WO2023116877A1 - 作为tead抑制剂的杂环化合物 - Google Patents

作为tead抑制剂的杂环化合物 Download PDF

Info

Publication number
WO2023116877A1
WO2023116877A1 PCT/CN2022/141373 CN2022141373W WO2023116877A1 WO 2023116877 A1 WO2023116877 A1 WO 2023116877A1 CN 2022141373 W CN2022141373 W CN 2022141373W WO 2023116877 A1 WO2023116877 A1 WO 2023116877A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
heterocyclic compound
methyl
pharmaceutically acceptable
tead
Prior art date
Application number
PCT/CN2022/141373
Other languages
English (en)
French (fr)
Inventor
张学军
李学强
王洪强
李超
叶大炳
王猛
李莉娥
杨俊�
Original Assignee
武汉人福创新药物研发中心有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武汉人福创新药物研发中心有限公司 filed Critical 武汉人福创新药物研发中心有限公司
Publication of WO2023116877A1 publication Critical patent/WO2023116877A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine, in particular, the invention relates to a heterocyclic compound as a TEAD inhibitor, its preparation method and 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 Transcriptional Enhanced Associate Domains, Transcriptional Enhanced Associate Domains
  • TEAD1 TEAD2, TEAD3 and TEAD4. All TEADs subtypes have one N-terminal that binds to DNA
  • the 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 connection between the TEA domain and the transactivation domain Subtypes are very different, the overall homology of the four TEADs subtypes ranged 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 is highly expressed, and the overactivation of YAP/TAZ-TEADs complex contributes to the promotion of tumor cell proliferation, metastasis, epithelial to mesenchymal transition (EMT) and maintenance of tumor stem cells (Liu, Huirong et al ., Oncology reports, 2018.).
  • EMT epithelial to mesenchymal transition
  • YAP and TEADs 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 tumor formation mediated by upstream gene mutations in the Hippo signaling pathway (Qi Y et al., Nature Communications, 2016, 7: ncomms11840.), which indicated that inhibiting the interaction of YAP/TAZ with TEADs has an anti-tumor 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).
  • 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 as a TEAD inhibitor, the heterocyclic compound can obviously inhibit the transcriptional activity of TEADs, and can be used for preventing and/or treating diseases related to the increased expression of TEAD.
  • heterocyclic compound as a TEAD inhibitor, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, so
  • the heterocyclic compound has a structure shown in formula I:
  • L is -CH 2 - or -NH-;
  • the L is optionally substituted by a substituent selected from the group consisting of: halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
  • Z 1 , Z 2 , Z 3 , and Z 4 each independently represent CR b or N; and Z 1 , Z 2 , Z 3 , and Z 4 are not CR b or N at the same time;
  • Ring A is a 5-membered heteroaromatic ring
  • Ra is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl
  • Q is unsubstituted or substituted by R c 4-8 membered heterocycloalkyl, unsubstituted or substituted by R c 5-6 membered heteroaryl, unsubstituted or substituted by R c -C 1 -C 6 alkane Base-NR 1 R 2 , unsubstituted or substituted by R c -C 1 -C 6 alkyl-C(O)-NR 3 R 4 ;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from the following substituents: cyano, C 1 -C 6 alkyl, -C(O)-C 1 -C 6 alkyl; wherein, the R 1 , R 2 , R 3 , and R 4 are each independently optionally substituted by a substituent selected from the group consisting of halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy base;
  • R 1 and R 2 together with the N atoms they are connected to form a 5-8 membered heterocycloalkyl group or a 5-6 membered heteroaryl group;
  • R c is a substituent selected from the group consisting of deuterium, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
  • R c is optionally substituted by a substituent selected from the group consisting of deuterium, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
  • R b is hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
  • Rb is hydrogen
  • the 4-8 membered heterocycloalkyl is a monocyclic or parallel heterocycloalkyl.
  • L is -NH-.
  • the Q being substituted by R c refers to being substituted by 1, 2, 3 or 4 R c ; when there are multiple substituents R c , the R c are the same or different.
  • the R c is a substituent selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl;
  • R c is methyl, ethyl, propyl, fluoromethyl, deuterated methyl.
  • Ring A is a 5-membered heteroaromatic ring having 1, 2 or 3 heteroatoms selected from N, O or S;
  • the ring A contains at most one O or S;
  • the ring A contains at least one N; preferably, the ring A contains at least two N; preferably, the ring A contains at least three N; preferably, the ring A contains at least Contains one O or S and contains two N;
  • the ring A is selected from oxadiazole ring, thiadiazole ring, triazole ring, pyrazole ring, imidazole ring;
  • the ring A is selected from:
  • the heterocyclic compound has the structure shown in structure Ia,
  • Z 1 , Z 2 , Z 3 , Z 4 and Q are as defined above.
  • the heterocyclic compound has the structure shown in structure Ib,
  • Z 1 , Z 2 , Z 3 , Z 4 and Q are as defined above.
  • said Q is an unsubstituted or substituted 4-8 membered lactam group; preferably, said Q is an unsubstituted or substituted monocyclic 4-6 membered A lactam group or a ring-connected 6-8 membered lactam group that is unsubstituted or substituted by R c .
  • said Q is unsubstituted or substituted by R c :
  • the Q is
  • the R c is a substituent selected from the group consisting of halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl;
  • R c is methyl, ethyl, propyl, fluoromethyl, deuterated methyl.
  • Q is C 1 -C 6 alkyl-NR 1 R 2 unsubstituted or substituted by R c ;
  • R 1 and R 2 are each independently selected from the following substituents: cyano, C 1 -C 6 alkyl;
  • R 1 and R 2 are each independently selected from the following substituents: cyano, C 1 -C 3 alkyl;
  • R c is methyl, ethyl, propyl, fluoromethyl, deuterated methyl.
  • the heterocyclic compound includes:
  • 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.
  • heterocyclic compounds as TEAD inhibitors as described in the first aspect of the present invention their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable
  • the salt or the purposes of prodrug, or the purposes of pharmaceutical composition as described in the second aspect, 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 cancer includes: a cancer selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwann cell tumor, lung cancer, bladder cancer, neurofibroma of the skin, prostate cancer, Pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.
  • a cancer selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwann cell tumor, lung cancer, bladder cancer, neurofibroma of the skin, prostate cancer, Pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocar
  • 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 .
  • hydroxyl alone or as part of another substituent, means -OH.
  • 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 occurring alkyl groups that are rich in carbon and/or hydrogen isotopes (i.e., 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 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 connected in 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.
  • 3-6 membered cycloalkyl refers to a cyclic alkyl group containing 3 to 6 carbon atoms, which may contain 1 to 2 rings.
  • the cyclic alkyl group includes monocyclic, bicyclic, spiro or bridged rings.
  • unsubstituted cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Cycloalkyl groups may be substituted with one or more substituents.
  • heterocycloalkyl or “heterocyclyl”, by themselves or as part of another substituent, refer to rings in which one or more (in some embodiments, 1-3) carbon atoms are replaced by heteroatoms Alkyl, said heteroatoms such as but not limited to N, O, S and P.
  • mn-membered heterocycloalkyl or " Cm - Cnheterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms.
  • 4-6 membered heterocycloalkyl is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 6 atoms.
  • a heterocycloalkyl group can be a heterocycloalkyl group fused to an aryl or heteroaryl group.
  • a prefix such as 4-6 membered is used to indicate heterocycloalkyl, the number of carbons is also meant to include heteroatoms.
  • 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.
  • 5-6 membered heteroaryl is used interchangeably with 5-6 membered heteroaryl” alone or as part of another substituent, and is understood to have 5 or 6 ring atoms and contain 1-3 Aromatic ring groups of heteroatoms independently selected from N, O and S.
  • the term “5-6 membered heteroaromatic ring” is to be understood as having 5 or 6 ring atoms—and containing 1-3—independently Aromatic ring radicals of heteroatoms selected from N, O and S.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl; or pyridine base, pyridazinyl, pyrimidinyl, pyrazinyl.
  • lactam group by itself or as part of another substituent, is a cyclic structure containing the structure -CONH-.
  • the "4- to 8-membered lactam group” refers to a ring structure including a -CONH- structure having a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring or an 8-membered ring.
  • lactams include, but are not limited to, beta-lactams (four-membered rings), gamma-lactams (five-membered rings), delta-lactams (six-membered rings).
  • 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, vehicle, excipient, glidant, sweetener, agent, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, 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.
