WO2022089296A1 - 一种噻吩并嘧啶类化合物、包含其药物组合物及其应用 - Google Patents

一种噻吩并嘧啶类化合物、包含其药物组合物及其应用 Download PDF

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WO2022089296A1
WO2022089296A1 PCT/CN2021/125246 CN2021125246W WO2022089296A1 WO 2022089296 A1 WO2022089296 A1 WO 2022089296A1 CN 2021125246 W CN2021125246 W CN 2021125246W WO 2022089296 A1 WO2022089296 A1 WO 2022089296A1
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substituted
unsubstituted
compound
alkyl
added
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PCT/CN2021/125246
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English (en)
French (fr)
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陈旭星
李京
陈艳红
赵兆
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上海优理惠生医药有限公司
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Priority to CN202180068194.7A priority Critical patent/CN116438183A/zh
Publication of WO2022089296A1 publication Critical patent/WO2022089296A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present application belongs to the field of medicinal chemistry, and specifically relates to a thienopyrimidine compound, a pharmaceutical composition containing the same, and applications thereof.
  • MLL Mixed-lineage leukemia
  • AML acute myeloblastic leukemia
  • ALL acute lymphoblastic leukemia
  • mixed lineage leukemia were found to be located in the q23 band of chromosome 11.
  • MLL gene often Translocation occurs to form an MLL fusion (MLL-r) protein with one of about 80 proteins (eg, AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7, etc.).
  • MLL-r protein retains about 1400 amino acids at the N-terminus of MLL protein, but lacks the methyltransferase active region at the C-terminus, and can abnormally regulate the transcription of various oncogenes including HOX and MEIS1, promote cell proliferation, and ultimately cause cancer.
  • Leukemia patients with chromosomal translocations of the MLL gene generally have a poor prognosis, with a 5-year survival rate of less than 40% (Slany, Haematologica, 2009, 94, 984-993).
  • Menin protein encoded by the Multiple Endocrine Neoplasia (MEN) gene, is a widely expressed nuclear protein that interacts with DNA replication and repair proteins, chromatin modification proteins, and various transcription factors (Agarwal et al., Horm Metab Res, 2005, 37, 369-374). Menin protein can bind to the N-terminus of MLL proteins including MLL1, MLL2 and MLL-r proteins, and this binding is necessary for the oncogenic activity of MLL proteins (Yokoyama et al., Cell, 2005, 123, 207-218; Cierpicki and Grembecka, Future Med. Chem., 2014, 6, 447-462).
  • MEN Multiple Endocrine Neoplasia
  • MLL-r leukemia cells Interfering with the interaction between menin and MLL-r protein can selectively inhibit the proliferation of MLL-r leukemia cells in vitro and in vivo (Grembecka et al., Nat.Chem.Biol., 2012, 8, 277-284; Borkin et al. , Cancer cell, 2015, 27, 589-602).
  • nucleoporin 98 NUP98 gene fusion
  • nucleophosmin NPM1 gene mutation
  • DNMT3A DNA methyltransferase 3A
  • MLL MLL gene amplification etc.
  • NUP98 nucleoporin 98
  • NPM1 nucleophosmin
  • DNMT3A DNA methyltransferase 3A
  • MLL gene amplification etc.
  • HOX gene expression In Ewing's sarcoma, backward HOXD genes, especially HOXD13, are abnormally overexpressed, accompanied by high levels of meinin and MLL1 proteins, and HOXD13 is a downstream gene regulated by menin and MLL1. Therefore, interfering with the interaction between menin and MLL proteins, especially through covalent binding, is a very promising strategy for the treatment of tumors.
  • the purpose of the present application is to provide a thienopyrimidine compound, a pharmaceutical composition comprising the same and an application thereof, the thienopyrimidine compound and the pharmaceutical composition comprising the same can interfere with menin and MLL proteins interaction.
  • the present application provides a thienopyrimidine compound, and the structural formula of the thienopyrimidine compound is shown in the following formula I:
  • R 1 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted C1 -C6 alkylcarbonyl, substituted or unsubstituted Substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C6 alkyl sulfone, substituted or unsubstituted C1-C6 alkyl sulfoxide, Wherein, R a and R b are each independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 member
  • R 2 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C16 aryl, substituted or unsubstituted 5-16 Member heteroaryl, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted C1-C6 alkylcarbonyl, substituted or unsubstituted Substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C6 alkyl sulfone, substituted or unsubstituted C1-C6 alkyl sulfoxide, Wherein, R c and R d are each independently selected from H, substituted or unsubstituted C1-C6 alkyl,
  • R 3 is independently selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylamino, -NH 2 , - NO 2 , -COOH, -CN, -OH, substituted or unsubstituted C1-C6 alkyl sulfone, substituted or unsubstituted C1-C6 alkyl sulfoxide, substituted or unsubstituted C1-C6 alkyl sulfide base, Wherein, R 3' is selected from H, methyl or fluorine; R 3" is selected from chlorine or bromine, Indicates the attachment position of the group;
  • Y and Z are independently selected from N or CH, and at least one of Y and Z is N;
  • W is selected from N or C
  • U 1 , U 2 , U 3 , U 4 , U 5 , U 6 , U 7 , U 8 are each independently selected from And at most one of U 1 , U 2 , U 3 , and U 4 is At most one of U 5 and U 6 is At most one of U 7 and U 8 is in, represents the attachment position of the group,
  • Each R' is independently selected from: H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, cyano;
  • Each R" is independently selected from: H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, cyano;
  • Each R"' is independently selected from: H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, cyano;
  • Each R" is independently selected from: H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, cyano;
  • A is selected from substituted or unsubstituted C6-C16 aryl, substituted or unsubstituted 5-16-membered heteroaryl, wherein the heteroaryl contains 1-3 selected from N, O, S, P heteroatom;
  • R L 1 is absent, in, Represents the attachment position of the group
  • R L1' , R L1" are independently selected from H, halogen, substituted or unsubstituted C1-C4 alkyl, or R L1' and R L1" are substituted or substituted with the connected carbon atom.
  • L 2 is selected from in, Indicates the attachment position of the group
  • X is selected from carbon atoms or
  • R 4 is selected from Wherein, R4' is selected from fluorine or chlorine, R4" is selected from H, methyl or fluorine, R4"' is selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy base, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted (C1-C4 alkyl) 2 amino, substituted or unsubstituted C1-C4 alkylthio, substituted or unsubstituted C3-C8 cycloalkane base, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted C2-C4 acyl group, the heterocyclic group contains 1-3 heteroatoms selected from N, O, S, P, wherein Indicates the attachment position of the group.
  • said R 1 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclyl, wherein , the heterocyclic group contains 1-3 heteroatoms selected from N, O, S, and P.
  • the R 1 is selected from substituted or unsubstituted C1-C6 alkyl, more preferably halogen-substituted C1-C6 alkyl, still more preferably trifluoroethyl.
  • said R 2 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C16 aryl, substituted or unsubstituted C6-C16 aryl Substituted 5-16-membered heteroaryl group, substituted or unsubstituted 4-8-membered heterocyclic group, wherein, the heteroaryl or heterocyclic group contains 1-3 heterocyclic groups selected from N, O, S, P atom, further preferably, the R 2 is H.
  • the R 3 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylamino, -NH 2 or -CN .
