WO2022258040A1 - Composé hétérocyclique pour inhibiteur de tead - Google Patents

Composé hétérocyclique pour inhibiteur de tead 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.

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Abstract

L'invention concerne un composé hétérocyclique pour un inhibiteur de TEAD. Le composé hétérocyclique a la structure représentée dans la formule I, et les groupes dans la formule I sont tels que définis dans la description. Le composé hétérocyclique est utilisé pour prévenir et/ou traiter des maladies associées à une expression accrue de TEAD, telles que des troubles de la prolifération cellulaire.
PCT/CN2022/098060 2021-06-11 2022-06-10 Composé hétérocyclique pour inhibiteur de tead WO2022258040A1 (fr)

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CN118005606A (zh) * 2022-11-10 2024-05-10 武汉人福创新药物研发中心有限公司 Tead抑制剂

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111542315A (zh) * 2017-08-21 2020-08-14 维瓦斯治疗公司 苯并磺酰基化合物
WO2020243423A1 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2020243415A2 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111542315A (zh) * 2017-08-21 2020-08-14 维瓦斯治疗公司 苯并磺酰基化合物
WO2020243423A1 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2020243415A2 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations

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