  • excipient include, without limitation, 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 present inventors have unexpectedly developed a heterocyclic compound as a TEAD inhibitor, and the heterocyclic compound has the structure as described in the first aspect of the present invention.
  • the heterocyclic compound can obviously inhibit the activity of TEADs transcription, and can be used for preventing and/or treating diseases related to the increased expression of TEADs.
  • the test results show that the compound of the present invention can significantly inhibit the transcription mediated by TEADs on the HEK293T-TEAD-LUC reporter cell line cells, can significantly inhibit the proliferation of NCI-H226 cells, and has a significant effect on inhibiting the growth of NCI-H226 mesothelioma, And show excellent pharmacokinetic properties, good druggability.
  • Fig. 1 is the NCI-H226 mesothelioma mouse tumor-bearing drug effect test result of compound I-7 in test example 4;
  • Fig. 2 is the result of drug efficacy test of compound I-10 in NCI-H226 mesothelioma mice in test example 4.
  • the synthetic route is as follows:
  • the second step Synthesis of 1-(tert-butyl) 3-methyl 3-methyl-2-oxopyrrolidine-1,3-dicarboxylate (A1-3)
  • the third step the synthesis of 3-methyl-2-oxopyrrolidine-3-carboxylic acid methyl ester (A1-4)
  • the fourth step the synthesis of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (A1)
  • the synthetic route is as follows:
  • the first step Synthesis of 3-benzyl 1-(tert-butyl) 2-oxopyrrolidine-1,3-dicarboxylate (A3-1)
  • the second step the synthesis of 3-benzyl 1-(tert-butyl) 3-methyl-2-oxopyrrolidine-1,3-dicarboxylate (A3-2)
  • the third step the synthesis of benzyl 3-methyl-2-oxopyrrolidine-3-formyl ester (A3-3)
  • the fourth step the synthesis of (R)-3-methyl-2-oxopyrrolidine-3-carboxylic acid benzyl ester (A3-4)
  • the fifth step the synthesis of (R)-3-methyl-2-oxopyrrolidine-3-carboxylic acid (A3)
  • Benzyl 3-methyl-2-oxopyrrolidine-3-carboxylate (A3-4) (13.0 g, 55.7 mmol) was dissolved in methanol (200 mL), and palladium hydroxide (1.30 g, 925 ⁇ mol ), replace hydrogen, stir at 25°C for 12h, filter after the reaction, concentrate, and purify with methyl tert-butyl ether to obtain white solid (R)-3-methyl-2-oxopyrrolidine-3-carboxylic acid (A3 ) (6.50 g, 81.4% yield).
  • Embodiment 1 the preparation of compound I-1
  • the synthetic route is as follows:
  • the first step the synthesis of methyl 2-((4-(chlorodifluoromethoxy)phenyl)amino)nicotinate (B1-2)
  • Methyl 2-chloronicotinate (3.99 g, 23.25 mmol) and 4-(chlorodifluoromethoxy)aniline were dissolved in ethylene glycol (5 ml), and stirred at 120° C. for 6 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 50 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 2-((4-(chlorodifluoromethoxy)phenyl)amino)nicotinic acid hydrazide (B1-3)
  • reaction liquid was slowly dropped into 50 mL of water, the mixture was extracted with ethyl acetate (50 mL x 3), the organic phase was collected, and washed with 50 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • Embodiment 2 the preparation of compound 1-2
  • the synthetic route is as follows:
  • the first step Synthesis of 3-((4-(chlorodifluoromethoxy)phenyl)amino)pyrazine-2-carboxylic acid methyl ester (B2-2)
  • the second step the synthesis of 3-((4-(chlorodifluoromethoxy)phenyl)amino)pyrazine-2-carboxhydrazide (B2-3)
  • the third step 3-((4-(chlorodifluoromethoxy)phenyl)amino)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)pyrazine-2-methyl Synthesis of Hydrazide (B2-4)
  • reaction liquid was slowly dropped into 50 mL of water, the mixture was extracted with ethyl acetate (50 mL x 3), the organic phase was collected, and washed with 50 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • Embodiment 3 the preparation of compound 1-3
  • the synthetic route is as follows:
  • the first step (3-(2-(2-((4-(chlorodifluoromethoxy)phenyl)amino)nicotinoyl)hydrazino)-3-oxopropyl)(methyl)carbamate Synthesis of tert-butyl ester (B3-1)
  • the second step (2-(5-(2-((4-(chlorodifluoromethoxy)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl ) ethyl) (methyl) tert-butyl carbamate (B3-2) synthesis
  • the third step N-(4-(chlorodifluoromethoxy)phenyl)-3-(5-(2-(methylamino)ethyl)-1,3,4-oxadiazole-2- base) the synthesis of pyridin-2-amine (B3-3)
  • N-(4-(chlorodifluoromethoxy)phenyl)-3-(5-(2-(methylamino)ethyl)-1,3,4-oxadiazol-2-yl)pyridine -2-Amine 158.3mg, 0.40mmol
  • N,N-diisopropylethylamine 159.6mg, 1.24mmol
  • bromoacetonitrile 65.4mg, 0.62mmol
  • Embodiment 4 the preparation of compound 1-4
  • Embodiment 5 the preparation of compound 1-5
  • the synthetic route is as follows:
  • Step 1 Synthesis of 2-(tert-butyl) 4-methyl 3-oxo-2-azabicyclo[3.1.0]hexane-2,4-dicarboxylate (B5-2)
  • the third step the synthesis of methyl 4-methyl-3-oxo-2-azabicyclo[3.1.0]hexane-4-carboxylate (B5-4)
  • the fourth step the synthesis of 4-methyl-3-oxo-2-azabicyclo[3.1.0]hexane-4-carboxylic acid (B5-5)
  • reaction liquid was slowly dropped into 50 mL of water, the mixture was extracted with ethyl acetate (50 mL x 3), the organic phase was collected, and washed with 50 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • the sixth step 4-(5-(2-((4-(chlorodifluoromethoxy)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl) -Synthesis of 4-methyl-2-azabicyclo[3.1.0]hexan-3-one (I-5)
  • N'-(2-((4-(chlorodifluoromethoxy)phenyl)amino)nicotinoyl)-4-methyl-3-oxo-2-azabicyclo[3.1.0]hexane -4-Formohydrazide 200mg, 0.429mmol was dissolved in DCM (10mL), p-toluenesulfonyl chloride (98mg, 0.515mmol) and triethylamine (0.18ml, 1.29mmol) were added, and stirred at room temperature for 1 hour.
  • Embodiment 6 the preparation of compound 1-6
  • the synthetic route is as follows:
  • the first step the synthesis of 2-((4-(chlorodifluoromethoxy)phenyl)amino)pyridine-3-thiohydrazine (B6-1)
  • Embodiment 7 the preparation of compound 1-7
  • Embodiment 8 the preparation of compound 1-8
  • the synthetic route is as follows:
  • N-(4-(chlorodifluoromethoxy)phenyl)-3-(5-((methylamino)methyl)-1,3,4-oxadiazol-2-yl)pyridine-2 -Amine (152.7mg, 0.40mmol) was dissolved in tetrahydrofuran (1mL), N,N-diisopropylethylamine (159.6mg, 1.24mmol) was added, bromoacetonitrile (65.4mg, 0.62mmol) was added, 25°C React for 1 hour.
  • Embodiment 9 the preparation of compound I-9
  • the synthetic route is as follows:
  • the second step the synthesis of 2-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (B9-3)
  • reaction liquid was slowly dropped into 50 mL of water, the mixture was extracted with ethyl acetate (50 mL x 3), the organic phase was collected, and washed with 50 mL of saturated brine. The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give crude product.
  • Embodiment 10 the preparation of compound I-10
  • the preparation of the reference compound I refers to the patent publication WO2021/102204Al, and the structure is as follows:
  • Test Example 1 TEADs-mediated transcriptional inhibition IC 50 evaluation test
  • HEK293T-TEAD Reporter assay was used to detect the inhibitory effect of exemplary compounds of the present invention on TEADs-mediated transcription.
  • HEK293T-TEAD-LUC reporter cell line was cultured with DMEM+10%FBS+1%PS+200 ⁇ g/ml Hygromycin as the complete medium, and the cells in the logarithmic phase were seeded in 384-well plates, 2500cell/well/35 ⁇ l, Incubate overnight at 37°C with 5% CO 2 , add 5uL of the diluted compound to each well the next day (final concentration of DMSO is 0.1%), and set up a positive control group with only DMSO added, and use 2 ⁇ M Okacid acid signal value as negative Control signal, then incubate at 37°C, 5% CO 2 for 48h, use after incubation luciferase assay system (Promega, E2550) and measure the fluorescence signal value 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
  • Inhibition rate% (signal of positive control group - signal of test well) / (signal of positive control group - signal of negative control group) * 100
  • Table 1 TEADs transcriptional inhibitory activity of test compounds on HEK293T-TEAD-LUC reporter cell line cells
  • test compound IC 50 (nM) Comparative compound I 8.20 I-1 9.07 I-7 5.07
  • the results of the HEK293T-TEAD Reporter test show that the compound of the present invention can significantly inhibit the transcription mediated by TEADs on HEK293T-TEAD-LUC reporter cell line cells.
  • 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) was cultured with RPMI1640+10%FBS+1%PS as the complete medium, and the cells in the logarithmic phase were seeded in a 96-well plate, 800cell/well/195 ⁇ l, 37°C, Incubate overnight in 5% CO 2 , add 5uL of the diluted compound (final concentration of DMSO is 0.1%) to each well the next day, and set up a positive control group with only DMSO added, and use 1 ⁇ M Staurosporine signal value as the signal of the negative control group, Then 37°C, 5% CO2 was incubated for 6 days, after the incubation was completed, 100 ⁇ l of the medium was aspirated, and the fluorescence signal value was measured on the Envision 2104 Multilabel Reader using the Celltiter Glo assay kit (Promega, G7573) 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
  • 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) Comparative compound I 10.6 I-1 6.42 I-2 13 I-3 6.64 I-7 2.77 I-10 8.6
  • 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, and the growth inhibitory effect of the administration group on the tumor was counted, and TGI was calculated. The results are shown in Figures 1 and 2.