  • the Y and Z are selected from N, respectively.
  • the W is C.
  • the U 1 , U 2 , U 3 , U 4 , U 5 , U 6 , U 7 , U 8 are independently selected from And at most one of U 1 , U 2 , U 3 , and U 4 is At most one of U 5 and U 6 is At most one of U 7 and U 8 is in, represents the attachment position of the group,
  • Each R' is independently selected from H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, cyano;
  • Each R" is independently selected from H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, cyano;
  • Each R"' is independently selected from H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, cyano;
  • Each R" is independently selected from H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, cyano;
  • the A is selected from substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12-membered heteroaryl, wherein the heteroaryl contains 1-3 selected from N, O , S, P heteroatoms.
  • A is a substituted or unsubstituted benzene ring, substituted or unsubstituted pyridine ring, substituted or unsubstituted pyridazine ring, substituted or unsubstituted pyrimidine ring, substituted or unsubstituted triazoxide ring, substituted or unsubstituted unsubstituted thiophene ring, substituted or unsubstituted thiazole ring, substituted or unsubstituted imidazole ring, substituted or unsubstituted pyrrole ring, substituted or unsubstituted pyrazole ring, substituted or unsubstituted oxazole ring, substituted or unsubstituted Unsubstituted isoxazole rings, substituted or unsubstituted triazole rings.
  • the L 1 is absent or -CH 2 -, preferably -CH 2 -.
  • the L 2 is selected from preferably
  • the X is selected from carbon atoms.
  • the R 4 is selected from Wherein, R4' is selected from fluorine or chlorine, R4" is selected from H, methyl or fluorine, R4"' is selected from H, substituted or unsubstituted C1-C4 alkyl, Indicates the attachment position of the group.
  • the structural formula of the spiro ring in the compound represented by the formula I is: in Indicates the attachment position of the group, selected from any one of the following groups:
  • the structural formula of the spiro ring in the compound represented by the formula I is: in Indicates the attachment position of the group, selected from any one of the following groups:
  • the structural formula in the formula I is shown in the junction section, where Indicates the attachment position of the group, selected from any one of the following groups:
  • Re and R f are independently selected from H, methyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, halogen, hydroxyl, amino, cyano, Methylamino, dimethylamino, ethylamino, methylethylamino, diethylamino, trifluoroethylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, methylethyl carbamoyl or diethylcarbamoyl.
  • the structural formula in the formula I is shown in the ring section, where Indicates the attachment position of the group, selected from any one of the following groups:
  • the R 4 is selected from -CH 2 F, -CH 2 Cl,
  • the compound shown in the formula I is selected from any one of the following compounds:
  • the thienopyrimidine compounds also include pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers of the compounds represented by formula I Any of , solvate, polymorph or deuterated form.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the thienopyrimidine compound according to the first aspect and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further includes other pharmaceutically acceptable therapeutic agents, especially other antitumor drugs.
  • the therapeutic agents include but are not limited to: drugs that act on the chemical structure of DNA, anti-tumor drugs such as cisplatin, anti-tumor drugs that affect nucleic acid synthesis, such as methotrexate (MTX), 5-fluorouracil (5FU), etc., affect nucleic acid transcription.
  • drugs that act on the chemical structure of DNA such as cisplatin
  • anti-tumor drugs that affect nucleic acid synthesis such as methotrexate (MTX), 5-fluorouracil (5FU), etc., affect nucleic acid transcription.
  • MTX methotrexate
  • 5FU 5-fluorouracil
  • Anti-tumor drugs such as doxorubicin, epirubicin, aclarithromycin, fucoidin, etc., anti-tumor drugs that act on tubulin synthesis such as paclitaxel, vinorelbine, etc., aromatase inhibitors such as aminolu Mitre, Lantron, Letrozole, Arinide, etc.
  • Cell signaling pathway inhibitors such as epidermal growth factor receptor inhibitors Imatinib, Gefitinib, Erlotinib ), Lapatinib, etc.
  • the present application provides a use of the thienopyrimidine compound according to the first aspect or the pharmaceutical composition according to the second aspect, the use is selected from the following (a)-(c ) any of the following:
  • the tumor related to MLL1, MLL2, MLL fusion protein, and/or menin protein activity is selected from the group consisting of leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T cell lymphoma, B cell Lymphoma, malignant rhabdoid, synovial sarcoma, colorectal cancer, endometrioma, gastric cancer, liver cancer, kidney cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, glioma, bile duct cancer, nasopharyngeal cancer, Cervical, head and neck, esophagus, thyroid and bladder cancers.
  • Oxygenes include, but are not limited to, autoimmune diseases, nonalcoholic hepatitis, and the like.
  • the term “about” means that the value may vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including (including)” can be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of,” or “consisting of.”
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refers to salts with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but are not limited to formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexamethylene Acid, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-tol
  • “Pharmaceutically acceptable base addition salts” refers to salts with inorganic or organic bases that retain the biological availability of the free acid without other adverse effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperazine pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohe
  • pharmaceutical composition refers to a formulation of a compound of the present application with a medium generally accepted in the art for delivering 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 facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • pharmaceutically acceptable refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse biological effects React or interact in an undesirable manner with any component contained in the composition.
  • “Pharmaceutically acceptable excipient” as used herein includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, Diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • tumor in this application includes, but is not limited to, glioma, sarcoma, melanoma, articular chondroma, cholangiomas, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer , Pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, colon cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophagus cancer, melanin Tumors, kidney cancer, oral cancer and other diseases.
  • prophylactic As used herein, the terms “prophylactic”, “preventing” and “preventing” include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.
  • treatment and other similar synonyms include the following meanings:
  • an "effective amount” for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition.
  • An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.
  • administering refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • Those skilled in the art are familiar with administration techniques useful for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • drug combination refers to drug treatments obtained by admixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form.
  • unfixed combination refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation at variable intervals to a patient as separate entities. These also apply to cocktail therapy, eg the administration of three or more active ingredients.
  • reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in this application.
  • the techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification.
  • groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2- .
  • C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • Hydroxyalkyl refers to an alkyl group as defined below substituted with hydroxy (-OH).
  • Niro refers to -NO2 .
  • Cyano refers to -CN.
  • Amino refers to -NH2 .
  • Substituted amino means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, eg, monoalkylamino, dialkylamino, alkyl amido, aralkylamino, heteroaralkylamino.
  • Carboxyl refers to -COOH.
  • alkyl refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon Atoms and hydrogen atoms, have, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and are attached to the rest of the molecule by a single bond, including, but not limited to, methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl , heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.
  • alkyl refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon Atoms and hydrogen atoms, have, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon
  • alkenyl means consisting solely of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more A straight or branched hydrocarbon chain group of preferably 2 to 6) carbon atoms and attached to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-ene base, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
  • alkynyl means consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (preferably 2 to 10) a straight or branched hydrocarbon chain group, such as, but not limited to, ethynyl, 1-propynyl, 1-butynyl, having two, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by a single bond Alkynyl, heptynyl, octynyl, etc.
  • cyclohydrocarbyl means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which may include fused ring systems, bridges, Ring system or spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which is saturated or unsaturated and can be passed through any suitable carbon atom A single bond is attached to the rest of the molecule. Unless specifically stated otherwise in this specification, carbon atoms in a cyclic hydrocarbon group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl
  • heterocyclyl means a stable 3 group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Member to 20 membered non-aromatic cyclic group.
