2) (12g, 30.9mmol) and double pina Add anhydrous potassium acetate (6.07g, 61.8mmol) and [1,1'-bis(diphenylphosphine base) ferrocene] palladium dichloride (2.262 g, 3.09 mmol). The reaction mixture was stirred at 110°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a crude product, which was separated and purified with a silica gel column (petroleum ether:ethyl acetate (V/V)=100:1-1:1 ) to give 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol Alk-2-yl)benzenesulfonamide (A4) (10.0 g, yield 74.7%).
中间体A5：中间体A5的制备Intermediate A5: Preparation of Intermediate A5
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000036
Figure PCTCN2022098060-appb-000036
中间体A3-2的合成参考专利公开WO2018130563A1，在0℃氮气保护下，向1-(4-甲氧 基苯基)-N-氘代甲基甲胺(A3-2)(3.3g,22mmol)和二异丙基乙胺(4.8ml,27.4mmol)的二氯甲烷(100ml)溶液中滴加5-溴-6-氯吡啶-3-磺酰氯(A3-1)(5.3g,18.3mmol)。反应混合物在氮气保护0℃下搅拌0.5小时。然后升温到25℃氮气保护下搅拌2小时。反应结束后，反应液用100mL二氯甲烷稀释，有机相用盐酸水溶液洗(0.5M,50mL x 3)，收集有机相，用无水Na 2SO 4干燥，过滤，浓缩得到粗品，粗品用石油醚/甲基叔丁基醚(10：1,v/v)(100mL)打浆得到5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(A5)(4.8g，收率66％)。 The synthesis of intermediate A3-2 refers to the patent publication WO2018130563A1, under the protection of nitrogen at 0°C, to 1-(4-methoxyphenyl)-N-deuteromethylmethylamine (A3-2) (3.3g, 22mmol ) and diisopropylethylamine (4.8ml, 27.4mmol) in dichloromethane (100ml) solution was added dropwise 5-bromo-6-chloropyridine-3-sulfonyl chloride (A3-1) (5.3g, 18.3mmol ). The reaction mixture was stirred at 0°C under nitrogen for 0.5 hours. Then the temperature was raised to 25° C. and stirred for 2 hours under the protection of nitrogen. After the reaction, the reaction solution was diluted with 100mL dichloromethane, the organic phase was washed with aqueous hydrochloric acid (0.5M, 50mL x 3), the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product, which was washed with petroleum Ether/methyl tert-butyl ether (10:1, v/v) (100mL) was beaten to obtain 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3- Sulfonamide (A5) (4.8 g, yield 66%).
实施例1：目标化合物I-1的制备Embodiment 1: the preparation of target compound I-1
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000037
Figure PCTCN2022098060-appb-000037
第一步：3-溴-N-(4-甲氧基苄基)-N-甲基-4-((5-(五氟-λ 6-硫烷基)吡啶-2-基)氨基)苯磺酰胺(B1-1)的合成 The first step: 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((5-(pentafluoro-λ 6 -sulfanyl)pyridin-2-yl)amino) Synthesis of Benzenesulfonamide (B1-1)
Figure PCTCN2022098060-appb-000038
Figure PCTCN2022098060-appb-000038
在0℃氮气保护下，向3-溴-4-氟-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(A2)(0.6g,1.545mmol)的N,N-二甲基甲酰胺(10mL)溶液中分批加入NaH(0.124g,3.09mmol,60％)，然后将5-(五氟-λ 6-硫烷基)吡啶-2-胺(0.408g,1.854mmol)缓慢加入到反应液中。反应液在25℃氮气保护下搅拌18小时。反应结束后，将反应液缓慢滴入50mL冰水混合物中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用80mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到3-溴-N-(4-甲氧基苄基)-N-甲基-4-((5-(五氟-λ 6-硫烷基)吡啶-2-基)氨基)苯磺酰胺(B1-1)(0.48g,收率53％)。 Under the protection of nitrogen at 0°C, the N,N- NaH (0.124g, 3.09mmol, 60%) was added in portions to a solution of dimethylformamide (10mL), and then 5-(pentafluoro-λ 6 -sulfanyl)pyridin-2-amine (0.408g, 1.854 mmol) was slowly added to the reaction solution. The reaction solution was stirred at 25° C. for 18 hours under nitrogen protection. After the reaction, the reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((5- (Pentafluoro-λ 6 -sulfanyl)pyridin-2-yl)amino)benzenesulfonamide (B1-1) (0.48g, yield 53%).
第二步：N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((5-(五氟-λ 6-硫烷基)吡啶-2-基)氨基)苯磺酰胺(B1-2)的合成 The second step: N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((5-(pentafluoro-λ 6 Synthesis of -sulfanyl)pyridin-2-yl)amino)benzenesulfonamide (B1-2)
Figure PCTCN2022098060-appb-000039
Figure PCTCN2022098060-appb-000039
在25℃氮气保护下，向3-溴-N-(4-甲氧基苄基)-N-甲基-4-((5-(五氟-λ6-硫烷基)吡啶-2-基)氨基)苯磺酰胺(B1-1)(0.48g,0.816mmol)和1-甲基-4-(三丁基锡烷基)-1H-咪唑(0.333g,0.897mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入四(三苯基膦)钯(0.047g,0.041mmol)。反应混合物在120℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((5-(五氟-λ 6-硫烷基)吡啶-2-基)氨基)苯磺酰胺(B1-2)(0.45g，收率93％)。 Under nitrogen protection at 25°C, 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((5-(pentafluoro-λ6-sulfanyl)pyridin-2-yl )amino)benzenesulfonamide (B1-1) (0.48g, 0.816mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (0.333g, 0.897mmol) of N,N-dimethyl Tetrakis(triphenylphosphine)palladium (0.047g, 0.041mmol) was added to a solution of phenylformamide (5mL). The reaction mixture was stirred at 120°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H- Imidazol-4-yl)-4-((5-(pentafluoro-λ 6 -sulfanyl)pyridin-2-yl)amino)benzenesulfonamide (B1-2) (0.45 g, yield 93%).
第三步：N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((5-(五氟-λ 6-硫烷基)吡啶-2-基)氨基)苯磺酰胺(I-1)的合成 The third step: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((5-(pentafluoro-λ 6 -sulfanyl)pyridin-2-yl)amino ) Synthesis of Benzenesulfonamide (I-1)
Figure PCTCN2022098060-appb-000040
Figure PCTCN2022098060-appb-000040
在25℃下，向N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((5-(五氟-λ 6-硫烷基)吡啶-2-基)氨基)苯磺酰胺(B1-2)(450mg,0.763mmol)的二氯甲烷(10mL)的溶液中加入三氟乙酸(1mL)。反应混合物在25℃搅拌18小时，反应结束后，将反应液浓缩得到粗品，粗品用二氯甲烷(20mL)稀释，有机相用饱和碳酸氢钠水溶液(10mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品用制备硅胶板分离纯化(乙酸乙酯)得到N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((5-(五氟-λ 6-硫烷基)吡啶-2-基)氨基)苯磺酰胺(I-1)(0.185g,收率53％)。 At 25°C, N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((5-(pentafluoro- To a solution of λ 6 -sulfanyl)pyridin-2-yl)amino)benzenesulfonamide (B1-2) (450 mg, 0.763 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 18 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((5-( Pentafluoro-λ 6 -sulfanyl)pyridin-2-yl)amino)benzenesulfonamide (I-1) (0.185g, yield 53%).
1H NMR(400MHz,CDCl 3)δ12.31(s,1H),8.88(d,J＝8.8Hz,1H),8.65(s,1H),8.00(d,J＝2.0Hz,1H),7.82(s,1H),7.84-7.81(m,1H),7.71-7.68(m,1H),7.56(s,1H),7.37(s,1H),6.86(d,J＝9.2Hz,1H),4.32(d,J＝4.8Hz,1H),3.80(s,3H),2.68(d,J＝5.6Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ12.31(s, 1H), 8.88(d, J=8.8Hz, 1H), 8.65(s, 1H), 8.00(d, J=2.0Hz, 1H), 7.82 (s,1H),7.84-7.81(m,1H),7.71-7.68(m,1H),7.56(s,1H),7.37(s,1H),6.86(d,J=9.2Hz,1H), 4.32 (d, J = 4.8Hz, 1H), 3.80 (s, 3H), 2.68 (d, J = 5.6Hz, 1H).
LC-MS,M/Z(ESI):470.1[M+H] +。 LC-MS, M/Z (ESI): 470.1 [M+H] + .
实施例2：化合物I-2的制备Embodiment 2: the preparation of compound 1-2
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000041
Figure PCTCN2022098060-appb-000041
第一步：3-溴-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B2-1)的合成 The first step: 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide Synthesis of (B2-1)
Figure PCTCN2022098060-appb-000042
Figure PCTCN2022098060-appb-000042
在0℃下，向4-(五氟-λ 6-硫烷基)苯胺(390mg,1.8mmol)的N,N-二甲基甲酰胺(10mL)溶液中分批加入NaH(300mg,7.5mmol,60％)，然后将3-溴-4-氟-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(585mg,1.5mmol)加入到反应液中。反应液在25℃下搅拌18小时。反应结束后，将反应液缓慢滴入50mL冰水混合物中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用80mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到3-溴-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B2-1)(618mg,收率70％)。 To a solution of 4-(pentafluoro-λ 6 -sulfanyl)aniline (390 mg, 1.8 mmol) in N,N-dimethylformamide (10 mL) was added NaH (300 mg, 7.5 mmol) in portions at 0°C , 60%), and then 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (585mg, 1.5mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 18 hours. After the reaction, the reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((4- (Pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B2-1) (618 mg, yield 70%).
第二步：N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B2-2)的合成 The second step: N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -Synthesis of sulfanyl)phenyl)amino)benzenesulfonamide (B2-2)
Figure PCTCN2022098060-appb-000043
Figure PCTCN2022098060-appb-000043
在25℃氮气保护下，向3-溴-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B2-1)(0.6g,1.02mmol)和1-甲基-4-(三丁基锡烷基)-1H-咪唑(417mg,1.12mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入四(三苯基膦)钯(59mg,0.051mmol)。反应混合物在120℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中， 混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B2-2)(390mg,收率67％)。 Under nitrogen protection at 25°C, to 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino ) N,N-dimethylformamide of benzenesulfonamide (B2-1) (0.6g, 1.02mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (417mg, 1.12mmol) (6 mL) solution was added tetrakis(triphenylphosphine)palladium (59 mg, 0.051 mmol). The reaction mixture was stirred at 120°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), and the organic phase was collected and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H- Imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B2-2) (390 mg, yield 67%).
第三步：N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-2)的合成 The third step: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonate Synthesis of Amide (I-2)
Figure PCTCN2022098060-appb-000044
Figure PCTCN2022098060-appb-000044
在25℃下，向N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B2-2)(390mg,0.68mmol)的二氯甲烷(10mL)的溶液中加入三氟乙酸(1mL)。反应混合物在25℃搅拌18小时，反应结束后，将反应液浓缩得到粗品，粗品用二氯甲烷(20mL)稀释，有机相用饱和碳酸氢钠水溶液(10mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品用制备硅胶板分离纯化(乙酸乙酯)得到N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-2)(0.21g,收率70％)。 At 25°C, N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro- To a solution of λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B2-2) (390 mg, 0.68 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 18 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-( Pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (I-2) (0.21 g, yield 70%).
1HNMR(400MHz,CDCl 3)δ10.98(s,1H),7.97(d,J＝2.4Hz,1H),7.69-7.66(m,2H),7.60-7.57(m,1H),7.61-7.49(m,2H),7.34-7.33(m,1H),7.27-7.25(m,1H),4.37-4.33(m,1H),3.78(s,3H),2.67(d,J＝5.6Hz,1H) 1 HNMR (400MHz, CDCl 3 ) δ10.98(s, 1H), 7.97(d, J=2.4Hz, 1H), 7.69-7.66(m, 2H), 7.60-7.57(m, 1H), 7.61-7.49 (m,2H),7.34-7.33(m,1H),7.27-7.25(m,1H),4.37-4.33(m,1H),3.78(s,3H),2.67(d,J＝5.6Hz,1H )
LC-MS,M/Z(ESI):469.0[M+H] +。 LC-MS, M/Z (ESI): 469.0 [M+H] + .
实施例3：目标化合物I-3的制备Embodiment 3: the preparation of target compound 1-3
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000045
Figure PCTCN2022098060-appb-000045
第一步：3-溴-N-(4-甲氧基苄基)-N-甲基-4-((3-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B3-1)的合成 The first step: 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((3-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide Synthesis of (B3-1)
Figure PCTCN2022098060-appb-000046
Figure PCTCN2022098060-appb-000046
在0℃下，向3-(五氟-λ 6-硫烷基)苯胺(260mg,1.2mmol)的N,N-二甲基甲酰胺(10mL)溶液中分批加入NaH(200mg,5.0mmol,60％)，然后将3-溴-4-氟-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(390mg,1.0mmol)加入到反应液中。反应液在25℃下搅拌18小时。反应结束后，将反应液缓慢滴入50mL冰水混合物中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用80mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到3-溴-N-(4-甲氧基苄基)-N-甲基-4-((3-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B3-1)(412mg,收率70％)。 To a solution of 3-(pentafluoro-λ 6 -sulfanyl)aniline (260 mg, 1.2 mmol) in N,N-dimethylformamide (10 mL) was added NaH (200 mg, 5.0 mmol) in portions at 0°C , 60%), and then 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (390mg, 1.0mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 18 hours. After the reaction, the reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((3- (Pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B3-1) (412 mg, yield 70%).
第二步：N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((3-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B3-2)的合成 The second step: N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((3-(pentafluoro-λ 6 -Synthesis of sulfanyl)phenyl)amino)benzenesulfonamide (B3-2)
Figure PCTCN2022098060-appb-000047
Figure PCTCN2022098060-appb-000047
在25℃氮气保护下，向3-溴-N-(4-甲氧基苄基)-N-甲基-4-((3-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B3-1)(0.6g,1.02mmol)和1-甲基-4-(三丁基锡烷基)-1H-咪唑(417mg,1.12mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入四(三苯基膦)钯(59mg,0.051mmol)。反应混合物在120℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((3-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B3-2)(400mg,收率67％)。 Under nitrogen protection at 25°C, to 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((3-(pentafluoro-λ 6 -sulfanyl)phenyl)amino ) N,N-dimethylformamide of benzenesulfonamide (B3-1) (0.6g, 1.02mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (417mg, 1.12mmol) (6 mL) solution was added tetrakis(triphenylphosphine)palladium (59 mg, 0.051 mmol). The reaction mixture was stirred at 120°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H- Imidazol-4-yl)-4-((3-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B3-2) (400 mg, yield 67%).
第三步：N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((3-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-3)的合成 The third step: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((3-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonate Synthesis of Amide (I-3)
Figure PCTCN2022098060-appb-000048
Figure PCTCN2022098060-appb-000048
在25℃下，向N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((3-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B3-2)(400mg,0.68mmol)的二氯甲烷(10mL)的溶液中加入三氟乙酸(1mL)。反应混合物在25℃搅拌18小时，反应结束后，将反应液浓缩得到粗品，粗品用二氯甲烷(20mL)稀释，有机相用饱和碳酸氢钠水溶液(10mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品用制备硅胶板分离纯化(乙酸乙酯)得到N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((3-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-3)(0.25g,收率80％)。 At 25°C, N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((3-(pentafluoro- To a solution of λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B3-2) (400 mg, 0.68 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 18 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain a crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((3-( Pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (I-3) (0.25g, yield 80%).
1H NMR(400MHz,CDCl 3)δ10.88(s,1H),7.96(d,J＝2.4Hz,1H),7.64(s,1H),7.57-7.54(m,1H),7.52(s,1H),7.43-7.41(m,3H),7.35-7.33(m,2H),4.27-4.23(m,1H),3.79(s,3H),2.67 (d,J＝5.6Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ10.88(s, 1H), 7.96(d, J=2.4Hz, 1H), 7.64(s, 1H), 7.57-7.54(m, 1H), 7.52(s, 1H), 7.43-7.41(m, 3H), 7.35-7.33(m, 2H), 4.27-4.23(m, 1H), 3.79(s, 3H), 2.67 (d, J=5.6Hz, 1H).
LC-MS,M/Z(ESI):469.2[M+H] +。 LC-MS, M/Z (ESI): 469.2 [M+H] + .
实施例4：目标化合物I-4的制备Embodiment 4: the preparation of target compound 1-4
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000049
Figure PCTCN2022098060-appb-000049
第一步：3-溴-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苄基)氨基)苯磺酰胺(B3-1)的合成 The first step: 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((4-(pentafluoro-λ 6 -sulfanyl)benzyl)amino)benzenesulfonamide Synthesis of (B3-1)
Figure PCTCN2022098060-appb-000050
Figure PCTCN2022098060-appb-000050
向(4-(五氟-λ 6-硫烷基)苯基)甲胺(280mg,1.2mmol)的N,N-二甲基甲酰胺(10mL)加入3-溴-4-氟-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(390mg,1.0mmol)加入到反应液中。反应液在140℃微波下搅拌2小时。反应结束后，将反应液缓慢滴入50mL冰水混合物中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用80mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到3-溴-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苄基)氨基)苯磺酰胺(B4-1)(500mg,收率83％)。 To (4-(pentafluoro-λ 6 -sulfanyl)phenyl)methanamine (280 mg, 1.2 mmol) in N,N-dimethylformamide (10 mL) was added 3-bromo-4-fluoro-N- (4-Methoxybenzyl)-N-methylbenzenesulfonamide (390 mg, 1.0 mmol) was added to the reaction solution. The reaction solution was stirred under microwave at 140° C. for 2 hours. After the reaction, the reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((4- (Pentafluoro-λ 6 -sulfanyl)benzyl)amino)benzenesulfonamide (B4-1) (500 mg, yield 83%).