Abstract

公开了一种作为TEAD抑制剂的杂环化合物，所述杂环化合物具有式(I)所示结构：式(I)中各个基团的定义如本文中所述；所述杂环化合物可用于预防和/或治疗与TEAD表达增加相关的疾病，如细胞增殖性病症疾病。

Description

作为TEAD抑制剂的杂环化合物
本申请要求2021年12月24日向中国国家知识产权局提交的，专利申请号为202111599305.5，发明名称为“作为TEAD抑制剂的杂环化合物”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。
技术领域
本发明属于医药领域，具体地，本发明涉及一种作为TEAD抑制剂的杂环化合物及制备方法和用途。
背景技术
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(Gibault F et al.,Journal of Medicinal Chemistry,2017:acs.jmedchem.7b00879.)。
TEADs(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。
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(Liu,Huirong et al.,Oncology reports,2018.)。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(Qi Y et al.,Nature Communications,2016,7:ncomms11840.)，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。
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。
发明内容
本发明提供了一种作为TEAD抑制剂的杂环化合物，所述杂环化合物能明显抑制TEADs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。
在本发明第一方面中，提供了一种作为TEAD抑制剂的杂环化合物、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，所述杂环化合物具有式I所示结构：
Figure PCTCN2022141373-appb-000001
其中，L为-CH 2-或-NH-；
所述L任选地被选自下列的取代基取代：卤素、C 1-C 6烷基、C 1-C 6卤代烷基；
Z 1、Z 2、Z 3、Z 4各自独立地表示CR b或N；且Z 1、Z 2、Z 3、Z 4不同时为CR b或N；
环A为5元杂芳环；
Ra为氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基；
Q为未取代或被R c取代的4-8元杂环烷基、未取代或被R c取代的5-6元杂芳基、未取代或被R c取代的-C 1-C 6烷基-NR 1R 2、未取代或被R c取代的-C 1-C 6烷基-C(O)-NR 3R 4；
R 1、R 2、R 3、R 4各自独立地选自下列的取代基：氰基、C 1-C 6烷基、-C(O)-C 1-C 6烷基；其中，所述R 1、R 2、R 3、R 4各自独立地任选地被选自下列的取代基取代：卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6烷氧基；
或者R 1、R 2与它们所连接的N原子一起形成5-8元杂环烷基或5-6元杂芳基；
R c为选自下列的取代基：氘、卤素、氰基、羟基、氨基、
Figure PCTCN2022141373-appb-000002
C 1-C 6烷基、氘代C 1-C 6烷基、C 1-C 6烷氧基；
其中，所述R c任选地被选自下列的取代基取代：氘、卤素、氰基、羟基、氨基、
Figure PCTCN2022141373-appb-000003
C 1-C 6烷基、C 1-C 6烷氧基；
R b为氢、氘、卤素、氰基、羟基、氨基、
Figure PCTCN2022141373-appb-000004
C 1-C 6烷基、C 1-C 6烷氧基。
在一优选实施方式中，R b为氢。
在一优选实施方式中，在Q中，所述4-8元杂环烷基为单环或并环的杂环烷基。
在一优选实施方式中，L为-NH-。
在一优选实施方式中，所述Q被R c取代是指被1、2、3或4个R c取代；当取代基R c为多个时，所述R c相同或不同。
在一优选实施方式中，所述R c为选自下列的取代基：卤素、氰基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6氘代烷基；
较佳地，R c为甲基、乙基、丙基、氟代甲基、氘代甲基。
在一优选实施方式中，环A为5元杂芳环，所述杂芳环具有1、2或3个选自N、O或S的杂原子；
较佳地，所述环A至多含有一个O或S；
较佳地，所述环A至少含有一个N；较佳地，所述环A至少含有两个N；较佳地，所述环A至少含有三个N；较佳地，所述环A至少含有一个O或S并且含有两个N；
较佳地，所述环A选自噁二唑环、噻二唑环、三唑环、吡唑环、咪唑环；
较佳地，所述环A选自：
Figure PCTCN2022141373-appb-000005
在一优选实施方式中，所述杂环化合物具有结构Ia所示结构，
Figure PCTCN2022141373-appb-000006
其中，Z 1、Z 2、Z 3、Z 4和Q的定义如上文所述。
在一优选实施方式中，所述杂环化合物具有结构Ib所示结构，
Figure PCTCN2022141373-appb-000007
其中，Z 1、Z 2、Z 3、Z 4和Q的定义如上文所述。
在一优选实施方式中，
Figure PCTCN2022141373-appb-000008
具有下述结构：
Figure PCTCN2022141373-appb-000009
Figure PCTCN2022141373-appb-000010
较佳地，
Figure PCTCN2022141373-appb-000011
具有结构
Figure PCTCN2022141373-appb-000012
在一优选实施方式中，
Figure PCTCN2022141373-appb-000013
具有结构
Figure PCTCN2022141373-appb-000014
在一优选实施方式中，所述Q为未取代或被R c取代的4-8元内酰胺基；较佳地，所述Q为未取代或被R c取代的单环的4-6元内酰胺基或未取代或被R c取代的并环的6-8元内酰胺基。
在一优选实施方式中，所述Q为未取代或被R c取代的：
Figure PCTCN2022141373-appb-000015
Figure PCTCN2022141373-appb-000016
在一优选实施方式中，所述Q为
Figure PCTCN2022141373-appb-000017
较佳地，所述
Figure PCTCN2022141373-appb-000018
为
Figure PCTCN2022141373-appb-000019
较佳地，所述
Figure PCTCN2022141373-appb-000020
为
Figure PCTCN2022141373-appb-000021
在一优选实施方式中，Q为
Figure PCTCN2022141373-appb-000022
在一优选实施方式中，所述R c为选自下列的取代基：卤素、氰基、C 1-C 6烷 基、C 1-C 6卤代烷基、C 1-C 6氘代烷基；
较佳地，R c为甲基、乙基、丙基、氟代甲基、氘代甲基。
在一优选实施方式中，Q为未取代或被R c取代的C 1-C 6烷基-NR 1R 2；R 1、R 2各自独立地选自下列的取代基：氰基、C 1-C 6烷基；
较佳地，R 1、R 2各自独立地选自下列的取代基：氰基、C 1-C 3烷基；
较佳地，R c为甲基、乙基、丙基、氟代甲基、氘代甲基。
在一优选实施方式中，所述杂环化合物包括：
Figure PCTCN2022141373-appb-000023
在本发明第二方面中，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。
在本发明第三方面中，提供了如本发明第一方面所述的作为TEAD抑制剂的杂环化合物、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，或如第二方面所述的药物组合物的用途，所述用途包括：
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。
在本发明一优选实施方式中，所述TEAD包括：TEAD1、TEAD2、TEAD3和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。
在一优选实施方式中，所述癌症包括：癌症选自间皮瘤、肝细胞癌、脑膜瘤、恶性周围神经鞘瘤、施万细胞瘤、肺癌、膀胱癌、皮肤神经纤维瘤、前列腺癌、胰腺癌、胶质母细胞瘤、子宫内膜腺鳞癌、甲状腺未分化癌、胃腺癌、食管腺癌、卵巢癌、卵巢浆液性腺癌、黑素瘤和乳腺癌。
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。
术语和定义
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。
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。
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。
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。
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 PCTCN2022141373-appb-000024
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。
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。
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。
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。
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。
如本文所用，在单独或作为其他取代基一部分时，术语"羟基"表示-OH。
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。
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。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。
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-)。
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，“3-6元环烷基”是指含有3至6个碳原子的环状烷基，它可能包含1至2个环。所述环状烷基包括单环、二环、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。环烷基可以被一个或多个取代基取代。
在单独或作为其他取代基一部分时，术语“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1-3个)碳原子被杂原子取代的环烷基，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“4-6元杂环烷基”应理解为表示具有4至6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4-6 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。
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。
在单独或作为其他取代基一部分时，术语“5-6元杂芳环”可与5-6元杂芳基”互换使用，应理解为具有5或6个环原子且包含1-3个独立选自N、O和S的杂原子的芳族环基团。术语“5-6元杂芳环”应理解为具有5或6个环原子——且其包含1-3个——独立选自N、O和S的杂原子的芳族环基团。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基；或吡啶基、哒嗪基、嘧啶基、吡嗪基。
在单独或作为其他取代基一部分时，术语“内酰胺基”是一种含有-CONH-结构的环状结构。“4-8元内酰胺基”是指具有4元环、5元环、6元环、7元环或8元环的含有-CONH-结构的环状结构。内酰胺的实例包括但不限于β-内酰胺(四元环)、γ-内酰胺(五元环)、δ-内酰胺(六元环)。
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。
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。
“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。
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。
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。
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。
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。
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。
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、媒介物、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。
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。
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。
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。