  • the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more ring ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon, or sulfur atoms of a can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated.
  • a heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and through a single bond.
  • one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • a heterocyclyl group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonyl Alk-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, Quinazinyl, Thiazolidinyl, Isothiazolidinyl, Isoxazolidinyl,
  • aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms.
  • an aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is The atoms on the aromatic ring are connected to the rest of the molecule by single bonds.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3(4H)-one-7-yl and the like.
  • arylalkyl herein refers to an alkyl group, as defined above, substituted with an aryl group, as defined above.
  • heteroaryl means a ring having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 atoms selected from nitrogen, oxygen and A 5- to 16-membered conjugated ring system group of a sulfur heteroatom.
  • a heteroaryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the heterocyclic group The aryl group is attached to the rest of the molecule by a single bond through an atom on the aromatic ring.
  • a nitrogen, carbon or sulfur atom in a heteroaryl group can optionally be oxidized; the nitrogen atom can optionally be quaternized.
  • a heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 selected heteroatoms.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , purinyl, quinolinyl, isoquinolinyl, diazanaphthyl, naphthyridinyl, quinoxalinyl, pteridyl, carbazolyl, carboline, phenanthridine, phenanthroline, acridine base, phena
  • heteroarylalkyl refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above.
  • substituted or unsubstituted means that a hydrogen in the structure is substituted with the stated substituent or the hydrogen is not substituted with a substituent.
  • an optionally substituted group may have a substituent at every substitutable position of the group, or may have a substituent at more than one (to the full substitution on the substituted structure) positions in the structure. be replaced.
  • substituted or “substituted” as used herein mean that one or more hydrogen atoms on a given atom or group are independently replaced by a Substituted with more, for example 1, 2, 3 or 4 substituents independently selected from: deuterium (D), halogen, -OH, mercapto, cyano, -CD3 , -C1 -C 6 alkyl (preferably -C 1-3 alkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl (preferably 3-8 membered cycloalkyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl, aryl-C 1 -C 6 alkyl-, heteroaryl-C 1 -C 6 alkyl-, C 1 -C 6 haloalkyl-, - OC 1 -C 6 alkyl (preferably -OC 1 -C 3 alkyl
  • substituents When an atom or group is substituted with multiple substituents, the substituents may be the same or different.
  • the terms "moiety”, “structural moiety”, “chemical moiety”, “group”, “chemical group” as used herein refer to a specific fragment or functional group in a molecule.
  • a chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.
  • Steps refer to compounds that consist of the same atoms, bonded by the same bonds, but have different three-dimensional structures. This application will cover the various stereoisomers and mixtures thereof.
  • the compounds of the present application are intended to include both E- and Z-geometric isomers.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present application are also intended to be included within the scope of the present application.
  • the compounds of the present application may contain one or more chiral carbon atoms, and thus may give rise to enantiomeric, diastereomeric, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • This application is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the compounds of the present application can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
  • (C1-C4 alkyl) 2 amino represents 2 C1-C4 alkyl substituted amines, for example, it can be Wait.
  • intermediate compound functional groups may need to be protected by suitable protecting groups.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable thiol protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like.
  • Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • the present application provides a compound of formula I for preparing a pharmaceutical composition for preventing and treating diseases related to the activity of MLL1, MLL2, MLL fusion protein, and/or menin protein.
  • This embodiment provides a compound 1 represented by formula I, and the structural formula of the compound 1 is as follows:
  • Triethylamine was added to a solution of trifluoroacetate (340 mg, 565 ⁇ mol) of compound 1-6 in N,N-dimethylformamide (8.0 mL) to adjust the pH to 8, followed by the addition of Intermediate A (289 mg, 1.13 mmol), and the reaction solution was stirred at 25 °C for 0.5 h.
  • Water (15.0 mL) was added to quench the reaction, extracted with ethyl acetate (10.0 mL ⁇ 3), the combined organic phases were washed with saturated brine (10.0 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure .
  • Trifluoroacetic acid 1.5 mL was added to a solution of compound 1-7 (100 mg, 0.14 mmol) in dichloromethane (4.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 1-8. The crude product was directly used in the next reaction.
  • the present embodiment provides a compound 2 shown in formula I, and the structural formula of the compound 2 is as follows:
  • the present embodiment provides a compound 3 shown in formula I, and the structural formula of the compound 3 is as follows:
  • Trifluoroacetic acid (3.0 mL) was added to a solution of compound 3-5 (150 mg, 584 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 3-6. The crude product was directly used in the next reaction.
  • Triethylamine (81 mg, 800 ⁇ mol) and Intermediate A (82 mg, 320 ⁇ mol) were added to a solution of the trifluoroacetate salt (130 mg, 267 ⁇ mol) of compound 3-6 in dichloromethane (3.0 mL), and the reaction solution Stir at 25°C for 1 hour.
  • Water (10.0 mL) was added to quench the reaction, extracted with ethyl acetate (20.0 mL ⁇ 1), the combined organic phases were washed with saturated brine (10.0 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure .
  • Trifluoroacetic acid 2.0 mL was added to a solution of compound 3-7 (143 mg, 202 ⁇ mol) in dichloromethane (8.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 3-8. The crude product was directly used in the next reaction;
  • This embodiment provides a compound 4 shown in formula I, and the structural formula of the compound 4 is as follows:
  • Crude product was prepared by high performance liquid chromatography (ACQUITY C18, 4.6mm ⁇ 30mm 1.7 ⁇ m, A: water (0.01% trifluoroacetic acid); B: acetonitrile (0.01% trifluoroacetic acid), 5%-95%: 1.5 minutes; 95 %: 1 min; 5%: 0.01 min) to obtain the trifluoroacetate salt of compound 4;
  • the present embodiment provides a compound 5 shown in formula I, and the structural formula of the compound 5 is as follows:
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 5-4 (53 mg, 74.9 ⁇ mol) in dichloromethane (4.0 mL), and the reaction solution was stirred at 25° C. for 20 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 5-5. The crude product was directly used in the next reaction.
  • the present embodiment provides a compound 6 shown in formula I, and the structural formula of the compound 6 is as follows:
  • Trifluoroacetic acid 2.0 mL was added to a solution of compound 6-4 (125 mg, 177 ⁇ mol) in dichloromethane (6.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 6-5. The crude product was directly used in the next reaction.
  • Triethylamine was added to a solution of intermediate 6-5 in trifluoroacetate (60 mg, 83.2 ⁇ mol) in dichloromethane (3.0 mL) to adjust the pH to 7, and compound 6-6 (16 mg, 99 ⁇ mol) was added. , the reaction solution was stirred at -78°C for 15 minutes. Water (10.0 mL) was added to quench the reaction, extracted with dichloromethane (20.0 mL ⁇ 2), the combined organic phases were washed with saturated brine (20.0 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure .
  • the present embodiment provides a compound 7 shown in formula I, and the structural formula of the compound 7 is as follows:
  • Triethylamine (8.4 mg, 83.3 ⁇ mol), compound 7-1 (27.6 mg, 167 ⁇ mol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (63.3mg, 167 ⁇ mol), the reaction solution was stirred at 25°C for 0.5 Hour. Water (20.0 mL) was added to quench the reaction, extracted with dichloromethane (20.0 mL ⁇ 3), the organic phase was washed with saturated brine (20.0 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure.