LC-MS,M/Z(ESI):601.2[M+H] +。 LC-MS, M/Z (ESI): 601.2 [M+H] + .
第二步：N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苄基)氨基)苯磺酰胺(B4-2)的合成 The second step: N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 Synthesis of -sulfanyl)benzyl)amino)benzenesulfonamide (B4-2)
Figure PCTCN2022098060-appb-000051
Figure PCTCN2022098060-appb-000051
在25℃氮气保护下，向3-溴-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苄基)氨基)苯磺酰胺(B4-1)(0.613g,1.02mmol)和1-甲基-4-(三丁基锡烷基)-1H-咪唑(417mg,1.12mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入四(三苯基膦)钯(59mg,0.051mmol)。反应混合物在120℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中， 混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苄基)氨基)苯磺酰胺(B4-2)(500mg,收率81％)。 Under nitrogen protection at 25°C, to 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((4-(pentafluoro-λ 6 -sulfanyl)benzyl)amino ) N,N-dimethylformamide of benzenesulfonamide (B4-1) (0.613g, 1.02mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (417mg, 1.12mmol) (6 mL) solution was added tetrakis(triphenylphosphine)palladium (59 mg, 0.051 mmol). The reaction mixture was stirred at 120°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), and the organic phase was collected and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H- Imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)benzyl)amino)benzenesulfonamide (B4-2) (500 mg, yield 81%).
LC-MS,M/Z(ESI):603.2[M+H] +。 LC-MS, M/Z (ESI): 603.2 [M+H] + .
第三步：N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苄基)氨基)苯磺酰胺(I-4)的合成 The third step: N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)benzyl)amino)benzenesulfonate Synthesis of Amide (I-4)
Figure PCTCN2022098060-appb-000052
Figure PCTCN2022098060-appb-000052
在25℃下，向N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苄基)氨基)苯磺酰胺(B4-2)(409mg,0.68mmol)的二氯甲烷(10mL)的溶液中加入三氟乙酸(1mL)。反应混合物在25℃搅拌18小时，反应结束后，将反应液浓缩得到粗品，粗品用二氯甲烷(20mL)稀释，有机相用饱和碳酸氢钠水溶液(10mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品用制备硅胶板分离纯化(乙酸乙酯)得到N-甲基-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苄基)氨基)苯磺酰胺(I-4)(0.2g,收率60.9％)。 At 25°C, N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro- To a solution of λ 6 -sulfanyl)benzyl)amino)benzenesulfonamide (B4-2) (409 mg, 0.68 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 18 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-( Pentafluoro-λ 6 -sulfanyl)benzyl)amino)benzenesulfonamide (I-4) (0.2 g, yield 60.9%).
LC-MS,M/Z(ESI):483.2[M+H] +。 LC-MS, M/Z (ESI): 483.2 [M+H] + .
实施例5：目标化合物I-5的制备Embodiment 5: the preparation of target compound 1-5
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000053
Figure PCTCN2022098060-appb-000053
第一步：5-溴-N-(4-甲氧基苄基)-N-甲基-6-((4-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B5-1)的合成 The first step: 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridine-3 -Synthesis of sulfonamide (B5-1)
Figure PCTCN2022098060-appb-000054
Figure PCTCN2022098060-appb-000054
在0℃下，向4-(五氟-λ 6-硫烷基)苯胺(390mg,1.8mmol)的N,N-二甲基甲酰胺(10mL)溶液中分批加入NaH(300mg,7.5mmol,60％)，然后将5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(A3)(608mg,1.5mmol)加入到反应液中。反应液在25℃下搅拌18小时。反应结束后，将反应液缓慢滴入50mL冰水混合物中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用80mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到5-溴-N-(4-甲氧基苄基)-N-甲基-6-((4-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B5-1)(600mg,收率68％)。 To a solution of 4-(pentafluoro-λ 6 -sulfanyl)aniline (390 mg, 1.8 mmol) in N,N-dimethylformamide (10 mL) was added NaH (300 mg, 7.5 mmol) in portions at 0°C , 60%), then 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A3) (608mg, 1.5mmol) was added to the reaction solution middle. The reaction solution was stirred at 25°C for 18 hours. After the reaction, the reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4- (Pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (B5-1) (600 mg, yield 68%).
LC-MS,M/Z(ESI):588.2[M+H] +。 LC-MS, M/Z (ESI): 588.2 [M+H] + .
第二步：N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B5-2)的合成 The second step: N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro-λ 6 Synthesis of -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (B5-2)
Figure PCTCN2022098060-appb-000055
Figure PCTCN2022098060-appb-000055
在25℃氮气保护下，向5-溴-N-(4-甲氧基苄基)-N-甲基-6-((4-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B5-1)(0.598g,1.02mmol)和1-甲基-4-(三丁基锡烷基)-1H-咪唑(417mg,1.12mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入四(三苯基膦)钯(59mg,0.051mmol)。反应混合物在120℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B5-2)(400mg,收率66％)。 Under the protection of nitrogen at 25°C, 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino ) pyridine-3-sulfonamide (B5-1) (0.598g, 1.02mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (417mg, 1.12mmol) N,N-dimethyl Tetrakis(triphenylphosphine)palladium (59mg, 0.051mmol) was added to a solution of phenylformamide (6mL). The reaction mixture was stirred at 120°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H- Imidazol-4-yl)-6-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (B5-2) (400 mg, yield 66%).
LC-MS,M/Z(ESI):590.1[M+H] +。 LC-MS, M/Z (ESI): 590.1 [M+H] + .
第三步：N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(I-5)的合成 The third step: N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridine- Synthesis of 3-sulfonamide (I-5)
Figure PCTCN2022098060-appb-000056
Figure PCTCN2022098060-appb-000056
在25℃下，向N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B5-2)(401mg,0.68mmol)的二氯甲烷(10mL)的溶液中加入三氟乙酸(1mL)。反应混合物在25℃搅拌18小时，反应结束后，将反应液浓缩得到粗品，粗品用二氯甲烷(20mL)稀释，有机相用饱和碳酸氢钠水溶液(10mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品用制备硅胶板分离纯化(乙酸乙酯)得到N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(I-5)(0.2g,收率63％)。 At 25°C, N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro- To a solution of λ 6 -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (B5-2) (401 mg, 0.68 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 18 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-( Pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (I-5) (0.2 g, yield 63%).
LC-MS,M/Z(ESI):470.1[M+H] +。 LC-MS, M/Z (ESI): 470.1 [M+H] + .
实施例6：目标化合物I-6的制备Embodiment 6: the preparation of target compound 1-6
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000057
Figure PCTCN2022098060-appb-000057
第一步：5-溴-N-(4-甲氧基苄基)-N-甲基-6-((3-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B6-1)的合成 The first step: 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((3-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridine-3 -Synthesis of sulfonamide (B6-1)
Figure PCTCN2022098060-appb-000058
Figure PCTCN2022098060-appb-000058
在0℃下，向3-(五氟-λ 6-硫烷基)苯胺(260mg,1.2mmol)的N,N-二甲基甲酰胺(10mL)溶液中分批加入NaH(200mg,5.0mmol,60％)，然后将5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(405mg,1.0mmol)加入到反应液中。反应液在25℃下搅拌18小时。反应结束后， 将反应液缓慢滴入50mL冰水混合物中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用80mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到5-溴-N-(4-甲氧基苄基)-N-甲基-6-((3-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B6-1)(400mg,收率68％)。 To a solution of 3-(pentafluoro-λ 6 -sulfanyl)aniline (260 mg, 1.2 mmol) in N,N-dimethylformamide (10 mL) was added NaH (200 mg, 5.0 mmol) in portions at 0°C , 60%), and then 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (405mg, 1.0mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 18 hours. After the reaction, the reaction solution was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((3- (Pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (B6-1) (400 mg, yield 68%).
LC-MS,M/Z(ESI):588.1[M+H] +。 LC-MS, M/Z (ESI): 588.1 [M+H] + .
第二步：N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((3-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B6-2)的合成 The second step: N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((3-(pentafluoro-λ 6 Synthesis of -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (B6-2)
Figure PCTCN2022098060-appb-000059
Figure PCTCN2022098060-appb-000059
在25℃氮气保护下，向5-溴-N-(4-甲氧基苄基)-N-甲基-6-((3-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B6-1)(0.598g,1.02mmol)和1-甲基-4-(三丁基锡烷基)-1H-咪唑(417mg,1.12mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入四(三苯基膦)钯(59mg,0.051mmol)。反应混合物在120℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((3-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B6-2)(400mg,收率67％)。 Under the protection of nitrogen at 25°C, to 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((3-(pentafluoro-λ 6 -sulfanyl)phenyl)amino ) pyridine-3-sulfonamide (B6-1) (0.598g, 1.02mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (417mg, 1.12mmol) N,N-dimethyl Tetrakis(triphenylphosphine)palladium (59mg, 0.051mmol) was added to a solution of phenylformamide (6mL). The reaction mixture was stirred at 120°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H- Imidazol-4-yl)-6-((3-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (B6-2) (400 mg, yield 67%).
LC-MS,M/Z(ESI):590.1[M+H] +。 LC-MS, M/Z (ESI): 590.1 [M+H] + .
第三步：N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((3-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(I-6)的合成 The third step: N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((3-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridine- Synthesis of 3-sulfonamide (I-6)
Figure PCTCN2022098060-appb-000060
Figure PCTCN2022098060-appb-000060
在25℃下，向N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((3-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(B6-2)(400mg,0.68mmol)的二氯甲烷(10mL)的溶液中加入三氟乙酸(1mL)。反应混合物在25℃搅拌18小时，反应结束后，将反应液浓缩得到粗品，粗品用二氯甲烷(20mL)稀释，有机相用饱和碳酸氢钠水溶液(10mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品用制备硅胶板分离纯化(乙酸乙酯)得到N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((3-(五氟-λ 6-硫烷基)苯基)氨基)吡啶-3-磺酰胺(I-6)(0.25g,收率78％)。 At 25°C, N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((3-(pentafluoro- To a solution of λ 6 -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (B6-2) (400 mg, 0.68 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 18 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((3-( Pentafluoro-λ 6 -sulfanyl)phenyl)amino)pyridine-3-sulfonamide (I-6) (0.25g, yield 78%).
LC-MS,M/Z(ESI):470.2[M+H] +。 LC-MS, M/Z (ESI): 470.2 [M+H] + .
实施例7：目标化合物I-7的制备Embodiment 7: the preparation of target compound 1-7
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000061
Figure PCTCN2022098060-appb-000061
第一步：5-溴-N-(4-甲氧基苄基)-N-甲基-6-((4-(五氟-λ 6-硫烷基)苄基)氨基)吡啶-3-磺酰胺(B7-1)的合成 The first step: 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(pentafluoro-λ 6 -sulfanyl)benzyl)amino)pyridine-3 -Synthesis of sulfonamide (B7-1)
Figure PCTCN2022098060-appb-000062
Figure PCTCN2022098060-appb-000062
向(4-(五氟-λ 6-硫烷基)苯基)甲胺(280mg,1.2mmol)的N,N-二甲基甲酰胺(10mL)加入5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(A3)(405mg,1.0mmol)加入到反应液中。反应液在140℃微波下搅拌2小时。反应结束后，将反应液缓慢滴入50mL冰水混合物中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用80mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到5-溴-N-(4-甲氧基苄基)-N-甲基-6-((4-(五氟-λ 6-硫烷基)苄基)氨基)吡啶-3-磺酰胺(B7-1)(500mg,收率83％)。 To (4-(pentafluoro-λ 6 -sulfanyl)phenyl)methanamine (280 mg, 1.2 mmol) in N,N-dimethylformamide (10 mL) was added 5-bromo-6-chloro-N- (4-Methoxybenzyl)-N-methylpyridine-3-sulfonamide (A3) (405 mg, 1.0 mmol) was added to the reaction solution. The reaction solution was stirred under microwave at 140° C. for 2 hours. After the reaction, the reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4- (Pentafluoro-λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B7-1) (500 mg, yield 83%).
LC-MS,M/Z(ESI):602.2[M+H] +。 LC-MS, M/Z (ESI): 602.2 [M+H] + .
第二步：N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ 6-硫烷基)苄基)氨基)吡啶-3-磺酰胺(B7-2)的合成 The second step: N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro-λ 6 Synthesis of -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B7-2)
Figure PCTCN2022098060-appb-000063
Figure PCTCN2022098060-appb-000063
在25℃氮气保护下，向5-溴-N-(4-甲氧基苄基)-N-甲基-6-((4-(五氟-λ 6-磺酰基)苄基)氨基)吡啶-3-磺酰胺(B7-1)(0.613g,1.02mmol)和1-甲基-4-(三丁基锡烷基)-1H-咪唑(417mg,1.12mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入四(三苯基膦)钯(59mg,0.051mmol)。反应混合物在120℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混 合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ 6-硫烷基)苄基)氨基)吡啶-3-磺酰胺(B7-2)(500mg,收率81％)。 Under the protection of nitrogen at 25°C, to 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(pentafluoro-λ 6 -sulfonyl)benzyl)amino) N,N-dimethyl of pyridine-3-sulfonamide (B7-1) (0.613g, 1.02mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (417mg, 1.12mmol) To the solution of formamide (6 mL) was added tetrakis(triphenylphosphine)palladium (59 mg, 0.051 mmol). The reaction mixture was stirred at 120°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H- Imidazol-4-yl)-6-((4-(pentafluoro-λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B7-2) (500 mg, yield 81%).
LC-MS,M/Z(ESI):604.2[M+H] +。 LC-MS, M/Z (ESI): 604.2 [M+H] + .
第三步：N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ 6-硫烷基)苄基)氨基)吡啶-3-磺酰胺(I-7)的合成 The third step: N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro-λ 6 -sulfanyl)benzyl)amino)pyridine- Synthesis of 3-sulfonamide (I-7)
Figure PCTCN2022098060-appb-000064
Figure PCTCN2022098060-appb-000064
在25℃下，向N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ 6-硫烷基)苄基)氨基)吡啶-3-磺酰胺(B7-2)(410mg,0.68mmol)的二氯甲烷(10mL)的溶液中加入三氟乙酸(1mL)。反应混合物在25℃搅拌18小时，反应结束后，将反应液浓缩得到粗品，粗品用二氯甲烷(20mL)稀释，有机相用饱和碳酸氢钠水溶液(10mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品用制备硅胶板分离纯化(乙酸乙酯)得到N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ 6-硫烷基)苄基)氨基)吡啶-3-磺酰胺(I-7)(0.2g,收率61％)。 At 25°C, N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro- To a solution of λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B7-2) (410 mg, 0.68 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 18 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-( Pentafluoro-λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (I-7) (0.2 g, yield 61%).
LC-MS,M/Z(ESI):484.2[M+H] +。 LC-MS, M/Z (ESI): 484.2 [M+H] + .
实施例8：目标化合物I-8的制备Embodiment 8: the preparation of target compound 1-8
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000065
Figure PCTCN2022098060-appb-000065
第一步：2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-胺(B8-2)的合成The first step: the synthesis of 2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridin-4-amine (B8-2)
Figure PCTCN2022098060-appb-000066
Figure PCTCN2022098060-appb-000066
在25℃氮气保护下，向2-氯-6-甲氧基吡啶-4-胺(B8-1)(1.61g,10.2mmol)和1-甲基-4-(三丁基锡烷基)-1H-咪唑(4.17g,11.2mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入四(三苯基膦)钯(590mg,0.51mmol)。反应混合物在120℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝3:1-1:1)得到2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-胺(B8-2)(1.8g,收率86％)。 Under nitrogen protection at 25°C, 2-chloro-6-methoxypyridin-4-amine (B8-1) (1.61g, 10.2mmol) and 1-methyl-4-(tributylstannyl)-1H - To a solution of imidazole (4.17g, 11.2mmol) in N,N-dimethylformamide (20mL) was added tetrakis(triphenylphosphine)palladium (590mg, 0.51mmol). The reaction mixture was stirred at 120°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1-1:1) to obtain 2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridin-4-amine (B8-2) (1.8 g, yield 86%).
LC-MS,M/Z(ESI):205.2[M+H] +。 LC-MS, M/Z (ESI): 205.2 [M+H] + .
第二步：4-溴-2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶(B8-3)的合成The second step: the synthesis of 4-bromo-2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridine (B8-3)
Figure PCTCN2022098060-appb-000067
Figure PCTCN2022098060-appb-000067
在0℃氮气保护下，向2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-胺(B8-2)(1.6g,7.8mmol)的四氢呋喃(20mL)溶液中加入溴化亚铜(1.28g，9mmol)，滴加亚硝酸异戊酯(1.05g，9mmol)。反应混合物在75℃下搅拌2小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝5:1-1:1)得到4-溴-2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶(B8-3)(1.5g,收率72％)。 Under nitrogen protection at 0°C, 2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridin-4-amine (B8-2) (1.6g, 7.8mmol) in tetrahydrofuran ( 20 mL) solution was added cuprous bromide (1.28 g, 9 mmol), and isoamyl nitrite (1.05 g, 9 mmol) was added dropwise. The reaction mixture was stirred at 75°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1-1:1) to obtain 4-bromo-2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridine (B8-3) (1.5 g, yield 72%).
LC-MS,M/Z(ESI):268.2[M+H] +。 LC-MS, M/Z (ESI): 268.2 [M+H] + .