在本申请中，术语“辅料”是指可药用惰性成分。术语“赋形剂”的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。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(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；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
有益效果
本发明人经过广泛而深入地研究，意外地开发了一种作为TEAD抑制剂的杂环化合物，所述杂环化合物具有如本发明第一方面所述结构。所述杂环化合物能明显抑制TEADs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。试验结果表明，本发明化合物在HEK293T-TEAD-LUC reporter细胞系细胞上能明显抑制TEADs介导的转录，能明显抑制NCI-H226细胞增殖，具有显 著的抑制NCI-H226间皮瘤生长的作用，并表现出优良的药代动力学性质，成药性好。
附图说明
图1是测试例4中化合物I-7的NCI-H226间皮瘤小鼠荷瘤药效试验结果；
图2是测试例4中化合物I-10的NCI-H226间皮瘤小鼠荷瘤药效试验结果。
具体实施方式
以下结合具体实施例，进一步说明本发明。需理解，以下的描述仅为本发明的最优选实施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中。
中间体A1制备
合成路线如下所示：
Figure PCTCN2022141373-appb-000025
第一步：1-(叔丁基)3-甲基2-氧代吡咯烷-1,3-二甲酸酯(A1-2)的合成
将2-氧代吡咯烷-1-甲酸叔丁酯(5g，27.0mmol)溶解在四氢呋喃(50ml)中，-78℃加入2M的LDA(21.6ml，43.2mmol)，搅拌0.5小时后，加入氯甲酸甲酯(3.06g，32.4mmol)，室温反应过夜。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50mL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1-(叔丁基)3-甲基2-氧代吡咯烷-1,3-二甲酸酯 (A1-2)(4g，产率60.8％)。
LC-MS,M/Z(ESI):244.1[M+H] +。
第二步：1-(叔丁基)3-甲基3-甲基-2-氧代吡咯烷-1,3-二甲酸酯(A1-3)的合成
将1-(叔丁基)3-甲基2-氧代吡咯烷-1,3-二甲酸酯(2.8g，11.51mmol)溶解在DMF(30ml)中，0℃加入碳酸钾(7.95g，57.6mmol)和碘甲烷(0.86ml，13.81mmol)，搅拌1小时。反应结束后，将反应液缓慢滴入30mL冰水混合物中，混合物用乙酸乙酯(30mL x 3)萃取，收集有机相，用50mL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1-(叔丁基)3-甲基3-甲基-2-氧代吡咯烷-1,3-二甲酸酯(A1-3)(2.5g，产率84.4％)。
LC-MS，M/Z(ESI):258.1[M+H] +。
第三步：3-甲基-2-氧代吡咯烷-3-甲酸甲酯(A1-4)的合成
将1-(叔丁基)3-甲基3-甲基-2-氧代吡咯烷-1,3-二甲酸酯(2g，7.77mmol)溶解在DCM(20ml)和三氟乙酸(21ml)中，室温搅拌12小时。反应结束后，旋干得到3-甲基-2-氧代吡咯烷-3-甲酸甲酯(A1-4)(1g，产率82％)。
LC-MS，M/Z(ESI):158.1[M+H] +。
第四步：3-甲基-2-氧代吡咯烷-3-甲酸(A1)的合成
Figure PCTCN2022141373-appb-000026
将3-甲基-2-氧代吡咯烷-3-甲酸甲酯(1g，6.36mmol)溶解在甲醇(10ml)和水(0.5ml)中，加入一水氢氧化锂(0.801g，19.09mmol)，室温搅拌12小时。反应结束后，调pH至2，用乙酸乙酯(30mL x 3)萃取，收集有机相，旋干得到3-甲基-2-氧代吡咯烷-3-甲酸(A1)(500mg，产率54.8％)。
LC-MS，M/Z(ESI):144.0[M+H] +。
中间体A2制备
Figure PCTCN2022141373-appb-000027
中间体3-(甲基-d3)-2-氧代吡咯烷-3-甲酸(A2)合成参考中间体A1，将第二步中碘甲烷替换成氘代碘甲烷。
中间体A3制备
合成路线如下所示：
Figure PCTCN2022141373-appb-000028
第一步：3-苯甲基1-(叔丁基)2-氧代吡咯烷-1,3-二甲酸酯(A3-1)的合成
Figure PCTCN2022141373-appb-000029
在0℃下，将二(三甲基甲硅烷基)锂酰胺(1.00M，567mL)滴加至四氢呋喃(200mL)中，在-78℃缓慢加入叔丁基2-氧代吡咯烷-1-甲酸酯(50.0g，269mmol)的四氢呋喃溶液(200mL)，滴加完毕后，再缓慢加入氯甲酸苄酯(46.0g，269mmol)的四氢呋喃溶液(100mL)，在-78℃反应1小时。反应结束后，将反应液加入到饱和氯化铵溶液(1.00L)中淬灭，用乙酸乙酯(2.10L)萃取，饱和食盐水(2.00L)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品黄色固体3-苯甲基1-(叔丁基)2-氧代吡咯烷-1,3-二甲酸酯(A3-1)(90.0g，粗品)，直接用于下一步。
1H NMR(400MHz,DMSO-d 6)δ7.36-7.22(m,5H),5.00(s,2H),3.50-3.44(m,2H),3.32(s,1H),2.48-2.42(m,2H),1.42(s,9H)
第二步：3-苯甲基1-(叔丁基)3-甲基-2-氧代吡咯烷-1,3-二甲酸酯(A3-2)的合成
Figure PCTCN2022141373-appb-000030
把3-苯甲基1-(叔丁基)2-氧代吡咯烷-1,3-二甲酸酯(A3-1)(90.0g，281mmol)加入到N,N-二甲基甲酰胺(500mL)中，在0℃加入碳酸钾(194g，1.41mol)，在0℃搅拌半小时，再加入碘化钾(48.0g，338mmol)，加完后，在25℃搅拌12h。反应结束后，加入冰水(1.0L)淬灭，用乙酸乙酯(2.0L)萃取，饱和食盐水(2.0L)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)纯化得到白色固体3-苯甲基1-(叔丁基)3-甲基-2-氧代吡咯烷-1,3-二甲酸酯(A3-2)(33.0g，产率35.1％)。
1H NMR(400MHz,CDCl 3)δ7.27-7.21(m,5H),5.21-5.05(m,2H),3.72-3.63(m,2H),2.43(ddd,1H),1.83(td,1H),1.47(s,9H),1.44(s,3H).
第三步:苯甲基3-甲基-2-氧代吡咯烷-3-甲酸基酯(A3-3)的合成
Figure PCTCN2022141373-appb-000031
在室温下，将3-苯甲基1-(叔丁基)3-甲基-2-氧代吡咯烷-1,3-二甲酸基酯(33.0g，98.9mmol)溶解在乙酸乙酯(150mL)，在0℃下加入盐酸/乙酸乙酯(4.00M，24.7mL)，充分搅拌，在25℃反应1h。反应结束后过滤，浓缩，直接用于SFC拆分。
第四步:(R)-3-甲基-2-氧代吡咯烷-3-羧酸苄酯(A3-4)的合成
Figure PCTCN2022141373-appb-000032
将上一步A3-3粗品拆分得到白色固体苯甲基3-甲基-2-氧代吡咯烷-3-甲酸 基酯(A3-4)(13.0g，产率55.6％)。
LC-MS,M/Z(ESI):234.1[M+H] +
第五步：(R)-3-甲基-2-氧代吡咯烷-3-甲酸(A3)的合成
Figure PCTCN2022141373-appb-000033
将苯甲基3-甲基-2-氧代吡咯烷-3-甲酸酯(A3-4)(13.0g，55.7mmol)溶解于甲醇(200mL)中，加入氢氧化钯(1.30g，925μmol)，置换氢气，在25℃搅拌12h，反应结束后过滤，浓缩，甲基叔丁基醚打浆纯化得到白色固体(R)-3-甲基-2-氧代吡咯烷-3-甲酸(A3)(6.50g，产率81.4％)。
1H NMR(400MHz,DMSO-d 6)δ12.70-12.49(m,1H),7.83(s,1H),3.25-3.16(m,2H),2.42(ddd,1H),1.89(ddd,1H),1.20(s,3H)
实施例1：化合物I-1的制备
合成路线如下所示：
Figure PCTCN2022141373-appb-000034
第一步：2-((4-(氯二氟甲氧基)苯基)氨基)烟酸甲酯(B1-2)的合成
将2-氯烟酸甲酯(3.99g，23.25mmol)和4-(氯二氟甲氧基)苯胺溶解在乙二醇 (5ml)中，120℃搅拌6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50mL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-((4-(氯二氟甲氧基)苯基)氨基)烟酸甲酯(B1-2)(5g，黄色固体，产率65.4％)。
LC-MS,M/Z(ESI):329.1[M+H] +。
第二步：2-((4-(氯二氟甲氧基)苯基)氨基)烟酰肼(B1-3)的合成
将2-((4-(氯二氟甲氧基)苯基)氨基)烟酸甲酯(2g，6.08mmol)溶解在甲醇(20ml)中，加入80％的水合肼(2.4ml，60.8mmol)，室温搅拌12小时。反应结束后，浓缩，粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝3:1-1:1)得到2-((4-(氯二氟甲氧基)苯基)氨基)烟酰肼(B1-3)(1.9g，黄色固体，产率95％)。
LC-MS,M/Z(ESI):329.1[M+H] +。
第三步：2-((4-(氯二氟甲氧基)苯基)氨基)-N'-(3-甲基-2-氧代吡咯烷-3-羰基)烟酰肼(B1-4)的合成
将2-((4-(氯二氟甲氧基)苯基)氨基)烟酰肼(505mg，1.537mmol)和3-甲基-2-氧代吡咯烷-3-甲酸(200mg，1.397mmol)溶解在DMF(5mL)中，加入N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(797mg，2.096mmol)和三乙胺(0.58ml，4.19mmol)，室温搅拌12小时。反应结束后，将反应液缓慢滴入50mL水中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用50mL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＝10:1-1:1)得到2-((4-(氯二氟甲氧基)苯基)氨基)-N'-(3-甲基-2-氧代吡咯烷-3-羰基)烟酰肼(B1-4)(300mg，黄色固体，产率47.3％)。
LC-MS,M/Z(ESI):454.1[M+H] +。
第四步：3-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)-3-甲基吡咯烷-2-酮(I-1)的合成
Figure PCTCN2022141373-appb-000035
将2-((4-(氯二氟甲氧基)苯基)氨基)-N'-(3-甲基-2-氧代吡咯烷-3-羰基)烟酰肼(230mg，0.507mmol)溶解在DCM(10ml)中，加入对甲苯磺酰氯(116mg，0.608mmol)和三乙胺(0.21ml，1.52mmol)，室温搅拌1小时。反应结束后，浓缩，粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝5:1-1:1)得到3-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)-3-甲基吡咯烷-2-酮(I-1)(150mg，产率67.9％)。
1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.41(t,1H),8.42-8.40(m,1H),8.18(s,1H),7.85(d,2H),7.33(d,2H),7.03-7.06(m,1H),3.40-3.46(m,2H),2.75-2.78(m,1H),2.23-2.25(m,1H),1.61(s,3H)。
LC-MS,M/Z(ESI):436.1[M+H] +。
实施例2：化合物I-2的制备
合成路线如下所示：
Figure PCTCN2022141373-appb-000036
第一步：3-((4-(氯二氟甲氧基)苯基)氨基)吡嗪-2-甲酸甲酯(B2-2)的合成
将3-氯吡嗪-2-甲酸甲酯(4.00g，23.18mmol)和4-(氯二氟甲氧基)苯胺溶解在乙二醇(5mL)中，120℃搅拌6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50mL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3-((4-(氯二氟甲氧基)苯基)氨基)吡嗪-2-甲 酸甲酯(B2-2)(4.75g，黄色固体，产率62.2％)。
LC-MS，M/Z(ESI):330.1[M+H] +。
第二步：3-((4-(氯二氟甲氧基)苯基)氨基)吡嗪-2-甲酰肼(B2-3)的合成
将3-((4-(氯二氟甲氧基)苯基)氨基)吡嗪-2-甲酸甲酯(2g，6.07mmol)溶解在甲醇(20mL)中，加入80％的水合肼(2.4mL，60.8mmol)，室温搅拌12小时。反应结束后，浓缩，粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝3:1-1:1)得到3-((4-(氯二氟甲氧基)苯基)氨基)吡嗪-2-甲酰肼(B2-3)(1.8g，黄色固体，产率90％)。
LC-MS，M/Z(ESI):330.1[M+H] +。
第三步：3-((4-(氯二氟甲氧基)苯基)氨基)-N'-(3-甲基-2-氧代吡咯烷-3-羰基)吡嗪-2-甲酰肼(B2-4)的合成
将3-((4-(氯二氟甲氧基)苯基)氨基)吡嗪-2-甲酰肼(507mg，1.537mmol)和3-甲基-2-氧代吡咯烷-3-甲酸(200mg，1.397mmol)溶解在DMF(5mL)中，加入N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(797mg，2.096mmol)和三乙胺(0.58mL，4.19mmol)，室温搅拌12小时。反应结束后，将反应液缓慢滴入50mL水中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用50mL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＝10:1-1:1)得到3-((4-(氯二氟甲氧基)苯基)氨基)-N'-(3-甲基-2-氧代吡咯烷-3-羰基)吡嗪-2-甲酰肼(B2-4)(305mg，产率48.0％)。