  • the present embodiment provides a compound 8 shown in formula I, and the structural formula of the compound 8 is as follows:
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 8-2 (218 mg, 493 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 8-3.
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 8-5 (94.3 mg, 160 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 8-6. The crude product was directly used in the next reaction.
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 8-7 (56.0 mg, 79.2 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 8-8. The crude product was directly used in the next reaction.
  • This embodiment provides a compound 9 shown in formula I, and the structural formula of the compound 9 is as follows:
  • Trifluoroacetic acid (2.5 mL) was added to a solution of compound 9-5 (100 mg, 179 ⁇ mol) in dichloromethane (10.0 mL), and the reaction solution was stirred at 25° C. for 0.5 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 9-6. The crude product was directly used in the next reaction.
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 9-7 (77.0 mg, 113 ⁇ mol) in dichloromethane (4.0 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 9-8. The crude product was directly used in the next reaction.
  • This embodiment provides a compound 10 shown in formula I, and the structural formula of the compound 10 is as follows:
  • This embodiment provides a compound 11 represented by formula I, and the structural formula of the compound 11 is as follows:
  • Triethylamine (8.42 mg, 83.3 ⁇ mol, 11.6 ⁇ L) was added to a solution of the trifluoroacetate salt (60.0 mg, 83.3 ⁇ mol) of compound 10-5 in Example 10 in dichloromethane (3.0 mL), Then 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (63.3 mg, 166 ⁇ mol) and the hydrochloride salt of compound 11-1 (63.3 mg, 166 ⁇ mol) were added. 27.6 mg, 166 ⁇ mol), the reaction solution was stirred at 25 °C for 0.5 hours.
  • This embodiment provides a compound 12 shown in formula I, and the structural formula of the compound 12 is as follows:
  • Trifluoroacetic acid 2.0 mL was added to a solution of compound 12-1 (190 mg, 320 ⁇ mol) in dichloromethane (6.0 mL), and the reaction solution was stirred at 25° C. for 10 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 12-2. The crude product was directly used in the next reaction.
  • This embodiment provides a compound 13 represented by formula I, and the structural formula of the compound 13 is as follows:
  • This embodiment provides a compound 14 shown in formula I, and the structural formula of the compound 14 is as follows:
  • Trifluoroacetic acid (441 mg, 3.87 mmol, 287 ⁇ L) was added to a solution of compound 14-1 (70.0 mg, 119 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 14-2. The crude product was directly used in the next reaction.
  • Trifluoroacetic acid (353 mg, 3.10 mmol, 229 ⁇ L) was added to a solution of compound 14-3 (39.0 mg, 55.1 ⁇ mol) in dichloromethane (2.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 14-4. The crude product was directly used in the next reaction.
  • This embodiment provides a compound 15 shown in formula I, and the structural formula of the compound 15 is as follows:
  • This embodiment provides a compound 16 shown in formula I, and the structural formula of the compound 16 is as follows:
  • Trifluoroacetic acid (3.08 g, 27.0 mmol, 2 mL) was added to a solution of compound 16-2 (350 mg, 589 ⁇ mol) in dichloromethane (8.0 mL), and the reaction solution was stirred at 25° C. for 10 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 16-3. The crude product was directly used in the next reaction.
  • Trifluoroacetic acid (3.08 g, 27.0 mmol, 2 mL) was added to a solution of compound 16-4 (210 mg, 295 ⁇ mol) in dichloromethane (6.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 16-5. The crude product was directly used in the next reaction.
  • This embodiment provides a compound 17 shown in formula I, and the structural formula of the compound 17 is as follows:
  • Triethylamine (14.6 mg, 144 ⁇ mol, 20.1 ⁇ L) was added to a solution of the trifluoroacetate salt (105 mg, 144 ⁇ mol) of compound 16-5 in Example 16 in dichloromethane (5.0 mL), followed by the compound 17-1 (19.6 mg, 217 ⁇ mol, 17.7 ⁇ L), the reaction solution was stirred at -78°C for 5 minutes.
  • Water (20.0 mL) was added to quench the reaction, extracted with dichloromethane (20.0 mL ⁇ 2), the organic phase was washed with saturated brine (20.0 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure.
  • the crude product was separated by high performance liquid chromatography (Xtimate C18 100mm ⁇ 30mm 10 ⁇ m, A: water (0.225% formic acid); B: acetonitrile, 10%-40%: 10 minutes) to obtain the formate salt of compound 17.
  • This embodiment provides a compound 18 represented by formula I, and the structural formula of the compound 18 is as follows:
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 18-3 (98 mg, 138 ⁇ mol) in dichloromethane (4.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 18-4. The crude product was directly used in the next reaction.
  • This embodiment provides a compound 19 represented by formula I, and the structural formula of the compound 19 is as follows:
  • Trifluoroacetic acid (3.0 mL) was added to a solution of compound 19-5 (1.26 g, 2.67 mmol) in dichloromethane (15.0 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 19-6.
  • Trifluoroacetic acid (3.0 mL) was added to a solution of compound 19-8 (700 mg, 1.14 mmol) in dichloromethane (15.0 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 19-9. The crude product was directly used in the next reaction.
  • This embodiment provides a compound 20 represented by formula I, and the structural formula of the compound 20 is as follows:
  • This embodiment provides a compound 21 represented by formula I, and the structural formula of the compound 21 is as follows:
  • This embodiment provides a compound 22 represented by formula I, and the structural formula of the compound 22 is as follows:
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 22-2 (90 mg, 152 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 22-3. The crude product was directly used in the next reaction.
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 22-4 (90 mg, 126 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 22-5. The crude product was directly used in the next reaction.
  • Triethylamine (8.35 mg, 82.6 ⁇ mol), N,N,N′, was added to a solution of intermediate 22-5 in trifluoroacetate (40.0 mg, 55 ⁇ mol) in dichloromethane (2.0 mL).
  • N'-tetramethyl-O-(7-azabenzotriazol-1-yl) urea hexafluorophosphate (27.21 mg, 71.55 ⁇ mol) was added to compound 24-6 (27.4 mg, 165 ⁇ mol), and the reaction solution was heated at 25 Stir at °C for 3 hours.
  • This embodiment provides a compound 23 represented by formula I, and the structural formula of the compound 23 is as follows:
  • This embodiment provides a compound 24 represented by formula I, and the structural formula of the compound 24 is as follows:
  • Triethylamine (44.3 mg, 438 ⁇ mol), compound E (87.8 mg, 328 ⁇ mol) were added to a methanol (5.0 mL) solution of the trifluoroacetate salt (100.0 mg, 219 ⁇ mol) of compound 3-3 in Example 3 ), sodium cyanoborohydride (55.1 mg, 876 ⁇ mol) was added, and the mixture was stirred at 25° C. for 12 hours.
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 24-1 (120 mg, 202 ⁇ mol) in dichloromethane (4.0 mL), and the reaction solution was stirred at 25° C. for 10 minutes. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 24-2. The crude product was directly used in the next reaction.
  • Trifluoroacetic acid (2.0 mL) was added to a solution of compound 24-3 (80.0 mg, 112 ⁇ mol) in dichloromethane (6.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 24-4. The crude product was directly used in the next reaction.