第三步：4-(苄硫基)-2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶(B8-4)的合成The third step: the synthesis of 4-(benzylthio)-2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridine (B8-4)
Figure PCTCN2022098060-appb-000068
Figure PCTCN2022098060-appb-000068
在25℃氮气保护下，向4-溴-2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶(B8-3)(1g,3.74mmol)和苯甲硫醇(0.5g,4mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入四(三苯基膦)钯(590mg,0.51mmol)。反应混合物在80℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝3:1-1:1)得到4-(苄硫基)-2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶(B8-4)(1g,收率86％)。 Under the protection of nitrogen at 25°C, 4-bromo-2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridine (B8-3) (1g, 3.74mmol) and benzylthio To a solution of alcohol (0.5g, 4mmol) in N,N-dimethylformamide (20mL) was added tetrakis(triphenylphosphine)palladium (590mg, 0.51mmol). The reaction mixture was stirred at 80°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1-1:1) to obtain 4-(benzylthio)-2-methoxy-6-(1-methyl-1H-imidazole-4 -yl)pyridine (B8-4) (1 g, yield 86%).
LC-MS,M/Z(ESI):312.2[M+H] +。 LC-MS, M/Z (ESI): 312.2 [M+H] + .
第四步：2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-磺酰氯(B8-5)的合成Step 4: Synthesis of 2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridine-4-sulfonyl chloride (B8-5)
Figure PCTCN2022098060-appb-000069
Figure PCTCN2022098060-appb-000069
在0℃氮气保护下，向4-(苄硫基)-2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶(B8-4)(1g,3.21mmol)的二氯甲烷(10mL)溶液中加入二氯海因(788mg,4mmol)。反应混合物在0℃下搅拌2小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝10:1-3:1)得到2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-磺酰氯(B8-5)(800mg,收率85％)。 Under nitrogen protection at 0°C, 4-(benzylthio)-2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridine (B8-4) (1g, 3.21mmol) Dichlorohydantoin (788 mg, 4 mmol) was added to a solution of dichloromethane (10 mL). The reaction mixture was stirred at 0°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1-3:1) to obtain 2-methoxy-6-(1-methyl-1H-imidazol-4-yl)pyridine-4-sulfonate Acid chloride (B8-5) (800 mg, yield 85%).
LC-MS,M/Z(ESI):288.2[M+H] +。 LC-MS, M/Z (ESI): 288.2 [M+H] + .
第五步：2-甲氧基-N-(4-甲氧基苄基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-磺酰胺(B8-6)的合成The fifth step: 2-methoxy-N-(4-methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridine-4-sulfonamide ( Synthesis of B8-6)
Figure PCTCN2022098060-appb-000070
Figure PCTCN2022098060-appb-000070
在0℃氮气保护下，向2-甲氧基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-磺酰氯(B8-5)(800mg,2.78mmol)的二氯甲烷(10mL)溶液中加N,N-二异丙基乙胺(1.07g,8.34mmol)和1-(4-甲氧基苯基)-N-甲基甲胺(453mg,3mmol)。反应混合物在0℃下搅拌2小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝10:1-3:1)得到2-甲氧基-N-(4-甲氧基苄基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-磺酰胺(B8-6)(900mg,收率81％)。 Under the protection of nitrogen at 0 ° C, the dichloro Add N,N-diisopropylethylamine (1.07g, 8.34mmol) and 1-(4-methoxyphenyl)-N-methylmethylamine (453mg, 3mmol) to the methane (10mL) solution. The reaction mixture was stirred at 0°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1-3:1) to obtain 2-methoxy-N-(4-methoxybenzyl)-N-methyl-6-(1 -Methyl-1H-imidazol-4-yl)pyridine-4-sulfonamide (B8-6) (900 mg, yield 81%).
LC-MS,M/Z(ESI):403.2[M+H] +。 LC-MS, M/Z (ESI): 403.2 [M+H] + .
第六步：2-羟基-N-(4-甲氧基苄基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-磺酰胺(B8-7)的合成The sixth step: 2-hydroxy-N-(4-methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridine-4-sulfonamide (B8- 7) Synthesis of
Figure PCTCN2022098060-appb-000071
Figure PCTCN2022098060-appb-000071
在0℃氮气保护下，向2-甲氧基-N-(4-甲氧基苄基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-磺酰胺(B8-6)(900mg,2.23mmol)的二氯甲烷(10mL)溶液中加三溴化硼(1.1g,4.46mmol)。反应混合物在0℃下搅拌2小时。反应结束后，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝10:1-3:1)得到2-羟基-N-(4-甲氧基苄基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-磺酰胺(B8-7)(500mg,收率57％)。 Under the protection of nitrogen at 0°C, 2-methoxy-N-(4-methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridine-4 - To a solution of sulfonamide (B8-6) (900 mg, 2.23 mmol) in dichloromethane (10 mL) was added boron tribromide (1.1 g, 4.46 mmol). The reaction mixture was stirred at 0°C for 2 hours. After the reaction, the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), and the organic phase was collected and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-3:1) to obtain 2-hydroxy-N-(4-methoxybenzyl)-N-methyl-6-(1-methyl yl-1H-imidazol-4-yl)pyridine-4-sulfonamide (B8-7) (500mg, yield 57%).
LC-MS,M/Z(ESI):389.2[M+H] +。 LC-MS, M/Z (ESI): 389.2 [M+H] + .
第七步：N-(4-甲氧基苄基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(五氟-λ 6-硫烷基)苄基)-1,2-二氢吡啶-4-磺酰胺(B8-8)的合成 The seventh step: N-(4-methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)-2-oxo-1-(4-(five Synthesis of Fluoro-λ 6 -sulfanyl)benzyl)-1,2-dihydropyridine-4-sulfonamide (B8-8)
Figure PCTCN2022098060-appb-000072
Figure PCTCN2022098060-appb-000072
向2-羟基-N-(4-甲氧基苄基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡啶-4-磺酰胺(B8-7)(500mg,1.28mmol)的二甲基亚砜(5mL)溶液中加碳酸铯(832mg,2.56mmol)和(4-(溴甲基)苯基)五氟-λ 6-硫烷(600mg,2mmol)。反应混合物在90℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(PE:EA＝5:1-3:1)得到N-(4-甲氧基苄基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(五氟-λ 6-硫烷基)苄基)-1,2-二氢吡啶-4-磺酰胺(B8-8)(300mg,收率42％)。 To 2-hydroxyl-N-(4-methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridine-4-sulfonamide (B8-7)( Add cesium carbonate (832mg, 2.56mmol) and (4-(bromomethyl)phenyl)pentafluoro-λ 6 -sulfane (600mg, 2mmol) to a solution of 500mg, 1.28mmol) in dimethyl sulfoxide (5mL) . The reaction mixture was stirred at 90°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (PE:EA=5:1-3:1) to obtain N-(4-methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazole-4 -yl)-2-oxo-1-(4-(pentafluoro-λ 6 -sulfanyl)benzyl)-1,2-dihydropyridine-4-sulfonamide (B8-8) (300mg, yield rate of 42%).
LC-MS,M/Z(ESI):547.2[M+H] +。 LC-MS, M/Z (ESI): 547.2 [M+H] + .
第八步：N-甲基-6-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(五氟-λ 6-硫烷基)苄基)-1,2-二氢吡啶-4-磺酰胺(I-8)的合成 The eighth step: N-methyl-6-(1-methyl-1H-imidazol-4-yl)-2-oxo-1-(4-(pentafluoro-λ 6 -sulfanyl)benzyl) Synthesis of -1,2-dihydropyridine-4-sulfonamide (I-8)
Figure PCTCN2022098060-appb-000073
Figure PCTCN2022098060-appb-000073
在25℃下，向N-(4-甲氧基苄基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(三氟甲基)苄基)-1,2-二氢吡啶-4-磺胺(B8-8)(300mg,0.5mmol)的二氯甲烷(10mL)的溶液中加入三氟乙酸(1mL)。反应混合物在25℃搅拌18小时，反应结束后，将反应液浓缩得到粗品，粗品用二氯甲烷(20mL)稀释，有机相用饱和碳酸氢钠水溶液(10mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，粗品用制备硅胶板分离纯化(乙酸乙酯)得到N-甲基-6-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(五氟-λ 6-硫烷基)苄基)-1,2-二氢吡啶-4-磺酰胺(I-8)(100mg,收率42％)。 At 25°C, to N-(4-methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)-2-oxo-1-(4- To a solution of (trifluoromethyl)benzyl)-1,2-dihydropyridine-4-sulfonamide (B8-8) (300 mg, 0.5 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 18 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL), and the organic phase was washed with anhydrous sodium sulfate Dry, filter, and concentrate to obtain the crude product, which is separated and purified on a preparative silica gel plate (ethyl acetate) to obtain N-methyl-6-(1-methyl-1H-imidazol-4-yl)-2-oxo-1- (4-(Pentafluoro-λ 6 -sulfanyl)benzyl)-1,2-dihydropyridine-4-sulfonamide (I-8) (100 mg, yield 42%).
LC-MS,M/Z(ESI):427.2[M+H] +。 LC-MS, M/Z (ESI): 427.2 [M+H] + .
实施例9：目标化合物I-9的制备Embodiment 9: the preparation of target compound 1-9
4-((4-(二氟(甲氧基)甲基)苯基)胺基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)苯磺酰胺4-((4-(Difluoro(methoxy)methyl)phenyl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzenesulfonamide
Figure PCTCN2022098060-appb-000074
Figure PCTCN2022098060-appb-000074
化合物I-9的合成参照化合物I-2的合成方法，将4-(五氟-λ 6-硫烷基)苯胺换为4-(二氟(甲氧基)甲基)苯胺，得到目标化合物4-((4-(二氟(甲氧基)甲基)苯基)氨基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)苯磺酰胺(I-9)。 Compound I-9 was synthesized with reference to the synthetic method of compound I-2, replacing 4-(pentafluoro-λ 6 -sulfanyl)aniline with 4-(difluoro(methoxy)methyl)aniline to obtain the target compound 4-((4-(difluoro(methoxy)methyl)phenyl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzenesulfonamide (I- 9).
LC-MS,M/Z(ESI):422.2[M+H] +。 LC-MS, M/Z (ESI): 422.2 [M+H] + .
实施例10：目标化合物I-10的制备Embodiment 10: the preparation of target compound I-10
4-((4-(环丙氧基二氟甲基)苯基)氨基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)苯磺酰胺4-((4-(cyclopropoxydifluoromethyl)phenyl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzenesulfonamide
Figure PCTCN2022098060-appb-000075
Figure PCTCN2022098060-appb-000075
化合物I-10的合成参照化合物I-2的合成方法，将4-(五氟-λ 6-硫烷基)苯胺换为4-(环丙氧 基二氟甲基)苯胺，得到目标化合物4-((4-(环丙氧基二氟甲基)苯基)氨基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)苯磺酰胺(I-10)。 Compound 1-10 was synthesized with reference to the synthetic method of compound 1-2, and 4-(pentafluoro-λ 6 -sulfanyl)aniline was replaced with 4-(cyclopropoxydifluoromethyl)aniline to obtain target compound 4 -((4-(cyclopropoxydifluoromethyl)phenyl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzenesulfonamide (I-10) .
LC-MS,M/Z(ESI):448.2[M+H] +。 LC-MS, M/Z (ESI): 448.2 [M+H] + .
实施例11：目标化合物I-11的制备Embodiment 11: Preparation of target compound I-11
4-((5-(二氟(甲氧基)甲基)吡啶-2-基)氨基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)苯磺酰胺4-((5-(Difluoro(methoxy)methyl)pyridin-2-yl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzenesulfonamide
Figure PCTCN2022098060-appb-000076
Figure PCTCN2022098060-appb-000076
化合物I-11的合成参照化合物I-2的合成方法，将4-(五氟-λ 6-硫烷基)苯胺换为5-(二氟(甲氧基)甲基)吡啶-2-胺，得到目标化合物4-((5-(二氟(甲氧基)甲基)吡啶-2-基)氨基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)苯磺酰胺(I-11)。 Compound I-11 was synthesized with reference to the synthetic method of compound I-2, replacing 4-(pentafluoro-λ 6 -sulfanyl)aniline with 5-(difluoro(methoxy)methyl)pyridin-2-amine , to obtain the target compound 4-((5-(difluoro(methoxy)methyl)pyridin-2-yl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl ) Benzenesulfonamide (I-11).
LC-MS,M/Z(ESI):423.2[M+H] +。 LC-MS, M/Z (ESI): 423.2 [M+H] + .
实施例12：目标化合物I-12的制备Embodiment 12: Preparation of target compound 1-12
4-((5-(环丙氧基二氟甲基)吡啶-2-基)氨基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)苯磺酰胺4-((5-(cyclopropoxydifluoromethyl)pyridin-2-yl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzenesulfonamide
Figure PCTCN2022098060-appb-000077
Figure PCTCN2022098060-appb-000077
化合物I-12的合成参照化合物I-2的合成方法，将4-(五氟-λ 6-硫烷基)苯胺换为5-(环丙氧基二氟甲基)吡啶-2-胺，得到目标化合物4-((5-(环丙氧基二氟甲基)吡啶-2-基)氨基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)苯磺酰胺(I-12)。 The synthesis of compound I-12 refers to the synthetic method of compound I-2, and 4-(pentafluoro-λ 6 -sulfanyl)aniline is replaced by 5-(cyclopropoxydifluoromethyl)pyridin-2-amine, To obtain the target compound 4-((5-(cyclopropoxydifluoromethyl)pyridin-2-yl)amino)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)benzene Sulfonamide (I-12).
LC-MS,M/Z(ESI):449.2[M+H] +。 LC-MS, M/Z (ESI): 449.2 [M+H] + .
实施例13：目标化合物I-13的制备Embodiment 13: Preparation of target compound 1-13
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000078
Figure PCTCN2022098060-appb-000078
第一步：4-氟-N-(4-甲氧苄基)-N-甲基-3-(5-甲基-1,3,4-噁二唑-2-基)苯磺酰胺(B13-1)的制备The first step: 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)benzenesulfonamide ( B13-1) Preparation
Figure PCTCN2022098060-appb-000079
Figure PCTCN2022098060-appb-000079
将2-溴-5-甲基-1,3,4-噁二唑(1.01g,6.20mmol)和4-氟-N-(4-甲氧苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯磺酰胺(A4，3.00g,5.97mmol)溶解在乙腈(30.0mL)和水(30.0mL)中，加碳酸钾(2.86g,20.7mmol)和1,1-双(二苯基膦)二茂铁氯化钯(504mg,689μmol)，然后在氮气保护下95℃搅拌反应10小时。将反应液浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-5:1)得到4-氟-N-(4-甲氧苄基)-N-甲基-3-(5-甲基-1,3,4-噁二唑-2-基)苯磺酰胺(B13-1，700mg，产率25.6％)。2-Bromo-5-methyl-1,3,4-oxadiazole (1.01g, 6.20mmol) and 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A4, 3.00 g, 5.97 mmol) was dissolved in acetonitrile (30.0 mL) and Add potassium carbonate (2.86g, 20.7mmol) and 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (504mg, 689μmol) to water (30.0mL), then stir the reaction at 95°C under nitrogen protection 10 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1-5:1) to obtain 4-fluoro-N-(4-methoxybenzyl)-N -Methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)benzenesulfonamide (B13-1, 700 mg, yield 25.6%).
LC-MS,M/Z(ESI):392.1[M+H] + LC-MS, M/Z(ESI):392.1[M+H] +
第二步：N-(4-甲氧基苄基)-N-甲基-3-(5-甲基-1,3,4-噁二唑-2-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B13-2)的制备 The second step: N-(4-methoxybenzyl)-N-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-4-((4- Preparation of (pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B13-2)
Figure PCTCN2022098060-appb-000080
Figure PCTCN2022098060-appb-000080
向4-氟-N-(4-甲氧苄基)-N-甲基-3-(5-甲基-1,3,4-噁二唑-2-基)苯磺酰胺(B13-1，700mg,1.79mmol)的二甲基亚砜(5.00mL)溶液中加入4-(五氟-λ 6-硫烷基)苯胺(431mg,1.97mmol)和氢氧化钾(201mg,3.58mmol)，在90℃反应10小时。反应完成后，将反应液用水(40.0mL)稀释，然后用乙酸乙酯(30.0mL*4)萃取，合并有机相，用水(30.0mL*3)洗涤，硫酸钠干燥，浓缩得到粗品。残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-3:1)得到N-(4-甲氧基苄基)-N-甲基-3-(5-甲基-1,3,4-噁二唑-2-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B13-2，600mg)，直接用于下一步。 To 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)benzenesulfonamide (B13-1 , 700mg, 1.79mmol) in dimethylsulfoxide (5.00mL) was added 4-(pentafluoro-λ 6 -sulfanyl)aniline (431mg, 1.97mmol) and potassium hydroxide (201mg, 3.58mmol), The reaction was carried out at 90° C. for 10 hours. After the reaction was complete, the reaction solution was diluted with water (40.0 mL), then extracted with ethyl acetate (30.0 mL*4), the organic phases were combined, washed with water (30.0 mL*3), dried over sodium sulfate, and concentrated to obtain a crude product. The residue was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-3:1) to obtain N-(4-methoxybenzyl)-N-methyl-3-(5 -Methyl-1,3,4-oxadiazol-2-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B13-2, 600mg ), used directly in the next step.