LC-MS，M/Z(ESI):455.1[M+H] +。
第四步：3-(5-(3-((4-(氯二氟甲氧基)苯基)氨基)吡嗪-2-基)-1,3,4-噁二唑-2-基)-3-甲基吡咯烷-2-酮(I-2)的合成
Figure PCTCN2022141373-appb-000037
将3-((4-(氯二氟甲氧基)苯基)氨基)-N'-(3-甲基-2-氧代吡咯烷-3-羰基)吡嗪-2-甲酰肼(225mg，0.495mmol)溶解在DCM(10ml)中，加入对甲苯磺酰氯(116mg，0.608mmol)和三乙胺(0.21ml，1.52mmol)，室温搅拌1小时。反应结束后，浓缩， 粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝5:1-1:1)得到3-(5-(3-((4-(氯二氟甲氧基)苯基)氨基)吡嗪-2-基)-1,3,4-噁二唑-2-基)-3-甲基吡咯烷-2-酮(I-2)(163mg，产率75.4％)。
1H NMR(400MHz,CDCl 3)δ10.29(s,1H),8.32(d,1H),8.18(d,1H),7.81–7.79(m,2H),7.24(d,2H),5.86(s,1H),3.70-3.64(m,1H),3.58-3.52(m,1H),3.02-2.98(m,1H),2.40-2.35(m,1H),1.85(s,3H).
LC-MS,M/Z(ESI):437.1[M+H] +。
实施例3：化合物I-3的制备
合成路线如下所示：
Figure PCTCN2022141373-appb-000038
第一步：(3-(2-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰基)肼基)-3-氧代丙基)(甲基)氨基甲酸叔丁酯(B3-1)的合成
将2-((4-(氯二氟甲氧基)苯基)氨基)烟酰肼(378mg，1.15mmol)与3-((叔丁氧基羰基)(甲基)氨基)丙酸(359.0mg，1.77mmol)溶于N,N-二甲基甲酰胺(4mL)，加入1-乙基-(3-二甲氨基丙基碳二亚胺盐酸盐(338.6mg，1.77mmol)、1-羟基苯并三唑(238.7mg，1.77mmol)、三乙胺(238.3mg，2.36mmol)。25℃反应过夜至反应完毕。加水(10mL)，乙酸乙酯萃取(20mL x 3)，合并有机相，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，浓缩，得到粗品。粗品用硅胶色谱柱纯化得(3-(2-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰基)肼基)-3-氧代丙基)(甲基)氨基 甲酸叔丁酯(B3-1)(202.7mg，黄色油状，产率34.3％)。
LC-MS，M/Z(ESI):514.1[M+H] +。
第二步：(2-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)乙基)(甲基)氨基甲酸叔丁酯(B3-2)的合成
将(3-(2-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰基)肼基)-3-氧代丙基)(甲基)氨基甲酸叔丁酯(205.6mg，0.40mmol)溶解在二氯甲烷(3mL)中，加入对甲基本磺酰氯(118.7mg，0.62mmol)与三乙胺(105.0mg，1.04mmol)。25℃反应1小时，加入水(10mL)，二氯甲烷萃取(20mL x 3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤，浓缩，得到粗品。粗品用硅胶色谱柱纯化得(2-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)乙基)(甲基)氨基甲酸叔丁酯(B3-2)(149.4mg，黄色固体，产率75.3％)。
LC-MS，M/Z(ESI):496.1[M+H] +。
第三步：N-(4-(氯二氟甲氧基)苯基)-3-(5-(2-(甲基氨基)乙基)-1,3,4-噁二唑-2-基)吡啶-2-胺(B3-3)的合成
将(2-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)乙基)(甲基)氨基甲酸叔丁酯(148.8mg，0.30mmol)溶解在二氯甲烷(1mL)中，加入三氟乙酸(1.10g，9.69mmol)，25℃反应2小时，浓缩得到粗品，乙酸乙酯(50mL)溶解，再用饱和碳酸氢钠溶液(30mL)洗，饱和食盐水洗(20mL)，有机相无水硫酸钠干燥，浓缩得N-(4-(氯二氟甲氧基)苯基)-3-(5-(2-(甲基氨基)乙基)-1,3,4-噁二唑-2-基)吡啶-2-胺(B3-3)(101mg，产率85.0％)。
LC-MS，M/Z(ESI):396.1[M+H] +。
第四步：N-(2-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)乙基)-N-甲基氰胺(I-3)的合成
Figure PCTCN2022141373-appb-000039
将N-(4-(氯二氟甲氧基)苯基)-3-(5-(2-(甲基氨基)乙基)-1,3,4-噁二唑-2-基)吡 啶-2-胺(158.3mg，0.40mmol)溶解在四氢呋喃(1mL)中，加入N，N-二异丙基乙胺(159.6mg，1.24mmol)，再加入溴乙腈(65.4mg，0.62mmol)，25℃反应1小时。加入水(10mL)，二氯甲烷萃取(20mL x 3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤，浓缩，得到粗品。粗品用硅胶色谱柱纯化得N-(2-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)乙基)-N-甲基氰胺(I-3)(94.8mg，产率56.3％)。
1H NMR(400MHz,CDCl3)δ10.08(s,1H),8.38(dd,1H),8.11(dd,1H),7.87–7.76(m,2H),7.21(d,2H),6.86(dd,1H),3.56(t,2H),3.31(t,2H),2.97(s,3H).
LC-MS,M/Z(ESI):421.1[M+H] +。
实施例4：化合物I-4的制备
3-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)-3-氘代甲基吡咯烷-2-酮
Figure PCTCN2022141373-appb-000040
化合物I-4合成参考I-1，将中间体A1换成中间体A2，LC-MS，M/Z(ESI):439.2[M+H] +。
实施例5：化合物I-5的制备
合成路线如下所示：
Figure PCTCN2022141373-appb-000041
第一步：2-(叔丁基)4-甲基3-氧代-2-氮杂双环[3.1.0]己烷-2,4-二甲酸酯(B5-2)的合成
将3-氧代-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯(5g，25.4mmol)溶解在四氢呋喃(50mL)中，-78℃加入2M的LDA(15.21ml，30.4mmol)，搅拌0.5小时后，加入氯甲酸甲酯(2.87g，30.4mmol)，室温反应过夜。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50mL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2-(叔丁基)4-甲基3-氧代-2-氮杂双环[3.1.0]己烷-2,4-二甲酸酯(B5-2)(3g，产率46.4％)。
LC-MS，M/Z(ESI):256.1[M+H] +。
第二步：2-(叔丁基)4-甲基4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-2,4-二甲酸酯(B5-3)的合成
将2-(叔丁基)4-甲基3-氧代-2-氮杂双环[3.1.0]己烷-2,4-二甲酸酯(2g，7.83mmol)溶解在DMF(20mL)中，0℃加入碳酸钾(3.25g，23.5mmol)和碘甲烷(1.67g，11.75mmol)，搅拌1小时。反应结束后，将反应液缓慢滴入30mL冰水混合物中，混合物用乙酸乙酯(30mL x 3)萃取，收集有机相，用50mL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2-(叔丁基)4-甲基-4-甲基-3-氧代-2-氮杂双环[3.1.0] 己烷-2,4-二甲酸酯(B5-3)(1.5g，产率71.1％)。
LC-MS，M/Z(ESI):270.1[M+H] +。
第三步：4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-4-甲酸甲酯(B5-4)的合成
将2-(叔丁基)4-甲基-4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-2,4-二甲酸酯(1.5g，35.57mmol)溶解在DCM(20mL)和三氟乙酸(21mL)中，室温搅拌12小时。反应结束后，旋干得到4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-4-甲酸甲酯(5-4)(800mg，产率：85％)。
LC-MS，M/Z(ESI):170.1[M+H] +。
第四步：4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-4-甲酸(B5-5)的合成
将4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-4-甲酸甲酯(800mg，4.73mmol)溶解在甲醇(10mL)和水(0.5mL)中，加入一水氢氧化锂(992mg，23.64mmol)，室温搅拌12小时。反应结束后，调pH至2，用乙酸乙酯(30mL x 3)萃取，收集有机相，旋干得到4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-4-甲酸(B5-5)(500mg，产率68.2％)。
LC-MS，M/Z(ESI):156.0[M+H] +。
第五步：N'-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰)-4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-4-甲酰肼(B5-6)的合成
将2-((4-(氯二氟甲氧基)苯基)氨基)烟酰肼(300mg，0.913mmol)和4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-4-甲酸(170mg，1.095mmol)溶解在DMF(5mL)中，加入N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(416mg，1.095mmol)和三乙胺(0.38ml，2.74mmol)，室温搅拌12小时。反应结束后，将反应液缓慢滴入50mL水中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用50mL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＝10:1-1:1)得到N'-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰)-4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-4-甲酰肼(B5-6)(200mg，黄色固体，产率47.0％)。
LC-MS，M/Z(ESI):466.1[M+H] +。
第六步：4-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)-4-甲基-2-氮杂双环[3.1.0]己烷-3-酮(I-5)的合成
Figure PCTCN2022141373-appb-000042
将N'-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰)-4-甲基-3-氧代-2-氮杂双环[3.1.0]己烷-4-甲酰肼(200mg，0.429mmol)溶解在DCM(10mL)中，加入对甲苯磺酰氯(98mg，0.515mmol)和三乙胺(0.18ml，1.29mmol)，室温搅拌1小时。反应结束后，浓缩，粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝5:1-1:1)得到4-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)-4-甲基-2-氮杂双环[3.1.0]己烷-3-酮(I-5)(50mg，产率26％)。
LC-MS，M/Z(ESI):448.1[M+H] +。
实施例6：化合物I-6的制备
合成路线如下所示：
Figure PCTCN2022141373-appb-000043
第一步：2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-硫代肼(B6-1)的合成
将2-((4-(氯二氟甲氧基)苯基)氨基)烟酰肼(1.11g，3.38mmol)溶解在甲苯(10.0mL)中，缓慢加入劳森试剂(1.64g，4.05mmol)，置换氮气，在110℃搅拌3小时，反应液中加入水淬灭，再用乙酸乙酯(45.0mL)萃取，合并有机相，然后用饱和食盐水(45.0mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，用硅胶板分离纯化(二氧化硅，石油醚:乙酸乙酯(V/V)＝1:1)得到2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-硫代肼(6-1)(150mg，产率12.87％)。
LC-MS，M/Z(ESI):345.0[M+H] +。
第二步：3-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噻二唑-2-基)-3-甲基吡咯烷-2-酮(I-6)的合成