  • Triethylamine (10.4 mg, 103 ⁇ mol), N,N,N′,N was added to a solution of intermediate 24-4 in trifluoroacetate (34.2 mg, 206 ⁇ mol) in dichloromethane (5.0 mL).
  • '-Tetramethyl-O-(7-azabenzotriazol-1-yl) urea hexafluorophosphate (78.5mg, 206 ⁇ mol) was added to compound 24-5 (75.0mg, 103 ⁇ mol), the reaction solution was heated at 25°C Stir for 30 minutes.
  • This embodiment provides a compound 25 represented by formula I, and the structural formula of the compound 25 is as follows:
  • Triethylamine (66.5 mg, 657 ⁇ mol), Compound C (344 mg, 1.31 mmol) were added to a solution of trifluoroacetate (300.0 mg, 657 ⁇ mol) in methanol (5.0 mL) of Compound 3-3 in Example 3 ), sodium cyanoborohydride (165 mg, 2.63 mmol) was added, and the mixture was stirred at 25° C. for 12 hours.
  • Trifluoroacetic acid (0.5 mL) was added to a solution of compound 25-3 (125 mg, 177 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 30 minutes. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 25-4. The crude product was directly used in the next reaction.
  • This embodiment provides a compound 26 represented by formula I, and the structural formula of the compound 26 is as follows:
  • Triethylamine (25.2 mg, 249 ⁇ mol) was added to a solution of the trifluoroacetate salt (60.0 mg, 83.1 ⁇ mol) of compound 25-4 in Example 25 in dichloromethane (2.0 mL), and compound 26- 1 (15.1 mg, 166 ⁇ mol), the reaction solution was stirred at -78 °C for 1 hour.
  • Water (30.0 mL) was added to the reaction solution, extracted with dichloromethane (50.0 mL), the combined organic phases were washed with saturated brine (30.0 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure.
  • This embodiment provides a compound 27 represented by formula I, and the structural formula of the compound 27 is as follows:
  • Triethylamine (177 mg, 1.75 mmol) was added to a solution of the trifluoroacetic acid salt (200.0 mg, 438 ⁇ mol) of compound 3-3 in Example 3 in dichloromethane (10.0 mL), compound 27-1 ( 112 mg, 525 ⁇ mol), sodium cyanoborohydride (55.0 mg, 876 ⁇ mol) was added, and the mixture was stirred at 25° C. for 12 hours.
  • Trifluoroacetic acid (3.0 mL) was added to a solution of compound 27-2 (200 mg, 370 ⁇ mol) in dichloromethane (9.0 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 27-3. The crude product was directly used in the next reaction.
  • This embodiment provides a compound 28 represented by formula I, and the structural formula of the compound 28 is as follows:
  • This embodiment provides a compound 29 shown in formula I, and the structural formula of the compound 29 is as follows:
  • Trifluoroacetic acid 2.0 mL was added to a solution of compound 29-5 (210 mg, 366 ⁇ mol) in dichloromethane (6.0 mL), and the reaction solution was stirred at 25° C. for 0.5 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 29-6. The crude product was directly used in the next reaction.
  • Trifluoroacetic acid 2.0 mL was added to a solution of compound 29-7 (195 mg, 274 ⁇ mol) in dichloromethane (6.0 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 29-8. The crude product was directly used in the next reaction.
  • This embodiment provides a compound 30 shown in formula I, and the structural formula of the compound 30 is as follows:
  • Trifluoroacetic acid (5.0 mL) was added to a solution of compound 30-2 (470 mg, 1.17 ⁇ mol) in dichloromethane (15.0 mL), and the reaction solution was stirred at 25° C. for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 30-3.
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 30-5 (78.0 mg, 140 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 0.5 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 30-6. The crude product was directly used in the next reaction.
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 30-7 (57.0 mg, 84.7 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 30-8. The crude product was directly used in the next reaction.
  • the crude product was separated by high performance liquid chromatography (Xtimate C18, 100mm ⁇ 30mm 10 ⁇ m, A: water (0.225% formic acid); B: acetonitrile, 15%-45%: 10 minutes) to obtain the formate salt of compound 30.
  • This embodiment provides a compound 31 shown in formula I, and the structural formula of the compound 31 is as follows:
  • Trifluoroacetic acid (1.0 mL) was added to a solution of compound 31-3 (46.0 mg, 68.3 ⁇ mol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 31-4. The crude product was directly used in the next reaction.
  • the crude product was separated by high performance liquid chromatography (Xtimate C18, 100mm ⁇ 30mm 10 ⁇ m, A: water (0.225% formic acid); B: acetonitrile, 15%-45%: 10 minutes) to obtain the formate salt of compound 31.
  • MV-4-11 is a human leukemia cell line with MLL translocation and expressing MLL fusion protein MLL-AF4.
  • the compounds involved in this application inhibit the proliferation of MV-4-11 by interfering with the menin/MLL protein/protein interaction.
  • Cell Counting Kit-8 was purchased from Shanghai Liji Biotechnology Co., Ltd. (Item No. D3100L4057); 96-well transparent bottom white cell culture plate was purchased from Corning Costar (Item No. 3610); fetal bovine serum was purchased from GIBCO (Item No. # 10099-141); Iskov's modified medium (IMDM) medium was purchased from Invitrogen (Cat. No. 12440046); desktop microplate reader SpectraMax i3X was purchased from Molecular Devices;
  • IMDM+10% fetal bovine serum (FBS) inoculated into a 96-well plate (add 100 ⁇ L of cell suspension to each well, that is, 15000 cells per well). Cells were incubated for 24 h in a 37 °C, 100% relative humidity, 5% CO2 incubator.
  • the compounds to be tested were dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution with a concentration of 10 mM, and were diluted 8 times with 4-fold gradient with DMSO. Dilute 20-fold with medium. Add 25 ⁇ L/well to the 96-well plate seeded with cells, so that the final concentrations of the compounds are: 100 ⁇ M, 25 ⁇ M, 6.25 ⁇ M, 1.56 ⁇ M, 0.39 ⁇ M, 0.098 ⁇ M, 0.024 ⁇ M, 0.006 ⁇ M, 0.0015 ⁇ M (4-fold dilution, 9 concentration).
  • DMSO dimethyl sulfoxide
  • the cells added with the compounds to be tested were placed in a 37°C, 100% relative humidity, 5% CO 2 incubator for 72 hours respectively; the cell viability was detected by the CCK-8 method: 10 ⁇ L of CCK-8 detection reagent was added to each well, placed in Continue to incubate for about 4 hours in the incubator. Use a benchtop microplate reader to read at a wavelength of 450 nM (reference wavelength of 650 nM).
  • the inhibitory rate of the drug on tumor cell growth was calculated as follows:
  • Tumor cell growth inhibition % [(ODc-ODs)/(ODc-ODb)] ⁇ 100%
  • ODs OD of the sample (cell + CCK-8 + test compound), ODc: OD of the negative control (cell + CCK-8 + DMSO), ODb: OD of the blank control (medium + CCK-8 + DMSO) ).
  • MV-4-11 is a human leukemia cell line with MLL translocation and expressing MLL fusion protein MLL-AF4.
  • the compounds involved in the present application inhibit the proliferation of MV-4-11 by interfering with the menin/MLL protein/protein interaction.