第三步：N-甲基-3-(5-甲基-1,3,4-噁二唑-2-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-13)的制备 The third step: N-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)benzene Base) amino) benzenesulfonamide (I-13) preparation
Figure PCTCN2022098060-appb-000081
Figure PCTCN2022098060-appb-000081
将N-(4-甲氧基苄基)-N-甲基-3-(5-甲基-1,3,4-噁二唑-2-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B13-2，500mg,847μmol)溶解在三氟乙酸(10.0mL)中，70℃反应2小时。反应完成后，把反应液用1M的氢氧化钠水溶液，调至pH＝7～8，然后用乙酸乙酯(30.0mL*3)萃取，合并有机相，硫酸钠干燥，浓缩得到粗品，用高效液相色谱仪分离纯化，分离方法为(柱子：Phenomenex C18 75*30mm*3μm；溶剂：A＝水+0.225体积％甲酸(99.0％)，B＝乙腈；梯度：42％-72％，7分钟)，得到N-甲基-3-(5-甲基-1,3,4-噁二唑-2-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-13，67.1mg,产率16.8％)。 N-(4-methoxybenzyl)-N-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-4-((4-(pentafluoro -λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B13-2, 500 mg, 847 μmol) was dissolved in trifluoroacetic acid (10.0 mL), and reacted at 70°C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH = 7-8 with 1M aqueous sodium hydroxide solution, then extracted with ethyl acetate (30.0 mL*3), the organic phases were combined, dried over sodium sulfate, concentrated to obtain the crude product, and used high-efficiency Separation and purification by liquid chromatography, the separation method is (column: Phenomenex C18 75*30mm*3μm; solvent: A=water+0.225vol% formic acid (99.0%), B=acetonitrile; gradient: 42%-72%, 7 minutes ), to give N-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl )amino)benzenesulfonamide (I-13, 67.1 mg, 16.8% yield).
1H NMR(400MHz,DMSO-d 6)δ9.71(s,1H),8.25-8.30(d,1H)7.86-7.95(d,2H),7.74-7.83(m,1H),7.63-7.71(m,1H),7.43-7.50(m,3H),2.63(s,3H),2.44(d,3H) 1 H NMR (400MHz,DMSO-d 6 )δ9.71(s,1H),8.25-8.30(d,1H)7.86-7.95(d,2H),7.74-7.83(m,1H),7.63-7.71( m,1H),7.43-7.50(m,3H),2.63(s,3H),2.44(d,3H)
LC-MS,M/Z(ESI):471.0[M+H] + LC-MS, M/Z(ESI):471.0[M+H] +
实施例14：目标化合物I-14的制备Embodiment 14: Preparation of Target Compound I-14
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000082
Figure PCTCN2022098060-appb-000082
第一步：3-(1,5-二甲基-1H-1,2,4-三唑-3-基)-4-氟-N-(4-甲氧苄基)-N-甲基苯磺酰胺(B14-1)的制备The first step: 3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-4-fluoro-N-(4-methoxybenzyl)-N-methyl Preparation of Benzenesulfonamide (B14-1)
Figure PCTCN2022098060-appb-000083
Figure PCTCN2022098060-appb-000083
将3-溴-1,5-二甲基-1H-1,2,4-三唑(807mg,4.58mmol)和4-氟-N-(4-甲氧苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯磺酰胺(A4，2.10g,4.82mmol)溶解在乙腈(40.0mL)和水(20.0mL)中，加入碳酸钾(1.33g,9.65mmol)和1,1-双(二苯基膦)二茂铁氯化钯(353mg,482μmol)，然后在氮气保护下95℃搅拌反应10小时。将反应液浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-5:1)得到3-(1,5-二甲基-1H-1,2,4-三唑-3-基)-4-氟-N-(4-甲氧苄基)-N-甲基苯磺酰胺(B14-1，500mg，产率25.6％)。Mix 3-bromo-1,5-dimethyl-1H-1,2,4-triazole (807mg, 4.58mmol) and 4-fluoro-N-(4-methoxybenzyl)-N-methyl- 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A4, 2.10g, 4.82mmol) was dissolved in acetonitrile (40.0 mL) and water (20.0mL), potassium carbonate (1.33g, 9.65mmol) and 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (353mg, 482μmol) were added, and then 95 The reaction was stirred at ℃ for 10 hours. The reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1-5:1) to obtain 3-(1,5-dimethyl-1H-1,2 ,4-triazol-3-yl)-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (B14-1, 500 mg, yield 25.6%).
第二步：3-(1,5-二甲基-1H-1,2,4-三唑-3-基)-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B14-2)的制备 The second step: 3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-N-(4-methoxybenzyl)-N-methyl-4- Preparation of ((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B14-2)
Figure PCTCN2022098060-appb-000084
Figure PCTCN2022098060-appb-000084
向3-(1,5-二甲基-1H-1,2,4-三唑-3-基)-4-氟-N-(4-甲氧苄基)-N-甲基苯磺酰胺(B14-1，500mg,1.24mmol)的2-甲基四氢呋喃(5.00mL)中，加入4-(五氟-λ 6-硫烷基)苯胺(298mg,1.36mmol)和氢氧化钾(139mg,2.47mmol)，反应在90℃下搅拌10小时。反应完成后，把反应液用水(30.0mL)稀释，然后用乙酸乙酯(30.0mL)萃取，合并有机层，有机相用水(30mL×3)洗涤，硫酸钠干燥，过滤浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-3:1)得到3-(1,5-二甲基-1H-1,2,4-三唑-3-基)-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B14-2，500mg)。直接用于下一步。 To 3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (B14-1, 500mg, 1.24mmol) in 2-methyltetrahydrofuran (5.00mL), add 4-(pentafluoro-λ 6 -sulfanyl)aniline (298mg, 1.36mmol) and potassium hydroxide (139mg, 2.47 mmol), and the reaction was stirred at 90 °C for 10 hours. After the reaction was completed, the reaction solution was diluted with water (30.0 mL), then extracted with ethyl acetate (30.0 mL), the organic layers were combined, washed with water (30 mL×3), dried over sodium sulfate, concentrated by filtration, and the residue was washed with silica gel Column separation and purification (petroleum ether: ethyl acetate (V/V) = 5:1-3:1) to obtain 3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl )-N-(4-methoxybenzyl)-N-methyl-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B14-2, 500mg ). used directly in the next step.
第三步：3-(1,5-二甲基-1H-1,2,4-三唑-3-基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-14)的制备 The third step: 3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-N-methyl-4-((4-(pentafluoro-λ 6 -sulfur Preparation of Alkyl)phenyl)amino)benzenesulfonamide (I-14)
Figure PCTCN2022098060-appb-000085
Figure PCTCN2022098060-appb-000085
将3-(1,5-二甲基-1H-1,2,4-三唑-3-基)-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B14-2，400mg,663μmol)溶解在三氟乙酸(10.0mL)中，反应在70℃下搅拌2小时。反应完成后，反应液用氢氧化钠水溶液(1.00M)调至pH＝7～8，然后用乙酸乙酯(30.0mL*3)萃取，合并有机层，硫酸钠干燥，过滤浓缩，粗品用乙酸乙酯(5.00mL)打浆，得到3-(1,5-二甲基-1H-1,2,4-三唑-3-基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-14，218mg,收率64.6％)。 3-(1,5-Dimethyl-1H-1,2,4-triazol-3-yl)-N-(4-methoxybenzyl)-N-methyl-4-((4 -(Pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B14-2, 400 mg, 663 μmol) was dissolved in trifluoroacetic acid (10.0 mL), and the reaction was stirred at 70° C. for 2 hours. After the reaction was completed, the reaction liquid was adjusted to pH=7~8 with aqueous sodium hydroxide solution (1.00M), then extracted with ethyl acetate (30.0mL*3), the organic layers were combined, dried over sodium sulfate, filtered and concentrated, and the crude product was washed with acetic acid Ethyl ester (5.00mL) was beaten to obtain 3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-N-methyl-4-((4-(pentafluoro -λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (I-14, 218 mg, yield 64.6%).
1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.49(d,1H),7.85-7.90(m,2H),7.63-7.70(m,2H),7.44-7.50(m,2H),7.25-7.30(m,1H),3.91(s,3H),2.24(s,3H),2.41(d,3H)。 1 H NMR (400MHz,DMSO-d 6 )δ10.35(s,1H),8.49(d,1H),7.85-7.90(m,2H),7.63-7.70(m,2H),7.44-7.50(m ,2H), 7.25-7.30(m,1H), 3.91(s,3H), 2.24(s,3H), 2.41(d,3H).
LC-MS,M/Z(ESI):483.8[M+H] + LC-MS, M/Z(ESI):483.8[M+H] +
实施例15：目标化合物I-15的制备Embodiment 15: Preparation of target compound I-15
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000086
Figure PCTCN2022098060-appb-000086
第一步：3-氰基-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ6-硫烷基)苯基)氨基)苯磺酰胺(B15-2)的制备The first step: 3-cyano-N-(4-methoxybenzyl)-N-methyl-4-((4-(pentafluoro-λ6-sulfanyl)phenyl)amino)benzenesulfonamide Preparation of (B15-2)
Figure PCTCN2022098060-appb-000087
Figure PCTCN2022098060-appb-000087
将3-溴-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ6-硫烷基)苯基)氨基)苯磺酰胺(B2-1，2.00g,3.40mmol)溶解在N,N-二甲基甲酰胺(20.0mL)中，加入氰化亚铜(1.52g,17.0mmol)，反应液加热至140℃反应10小时。将反应液降至25℃后加入水(100mL)，然后用乙酸乙酯(50.0mL*3)萃取，用饱和食盐水(100mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品，粗品经层析柱(石油醚：乙酸乙酯＝50：1到5：1)纯化后，得到3-氰基-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B15-2，1.10g，产率60.6％)。 3-bromo-N-(4-methoxybenzyl)-N-methyl-4-((4-(pentafluoro-λ6-sulfanyl)phenyl)amino)benzenesulfonamide (B2-1 , 2.00g, 3.40mmol) was dissolved in N,N-dimethylformamide (20.0mL), and cuprous cyanide (1.52g, 17.0mmol) was added, and the reaction solution was heated to 140°C for 10 hours. After the reaction solution was lowered to 25°C, water (100 mL) was added, then extracted with ethyl acetate (50.0 mL*3), the organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to obtain a crude product, which was subjected to chromatography After column (petroleum ether:ethyl acetate=50:1 to 5:1) purification, 3-cyano-N-(4-methoxybenzyl)-N-methyl-4-((4-( Pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B15-2, 1.10 g, yield 60.6%).
LC-MS,M/Z(ESI):534.1[M+H] + LC-MS, M/Z(ESI):534.1[M+H] +
第二步：N-羟基-5-(N-(4-甲氧基苄基)-N-甲基氨磺酰)-2-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯甲脒(B15-3)的制备 The second step: N-hydroxy-5-(N-(4-methoxybenzyl)-N-methylsulfamoyl)-2-((4-(pentafluoro-λ 6 -sulfanyl)benzene base) amino) benzamidine (B15-3) preparation
Figure PCTCN2022098060-appb-000088
Figure PCTCN2022098060-appb-000088
将3-氰基-N-(4-甲氧基苄基)-N-甲基-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B15-2，1.00g,1.87mmol)溶解在乙酸乙酯(20.0mL)和水(4.00mL)中，再加入三乙胺(569mg,5.62mmol) 和盐酸羟胺(156mg,2.25mmol)，然后在60℃搅拌反应2小时。向反应液加入水(50.0mL)，然后用乙酸乙酯(50.0mL*3)萃取，用饱和食盐水(50mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品，N-羟基-5-(N-(4-甲氧基苄基)-N-甲基氨磺酰-4-((4-(五氟-λ6-硫烷基)苯基)氨基)苯甲脒(B15-3，1.00g，产率94.2％)。 3-cyano-N-(4-methoxybenzyl)-N-methyl-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B15 -2, 1.00g, 1.87mmol) was dissolved in ethyl acetate (20.0mL) and water (4.00mL), then added triethylamine (569mg, 5.62mmol) and hydroxylamine hydrochloride (156mg, 2.25mmol), then in 60 The reaction was stirred at °C for 2 hours. Water (50.0 mL) was added to the reaction solution, then extracted with ethyl acetate (50.0 mL*3), the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain a crude product, N-hydroxy-5-(N -(4-Methoxybenzyl)-N-methylsulfamoyl-4-((4-(pentafluoro-λ6-sulfanyl)phenyl)amino)benzamidine (B15-3, 1.00g , yield 94.2%).
LC-MS,M/Z(ESI):567.2[M+H] + LC-MS, M/Z(ESI):567.2[M+H] +
第三步：N-(4-甲氧基苄基)-N-甲基-3-(5-甲基-1,2,4-噁二唑-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B15-4)的制备 The third step: N-(4-methoxybenzyl)-N-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-4-((4- Preparation of (pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B15-4)
Figure PCTCN2022098060-appb-000089
Figure PCTCN2022098060-appb-000089
将N-羟基-5-(N-(4-甲氧基苄基)-N-甲基氨磺酰)-2-((4-(五氟-λ6-硫烷基)苯基)氨基)苯甲脒(B15-3，500mg,883μmol)溶解在四氢呋喃(10.0mL)中，再加入醋酸(63.6mg,1.06mmol)和1,1-羰基二咪唑(215mg,1.32mmol)，然后在70℃搅拌反应3小时。向反应液加入水(200mL)，然后用乙酸乙酯(200mL*3)萃取，用饱和食盐水(200mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品，为N-(4-甲氧基苄基)-N-甲基-3-(5-甲基-1,2,4-噁二唑-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B15-4，800mg，产率76.8％)。 N-hydroxyl-5-(N-(4-methoxybenzyl)-N-methylsulfamoyl)-2-((4-(pentafluoro-λ6-sulfanyl)phenyl)amino) Benzamidine (B15-3, 500mg, 883μmol) was dissolved in tetrahydrofuran (10.0mL), then acetic acid (63.6mg, 1.06mmol) and 1,1-carbonyldiimidazole (215mg, 1.32mmol) were added, and then heated at 70°C The reaction was stirred for 3 hours. Add water (200mL) to the reaction solution, then extract with ethyl acetate (200mL*3), wash the organic phase with saturated brine (200mL), dry over sodium sulfate, and concentrate to obtain the crude product, N-(4-methoxybenzyl base)-N-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl )amino)benzenesulfonamide (B15-4, 800 mg, 76.8% yield).
LC-MS,M/Z(ESI):591.1[M+H] + LC-MS, M/Z(ESI):591.1[M+H] +
第四步：N-甲基-3-(5-甲基-1,2,4-噁二唑-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-15) The fourth step: N-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)benzene Base) amino) benzenesulfonamide (I-15)
Figure PCTCN2022098060-appb-000090
Figure PCTCN2022098060-appb-000090
将N-(4-甲氧基苄基)-N-甲基-3-(5-甲基-1,2,4-噁二唑-3-基)-4-((4-(五氟-λ6-硫烷基)苯基)氨基)苯磺酰胺溶解在三氟乙酸(10.0mL)中，在70℃反应1小时。把反应液加到水(50.0mL)中，然后用乙酸乙酯(50.0mL*3)萃取，用饱和食盐水(50.0mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。然后通过反相高效液相色谱法进行分离，分离方法为(柱子:Waters Xbridge 150*25mm*5um；溶剂：溶剂：A＝水+氨水(0.05％)，B＝乙腈；梯度：35％-63％，9分钟)，然后冻干得到N-甲基-3-(5-甲基-1,2,4-噁二唑-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-15，390mg，产率60.0％)。 N-(4-methoxybenzyl)-N-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-4-((4-(pentafluoro -λ6-sulfanyl)phenyl)amino)benzenesulfonamide was dissolved in trifluoroacetic acid (10.0 mL), and reacted at 70°C for 1 hour. The reaction solution was added to water (50.0 mL), then extracted with ethyl acetate (50.0 mL*3), the organic phase was washed with saturated brine (50.0 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Then separate by reverse phase high performance liquid chromatography, separation method is (column: Waters Xbridge 150*25mm*5um; Solvent: solvent: A=water+ammonia (0.05%), B=acetonitrile; Gradient: 35%-63 %, 9 minutes), and then lyophilized to obtain N-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (I-15, 390 mg, 60.0% yield).
1H NMR(400MHz,DMSO-d 6)δ10.93-11.04(m,1H),8.58(d,1H),8.10-8.19(m,3H),8.03(d,2H),7.89(dd,1H),7.51(d,1H),2.43(d,3H),2.22(s,3H) 1 H NMR (400MHz,DMSO-d 6 )δ10.93-11.04(m,1H),8.58(d,1H),8.10-8.19(m,3H),8.03(d,2H),7.89(dd,1H ),7.51(d,1H),2.43(d,3H),2.22(s,3H)
LC-MS,M/Z(ESI):471.0[M+H] + LC-MS, M/Z(ESI):471.0[M+H] +
实施例16：目标化合物I-16的制备Embodiment 16: Preparation of Target Compound I-16
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000091
Figure PCTCN2022098060-appb-000091
第一步：4-氟-N-(4-甲氧苄基)-N-甲基-3-(1-甲基-6-氧代-1,6-二氢哒嗪-3-基)苯磺酰胺(B16-1)的制备The first step: 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl) Preparation of Benzenesulfonamide (B16-1)
Figure PCTCN2022098060-appb-000092
Figure PCTCN2022098060-appb-000092
将6-溴-2-甲基哒嗪-3(2H)-酮(1.24g,6.55mmol)和4-氟-N-(4-甲氧苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯磺酰胺(A4，3.00g,6.89mmol)溶解在乙腈(30.0mL)和水(30.0mL)中，加碳酸钾(2.86g,20.7mmol)和1,1-双(二苯基膦)二茂铁氯化钯(504mg,689μmol)，然后在氮气保护下95℃搅拌反应10小时。将反应液浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-5:1)得到4-氟-N-(4-甲氧苄基)-N-甲基-3-(1-甲基-6-氧代-1,6-二氢哒嗪-3-基)苯磺酰胺(B16-1，1.30g，产率45.2％)。6-Bromo-2-methylpyridazin-3(2H)-one (1.24g, 6.55mmol) and 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A4, 3.00 g, 6.89 mmol) was dissolved in acetonitrile (30.0 mL) and water (30.0mL), add potassium carbonate (2.86g, 20.7mmol) and 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (504mg, 689μmol), then stir the reaction at 95°C under nitrogen protection for 10 Hour. The reaction solution was concentrated to obtain a crude product, which was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1-5:1) to obtain 4-fluoro-N-(4-methoxybenzyl)-N -Methyl-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzenesulfonamide (B16-1, 1.30 g, yield 45.2%).