Figure PCTCN2022141373-appb-000044
将2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-硫代肼(110mg，320μmol)溶解在二氯甲烷(1.00mL)中，加入三正丙基环磷酸酐(380uL，640umol)和3-甲基-2-氧代吡咯烷-3-甲酸(69.0mg，480μmol)，在室温下搅拌12小时。加水淬灭，用二氯甲烷(5.00mL)萃取，饱和食盐水(5.00mL)洗涤，无水硫酸钠干燥，过滤，浓缩，用甲醇打浆得到产品3-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噻二唑-2-基)-3-甲基吡咯烷-2-酮(I-6)(30mg，产率20.75％)。
LC-MS,M/Z(ESI):452.1[M+H] +。
实施例7：化合物I-7的制备
Figure PCTCN2022141373-appb-000045
合成参考I-1，将中间体A1换成中间体A3，制备得到化合物(S)-3-(5-(2-(4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)-3-甲基吡咯烷-2-酮(I-7)
1H NMR(400MHz,DMSO-d 6)δ12.70-12.49(m,1H),7.83(s,1H),3.25-3.16(m,2H),2.42(ddd,1H),1.89(ddd,1H),1.20(s,3H)
LC-MS,M/Z(ESI):436.1[M+H] +。
实施例8：化合物I-8的制备
合成路线如下所示：
Figure PCTCN2022141373-appb-000046
第一步：(2-(2-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰基)肼基)-2-氧代乙基)(甲基)氨基甲酸叔丁酯(B8-1)的合成
将2-((4-(氯二氟甲氧基)苯基)氨基)烟酰肼(378mg，1.15mmol)与N-(叔丁氧羰基)-N-甲基甘氨酸(335.0mg，1.77mmol)溶于N,N-二甲基甲酰胺(4mL)，加入1-乙基-(3-二甲氨基丙基碳二亚胺盐酸盐(338.6mg，1.77mmol)、1-羟基苯并三唑(238.7mg，1.77mmol)、三乙胺(238.3mg，2.36mmol)，25℃反应过夜至反应完毕。加水(10mL)，乙酸乙酯萃取(20mL*3)，合并有机相，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，浓缩，得到粗品。粗品用硅胶色谱柱纯化得(2-(2-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰基)肼基)-2-氧代乙基)(甲基)氨基甲酸叔丁酯(B8-1)(201.2mg，黄色油状，产率35.0％)。
LC-MS，M/Z(ESI):500.1[M+H] +。
第二步：((5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基) 甲基)(甲基)氨基甲酸叔丁酯(B8-2)的合成
将(2-(2-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰基)肼基)-2-氧代乙基)(甲基)氨基甲酸叔丁酯(200.0mg，0.40mmol)溶解在二氯甲烷(3ml)中，加入对甲基本磺酰氯(118.7mg，0.62mmol)与三乙胺(105.0mg，1.04mmol)，25℃反应1小时，加入水(10mL)，二氯甲烷萃取(20mL*3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤，浓缩，得到粗品。粗品用硅胶色谱柱纯化得((5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)甲基)(甲基)氨基甲酸叔丁酯(B8-2)(146.7mg，黄色固体，产率76.1％)。
LC-MS，M/Z(ESI):482.1[M+H] +。
第三步：N-(4-(氯二氟甲氧基)苯基)-3-(5-((甲基氨基)甲基)-1,3,4-噁二唑-2-基)吡啶-2-胺(B8-3)的合成
将((5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)甲基)(甲基)氨基甲酸叔丁酯(144.6mg，0.30mmol)溶解在二氯甲烷(1ml)中，加入三氟乙酸(1.10g，9.69mmol)，25℃反应2小时，浓缩得到粗品，乙酸乙酯(50mL)溶解，再用饱和碳酸氢钠溶液(30mL)洗，饱和食盐水洗(20mL)，有机相无水硫酸钠干燥，浓缩得N-(4-(氯二氟甲氧基)苯基)-3-(5-((甲基氨基)甲基)-1,3,4-恶二唑-2-基)吡啶-2-胺(B8-3)(99.6mg，黄色油状，产率87.0％)。
LC-MS，M/Z(ESI):382.1[M+H] +。
第四步：N-((5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)甲基)-N-甲基氰胺(I-8)的合成
Figure PCTCN2022141373-appb-000047
将N-(4-(氯二氟甲氧基)苯基)-3-(5-((甲基氨基)甲基)-1,3,4-噁二唑-2-基)吡啶 -2-胺(152.7mg，0.40mmol)溶解在四氢呋喃(1mL)中，加入N，N-二异丙基乙胺(159.6mg，1.24mmol)，再加入溴乙腈(65.4mg，0.62mmol)，25℃反应1小时。加入水(10mL)，二氯甲烷萃取(20mL*3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤，浓缩，得到粗品。粗品用硅胶色谱柱纯化得N-((5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)甲基)-N-甲基氰胺(I-8)(100.9mg，产率62.0％)。
1H NMR(400MHz,CDCl 3)δ10.04(s,1H),8.44(dd,1H),8.18(dd,1H),7.83(dd,2H),7.25(d,2H),6.91(dd,1H),4.53(s,2H),3.04(s,3H).
LC-MS,M/Z(ESI):407.1[M+H] +。
实施例9：化合物I-9的制备
合成路线如下所示：
Figure PCTCN2022141373-appb-000048
第一步：2-氧代-3-氮杂双环[3.1.0]己烷-1-甲酸甲酯(B9-2)的合成
将3-(叔丁基)1-甲基2-氧代-3-氮杂双环[3.1.0]己烷-1,3-二甲酸酯(1.5g，5.88mmol)溶解在DCM(20ml)和三氟乙酸(21ml)中，室温搅拌12小时。反应结束后， 旋干得到2-氧代-3-氮杂双环[3.1.0]己烷-1-甲酸甲酯(B9-2)(850mg，产率：93％)。
LC-MS，M/Z(ESI):156.1[M+H] +。
第二步：2-氧代-3-氮杂双环[3.1.0]己烷-1-甲酸(B9-3)的合成
将2-氧代-3-氮杂双环[3.1.0]己烷-1-甲酸甲酯(850mg，5.48mmol)溶解在甲醇(10mL)和水(0.5mL)中，加入一水氢氧化锂(992mg，23.64mmol)室温搅拌12小时。反应结束后，调pH至2，用乙酸乙酯(30mL x 3)萃取，收集有机相，旋干得到2-氧代-3-氮杂双环[3.1.0]己烷-1-甲酸(B9-3)(657mg，产率85.0％)。
LC-MS，M/Z(ESI):140.1[M-H] +。
第三步：N'-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰基)-2-氧代-3-氮杂双环[3.1.0]己烷-1-甲酰肼(B9-4)的合成
将2-((4-(氯二氟甲氧基)苯基)氨基)烟酰肼(300mg，0.913mmol)和2-氧代-3-氮杂双环[3.1.0]己烷-1-甲酸(154mg，1.095mmol)溶解在DMF(5mL)中，加入N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(416mg，1.095mmol)和三乙胺(0.38ml，2.74mmol)，室温搅拌12小时。反应结束后，将反应液缓慢滴入50mL水中，混合物用乙酸乙酯(50mL x 3)萃取，收集有机相，用50mL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＝10:1-1:1)得到N'-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰基)-2-氧代-3-氮杂双环[3.1.0]己烷-1-甲酰肼(B9-4)(211mg，产率51.1％)。
LC-MS，M/Z(ESI):452.1[M+H] +。
第四步：1-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)-3-氮杂双环[3.1.0]己烷-2-酮(I-9)的合成
Figure PCTCN2022141373-appb-000049
将N'-(2-((4-(氯二氟甲氧基)苯基)氨基)烟酰基)-2-氧代-3-氮杂双环[3.1.0]己烷-1-甲酰肼(194mg，0.429mmol)溶解在DCM(10mL)中，加入对甲苯磺酰氯(98mg，0.515mmol)和三乙胺(0.18ml，1.29mmol)，室温搅拌1小时。反应结束后，浓缩，粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝5:1-1:1)得到1-(5-(2-((4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)-3-氮杂双环[3.1.0]己烷-2-酮(I-9)(99mg，产率53％)。
1H NMR(400MHz,CDCl 3)δ10.13(s,1H),8.39(dd,1H),8.20(dd,1H),7.83(dd,2H),7.23(d,2H),6.87(dd,1H),5.30(s,1H),3.81-3.75(m,1H),3.50(d,1H),2.73-2.69(m,1H),2.20-2.13(m,1H),1.41-1.34(m,2H).
LC-MS,M/Z(ESI):434.1[M+H] +。
实施例10：化合物I-10的制备
Figure PCTCN2022141373-appb-000050
合成参考I-2，将中间体A1换成中间体A3，制备得到化合物(S)-3-(5-(2-(4-(氯二氟甲氧基)苯基)氨基)吡啶-3-基)-1,3,4-噁二唑-2-基)-3-甲基吡咯烷-2-酮(I-10)
LC-MS,M/Z(ESI):437.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ10.29(s,1H),8.32(d,1H),8.18(d,1H),7.81-7.79(m,2H),7.24(d,2H),5.81(s,1H),3.70-3.64(m,1H),3.58-3.52(m,1H),3.02-2.98(m,1H),2.40-2.35(m,1H),1.85(s,3H).
本发明的测试例中，对照化合物I的制备参考专利公开WO2021/102204Al，结构如下所示：
Figure PCTCN2022141373-appb-000051
测试例1：TEADs介导的转录抑制IC 50评价试验
采用HEK293T-TEAD Reporter试验检测本发明的示例性化合物对TEADs介导的转录抑制作用。
HEK293T-TEAD-LUC reporter细胞系以DMEM+10％FBS+1％PS+200μg/ml Hygromycin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5uL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 PCTCN2022141373-appb-000052
luciferase assay system(Promega，E2550)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。
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)*100
表1：测试化合物在HEK293T-TEAD-LUC reporter细胞系细胞上的TEADs转录抑制活性
测试化合物 IC 50(nM)
对照化合物I 8.20
I-1 9.07
I-7 5.07
HEK293T-TEAD Reporter试验结果表明，本发明化合物在HEK293T-TEAD-LUC reporter细胞系细胞上能明显抑制TEADs介导的转录。
测试例2：抑制恶性间皮瘤细胞增殖试验
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。
NCI-H226(ATCC，cat#CRL5826)以RPMI1640+10％FBS+1％PS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/195μl，37℃，5％CO 2孵育过夜，第二天每孔加入5uL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。
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)*100
表2：测试化合物在NCI-H226细胞上的增殖抑制活性
测试化合物 IC 50(nM)
对照化合物I 10.6
I-1 6.42
I-2 13
I-3 6.64
I-7 2.77
I-10 8.6
化合物对恶性间皮瘤细胞增殖抑制试验结果表明，本发明化合物能明显抑制NCI-H226细胞增殖，与对照化合物I相比，具有更优的抑制活性。
测试例3：小鼠药代动力学试验
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。
表3：小鼠药代动力学试验结果
Figure PCTCN2022141373-appb-000053
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。
测试例4：NCI-H226间皮瘤小鼠荷瘤药效试验
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为对照，统计给药组对肿瘤的生长抑制作用，计算TGI。结果示于图1和图2中。
荷瘤小鼠药效试验结果表明，本发明化合物具有显著的抑制NCI-H226间皮瘤生长的作用。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (14)