  • CellTiter-Glo was purchased from Promega (item #G7571); IMDM medium was purchased from Gibco (item #12440061); fetal bovine serum was purchased from Excell (item #FND500); dimethyl sulfoxide (DMSO) was purchased from Sigma (Cat. #D2650); 384-well cell culture plates from Corning (Cat. #3756); automated cell counters from Life technologies (model Countess II); microplate readers from PerkinElmer (model EnVision Multilabel Reader).
  • the cells in logarithmic growth phase were resuspended in growth medium (IMDM+10%FBS) and diluted to the target density (50000/mL).
  • the above cell suspension was seeded into a 384-well plate at 50 ⁇ L per well; incubated overnight in a 37°C, 5% CO 2 incubator.

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Abstract

本文公布了一种噻吩并嘧啶类化合物、包含其药物组合物及其应用。所述噻吩并嘧啶类化合物的结构式具有式I所示结构。所述的化合物干扰menin蛋白与MLL1或MLL2或MLL-融合癌蛋白之间的相互作用，有望成为治疗依赖于MLL1、MLL2、MLL融合蛋白、和/或menin蛋白活性的肿瘤、糖尿病和其他疾病的药物。

Description

一种噻吩并嘧啶类化合物、包含其药物组合物及其应用 技术领域
本申请属于药物化学领域，具体涉及一种噻吩并嘧啶类化合物、包含其的药物组合物及其应用。
背景技术
混合系白血病(mixed-lineage leukemia，MLL)蛋白是一种组蛋白甲基转移酶，在基因转录调控过程中起着重要作用。包括急性髓性白血病(acute myeloblastic leukemia，AML)、急性淋巴细胞白血病(acute lymphoblastic leukemia，ALL)和混合系白血病在内的大部分急性白血病均被发现位于11号染色体q23带位置上的MLL基因常常发生易位，与大约80种蛋白(如AF4、AF9、ENL、AF10、ELL、AF6、AF1p、GAS7等)的其中之一形成MLL融合(MLL-r)蛋白。MLL-r蛋白大约保留了MLL蛋白N端1400个氨基酸序列，而缺少C端的甲基转移酶活性区域，并且能异常调节包括HOX与MEIS1在内的多种癌基因的转录，促进细胞增殖，最终导致癌症的发生。MLL基因染色体易位的白血病患者通常预后较差，5年生存率低于40％(Slany,Haematologica,2009,94,984-993)。
Menin蛋白，由多发性内分泌腺肿瘤(Multiple Endocrine Neoplasia，MEN)基因编码，是一种广泛表达的核蛋白，与DNA的复制和修复蛋白、染色质修饰蛋白、多种转录因子进行相互作用(Agarwal et al.,Horm Metab Res,2005,37,369-374)。Menin蛋白能与包括MLL1、MLL2和MLL-r蛋白等MLL蛋白的N端进行结合，这种结合对MLL蛋白的致癌活性是所必须的(Yokoyama et al.,Cell,2005,123,207-218；Cierpicki and Grembecka,Future Med.Chem.,2014,6,447-462)。干扰menin和MLL-r蛋白之间的相互作用，能够体内外选择性地抑 制MLL-r白血病细胞的增殖(Grembecka et al.,Nat.Chem.Biol.,2012,8,277-284；Borkin et al.,Cancer cell,2015,27,589-602)。
在特定的血液瘤中存在某些特定基因异常或突变，例如核孔蛋白98(NUP98)基因融合，核磷蛋白(NPM1)基因突变，DNA甲基转移酶3A(DNMT3A)突变，MLL基因扩增等，这些异常或突变，往往也伴随着高水平的HOX基因的表达。尤文氏肉瘤中后向HOXD基因尤其是HOXD13异常过表达，并伴随着高水平的meinin和MLL1蛋白，而HOXD13是menin和MLL1调控的下游基因。因此，干扰menin和MLL蛋白之间的相互作用，尤其是通过共价结合干扰menin和MLL蛋白之间的相互作用是一个非常有前景的***的策略。
因此，目前本领域尚迫切需要研发出能够干扰menin和MLL蛋白相互作用的有效药物。
发明内容
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的保护范围。
针对现有技术的不足，本申请的目的在于提供一种噻吩并嘧啶类化合物、包含其药物组合物及其应用，所述噻吩并嘧啶类化合物、包含其的药物组合物能够干扰menin和MLL蛋白相互作用。
为达此目的，本申请采用以下技术方案：
第一方面，本申请提供一种噻吩并嘧啶类化合物，所述噻吩并嘧啶类化合物的结构式如下式I所示：
Figure PCTCN2021125246-appb-000001
其中，
R 1选自H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基、取代或未取代的C1-C6烷基羰基、取代或未取代的
Figure PCTCN2021125246-appb-000002
取代或未取代的C2-C8烯基、取代或未取代的C2-C8炔基、取代或未取代的C1-C6烷基砜基、取代或未取代的C1-C6烷基亚砜基、
Figure PCTCN2021125246-appb-000003
其中，R a、R b各自独立地选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基、或R a与R b与N相连形成的取代或未取代的4-8元杂环，其中，R a与R b与N相连形成杂环包含1-3个选自N、O、S、P的杂原子；
R 2选自H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C16芳基、取代或未取代的5-16元杂芳基、取代或未取代的4-8元杂环基、取代或未取代的C1-C6烷基羰基、取代或未取代的
Figure PCTCN2021125246-appb-000004
取代或未取代的C2-C8烯基、取代或未取代的C2-C8炔基、取代或未取代的C1-C6烷基砜基、取代或未取代的C1-C6烷基亚砜基、
Figure PCTCN2021125246-appb-000005
其中，R c、R d各自独立地选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基、或R c与R d与N相连形成的取代或未取代的4-8元杂环，其中，R c与R d与N相连形成的杂环包含1-3个选 自N、O、S、P的杂原子；
R 3分别独立地选自H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C1-C4烷氨基、-NH 2、-NO 2、-COOH、-CN、-OH、取代或未取代的C1-C6烷基砜基、取代或未取代的C1-C6烷基亚砜基、取代或未取代的C1-C6烷基硫基、
Figure PCTCN2021125246-appb-000006
Figure PCTCN2021125246-appb-000007
其中，R 3'选自H、甲基或氟；R 3”选自氯或溴，
Figure PCTCN2021125246-appb-000008
表示基团的连接位置；
Y、Z分别独立地选自N或CH，且Y和Z中至少有一个为N；
W选自N或C；
U 1、U 2、U 3、U 4、U 5、U 6、U 7、U 8分别独立地选自
Figure PCTCN2021125246-appb-000009
Figure PCTCN2021125246-appb-000010
且U 1、U 2、U 3、U 4中至多有一个为
Figure PCTCN2021125246-appb-000011
Figure PCTCN2021125246-appb-000012
U 5、U 6中至多有一个为
Figure PCTCN2021125246-appb-000013
Figure PCTCN2021125246-appb-000014
U 7、U 8中至多有一个为
Figure PCTCN2021125246-appb-000015
Figure PCTCN2021125246-appb-000016
其中，
Figure PCTCN2021125246-appb-000017
表示基团的连接位置，
每一个R'分别独立地选自：H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
每一个R”分别独立地选自：H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
每一个R”'分别独立地选自：H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
每一个R””分别独立地选自：H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；；
A选自取代或未取代的C6-C16芳基、取代或未取代的5-16元杂芳基，其中，所述的杂芳基包含1-3个选自N、O、S、P的杂原子；
L 1为不存在、
Figure PCTCN2021125246-appb-000018
其中，
Figure PCTCN2021125246-appb-000019
表示基团的连接位置，R L1'、R L1”分别独立地选自H、卤素、取代或未取代的C1-C4烷基，或R L1'与R L1”与相连的碳原子形成取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环，其中，R L1'与R L1”与相连的碳原子形成的杂环包含1-3个选自N、O、S、P的杂原子；
L 2选自
Figure PCTCN2021125246-appb-000020
其中，