LC-MS,M/Z(ESI):417.9[M+H] + LC-MS, M/Z(ESI):417.9[M+H] +
第二步：N-(4-甲氧苄基)-N-甲基-3-(1-甲基-6-氧代-1,6-二氢哒嗪-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B16-2)的制备 The second step: N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4-( Preparation of (4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B16-2)
Figure PCTCN2022098060-appb-000093
Figure PCTCN2022098060-appb-000093
将4-氟-N-(4-甲氧苄基)-N-甲基-3-(1-甲基-6-氧代-1,6-二氢哒嗪-3-基)苯磺酰胺(B16-1，1.20g,2.87mmol)和4-(五氟-λ 6-硫烷基)苯胺(693mg,3.16mmol)溶解在二甲基亚砜(20.0mL)中，在0℃下加入碳酸铯(2.81g,8.62mmol)，氮气保护下90℃反应4小时。把反应液滴加到水(200mL)中，然后用乙酸乙酯(200mL)萃取，用饱和食盐水(200mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-5:1)得到N-(4-甲氧苄基)-N-甲基-3-(1-甲基-6-氧代-1,6-二氢哒嗪-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B16-2，900mg，产率50.8％)。 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzenesulfonamide (B16-1, 1.20g, 2.87mmol) and 4-(pentafluoro-λ 6 -sulfanyl)aniline (693mg, 3.16mmol) were dissolved in dimethyl sulfoxide (20.0mL), added at 0°C Cesium carbonate (2.81g, 8.62mmol) was reacted at 90°C for 4 hours under the protection of nitrogen. The reaction solution was added dropwise to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Separation and purification with silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1-5:1) to obtain N-(4-methoxybenzyl)-N-methyl-3-(1-methyl -6-oxo-1,6-dihydropyridazin-3-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B16-2, 900 mg, yield 50.8%).
LC-MS,M/Z(ESI):617.2[M+H] + LC-MS, M/Z(ESI):617.2[M+H] +
第三步：N-甲基-3-(1-甲基-6-氧代-1,6-二氢哒嗪-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-16)的制备 The third step: N-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4-((4-(pentafluoro-λ 6 -sulfur Preparation of Alkyl)phenyl)amino)benzenesulfonamide (I-16)
Figure PCTCN2022098060-appb-000094
Figure PCTCN2022098060-appb-000094
将N-(4-甲氧苄基)-N-甲基-3-(1-甲基-6-氧代-1,6-二氢哒嗪-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B16-2，900mg,1.46mmol)溶解在三氟乙酸(20.0mL)中，70℃反应1小时。反应完成后，把反应液加到水(200mL)中，然后用乙酸乙酯(200mL)萃取，用饱和食盐水(50mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-5:1)得到N-甲基-3-(1-甲基-6-氧代-1,6-二氢哒嗪-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-16，210mg，产率28.9％)。 N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4-((4- (Pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B16-2, 900mg, 1.46mmol) was dissolved in trifluoroacetic acid (20.0mL), and reacted at 70°C for 1 hour. After the reaction was complete, the reaction solution was added to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Separation and purification with silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1-5:1) to obtain N-methyl-3-(1-methyl-6-oxo-1,6-di Hydropyridazin- 3 -yl)-4-((4-(pentafluoro-λ6-sulfanyl)phenyl)amino)benzenesulfonamide (I-16, 210 mg, 28.9% yield).
1H NMR(400MHz,DMSO-d 6)δ8.94(br s,1H),7.86(d,1H),7.71-7.79(m,3H),7.56-7.66(m,2H),7.45(s,1H),7.17(d,2H),6.98(d,1H),3.74(s,3H),2.45(s,3H) 1 H NMR (400MHz,DMSO-d 6 )δ8.94(br s,1H),7.86(d,1H),7.71-7.79(m,3H),7.56-7.66(m,2H),7.45(s, 1H),7.17(d,2H),6.98(d,1H),3.74(s,3H),2.45(s,3H)
LC-MS,M/Z(ESI):497.1[M+H] + LC-MS, M/Z(ESI):497.1[M+H] +
实施例17：目标化合物I-17的制备Embodiment 17: Preparation of target compound I-17
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000095
Figure PCTCN2022098060-appb-000095
第一步：4-氟-N-(4-甲氧苄基)-N-甲基-3-(4-甲基-5-氧代-4,5-二氢吡嗪-2-基)苯磺酰胺(B17-1)的合成The first step: 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl) Synthesis of Benzenesulfonamide (B17-1)
Figure PCTCN2022098060-appb-000096
Figure PCTCN2022098060-appb-000096
将5-溴-1-甲基吡嗪-2(1H)-酮(1.07g,5.67mmol)和4-氟-N-(4-甲氧苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯磺酰胺(A4，2.60g,5.97mmol)溶解在乙腈(30.0mL)和水(30.0mL)中，加碳酸钾(2.48g,17.9mmol)和1,1-双(二苯基膦)二茂铁氯化钯(437mg,597μmol)，然后在氮气保护下95℃搅拌反应10小时。将反应液浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-5:1)得到4-氟-N-(4-甲氧苄基)-N-甲基-3-(4-甲基-5-氧代-4,5-二氢吡嗪-2-基)苯磺酰胺(B17-1，1.30g，产率52.1％)。5-Bromo-1-methylpyrazin-2(1H)-one (1.07g, 5.67mmol) and 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A4, 2.60 g, 5.97 mmol) was dissolved in acetonitrile (30.0 mL) and water (30.0mL), add potassium carbonate (2.48g, 17.9mmol) and 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (437mg, 597μmol), then stir the reaction at 95°C under nitrogen protection for 10 Hour. The reaction solution was concentrated to obtain a crude product, which was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1-5:1) to obtain 4-fluoro-N-(4-methoxybenzyl)-N -Methyl-3-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)benzenesulfonamide (B17-1, 1.30 g, yield 52.1%).
LC-MS,M/Z(ESI):418.1[M+H] + LC-MS, M/Z(ESI):418.1[M+H] +
第二步：N-(4-甲氧苄基)-N-甲基-3-(4-甲基-5-氧代-4,5-二氢吡嗪-2-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B17-2)的制备 The second step: N-(4-methoxybenzyl)-N-methyl-3-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-4-( Preparation of (4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B17-2)
Figure PCTCN2022098060-appb-000097
Figure PCTCN2022098060-appb-000097
将4-氟-N-(4-甲氧苄基)-N-甲基-3-(4-甲基-5-氧代-4,5-二氢吡嗪-2-基)苯磺酰胺(B17-1，650mg,1.56mmol)和4-(五氟-λ 6-硫烷基)苯胺(341mg,1.56mmol)溶解在二甲基亚砜(20.0mL)中，在0℃下加入碳酸铯(1.52g,4.67mmol)，氮气保护下60℃反应5小时。把反应液滴加到水(200mL)中，然后用乙酸乙酯(200mL)萃取，用饱和食盐水(200mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-5:1)得到N-(4-甲氧苄基)-N-甲基-3-(4-甲基-5-氧代-4,5-二氢吡嗪-2-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B17-2，300mg，产率31.3％)。 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)benzenesulfonamide (B17-1, 650 mg, 1.56 mmol) and 4-(pentafluoro-λ 6 -sulfanyl) aniline (341 mg, 1.56 mmol) were dissolved in dimethyl sulfoxide (20.0 mL), and carbonic acid was added at 0°C Cesium (1.52g, 4.67mmol) was reacted at 60°C for 5 hours under nitrogen protection. The reaction solution was added dropwise to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Separation and purification with silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1-5:1) to obtain N-(4-methoxybenzyl)-N-methyl-3-(4-methyl -5-oxo-4,5-dihydropyrazin-2-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B17-2, 300 mg, yield 31.3%).
LC-MS,M/Z(ESI):617.2[M+H] + LC-MS, M/Z(ESI):617.2[M+H] +
第三步：N-甲基-3-(4-甲基-5-氧代-4,5-二氢吡嗪-2-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-17)的制备 The third step: N-methyl-3-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-4-((4-(pentafluoro-λ 6 -sulfur Preparation of Alkyl)phenyl)amino)benzenesulfonamide (I-17)
Figure PCTCN2022098060-appb-000098
Figure PCTCN2022098060-appb-000098
将N-(4-甲氧苄基)-N-甲基-3-(4-甲基-5-氧代-4,5-二氢吡嗪-2-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B17-2，300mg,487μmol)溶解在三氟乙酸(20.0mL)中，70℃反应1小时。反应完成后，将反应液加到水(200mL)中，然后用乙酸乙酯(200mL)萃取，用饱和食盐水(50mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-5:1) 得到N-甲基-3-(4-甲基-5-氧代-4,5-二氢吡嗪-2-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-17，80.0mg，产率32.5％)。 N-(4-methoxybenzyl)-N-methyl-3-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-4-((4- (Pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B17-2, 300 mg, 487 μmol) was dissolved in trifluoroacetic acid (20.0 mL), and reacted at 70°C for 1 hour. After the reaction was complete, the reaction solution was added to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Separation and purification with silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1-5:1) to obtain N-methyl-3-(4-methyl-5-oxo-4,5-di Hydropyrazin- 2 -yl)-4-((4-(pentafluoro-λ6-sulfanyl)phenyl)amino)benzenesulfonamide (I-17, 80.0 mg, 32.5% yield).
1H NMR(400MHz,DMSO-d 6)δ8.85(s,1H)8.09(d,2H)7.86(d,,1H)7.74(d,2H)7.65-7.70(m,1H)7.57-7.62(m,1H)7.36-7.42(m,1H)7.18(d,2H)3.48(s,3H)2.44(d,3H) 1 H NMR (400MHz,DMSO-d 6 )δ8.85(s,1H)8.09(d,2H)7.86(d,,1H)7.74(d,2H)7.65-7.70(m,1H)7.57-7.62( m,1H)7.36-7.42(m,1H)7.18(d,2H)3.48(s,3H)2.44(d,3H)
LC-MS,M/Z(ESI):497.1[M+H] + LC-MS, M/Z(ESI):497.1[M+H] +
实施例18：目标化合物I-18的制备Embodiment 18: Preparation of target compound I-18
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000099
Figure PCTCN2022098060-appb-000099
第一步：4-氟-N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯磺酰胺(B18-1)的制备The first step: 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzenesulfonate Preparation of Amide (B18-1)
Figure PCTCN2022098060-appb-000100
Figure PCTCN2022098060-appb-000100
将3-溴-1-甲基-1H-1,2,4-三唑(259mg,1.6mmol)溶解于二氧六环(10ml)和水(2ml)中，加入4-氟-N-(4-甲氧基苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯磺酰胺(A4，700mg，1.6mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(117mg，0.16mmol)和碳酸钠(424mg，4mmol)，100℃搅拌12h。加入水(10ml)，用乙酸乙酯(10mL x 3)萃取，收集有机相，用10mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝50:1-10:1)得到4-氟-N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-1,2,4-三唑唑-3-基)苯磺酰胺(B18-1，600mg，产率：96％)。 3-Bromo-1-methyl-1H-1,2,4-triazole (259mg, 1.6mmol) was dissolved in dioxane (10ml) and water (2ml), and 4-fluoro-N-( 4-methoxybenzyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A4, 700mg, 1.6mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (117mg, 0.16mmol) and sodium carbonate (424mg, 4mmol), stirred at 100°C for 12h . Water (10ml) was added, extracted with ethyl acetate (10mL x 3), and the organic phase was collected and washed with 10mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1-10:1) to obtain 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(1-methyl yl-1H-1,2,4-triazol-3-yl)benzenesulfonamide (B18-1, 600 mg, yield: 96%).
LC-MS,M/Z(ESI):391.1[M+H] +。 LC-MS, M/Z (ESI): 391.1 [M+H] + .
第二步：N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B18-2)的合成 The second step: N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)-4-((4 -Synthesis of (pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B18-2)
Figure PCTCN2022098060-appb-000101
Figure PCTCN2022098060-appb-000101
将4-氟-N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯磺酰胺(B18-1，200mg,0.512mmol)溶解在N,N-二甲基甲酰胺(5ml)中，降温至0℃，加入氢化钠(102mg,2.56mmol，60％)，搅拌0.5h，再加入4-(五氟-λ6-硫烷基)苯胺(225mg,1.025mmol)，逐渐升至室温后搅拌12h。将反应液加入到水(10ml)中，用乙酸乙酯(10mL X 3)萃取，收集有机相，用10mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝20:1-3:1)得到N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B18-2，200mg，产率：66.2％)。 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzenesulfonamide (B18 -1, 200mg, 0.512mmol) was dissolved in N,N-dimethylformamide (5ml), cooled to 0°C, added sodium hydride (102mg, 2.56mmol, 60%), stirred for 0.5h, and then added 4- (Pentafluoro-λ6-sulfanyl)aniline (225mg, 1.025mmol), gradually raised to room temperature and stirred for 12h. The reaction liquid was added into water (10ml), extracted with ethyl acetate (10mL X 3), and the organic phase was collected and washed with 10mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-3:1) to obtain N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H- 1,2,4-triazol-3-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B18-2, 200mg, yield: 66.2 %).
LC-MS,M/Z(ESI):590.1[M+H] +。 LC-MS, M/Z (ESI): 590.1 [M+H] + .
第三步：N-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-18)的制备 The third step: N-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl) Preparation of phenyl)amino)benzenesulfonamide (I-18)
Figure PCTCN2022098060-appb-000102
Figure PCTCN2022098060-appb-000102
将N-(4-甲氧基苄基)-N-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B18-2，180mg,0.305mmol)溶解在二氯甲烷(5ml)中，加入三氟乙酸(1ml)，搅拌12h。旋干，粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝20:1-1:1)得到N-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-18)(100mg，产率69.9％)。 N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)-4-((4-(five Fluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B18-2, 180mg, 0.305mmol) was dissolved in dichloromethane (5ml), added trifluoroacetic acid (1ml), and stirred for 12h. Spin-dried, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-1:1) to obtain N-methyl-3-(1-methyl-1H-1,2,4-triazole- 3-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (I-18) (100 mg, yield 69.9%).
1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),8.73(s,1H),8.50(d,1H),7.82(d,2H),7.64-7.68(m,2H),7.42(d,2H),7.36(q,1H),3.99(s,3H),2.40(d,3H) 1 H NMR (400MHz,DMSO-d 6 )δ10.26(s,1H),8.73(s,1H),8.50(d,1H),7.82(d,2H),7.64-7.68(m,2H), 7.42(d,2H),7.36(q,1H),3.99(s,3H),2.40(d,3H)
LC-MS,M/Z(ESI):470.1[M+H] +。 LC-MS, M/Z (ESI): 470.1 [M+H] + .
实施例19：化合物I-19的制备Embodiment 19: Preparation of Compound I-19
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000103
Figure PCTCN2022098060-appb-000103
第一步：3-溴-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯甲酸甲酯(B19-2)的制备 Step 1: Preparation of methyl 3-bromo-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzoate (B19-2)
Figure PCTCN2022098060-appb-000104
Figure PCTCN2022098060-appb-000104
在25℃氮气保护下，向3-溴-4-碘苯甲酸甲酯(0.50g,1.47mmol)和4-(五氟-λ 6-硫烷基)苯胺(B19-1，0.32g,1.47mmol)的1,4-二氧六环(20mL)溶液中加入三(二亚苄基丙酮)二钯(137.3mg,0.15mmol)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(173.58mg,0.30mmol)，碳酸铯(1.44g,4.41mmol)。反应混合物在100℃下搅拌12小时。反应结束后，将反应液冷却到室温，减压蒸馏浓缩，混合物加水(30mL)，用乙酸乙酯(30mL x 3)萃取，收集有机相，用30mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到3-溴-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯甲酸甲酯(B19-2，520mg,收率82％)。 Under nitrogen protection at 25°C, methyl 3-bromo-4-iodobenzoate (0.50g, 1.47mmol) and 4-(pentafluoro-λ 6 -sulfanyl)aniline (B19-1, 0.32g, 1.47 mmol) in 1,4-dioxane (20 mL) was added tris(dibenzylideneacetone) dipalladium (137.3 mg, 0.15 mmol), 4,5-bis(diphenylphosphine)-9,9 - Dimethylxanthene (173.58 mg, 0.30 mmol), cesium carbonate (1.44 g, 4.41 mmol). The reaction mixture was stirred at 100°C for 12 hours. After the reaction, the reaction liquid was cooled to room temperature, concentrated by distillation under reduced pressure, the mixture was added with water (30 mL), extracted with ethyl acetate (30 mL x 3), and the organic phase was collected and washed with 30 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain 3-bromo-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzene Methyl formate (B19-2, 520 mg, yield 82%).
第二步：3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯甲酸甲酯(B19-3)的制备 The second step: methyl 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzoate (B19- 3) Preparation
Figure PCTCN2022098060-appb-000105
Figure PCTCN2022098060-appb-000105
在25℃氮气保护下，向3-溴-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯甲酸甲酯(B19-2，0.44g, 1.02mmol)和1-甲基-4-(三丁基锡烷基)-1H-咪唑(417mg,1.12mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入四(三苯基膦)钯(59mg,0.051mmol)。反应混合物在120℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯甲酸甲酯(B19-3，330mg,收率75％)。 Under nitrogen protection at 25°C, methyl 3-bromo-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzoate (B19-2, 0.44g, 1.02mmol) and Add tetrakis(triphenylphosphine) palladium (59mg, 0.051 mmol). The reaction mixture was stirred at 120°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-1:1) to obtain 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro- λ 6 -sulfanyl)phenyl)amino)methylbenzoate (B19-3, 330 mg, yield 75%).