  1. 作为TEAD抑制剂的杂环化合物、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，所述杂环化合物具有式I所示结构：
    Figure PCTCN2022141373-appb-100001
    其中，L为-CH 2-或-NH-；
    所述L任选地被选自下列的取代基取代：卤素、C 1-C 6烷基、C 1-C 6卤代烷基；
    Z 1、Z 2、Z 3、Z 4各自独立地表示CR b或N；且Z 1、Z 2、Z 3、Z 4不同时为CR b或N；
    环A为5元杂芳环；
    Ra为氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基；
    Q为未取代或被R c取代的4-8元杂环烷基、未取代或被R c取代的5-6元杂芳基、未取代或被R c取代的-C 1-C 6烷基-NR 1R 2、未取代或被R c取代的-C 1-C 6烷基-C(O)-NR 3R 4；
    R 1、R 2、R 3、R 4各自独立地选自下列的取代基：氰基、C 1-C 6烷基、-C(O)-C 1-C 6烷基；其中，所述R 1、R 2、R 3、R 4各自独立地任选地被选自下列的取代基取代：卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6烷氧基；
    或者R 1、R 2与它们所连接的N原子一起形成5-8元杂环烷基或5-6元杂芳基；
    R c为选自下列的取代基：氘、卤素、氰基、羟基、氨基、
    Figure PCTCN2022141373-appb-100002
    C 1-C 6烷基、氘代C 1-C 6烷基、C 1-C 6烷氧基；
    其中，所述R c任选地被选自下列的取代基取代：氘、卤素、氰基、羟基、氨基、
    Figure PCTCN2022141373-appb-100003
    C 1-C 6烷基、C 1-C 6烷氧基；
    R b为氢、氘、卤素、氰基、羟基、氨基、
    Figure PCTCN2022141373-appb-100004
    C 1-C 6烷基、C 1-C 6烷氧基。
  2. 如权利要求1所述的作为TEAD抑制剂的杂环化合物、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 b为氢；和/或
    在Q中，所述4-8元杂环烷基为单环或并环的杂环烷基；和/或
    L为-NH-；和/或
    所述Q被R c取代是指被1、2、3或4个R c取代；当取代基R c为多个时，所述R c相同或不同；和/或
    所述R c为选自下列的取代基：卤素、氰基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6氘代烷基；
    较佳地，R c为甲基、乙基、丙基、氟代甲基、氘代甲基。
  3. 如权利要求1所述的作为TEAD抑制剂的杂环化合物、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为5元杂芳环，所述杂芳环具有1、2或3个选自N、O或S的杂原子；
    较佳地，所述环A至多含有一个O或S；
    较佳地，所述环A至少含有一个N；
    较佳地，所述环A选自：
    Figure PCTCN2022141373-appb-100005
  4. 如权利要求1所述的作为TEAD抑制剂的杂环化合物、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，所述杂环化合物具有结构Ia所示结构，
    Figure PCTCN2022141373-appb-100006
    其中，Z 1、Z 2、Z 3、Z 4和Q的定义如权利要求1中所述。
  5. 如权利要求1所述的作为TEAD抑制剂的杂环化合物、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，所述杂环化合物具有结构Ib所示结构，
    Figure PCTCN2022141373-appb-100007
    其中，Z 1、Z 2、Z 3、Z 4和Q的定义如权利要求1中所述。
  6. 如权利要求1所述的作为TEAD抑制剂的杂环化合物、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，
    Figure PCTCN2022141373-appb-100008
    具有结构
    Figure PCTCN2022141373-appb-100009
  7. 如权利要求1所述的作为TEAD抑制剂的杂环化合物、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，所述Q为未取代或被Rc取代的4-8元内酰胺基；较佳地，所述Q为未取代或被Rc取代的单环的4-6元内酰胺基或未取代或被Rc取代的并环的6-8元内酰胺基。
  8. 如权利要求1所述的作为TEAD抑制剂的杂环化合物、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，所述Q为
    Figure PCTCN2022141373-appb-100010
    较佳地，所述
    Figure PCTCN2022141373-appb-100011
    为
    Figure PCTCN2022141373-appb-100012
    较佳地，所述
    Figure PCTCN2022141373-appb-100013
    为
    Figure PCTCN2022141373-appb-100014
  9. 如权利要求1所述的作为TEAD抑制剂的杂环化合物、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，所述R c为选自下列的取代基：卤素、氰基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6氘代烷基；
    较佳地，R c为甲基、乙基、丙基、氟代甲基、氘代甲基。
  10. 如权利要求1所述的作为TEAD抑制剂的杂环化合物、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，Q为未取代或被Rc取代的C 1-C 6烷基-NR 1R 2；
    R 1、R 2各自独立地选自下列的取代基：氰基、C 1-C 6烷基；
    较佳地，R 1、R 2各自独立地选自下列的取代基：氰基、C 1-C 3烷基；
    较佳地，R c为甲基、乙基、丙基、氟代甲基、氘代甲基；
    较佳地，所述Q为
    Figure PCTCN2022141373-appb-100015
  11. 如权利要求1所述的作为TEAD抑制剂的杂环化合物、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，所 述杂环化合物包括：
    Figure PCTCN2022141373-appb-100016
  12. 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1-11中任一所述的作为TEAD抑制剂的杂环化合物、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。
  13. 如权利要求1-11中任一所述的作为TEAD抑制剂的杂环化合物、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10所述的药物组合物的用途，所述用途包括：
    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。
  14. 如权利要求13所述的用途，其特征在于，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。
PCT/CN2022/141373 2021-12-24 2022-12-23 作为tead抑制剂的杂环化合物 WO2023116877A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111599305 2021-12-24
CN202111599305.5 2021-12-24