Figure PCTCN2021125246-appb-000021
表示基团的连接位置；
X选自碳原子或
Figure PCTCN2021125246-appb-000022
R 4选自
Figure PCTCN2021125246-appb-000023
其中，R4'选自氟或氯，R4”选自H、甲基或氟，R4”'选自H、取代或未取代的C1-C4烷基、取代或未取代的的C1-C4烷氧基、取代或未取代的C1-C4烷氨基、取代或未取代的(C1-C4烷基) 2氨基、取代或未取代的C1-C4烷硫基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基、取代或未取代的C2-C4酰基，所述杂环基包含1-3个选自N、O、S、P的杂原子，其中
Figure PCTCN2021125246-appb-000024
表示基团的连接位置。
优选地，所述R 1选自H、卤素、取代或未取代的C1-C6烷基、取代或未取 代的C3-C8环烷基、取代或未取代的4-8元杂环基，其中，所述杂环基包含1-3个选自N、O、S、P的杂原子。
优选地，所述R 1选自取代或未取代的C1-C6烷基，进一步优选为卤素取代的C1-C6烷基，更进一步优选为三氟乙基。
优选地，所述R 2选自H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C16芳基、取代或未取代的5-16元杂芳基、取代或未取代的4-8元杂环基，其中，所述杂芳基或杂环基包含1-3个选自N、O、S、P的杂原子，进一步优选地，所述R 2为H。
优选地，所述R 3为H、取代或未取代的C1-C6烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C1-C4烷氨基、-NH 2或-CN。
优选地，所述Y、Z分别选自N。
优选地，所述W为C。
优选地，所述U 1、U 2、U 3、U 4、U 5、U 6、U 7、U 8分别独立地选自
Figure PCTCN2021125246-appb-000025
Figure PCTCN2021125246-appb-000026
且U 1、U 2、U 3、U 4中至多有一个为
Figure PCTCN2021125246-appb-000027
U 5、U 6中至多有一个为
Figure PCTCN2021125246-appb-000028
U 7、U 8中至多有一个为
Figure PCTCN2021125246-appb-000029
其中，
Figure PCTCN2021125246-appb-000030
表示基团的连接位置，
每一个R'分别独立地选自H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
每一个R”分别独立地选自H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
每一个R”'分别独立地选自H、卤素、取代或未取代的C1-C4烷基、取代或 未取代的C1-C4烷氧基、氰基；
每一个R””分别独立地选自H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；。
优选地，所述A选自取代或未取代的C6-C10芳基、取代或未取代的5-12元杂芳基，其中，所述的杂芳基包含1-3个选自N、O、S、P的杂原子。
优选地，A为取代或未取代的苯环、取代或未取代的吡啶环、取代或未取代的哒嗪环、取代或未取代的嘧啶环、取代或未取代的三氮嗪环、取代或未取代的噻吩环、取代或未取代的噻唑环、取代或未取代的咪唑环、取代或未取代的吡咯环、取代或未取代的吡唑环、取代或未取代的噁唑环、取代或未取代的异噁唑环、取代或未取代的三氮唑环。
优选地，所述L 1为不存在或-CH 2-，优选为-CH 2-。
优选地，所述L 2选自
Figure PCTCN2021125246-appb-000031
优选为
Figure PCTCN2021125246-appb-000032
优选地，所述X选自碳原子。
优选地，所述R 4选自
Figure PCTCN2021125246-appb-000033
其中，R4'选自氟或氯，R4”选自H、甲基或氟，R4”'选自H、取代或未取代的C1-C4烷基，
Figure PCTCN2021125246-appb-000034
表示基团的连接位置。
优选地，所述式I所示的化合物中螺环部分结构式为
Figure PCTCN2021125246-appb-000035
其中
Figure PCTCN2021125246-appb-000036
表示基团的连接位置，选自如下基团中的任意一种：
Figure PCTCN2021125246-appb-000037
优选地，所述式I所示的化合物中螺环部分结构式为
Figure PCTCN2021125246-appb-000038
其中
Figure PCTCN2021125246-appb-000039
表示基团的连接位置，选自如下基团中的任意一种：
Figure PCTCN2021125246-appb-000040
优选地，所述式I中结构式为
Figure PCTCN2021125246-appb-000041
所示的并环部分，其中
Figure PCTCN2021125246-appb-000042
表示基团的连接位置，选自如下基团中的任意一种：
Figure PCTCN2021125246-appb-000043
Figure PCTCN2021125246-appb-000044
其中，R e、R f分别独立地选自H、甲基、三氟甲基、二氟甲基、甲氧基、乙氧基、三氟甲氧基、卤素、羟基、氨基、氰基、甲氨基、二甲氨基、乙氨基、甲乙氨基、二乙氨基、三氟乙氨基、羧基、甲氧基羰基、乙氧基羰基、氨基甲酰基、甲氨基甲酰基、二甲氨基甲酰基、甲乙氨基甲酰基或二乙氨基甲酰基。
优选地，所述式I中结构式为
Figure PCTCN2021125246-appb-000045
所示的环状部分，其中
Figure PCTCN2021125246-appb-000046
表示基团的连接位置，选自如下基团中的任意一种：
Figure PCTCN2021125246-appb-000047
优选地，所述R 4选自-CH 2F、-CH 2Cl、
Figure PCTCN2021125246-appb-000048
Figure PCTCN2021125246-appb-000049
优选地，所述式I所示的化合物选自下述化合物中的任意一种：
Figure PCTCN2021125246-appb-000050
Figure PCTCN2021125246-appb-000051
Figure PCTCN2021125246-appb-000052
Figure PCTCN2021125246-appb-000053
Figure PCTCN2021125246-appb-000054
优选地，所述噻吩并嘧啶类化合物还包括式I所示的化合物的药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物或氘代物中的任意一种。
第二方面，本申请提供一种药物组合物，所述药物组合物包括如第一方面所述的噻吩并嘧啶类化合物和药学上可接受的载体。
优选地，该药物组合物还进一步包括其他药学上可接受的治疗剂，特别是其他抗肿瘤药物。所述治疗剂包括但不限于：作用于DNA化学结构的药物抗肿瘤药如顺铂，影响核酸合成的抗肿瘤药物如甲氨蝶呤(MTX)、5-氟尿嘧啶(5FU)等，影响核酸转录的抗肿瘤药物如阿霉素、表阿霉素、阿克拉霉素、光辉霉素等，作用于微管蛋白合成的抗肿瘤药物如紫杉醇、长春瑞滨等，芳香化酶抑制剂如氨鲁米特、兰特隆、来曲唑、瑞宁德等，细胞信号通路抑制剂如表皮生长因子受体抑制剂伊马替尼(Imatinib)、吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、拉帕替尼(Lapatinib)等。
第三方面，本申请提供一种如第一方面所述所述的噻吩并嘧啶类化合物或如第二方面所述的药物组合物的用途，所述用途选自下述(a)-(c)中的任意一种：
(a)制备用于预防或治疗与MLL1、MLL2、MLL融合蛋白、和/或menin蛋白活性有关的肿瘤、糖尿病和其他疾病的药物；
(b)制备用于体外非治疗性与MLL1、MLL2、MLL融合蛋白、和/或menin蛋白的活性有关的抑制剂；
(c)制备用于体外非治疗性肿瘤细胞的增殖抑制剂。
在一优选例中，所述与MLL1、MLL2、MLL融合蛋白、和/或menin蛋白活性有关的肿瘤选自下组：白血病、尤文氏肉瘤、乳腺癌、***癌、T细胞淋巴瘤、B细胞淋巴瘤、恶性横纹肌瘤、滑膜肉瘤、结直肠癌、子宫内膜瘤、胃癌、肝癌、肾癌、肺癌、黑色素瘤、卵巢癌、胰腺癌、脑胶质瘤、胆管癌、鼻咽癌、***、头颈癌、食管癌、甲状腺癌和膀胱癌。
“其他疾病”包括但不限于自身免疫疾病、非酒精性肝炎等。
术语说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本申请所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
在本申请中，术语“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。
“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。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸 盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“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。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
在本申请中，“药物组合物”是指本申请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。
本文所用术语“药学上可接受的”是指不影响本申请化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造 成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
本文中“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本申请所述“肿瘤”包括但不限于神经胶质瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