第三步：3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯甲酸(B19-4)的合成 The third step: 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzoic acid (B19-4) Synthesis
Figure PCTCN2022098060-appb-000106
Figure PCTCN2022098060-appb-000106
在25℃下，向3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯甲酸甲酯(B19-3，330mg,0.76mmol)的四氢呋喃(5mL)溶液中加甲醇(5mL)与氢氧化锂水溶液(4mL,1M)。反应混合物在25℃搅拌12小时，反应结束后，将反应液浓缩除去甲醇与四氢呋喃，得到粗品，粗品加水(15mL)稀释，用稀盐酸(2M)调节pH至5，再用乙酸乙酯萃取(20mL×3)，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩得到粗品直接用于下一步反应，得到3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯甲酸(B19-4，285mg,收率89％)。 At 25°C, methyl 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzoate ( To a solution of B19-3, 330mg, 0.76mmol) in tetrahydrofuran (5mL), add methanol (5mL) and aqueous lithium hydroxide solution (4mL, 1M). The reaction mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was concentrated to remove methanol and tetrahydrofuran to obtain a crude product, which was diluted with water (15 mL), adjusted to pH 5 with dilute hydrochloric acid (2M), and extracted with ethyl acetate ( 20mL×3), the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product that was directly used in the next step to obtain 3-(1-methyl-1H-imidazol-4-yl)-4- ((4-(Pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzoic acid (B19-4, 285 mg, yield 89%).
第四步：3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)-N-(吡啶-2-基甲基)苯甲酰胺(I-19)的制备 The fourth step: 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)-N-(pyridine-2 Preparation of -methyl)benzamide (I-19)
Figure PCTCN2022098060-appb-000107
Figure PCTCN2022098060-appb-000107
在25℃下，向3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯甲酸(B19-4，285mg,0.68mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入N,N-二异丙基乙胺(263.7mg,2.04mmol),O-(7-氮杂苯并三唑-1-基)-N,N,N,N-四甲基糖醛正离子六氟磷酸盐(HATU，311mg,0.82mmol)。反应混合物在25℃搅拌0.5小时，再加入吡啶-2-基甲胺(76mg,0.70mmol)。反应混合物在25℃搅拌2小时。反应结束后，往反应液加水(30mL)，再用乙酸乙酯萃取(20mL×3)，合并有机相，有机相用无水硫酸钠干燥，过滤，粗品用硅胶色谱柱纯化(二氯甲烷:甲醇＝100:1-100:3)得到3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)-N-(吡啶-2-基甲基)苯甲酰胺(I-19)(280mg,收率81％)。 At 25°C, 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzoic acid (B19- 4. To a solution of 285 mg, 0.68 mmol) of N, N-dimethylformamide (10 mL), N, N-diisopropylethylamine (263.7 mg, 2.04 mmol), O-(7-azabenzo Triazol-1-yl)-N,N,N,N-tetramethylfurcuronium hexafluorophosphate (HATU, 311 mg, 0.82 mmol). The reaction mixture was stirred at 25°C for 0.5 hours, and then pyridin-2-ylmethylamine (76 mg, 0.70 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. After the reaction, add water (30mL) to the reaction solution, then extract with ethyl acetate (20mL×3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and purify the crude product with a silica gel column (dichloromethane: Methanol=100:1-100:3) to get 3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino) -N-(pyridin-2-ylmethyl)benzamide (I-19) (280 mg, yield 81%).
1H NMR(400MHz,CDCl 3)δ10.78(s,1H),8.57(s,1H),8.11(s,1H),7.79–7.54(m,5H),7.53–7.42(m,2H),7.37(d,,1H),7.28(s,1H),7.22(d,3H),4.77(d,2H),3.75(s,3H). 1 H NMR (400MHz, CDCl 3 )δ10.78(s,1H),8.57(s,1H),8.11(s,1H),7.79–7.54(m,5H),7.53–7.42(m,2H), 7.37(d,,1H),7.28(s,1H),7.22(d,3H),4.77(d,2H),3.75(s,3H).
LC-MS,M/Z(ESI):510.2[M+H] +。 LC-MS, M/Z (ESI): 510.2 [M+H] + .
实施例20：化合物I-20的制备Embodiment 20: Preparation of Compound I-20
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000108
Figure PCTCN2022098060-appb-000108
第一步：2-(4-溴-1-甲基-1H-咪唑-2-基)丙烷-2-醇(B20-2)的合成The first step: the synthesis of 2-(4-bromo-1-methyl-1H-imidazol-2-yl)propan-2-ol (B20-2)
Figure PCTCN2022098060-appb-000109
Figure PCTCN2022098060-appb-000109
将4-溴-1-甲基-1H-咪唑-2-甲酸甲酯(B20-1)(5g,22.8mmol)溶于无水四氢呋喃(30mL)，氮气保护，0℃滴加甲基溴化镁的四氢呋喃溶液(1.0M,45.6mL,45.6mmol)，滴完后继续0℃搅拌45分钟后加30mL饱和氯化铵淬灭反应，乙酸乙酯(50mL x 3)萃取，有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝10:1-1:1)得到2-(4-溴-1-甲基-1H-咪唑-2-基)丙烷-2-醇(B20-2)(4.5g，产率：90％)。 Dissolve 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid methyl ester (B20-1) (5g, 22.8mmol) in anhydrous tetrahydrofuran (30mL), under nitrogen protection, add methyl bromide dropwise at 0°C Magnesium tetrahydrofuran solution (1.0M, 45.6mL, 45.6mmol), continued to stir at 0°C for 45 minutes after dropping, then added 30mL saturated ammonium chloride to quench the reaction, extracted with ethyl acetate (50mL x 3), and the organic phase was washed with anhydrous Dry over Na2SO4 , filter and concentrate to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain 2-(4-bromo-1-methyl-1H-imidazol-2-yl)propan-2-ol (B20 -2) (4.5 g, yield: 90%).
LC-MS,M/Z(ESI):219.11[M+H] +。 LC-MS, M/Z (ESI): 219.11 [M+H] + .
第二步：4-氟-3-(2-(2-羟基丙烷-2-基)-1-甲基-1H-咪唑-4-基)-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(B20-3)的合成The second step: 4-fluoro-3-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-N-(4-methoxybenzyl)- Synthesis of N-Methylbenzenesulfonamide (B20-3)
Figure PCTCN2022098060-appb-000110
Figure PCTCN2022098060-appb-000110
将4-氟-N-(4-甲氧基苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯磺酰胺(2.28g,5.25mmol)与2-(4-溴-1-甲基-1H-咪唑-2-基)丙烷-2-醇(1.15g,5.25mmol)溶于1,4-二氧六环(20mL)，再加入1,1’-双二苯基膦二茂铁二氯化钯(0.38g,0.52mmol)、碳酸钠(1.38g,12.98mmol)、水(4mL)。氮气置换3次，氮气保护于100℃反应21小时。冷却至室温，减蒸除去反应溶剂，加水(40mL)，乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥。硅胶柱层析纯化(石油醚:乙酸乙酯＝1:1-1:2)，得到4-氟-3-(2-(2-羟基丙烷-2-基)-1-甲基-1H-咪唑-4-基)-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(B20-3)(1.21g，产率：51.7％)。4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)benzenesulfonamide (2.28g, 5.25mmol) and 2-(4-bromo-1-methyl-1H-imidazol-2-yl)propan-2-ol (1.15g, 5.25mmol) were dissolved in 1,4-Dioxane (20mL), then add 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (0.38g, 0.52mmol), sodium carbonate (1.38g, 12.98mmol), water (4 mL). Nitrogen replacement was performed 3 times, and the reaction was carried out at 100° C. for 21 hours under nitrogen protection. Cool to room temperature, remove the reaction solvent by subtractive evaporation, add water (40 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, and dry over anhydrous sodium sulfate. Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1-1:2) to obtain 4-fluoro-3-(2-(2-hydroxypropan-2-yl)-1-methyl-1H- Imidazol-4-yl)-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (B20-3) (1.21 g, yield: 51.7%).
LC-MS,M/Z(ESI):448.2[M+H] +。 LC-MS, M/Z (ESI): 448.2 [M+H] + .
第三步：3-(2-(2-羟基丙烷-2-基)-1-甲基-1H-咪唑-4-基)-N-(4-甲氧基苄基)-N-甲基-4-(4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B20-4)的合成 The third step: 3-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-N-(4-methoxybenzyl)-N-methyl -Synthesis of 4-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B20-4)
Figure PCTCN2022098060-appb-000111
Figure PCTCN2022098060-appb-000111
在室温下下，向4-(五氟-λ 6-硫烷基)苯胺(390mg,1.8mmol)的干燥N,N-二甲基甲酰胺(10mL)溶液中加入叔丁醇钾(403mg,3.6mmol)，然后将4-氟-3-(2-(2-羟基丙烷-2-基)-1-甲基-1H-咪唑-4-基)-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(B20-3)(671mg,1.5mmol)加入到反应液中。反应液在120℃下反应12小时。反应结束后，将反应液缓慢滴入50mL冰水混合物中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用80mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到3-(2-(2-羟基丙烷-2-基)-1-甲基-1H-咪唑-4-基)-N-(4-甲氧基苄基)-N-甲基-4-(4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B20-4)(500mg,收率43％)。 To a solution of 4-(pentafluoro-λ 6 -sulfanyl)aniline (390 mg, 1.8 mmol) in dry N,N-dimethylformamide (10 mL) was added potassium tert-butoxide (403 mg, 3.6mmol), then 4-fluoro-3-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-N-(4-methoxybenzyl )-N-methylbenzenesulfonamide (B20-3) (671mg, 1.5mmol) was added to the reaction solution. The reaction solution was reacted at 120° C. for 12 hours. After the reaction, the reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1-1:1) to obtain 3-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazole-4- Base)-N-(4-methoxybenzyl)-N-methyl-4-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B20-4)( 500mg, yield 43%).
LC-MS,M/Z(ESI):647.3[M+H] +。 LC-MS, M/Z (ESI): 647.3 [M+H] + .
第四步：3-(2-(2-羟基丙烷-2-基)-1-甲基-1H-咪唑-4-基)-N-甲基-4-(4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-20)的合成 The fourth step: 3-(2-(2-hydroxypropane-2-yl)-1-methyl-1H-imidazol-4-yl)-N-methyl-4-(4-(pentafluoro-λ 6 Synthesis of -sulfanyl)phenyl)amino)benzenesulfonamide (I-20)
Figure PCTCN2022098060-appb-000112
Figure PCTCN2022098060-appb-000112
将3-(2-(2-羟基丙烷-2-基)-1-甲基-1H-咪唑-4-基)-N-(4-甲氧基苄基)-N-甲基-4-(4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B20-4)(0.61g,0.94mmol)溶解在二氯甲烷(8ml)中，加入三氟乙酸(4mL)，室温搅拌3小时。反应结束后，浓缩，再加乙酸乙酯(50mL)溶解，用饱和碳酸氢钠溶液洗至水相pH 7-8，粗品用硅胶色谱柱纯化(二氯甲烷:甲醇＝20:1)得到3-(2-(2-羟基丙烷-2-基)-1-甲基-1H-咪唑-4-基)-N-甲基-4-(4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-20)(368mg，产率：74％)。 3-(2-(2-Hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-N-(4-methoxybenzyl)-N-methyl-4- (4-(Pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B20-4) (0.61g, 0.94mmol) was dissolved in dichloromethane (8ml), and trifluoroacetic acid (4mL ), stirred at room temperature for 3 hours. After the reaction was completed, it was concentrated, dissolved in ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution until the pH of the aqueous phase was 7-8, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 3 -(2-(2-Hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-N-methyl-4-(4-(pentafluoro-λ 6 -sulfanyl) Phenyl)amino)benzenesulfonamide (I-20) (368 mg, yield: 74%).
LC-MS,M/Z(ESI):527.2[M+H] +。 LC-MS, M/Z (ESI): 527.2 [M+H] + .
实施例21：化合物I-21的制备Embodiment 21: Preparation of Compound I-21
合成路线如下所示：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000113
Figure PCTCN2022098060-appb-000113
第一步：3-溴-4-氟-N-(2-羟乙基)苯磺酰胺(B21-1)The first step: 3-bromo-4-fluoro-N-(2-hydroxyethyl)benzenesulfonamide (B21-1)
Figure PCTCN2022098060-appb-000114
Figure PCTCN2022098060-appb-000114
在0℃氮气保护下，向乙醇胺(837mg,13.7mmol)和三乙胺(2.5ml,18.3mmol)的二氯甲烷(100ml)溶液中滴加3-溴-4-氟苯-1-磺酰氯(A2-1)(2.5g,9.15mmol)。反应混合物在氮气保护0℃下搅拌0.5小时。然后升温到25℃氮气保护下搅拌过夜小时。反应结束后，反应液用100mL二氯甲烷稀释，有机相用盐酸水溶液洗(0.5M,50mL x 3)，收集有机相，用无水Na 2SO 4干燥，过滤，浓缩得到粗品，粗品用硅胶柱层析纯化得到3-溴-4-氟-N-(2-羟乙基)苯磺酰胺(B21-1)(2.2g,收率80.1％)。 Under nitrogen protection at 0°C, 3-bromo-4-fluorobenzene-1-sulfonyl chloride was added dropwise to a solution of ethanolamine (837mg, 13.7mmol) and triethylamine (2.5ml, 18.3mmol) in dichloromethane (100ml) (A2-1) (2.5 g, 9.15 mmol). The reaction mixture was stirred at 0°C under nitrogen for 0.5 hours. Then the temperature was raised to 25° C. and stirred overnight under nitrogen protection for an hour. After the reaction, the reaction solution was diluted with 100 mL of dichloromethane, the organic phase was washed with aqueous hydrochloric acid (0.5M, 50 mL x 3), the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the crude product, which was washed with silica gel Purified by column chromatography to obtain 3-bromo-4-fluoro-N-(2-hydroxyethyl)benzenesulfonamide (B21-1) (2.2g, yield 80.1%).
LC-MS,M/Z(ESI):297.9[M+H] +。 LC-MS, M/Z (ESI): 297.9 [M+H] + .
第二步：3-溴-N-(2-羟乙基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B21-2) The second step: 3-bromo-N-(2-hydroxyethyl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B21-2)
Figure PCTCN2022098060-appb-000115
Figure PCTCN2022098060-appb-000115
在室温下，向4-(五氟-λ 6-硫烷基)苯胺(500mg,2.3mmol)的干燥N,N-二甲基甲酰胺(15mL)溶液中加入叔丁醇钾(515mg,4.6mmol)，然后将3-溴-4-氟-N-(2-羟乙基)苯磺酰胺(B21-1)(345mg,1.15mmol)加入到反应液中。反应液在120℃下反应12小时。反应结束后，将反应液缓慢滴入50mL冰水混合物中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用80mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化得到3-溴-N-(2-羟乙基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B21-2)(172mg,收率30％)。 To a solution of 4-(pentafluoro-λ 6 -sulfanyl)aniline (500 mg, 2.3 mmol) in dry N,N-dimethylformamide (15 mL) was added potassium tert-butoxide (515 mg, 4.6 mmol), and then 3-bromo-4-fluoro-N-(2-hydroxyethyl)benzenesulfonamide (B21-1) (345mg, 1.15mmol) was added to the reaction solution. The reaction solution was reacted at 120° C. for 12 hours. After the reaction, the reaction liquid was slowly dropped into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected and washed with 80 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography to obtain 3-bromo-N-(2-hydroxyethyl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B21-2 ) (172mg, yield 30%).
LC-MS,M/Z(ESI):496.9[M+H] +。 LC-MS, M/Z (ESI): 496.9 [M+H] + .
第三步：N-(2-羟乙基)-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-21) The third step: N-(2-hydroxyethyl)-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl )amino)benzenesulfonamide (I-21)
Figure PCTCN2022098060-appb-000116
Figure PCTCN2022098060-appb-000116
在25℃氮气保护下，向3-溴-N-(2-羟乙基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(B21-2)(172mg,0.35mmol)和1-甲基-4-(三丁基锡烷基)-1H-咪唑(134mg,0.36mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入四(三苯基膦)钯(0.047g,0.041mmol)。反应混合物在120℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液缓慢倒入50mL冰水混合物中，混合物用乙酸乙酯(40mL x 3)萃取，收集有机相，用60mL饱和食盐水洗。有机相用无水Na 2SO 4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝100:1-1:1)得到N-(2-羟乙基)-3-(1-甲基-1H-咪唑-4-基)-4-((4-(五氟-λ 6-硫烷基)苯基)氨基)苯磺酰胺(I-21)(0.45g，收率85％)。 Under nitrogen protection at 25°C, 3-bromo-N-(2-hydroxyethyl)-4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (B21- 2) Add tetrakis( Triphenylphosphine) palladium (0.047 g, 0.041 mmol). The reaction mixture was stirred at 120°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was slowly poured into 50 mL of ice-water mixture, the mixture was extracted with ethyl acetate (40 mL x 3), the organic phase was collected, and washed with 60 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1-1:1) to obtain N-(2-hydroxyethyl)-3-(1-methyl-1H-imidazol-4-yl)- 4-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)amino)benzenesulfonamide (I-21) (0.45 g, yield 85%).
LC-MS,M/Z(ESI):499.1[M+H] +。 LC-MS, M/Z (ESI): 499.1 [M+H] + .