Publications (1)

Publication Number Publication Date
WO2023116877A1 true WO2023116877A1 (zh) 2023-06-29

Family

ID=86879671

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/141373 WO2023116877A1 (zh) 2021-12-24 2022-12-23 作为tead抑制剂的杂环化合物

Country Status (2)

Country Link
CN (1) CN116332922A (zh)
WO (1) WO2023116877A1 (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019222431A1 (en) * 2018-05-16 2019-11-21 Vivace Therapeutics, Inc. Oxadiazole compounds
CN111132673A (zh) * 2017-05-03 2020-05-08 维瓦斯治疗公司 非稠合三环化合物
CN111542315A (zh) * 2017-08-21 2020-08-14 维瓦斯治疗公司 苯并磺酰基化合物
WO2020243423A1 (en) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2021018869A1 (en) * 2019-07-29 2021-02-04 Basilea Pharmaceutica International AG 1,2,4-oxadiazol-5-one derivatives for the treatment of cancer
WO2021102204A1 (en) * 2019-11-20 2021-05-27 Vivace Therapeutics, Inc. Heteroaryl compounds

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111132673A (zh) * 2017-05-03 2020-05-08 维瓦斯治疗公司 非稠合三环化合物
CN111542315A (zh) * 2017-08-21 2020-08-14 维瓦斯治疗公司 苯并磺酰基化合物
WO2019222431A1 (en) * 2018-05-16 2019-11-21 Vivace Therapeutics, Inc. Oxadiazole compounds
WO2020243423A1 (en) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2021018869A1 (en) * 2019-07-29 2021-02-04 Basilea Pharmaceutica International AG 1,2,4-oxadiazol-5-one derivatives for the treatment of cancer
WO2021102204A1 (en) * 2019-11-20 2021-05-27 Vivace Therapeutics, Inc. Heteroaryl compounds

Also Published As

Publication number Publication date
CN116332922A (zh) 2023-06-27

Similar Documents

Publication Publication Date Title
CN106029659B (zh) 谷氨酰胺酶抑制剂
KR101749192B1 (ko) 트리아진, 피리미딘 및 피리딘 유사체 및 이의 치료제 및 진단 프로브로의 용도
TW201833108A (zh) 醯胺類衍生物抑制劑及其製備方法和應用
TWI662026B (zh) 吡啶酮類衍生物、其製備方法及其在醫藥上的應用
CN110573500B (zh) N-(氮杂芳基)环内酰胺-1-甲酰胺衍生物及其制备方法和应用
WO2022166974A1 (zh) 吡啶并嘧啶酮类衍生物及其制备方法和用途
JP7397187B2 (ja) 小分子化合物
CN108349896B (zh) 作为fgfr抑制剂的杂环化合物
JP7175481B2 (ja) ベンゾイソオキサゾール化合物
WO2021093795A1 (zh) 一种rock抑制剂及其制备方法和用途
WO2021175283A1 (zh) 新型ep4拮抗剂的合成及其在癌症和炎症中的用途
WO2020038460A1 (zh) 一种新型的喹啉衍生物抑制剂
CN115605267A (zh) 突变体lrrk2蛋白水解的选择性调节剂和相关使用方法
WO2020192650A1 (zh) 酰胺类化合物制备方法及其在医药领域的应用
WO2023280237A1 (zh) 一种磷酸酶降解剂的合成和应用
CN108299420B (zh) 作为选择性雌激素受体下调剂的五环类化合物及其应用
WO2019062657A1 (zh) 氮杂环类衍生物、其制备方法及其医药用途
WO2023134751A1 (zh) 微管蛋白-Src双靶点抑制剂和用途
WO2023116877A1 (zh) 作为tead抑制剂的杂环化合物
CN112601745A (zh) 一种氮杂芳基酰胺衍生物及其制备方法和应用
WO2020103817A1 (zh) TGF-βR1抑制剂及其应用
CN107428682B (zh) 酰胺类衍生物、其制备方法及其在医药上的用途
WO2022002241A1 (zh) 芳基磷氧类化合物及其用途
WO2022258040A1 (zh) 用于tead抑制剂的杂环化合物
WO2022257960A1 (zh) 用于治疗ep2、ep4受体介导的疾病的双环化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22910188

Country of ref document: EP

Kind code of ref document: A1