实施例22：化合物1-22的制备Embodiment 22: Preparation of compound 1-22
合成路线如下：The synthetic route is as follows:
Figure PCTCN2022098060-appb-000117
Figure PCTCN2022098060-appb-000117
第一步：4-(五氟-λ 6-硫烷基)苯酚的制备 Step 1: Preparation of 4-(pentafluoro-λ 6 -sulfanyl)phenol
Figure PCTCN2022098060-appb-000118
Figure PCTCN2022098060-appb-000118
将4-(五氟-λ 6-硫烷基)苯胺(5.00g,22.81mmol)溶于浓硫酸(25.0mL)和水(25.0mL)中，降温至0℃，向其中加入亚硝酸钠(1.65g,23.95mmol)，搅拌15min后，将其缓慢加入到100℃浓硫酸(25.0mL)和水(25.0mL)混合溶液中，反应2h。反应结束后，用乙酸乙酯(50.0mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)纯化得到4-(五氟-λ 6-硫烷基)苯酚(1.51g,产率30.1％) Dissolve 4-(pentafluoro-λ 6 -sulfanyl)aniline (5.00g, 22.81mmol) in concentrated sulfuric acid (25.0mL) and water (25.0mL), cool down to 0°C, add sodium nitrite ( 1.65g, 23.95mmol), after stirring for 15min, it was slowly added to a mixed solution of concentrated sulfuric acid (25.0mL) and water (25.0mL) at 100°C, and reacted for 2h. After the reaction, it was extracted three times with ethyl acetate (50.0 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=3:1) to obtain 4-(pentafluoro-λ 6 -sulfanyl)phenol (1.51g, yield 30.1%)
LC-MS,M/Z(ESI):221.1[M+H] +。 LC-MS, M/Z (ESI): 221.1 [M+H] + .
第二步 5-溴-N-(4-甲氧基苄基)-N-甲基-6-(4-(五氟-λ 6-硫烷基)苯氧基)吡啶-3-磺酰胺的制备 The second step 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-(4-(pentafluoro-λ 6 -sulfanyl)phenoxy)pyridine-3-sulfonamide preparation of
Figure PCTCN2022098060-appb-000119
Figure PCTCN2022098060-appb-000119
将4-(五氟-λ 6-硫烷基)苯酚(1.20g,5.45mmol)溶于DMF(25.0mL)中，向其中加入碳酸铯(3.55g,10.90mmol)和5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(2.10g,5.18mmol)，加热至到100℃反应2h。反应结束后，向体系中加入水(50.0mL)，用乙酸乙酯(50.0mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)纯化得到5-溴-N-(4-甲氧基苄基)-N-甲基-6-(4-(五氟-λ 6-硫烷基)苯氧基)吡啶-3-磺酰胺(1.80g,产率56.0％) 4-(pentafluoro-λ 6 -sulfanyl)phenol (1.20g, 5.45mmol) was dissolved in DMF (25.0mL), cesium carbonate (3.55g, 10.90mmol) and 5-bromo-6- Chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (2.10g, 5.18mmol), heated to 100°C for 2h. After the reaction, add water (50.0 mL) to the system, extract three times with ethyl acetate (50.0 mL), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain Crude. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=3:1) to obtain 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-(4 -(pentafluoro-λ 6 -sulfanyl)phenoxy)pyridine-3-sulfonamide (1.80g, yield 56.0%)
LC-MS,M/Z(ESI):589.0[M+H] +。 LC-MS, M/Z (ESI): 589.0 [M+H] + .
第三步 合成N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-(4-(五氟-λ 6-硫烷基)苯氧基)吡啶-3-磺酰胺的制备 The third step is to synthesize N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-(4-(pentafluoro-λ 6 - Preparation of sulfanyl)phenoxy)pyridine-3-sulfonamide
Figure PCTCN2022098060-appb-000120
Figure PCTCN2022098060-appb-000120
氮气保护下，将5-溴-N-(4-甲氧基苄基)-N-甲基-6-(4-(五氟-λ 6-硫烷基)苯氧基)吡啶-3-磺酰胺(1.50g,2.55mmol)，1-甲基-4-(三丁基甲锡烷基)-1H-咪唑(1.04g,2.80mmol)，四(三苯基膦)钯(294.1mg,0.25mmol)溶于DMF(15.0mL),升温至110℃反应15h.反应结束后，加3M氟化钾溶液(20.0mL)淬灭，用乙酸乙酯(20.0mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:1)纯化得到N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-(4-(五氟-λ 6-硫烷基)苯氧基)吡啶-3-磺酰胺(1.21g,产率80.5％)。 Under nitrogen protection, 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-(4-(pentafluoro-λ 6 -sulfanyl)phenoxy)pyridine-3- Sulfonamide (1.50g, 2.55mmol), 1-methyl-4-(tributylstannyl)-1H-imidazole (1.04g, 2.80mmol), tetrakis(triphenylphosphine)palladium (294.1mg, 0.25mmol ) was dissolved in DMF (15.0mL), heated to 110°C and reacted for 15h. After the reaction was completed, it was quenched by adding 3M potassium fluoride solution (20.0mL), extracted three times with ethyl acetate (20.0mL), combined the organic phases, and washed with saturated Wash with brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:1) to obtain N-(4-methoxybenzyl)-N-methyl-5-(1-methyl- 1H-imidazol-4-yl)-6-(4-(pentafluoro-λ6 - sulfanyl)phenoxy)pyridine-3-sulfonamide (1.21 g, 80.5% yield).
LC-MS,M/Z(ESI):591.1[M+H] +。 LC-MS, M/Z (ESI): 591.1 [M+H] + .
第四步 N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-(4-(五氟-λ 6-硫烷基)苯氧基)吡啶-3-磺酰胺(I-22) The fourth step N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-(4-(pentafluoro-λ 6 -sulfanyl)phenoxy)pyridine-3-sulfonate Amide (I-22)
Figure PCTCN2022098060-appb-000121
Figure PCTCN2022098060-appb-000121
将N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-(4-(五氟-λ 6-硫烷基)苯氧基)吡啶-3-磺酰胺(1.20g,2.03mmol)溶于二氯甲烷(10.0mL)中，向其中加入三氟乙酸(10.0mL),室温下搅拌2h。反应结束后，反应液浓缩得到粗产品，粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:3)纯化得到N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-(4-(五氟-λ 6-硫烷基)苯氧基)吡啶-3-磺酰胺(750mg,产率78.5％) N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-(4-(pentafluoro-λ 6 -sulfanyl )phenoxy)pyridine-3-sulfonamide (1.20g, 2.03mmol) was dissolved in dichloromethane (10.0mL), trifluoroacetic acid (10.0mL) was added thereto, and stirred at room temperature for 2h. After the reaction, the reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 1:3) and purified to obtain N-methyl-5-(1-methyl-1H -Imidazol-4-yl)-6-(4-(pentafluoro-λ 6 -sulfanyl)phenoxy)pyridine-3-sulfonamide (750mg, yield 78.5%)
1H NMR(400MHz,DMSO)δ8.83–8.80(m,1H),8.29(d,J＝2.5Hz,1H),8.04–7.99(m,2H),7.82(d,J＝1.7Hz,2H),7.69(q,J＝4.7Hz,1H),7.52(d,J＝9.0Hz,2H),3.72(s,3H),2.46(d,J＝4.7Hz,3H). 1 H NMR (400MHz, DMSO) δ8.83–8.80(m,1H),8.29(d,J=2.5Hz,1H),8.04–7.99(m,2H),7.82(d,J=1.7Hz,2H ), 7.69(q, J=4.7Hz, 1H), 7.52(d, J=9.0Hz, 2H), 3.72(s, 3H), 2.46(d, J=4.7Hz, 3H).
LC-MS,M/Z(ESI):471.0[M+H] +。 LC-MS, M/Z (ESI): 471.0 [M+H] + .
实施例23：化合物1-23的制备Embodiment 23: Preparation of compound 1-23
N-甲基-5-(1-(氘代甲基)-1H-咪唑-4-基)-6-(4-(五氟-λ 6-硫烷基)苯氧基)吡啶-3-磺酰胺 N-methyl-5-(1-(deuteromethyl)-1H-imidazol-4-yl)-6-(4-(pentafluoro-λ 6 -sulfanyl)phenoxy)pyridine-3- Sulfonamide
Figure PCTCN2022098060-appb-000122
Figure PCTCN2022098060-appb-000122
I-23的合成路线参考I-22，将第三步的原料1-甲基-4-(三丁基甲锡烷基)-1H-咪唑替换为1-氘代甲基-4-(三丁基甲锡烷基)-1H-咪唑，LC-MS,M/Z(ESI):474.1[M+H] +。 The synthetic route of I-23 refers to I-22, and the raw material 1-methyl-4-(tributylstannyl)-1H-imidazole of the third step is replaced by 1-deuteromethyl-4-(tributylstannyl Alkyl)-1H-imidazole, LC-MS, M/Z (ESI): 474.1[M+H] + .
实施例24化合物I-24的制备The preparation of embodiment 24 compound I-24
N-(氘代甲基)-5-(1-甲基-1H-咪唑-4-基)-6-(4-(五氟-λ6-硫烷基)苯氧基)吡啶-3-磺酰胺(I-24)。N-(deuteromethyl)-5-(1-methyl-1H-imidazol-4-yl)-6-(4-(pentafluoro-λ6-sulfanyl)phenoxy)pyridine-3-sulfonyl Amide (I-24).
Figure PCTCN2022098060-appb-000123
Figure PCTCN2022098060-appb-000123
化合物I-24的制备参考化合物I-22的制备方法得到。LC-MS,M/Z(ESI):474.1[M+H] +。 The preparation of compound I-24 was obtained by referring to the preparation method of compound I-22. LC-MS, M/Z (ESI): 474.1 [M+H] + .
在本发明的测试例中，对照化合物的制备参考专利公开WO2020243415A2，结构如下：In the test example of the present invention, the preparation of the reference compound refers to the patent publication WO2020243415A2, and the structure is as follows:
Figure PCTCN2022098060-appb-000124
Figure PCTCN2022098060-appb-000124
测试例1：TEADs介导的转录抑制IC 50评价试验 Test Example 1: TEADs-mediated transcriptional inhibition IC 50 evaluation test
采用HEK293T-TEAD Reporter Assay检测小分子化合物对TEADs介导的转录抑制作用。HEK293T-TEAD Reporter Assay was used to detect the inhibitory effect of small molecule compounds on TEADs-mediated transcription.
HEK293T-TEAD-LUC reporter cell line以DMEM(达尔伯克(氏)改良伊格尔(氏)培养基)+10％FBS(胎牛血清)+1％PS(青霉素-链霉素)+200μg/ml Hygromycin(潮霉素)为完全培养基进行培养，将处于对数期的细胞接种于384孔板中，2500cell/孔/35μL，37℃，5％CO 2孵育过夜，第二天每孔加入5μL稀释好的化合物(DMSO终浓度为0.1％)，同时设置只加入DMSO的阳性对照组，并以2μM的Okacid acid信号值作为阴性对照组信号，然后37℃，5％CO 2孵育48h，孵育完成后使用
Figure PCTCN2022098060-appb-000125
luciferase assay system(Promega，E2550)并按照供应商提供的说明书在Envision 2104Multilabel Reader上测定荧光信号值。通过以下公式计算抑制率，然后以抑制剂的浓度Log值为X轴，抑制率为Y轴绘制曲线，用Graphpad 7.0计算得出IC 50。 HEK293T-TEAD-LUC reporter cell line is prepared with DMEM (Dulbecco's modified Eagle's medium) + 10% FBS (fetal bovine serum) + 1% PS (penicillin-streptomycin) + 200μg/ ml Hygromycin (hygromycin) is used as a complete medium for culture, cells in the logarithmic phase are seeded in a 384-well plate, 2500cell/well/35μL, 37°C, 5% CO 2 Incubate overnight, add to each well the next day 5 μL of the diluted compound (the final concentration of DMSO is 0.1%), set up a positive control group with only DMSO added at the same time, and use the signal value of 2 μM Okacid acid as the signal of the negative control group, then incubate at 37°C, 5% CO 2 for 48 hours, and incubate when done use
Figure PCTCN2022098060-appb-000125
luciferase assay system (Promega, E2550) and measure the fluorescence signal value on Envision 2104Multilabel Reader according to the instructions provided by the supplier. The inhibition rate was calculated by the following formula, and then the log value of the concentration of the inhibitor was plotted on the X-axis, and the inhibition rate was drawn on the Y-axis, and the IC 50 was calculated with Graphpad 7.0.
抑制率％＝(阳性对照组信号-测试孔信号)/(阳性对照组信号-阴性对照组信号)*100Inhibition rate% = (signal of positive control group - signal of test well) / (signal of positive control group - signal of negative control group) * 100
表1 测试化合物在HEK293T-TEAD-LUC reporter cell line细胞上的TEADs转录抑制活性Table 1 TEADs transcriptional inhibitory activity of test compounds on HEK293T-TEAD-LUC reporter cell line cells
测试化合物test compound IC 50(nM) IC 50 (nM)
对照化合物Control compound 7070
I-1I-1 1616
I-2I-2 1414
I-3I-3 88
I-14I-14 27.527.5
I-18I-18 76.976.9
HEK293T-TEAD Reporter Assay结果表明，本发明化合物在HEK293T-TEAD-LUC reporter cell line细胞上能明显抑制TEADs转录的活性，与对照化合物相比，显示出更优异的抑制作用。The results of HEK293T-TEAD Reporter Assay show that the compounds of the present invention can significantly inhibit the transcriptional activity of TEADs on HEK293T-TEAD-LUC reporter cell line cells, and show a better inhibitory effect than the control compound.
测试例2：抑制恶性间皮瘤细胞增殖试验Test Example 2: Inhibition of malignant mesothelioma cell proliferation test
采用NF2突变的NCI-H226细胞增殖试验检测小分子化合物对恶性间皮瘤细胞增殖抑制作用。The NCI-H226 cell proliferation assay with NF2 mutation was used to detect the inhibitory effect of small molecule compounds on the proliferation of malignant mesothelioma cells.
NCI-H226(ATCC，cat#CRL5826)以RPMI1640(RPMI 1640培养基)+10％FBS(胎牛血清)+1％PS(青霉素-链霉素)为完全培养基进行培养，将处于对数期的细胞接种于96孔板中，800cell/孔/195uL，37℃，5％CO 2孵育过夜，第二天每孔加入5μL稀释好的化合物(DMSO终浓度为0.1％)，同时设置只加入DMSO的阳性对照组，并以1μM的Staurosporine信号值作为阴性对照组信号，然后37℃，5％CO 2孵育6天，孵育完成后，吸出100μL培养基，使用Celltiter Glo assay kit(Promega，G7573)并按照供应商提供的说明书在Envision 2104 Multilabel Reader上测定荧光信号值。通过以下公式计算抑制率，然后以抑制剂的浓度Log值为X轴，抑制率为Y轴绘制曲线，用Graphpad 7.0计算得出IC 50。 NCI-H226 (ATCC, cat#CRL5826) is cultured with RPMI1640 (RPMI 1640 medium) + 10% FBS (fetal bovine serum) + 1% PS (penicillin-streptomycin) as a complete medium, and will be in logarithmic phase Seed the cells in a 96-well plate, 800cell/well/195uL, incubate overnight at 37°C, 5% CO 2 , add 5 μL of the diluted compound to each well the next day (the final concentration of DMSO is 0.1%), and set only DMSO to be added positive control group, and the signal value of Staurosporine at 1 μM was used as the signal value of the negative control group, and then incubated at 37°C, 5% CO 2 for 6 days. Fluorescent signal values were measured on Envision 2104 Multilabel Reader according to the instructions provided by the supplier. The inhibition rate was calculated by the following formula, and then the log value of the concentration of the inhibitor was plotted on the X-axis, and the inhibition rate was drawn on the Y-axis, and the IC 50 was calculated with Graphpad 7.0.
抑制率％＝(阳性对照组信号-测试孔信号)/(阳性对照组信号-阴性对照组信号)*100Inhibition rate% = (signal of positive control group - signal of test well) / (signal of positive control group - signal of negative control group) * 100
NCI-H226细胞增殖试验结果表明，本发明化合物能明显抑制NCI-H226(ATCC，cat#CRL5826)的增殖。The results of NCI-H226 cell proliferation test show that the compound of the present invention can obviously inhibit the proliferation of NCI-H226 (ATCC, cat#CRL5826).
表2 测试化合物对H226细胞增殖抑制活性Table 2 Test compounds have inhibitory activity on H226 cell proliferation
测试化合物test compound IC 50(nM) IC 50 (nM)
对照化合物Control compound 32.632.6
I-1I-1 19.019.0
I-2I-2 22.922.9
I-5I-5 16.716.7
I-7I-7 26.726.7
I-14I-14 18.218.2
I-18I-18 8.928.92
测试例3：药代动力学试验Test Example 3: Pharmacokinetic Test
小鼠药代动力学试验，使用3只雄性ICR小鼠，20-25g，禁食过夜，口服灌胃给药(10mg/kg)。在给药前和给药后15、30分钟以及1、2、4、8、24小时采血。血液样品于6800g，2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。For the mouse pharmacokinetics test, three male ICR mice, 20-25g in weight, were fasted overnight and administered orally (10 mg/kg) by gavage. Blood was collected before administration and 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes to collect plasma and stored at -80°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.
表3：小鼠药代动力学试验结果Table 3: Pharmacokinetic test results in mice
Figure PCTCN2022098060-appb-000126
Figure PCTCN2022098060-appb-000126
小鼠药代动力学试验结果表明，本发明化合物表现出优良的药代动力学性质，成药性良好。The mouse pharmacokinetic test results show that the compound of the present invention exhibits excellent pharmacokinetic properties and good druggability.
测试例4：NCI-H226间皮瘤小鼠荷瘤药效试验Test Example 4: Drug efficacy test of NCI-H226 mesothelioma mice
Nu/Nu裸鼠(CRL)适应性饲养一周后，将处于对数期的NCI-H226细胞重悬于PBS，按100μL/只将5×10 6NCI-H226细胞接种于小鼠右侧后部处皮下，定期观察肿瘤生长情况，待肿瘤生长至平均体积80-100mm 3时，根据肿瘤大小和小鼠体重随机分为模型组和给药组，给药前和给药过程中测量、记录肿瘤体积和动物体重，治疗结束后以模型组作为对照组，统计给药组对肿瘤的生长抑制作用，计算TGI。 After one week of adaptive feeding of Nu/Nu nude mice (CRL), resuspend the NCI-H226 cells in logarithmic phase in PBS, and inoculate 5×10 6 NCI-H226 cells on the right rear of the mice at 100 μL/mouse Subcutaneously, observe the tumor growth regularly. When the tumor grows to an average volume of 80-100mm3 , the mice are randomly divided into the model group and the administration group according to the tumor size and body weight, and the tumor is measured and recorded before and during the administration. Volume and animal weight. After the treatment, the model group was used as the control group, and the growth inhibitory effect of the administration group on the tumor was counted, and TGI was calculated.
荷瘤小鼠药效试验结果表明(如图1所示)，本发明化合物具有显著的抑制NCI-H226间皮瘤生长的作用。The results of the drug efficacy test on tumor-bearing mice showed (as shown in FIG. 1 ) that the compound of the present invention has a significant effect of inhibiting the growth of NCI-H226 mesothelioma.
以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。The implementation manners of the technical solutions of the present invention are described above as examples. It should be understood that the protection scope of the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included within the protection scope of the claims of the present application.

Claims (19)

  1. 一种杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，所述杂环类化合物具有式I所示结构：A heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, the heterocyclic compound has the structure shown in formula I:
    Figure PCTCN2022098060-appb-100001
    Figure PCTCN2022098060-appb-100001
    其中，环A为苯环、5-6元杂环或5-6元杂芳环；Wherein, Ring A is a benzene ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring;
    环B为苯环或5-6元杂芳环；Ring B is a benzene ring or a 5-6 membered heteroaromatic ring;
    Z为-O-、-NH-或-CH 2-；所述-NH-或-CH 2-中的氢原子任选地被一个或两个Ra取代；各个Ra各自独立地选自甲基、乙基或丙基； Z is -O-, -NH- or -CH 2 -; the hydrogen atoms in the -NH- or -CH 2 - are optionally substituted by one or two Ra; each Ra is independently selected from methyl, ethyl or propyl;
    L不存在或为C 1-C 3亚烷基； L is absent or is C 1 -C 3 alkylene;
    所述L任选地被卤素或C 1-C 3烷基中的一个或更多个各自独立地取代； Said L is optionally substituted by one or more of halogen or C 1 -C 3 alkyl, each independently;
    环E为5-6元杂环或5-6元杂芳环；n选自0、1、2、3、4或5；Ring E is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; n is selected from 0, 1, 2, 3, 4 or 5;
    每个R 0相同或不同，各自独立地为氢、氧代
    Figure PCTCN2022098060-appb-100002
    C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6氘代烷基、3-6元环烷基、3-6元卤代环烷基；     Each R 0 is the same or different, independently hydrogen, oxo
    Figure PCTCN2022098060-appb-100002
    C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
    R 1选自下列的取代基：
    Figure PCTCN2022098060-appb-100003
    R 1 is selected from the following substituents:
    Figure PCTCN2022098060-appb-100003
    R 11、R 12、R 13、R 14各自独立地为氢或任选被1个、2个或更多个Rb取代的下列基团：C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基、4-6元杂环烷基；每个Rb相同或不同，各自独立地选自氘、苯基或5-6元杂芳基； R 11 , R 12 , R 13 , R 14 are each independently hydrogen or the following groups optionally substituted by 1, 2 or more Rb: C 1 -C 6 alkyl, C 1 -C 6 haloalkane Base, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 4-6 membered heterocycloalkyl; each Rb is the same or different, each independently selected from deuterium, phenyl or 5-6 membered Heteroaryl;
    R 2为氢或选自下列的取代基：
    Figure PCTCN2022098060-appb-100004
    卤素、C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基；     R is hydrogen or a substituent selected from the following:
    Figure PCTCN2022098060-appb-100004
    Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
    R 3为-SF 5或-CF 2-O-R 31； R 3 is -SF 5 or -CF 2 -OR 31 ;
    R 31为C 1-C 6烷基、3-6元环烷基、3-6元杂环烷基； R 31 is C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
    R 31任选地被选自下组的取代基取代：卤素、羟基、-SF 5、C 1-C 6烷基、C 1-C 6烷氧基、3-6元环烷基、3-6元杂环烷基； R 31 is optionally substituted by a substituent selected from the group consisting of halogen, hydroxyl, -SF 5 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl;
    R 4为氢或选自下列的取代基：卤素、C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基； R 4 is hydrogen or a substituent selected from the following: halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
    较佳地，式I所示化合物具有式II所示的结构：Preferably, the compound shown in formula I has the structure shown in formula II:
    Figure PCTCN2022098060-appb-100005
    Figure PCTCN2022098060-appb-100005
    其中，环A为苯环或5-6元杂芳环；Wherein, Ring A is a benzene ring or a 5-6 membered heteroaromatic ring;
    环B为苯环或5-6元杂芳环；Ring B is a benzene ring or a 5-6 membered heteroaromatic ring;
    Z为-NH-或-CH 2-；所述-NH-或-CH 2-中的氢原子任选地被Ra取代；Ra为甲基、乙基或丙基； Z is -NH- or -CH 2 -; the hydrogen atom in the -NH- or -CH 2 - is optionally substituted by Ra; Ra is methyl, ethyl or propyl;
    L不存在或为C 1-C 3亚烷基； L is absent or is C 1 -C 3 alkylene;
    所述L任选地被卤素或C 1-C 3烷基取代； Said L is optionally substituted by halogen or C 1 -C 3 alkyl;
    R 1选自下列的取代基：
    Figure PCTCN2022098060-appb-100006
    R 1 is selected from the following substituents:
    Figure PCTCN2022098060-appb-100006
    R 11、R 12、R 13、R 14各自独立地为氢或选自下列的取代基：C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基、4-6元杂环烷基； R 11 , R 12 , R 13 , and R 14 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3- 6-membered halocycloalkyl, 4-6-membered heterocycloalkyl;
    R 2为氢或选自下列的取代基：
    Figure PCTCN2022098060-appb-100007
    卤素、C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基；     R is hydrogen or a substituent selected from the following:
    Figure PCTCN2022098060-appb-100007
    Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
    R 3为-SF 5或-CF 2-O-R 31； R 3 is -SF 5 or -CF 2 -OR 31 ;
    R 31为C 1-C 6烷基、3-6元环烷基、3-6元杂环烷基； R 31 is C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
    R 31任选地被选自下组的取代基取代：卤素、羟基、-SF 5、C 1-C 6烷基、C 1-C 6烷氧基、3-6元环烷基、3-6元杂环烷基； R 31 is optionally substituted by a substituent selected from the group consisting of halogen, hydroxyl, -SF 5 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, 3- 6-membered heterocycloalkyl;
    R 4为氢或选自下列的取代基：卤素、C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基、3-6元卤代环烷基； R 4 is hydrogen or a substituent selected from the following: halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl;
    R 5、R 6各自独立地为氢或选自下列的取代基：C 1-C 6烷基、C 1-C 6卤代烷基、、3-6元环烷基、3-6元卤代环烷基。 R 5 and R 6 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halogenated ring alkyl.
  2. 如权利要求1所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，环A选自：苯环、吡啶、嘧啶、
    Figure PCTCN2022098060-appb-100008
    较佳地，环A为苯环或吡啶。     The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, is characterized in that, ring A is selected from: benzene ring, pyridine, pyrimidine,
    Figure PCTCN2022098060-appb-100008
    Preferably, ring A is a benzene ring or pyridine.
  3. 如权利要求1所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 2为氢或选自下列的取代基：
    Figure PCTCN2022098060-appb-100009
    C 1-C 6烷基、C 1-C 6卤代烷基。     The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, is characterized in that, R 2 is hydrogen or selected Substituents from the following:
    Figure PCTCN2022098060-appb-100009
    C 1 -C 6 alkyl, C 1 -C 6 haloalkyl.
  4. 如权利要求1所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 2为氢或
    Figure PCTCN2022098060-appb-100010
    The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, is characterized in that, R 2 is hydrogen or
    Figure PCTCN2022098060-appb-100010
    较佳地，R 2为氢或
    Figure PCTCN2022098060-appb-100011
    且环A为吡啶。     Preferably, R 2 is hydrogen or
    Figure PCTCN2022098060-appb-100011
    And ring A is pyridine.
  5. 如权利要求1所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化 物、药学上可接受的盐或前药，其特征在于，Z为-O-、-NH-或-CH 2-；L不存在或为-CH 2-、-CH(CH 3)-；较佳地，基团-Z-L-为-O-、-Z-L-为-NH-、-CH 2-或-NH-CH 2-； The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 1, wherein Z is -O-, -NH- or -CH 2 -; L does not exist or is -CH 2 -, -CH(CH 3 )-; preferably, the group -ZL- is -O-, -ZL- is -NH-, - CH 2 -or -NH-CH 2 -;
    较佳地，Z为-NH-或-CH 2-；L不存在或为-CH 2-、-CH(CH 3)-； Preferably, Z is -NH- or -CH 2 -; L does not exist or is -CH 2 -, -CH(CH 3 )-;
    较佳地，基团-Z-L-为-NH-、-CH 2-或-NH-CH 2-。 Preferably, the group -ZL- is -NH-, -CH 2 - or -NH-CH 2 -.
  6. 如权利要求1所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，环B选自：苯环、吡啶、嘧啶；较佳地，环B为苯环或吡啶；The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, is characterized in that, ring B is selected from: benzene ring, pyridine, pyrimidine; preferably, ring B is a benzene ring or pyridine;
    较佳地，环E选自：
    Figure PCTCN2022098060-appb-100012
    较佳地，环E选自
    Figure PCTCN2022098060-appb-100013
    较佳地，各个R 0各自独立地选自甲基、氧代、三氘代甲基；     Preferably, ring E is selected from:
    Figure PCTCN2022098060-appb-100012
    Preferably, ring E is selected from
    Figure PCTCN2022098060-appb-100013
    Preferably, each R 0 is independently selected from methyl, oxo, and trideuteriomethyl;
    较佳地，n选自0、1、2或3；Preferably, n is selected from 0, 1, 2 or 3;
    较佳地，
    Figure PCTCN2022098060-appb-100014
    选自
    Figure PCTCN2022098060-appb-100015
    Figure PCTCN2022098060-appb-100016
    Preferably,
    Figure PCTCN2022098060-appb-100014
    selected from
    Figure PCTCN2022098060-appb-100015
    Figure PCTCN2022098060-appb-100016
  7. 如权利要求1所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，具有式Ia或Ib所示结构：The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, is characterized in that, has formula Ia or Ib display structure:
    Figure PCTCN2022098060-appb-100017
    Figure PCTCN2022098060-appb-100017
    其中，W表示CRw、N；Among them, W represents CRw, N;
    Rw为氢、卤素、C 1-C 6烷基、3-6元环烷基、C 1-C 6卤代烷基、3-6元卤代环烷基； Rw is hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 haloalkyl, 3-6 membered halogenated cycloalkyl;
    Y 1、Y 2各自独立地选自CR 4或N； Y 1 and Y 2 are each independently selected from CR 4 or N;
    Y 3、Y 4、Y 5各自独立地选自CR 3或N； Y 3 , Y 4 , Y 5 are each independently selected from CR 3 or N;
    且Y 1、Y 2、Y 3、Y 4、Y 5中至多有两个N； And Y 1 , Y 2 , Y 3 , Y 4 , Y 5 have at most two Ns;
    L、R 1、R 3、R 4、R 5的定义如权利要求1中所述。 The definitions of L, R 1 , R 3 , R 4 and R 5 are as described in claim 1.
  8. 如权利要求1或7所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，Rw为氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基；较佳地，Rw为氢。 The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1 or 7, is characterized in that Rw is hydrogen, Halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; preferably, Rw is hydrogen.
  9. 如权利要求1或7所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 1为
    Figure PCTCN2022098060-appb-100018
    R 11、R 12各自独立地为氢或任选被1个、2个或更多个Rb取代的下列基团：C 1-C 6烷基、C 1-C 6卤代烷基；每个Rb相同或不同，各自独立地选自氘或5-6元杂芳基；；     The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1 or 7, is characterized in that, R is
    Figure PCTCN2022098060-appb-100018
    R 11 , R 12 are each independently hydrogen or the following groups optionally substituted by 1, 2 or more Rb: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; each Rb is the same or different, each independently selected from deuterium or 5-6 membered heteroaryl;;
    较佳地，R 1为
    Figure PCTCN2022098060-appb-100019
    R 11、R 12各自独立地为氢或选自下列的取代基：C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6氘代烷基、吡啶基-C 1-C 6烷基；     Preferably, R 1 is
    Figure PCTCN2022098060-appb-100019
    R 11 and R 12 are each independently hydrogen or a substituent selected from the following: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, pyridyl-C 1 - C 6 alkyl;
    较佳地，R 11、R 12各自独立地为氢、甲基、乙基、丙基、三氘代甲基、吡啶基甲基； Preferably, R 11 and R 12 are each independently hydrogen, methyl, ethyl, propyl, trideuteromethyl, pyridylmethyl;
    更佳地，R 11为氢，R 12为甲基。 More preferably, R 11 is hydrogen and R 12 is methyl.
  10. 如权利要求1或7所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 5为氢或选自下列的取代基：甲基、乙基、环丙基、环丁基； The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1 or 7, is characterized in that, R 5 is hydrogen Or a substituent selected from the following: methyl, ethyl, cyclopropyl, cyclobutyl;
    较佳地，R 5为甲基。 Preferably, R 5 is methyl.
  11. 如权利要求1或7所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，L为-CH 2-或-CH(CH 3)-。 The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 1 or 7, wherein L is -CH 2 - or -CH(CH 3 )-.
  12. 如权利要求1或7所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 3为-SF 5或-CF 2-O-R 31； The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1 or 7, is characterized in that, R 3 is- SF 5 or -CF 2 -OR 31 ;
    R 31选自甲基、乙基、丙基、丁基、环丙烷、环丁烷、环戊烷、环己烷； R is selected from methyl, ethyl, propyl, butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane;
    较佳地，R 31为甲基或环丙烷。 Preferably, R 31 is methyl or cyclopropane.
  13. 如权利要求12所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 3为-SF 5、-CF 2-O-CH 3或
    Figure PCTCN2022098060-appb-100020
    The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 12, wherein R 3 is -SF 5 , -CF 2 -O-CH 3 or
    Figure PCTCN2022098060-appb-100020
  14. 如权利要求1或7所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 4为氢或选自下列的取代基：卤素、C 1-C 6烷基、C 1-C 6卤代烷基；较佳地，R 4为氢。 The heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1 or 7, is characterized in that, R 4 is hydrogen Or a substituent selected from the following: halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; preferably, R 4 is hydrogen.
  15. 如权利要求1所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，选自：The heterocyclic compound as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that, is selected from:
    Figure PCTCN2022098060-appb-100021
    Figure PCTCN2022098060-appb-100021
    Figure PCTCN2022098060-appb-100022
    Figure PCTCN2022098060-appb-100022
    Figure PCTCN2022098060-appb-100023
    Figure PCTCN2022098060-appb-100023
  16. 一种药物组合物，其特征在于，所述药物组合物包括：如权利要求1-15中任一所述的作为TEAD抑制剂的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；和药学上可接受的载体。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: the heterocyclic compound, its tautomer, and stereoisomer as any one of claims 1-15 as a TEAD inhibitor , hydrate, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier.
  17. 一种如权利要求1-15中任一所述的杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途，或如权利要求16所述的药物组合物的用途，所述用途包括：A use of the heterocyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as described in any one of claims 1-15, or The purposes of pharmaceutical composition as claimed in claim 16, described purposes comprises:
    制备用于预防和/或治疗与TEAD表达增加相关的疾病的药物、药物组合物或制剂；和/或，Preparation of a medicament, pharmaceutical composition or formulation for the prevention and/or treatment of diseases associated with increased expression of TEAD; and/or,
    制备用于降低/抑制TEAD表达、TEAD活性增加的药物、药物组合物或制剂；和/或，Preparation of medicaments, pharmaceutical compositions or preparations for reducing/inhibiting TEAD expression, increasing TEAD activity; and/or,
    制备用于降低/抑制Hippo信号通路的药物、药物组合物或制剂。Medicines, pharmaceutical compositions or preparations for reducing/inhibiting Hippo signaling pathways are prepared.
  18. 如权利要求17所述的用途，其特征在于，所述TEAD包括：TEAD1、TEAD2、TEAD3和TEAD4。The use according to claim 17, wherein the TEAD comprises: TEAD1, TEAD2, TEAD3 and TEAD4.
  19. 如权利要求17所述的用途，其特征在于，所述疾病是细胞增殖性病症；The use according to claim 17, wherein the disease is a cell proliferative disorder;
    较佳地，所述细胞增殖性病症为癌症。Preferably, said cell proliferative disorder is cancer.
PCT/CN2022/098060 2021-06-11 2022-06-10 Heterocyclic compound for tead inhibitor WO2022258040A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111542315A (en) * 2017-08-21 2020-08-14 维瓦斯治疗公司 Benzosulfonyl compounds
WO2020243423A1 (en) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2020243415A2 (en) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111542315A (en) * 2017-08-21 2020-08-14 维瓦斯治疗公司 Benzosulfonyl compounds
WO2020243423A1 (en) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2020243415A2 (en) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof

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