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。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试 验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
基团定义
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."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申请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-。
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。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-C6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
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。
本文中术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(＝O)-基团。
“硝基”是指-NO 2。
“氰基”是指-CN。
“氨基”是指-NH 2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
本文中作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子，且通过单键与分子的其余部分连接，例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本申请而言，术语“烷基”指含有1至6个碳原子的烷基。
本文中作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2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，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
本文中作为基团或是其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个碳-碳三键、具有例如2至14个(优选为2至10个，更优选为2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，例如但不限于乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
本文中作为基团或是其它基团的一部分，术语“环烃基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选 具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烃基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
本文中作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本申请的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻 喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡唑啉基、吡唑烷基、邻苯二甲酰亚氨基等。
本文中作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本申请的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
本文中术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
本文中作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本申请的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪 基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、-中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
本文中术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
本文中术语“取代或未取代”代表该结构中的氢被所述取代基取代或该氢未被取代基取代。除非另有说明，任选取代的基团可以在该基团每一个可取代的位置上具有取代基，或者在结构中的多于一个(至该被取代的结构上取代位占满)位置可以被取代。
例如，在没有明确列出取代基的情况下，本文所用的术语“被取代的”或“被……取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代，所述取代基独立地选自：氘(D)、卤素、-OH、巯基、氰基、-CD 3、-C 1-C 6烷基(优选-C 1-3烷基)、C 2-C 6烯基、C 2-C 6炔基、环烷基(优选3-8元环烷基)、芳基、杂环基(优选3-8元杂环基)、杂芳基、芳基-C 1-C 6烷基-、杂芳基-C 1-C 6烷基-、C 1-C 6卤代烷基-、-OC 1-C 6烷基(优选-OC 1-C 3烷基)、-OC 2-C 6烯基、-OC 1-C 6烷基苯基、-C 1-C 6烷基-OH(优选-C 1-C 4烷基-OH)、-C 1-C 6烷基-SH、-C 1-C 6烷基-O-C 1-C 6烷基、-OC 1-C 6卤代烷基、-NH 2、-C 1-C 6烷基-NH 2(优选-C 1-C 3烷基-NH 2)、-N(C 1-C 6烷基) 2(优选-N(C 1-C 3烷基) 2)、-NH(C 1-C 6烷基)(优选-NH(C 1-C 3烷基))、-N(C 1-C 6烷基)(C 1-C 6烷基苯基)、-NH(C 1-C 6烷基苯基)、硝 基、-C(O)-OH、-C(O)OC 1-C 6烷基(优选-C(O)OC 1-C 3烷基)、-CONRiRii(其中Ri和Rii是H、D和C 1-6烷基，优选C 1-3烷基)、-NHC(O)(C 1-C 6烷基)、-NHC(O)(苯基)、-N(C 1-C 6烷基)C(O)(C 1-C 6烷基)、-N(C 1-C 6烷基)C(O)(苯基)、-C(O)C 1-C 6烷基、-C(O)杂芳基(优选-C(O)-5-7元杂芳基)、-C(O)C 1-C 6烷基苯基、-C(O)C 1-C 6卤代烷基、-OC(O)C 1-C 6烷基(优选-OC(O)C 1-C 3烷基)、-S(O) 2-C 1-C 6烷基、-S(O)-C 1-C 6烷基、-S(O) 2-苯基、-S(O) 2-C 1-C 6卤代烷基、-S(O) 2NH 2、-S(O) 2NH(C 1-C 6烷基)、-S(O) 2NH(苯基)、-NHS(O) 2(C 1-C 6烷基)、-NHS(O) 2(苯基)和-NHS(O) 2(C 1-C 6卤代烷基)，其中所述的烷基、环烷基、苯基、芳基、杂环基和杂芳基中的每一个任选被一个或多个选自以下的取代基进一步取代：卤素、-OH、-NH 2、环烷基、3-8元杂环基、C 1-C 4烷基、C 1-C 4卤代烷基-、-OC 1-C 4烷基、-C 1-C 4烷基-OH、-C 1-C 4烷基-O-C 1-C 4烷基、-OC 1-C 4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC 1-C 6烷基、-CON(C 1-C 6烷基) 2、-CONH(C 1-C 6烷基)、-CONH 2、-NHC(O)(C 1-C 6烷基)、-NH(C 1-C 6烷基)C(O)(C 1-C 6烷基)、-SO 2(C 1-C 6烷基)、-SO 2(苯基)、-SO 2(C 1-C 6卤代烷基)、-SO 2NH 2、-SO 2NH(C 1-C 6烷基)、-SO 2NH(苯基)、-NHSO 2(C 1-C 6烷基)、-NHSO 2(苯基)和-NHSO 2(C 1-C 6卤代烷基)。当一个原子或基团被多个取代基取代时，所述取代基可以相同或不同。本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团“是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“不存在”是指被上文所定义的基团的两侧直接通过化学键相连。例如，“A-B-C中B是不存在”表示“A-C”。。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本申请将涵盖各种立体异构体及其混合物。
当本申请的化合物中含有烯双键时，除非另有说明，否则本申请的化合物 旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本申请的化合物的所有互变异构形式也将包含在本申请的范围内。
本申请的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本申请旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本申请的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
在本申请中，
Figure PCTCN2021125246-appb-000055
代表C1-C6烷基取代的酯基，例如可以是
Figure PCTCN2021125246-appb-000056
在本申请中，(C1-C4烷基) 2氨基，代表2个C1-C4烷基取代的胺，例如可以是
Figure PCTCN2021125246-appb-000057
等。
在本申请中，“每一个R'”、“每一个R””、“每一个R”'”、“每一个R”””指的是出现在式I所示的噻吩并嘧啶类化合物中的“每一个R'”、“每一个R””、“每一个R”'”、“每一个R”””。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and  Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
相对于现有技术，本申请具有以下有益效果：
(1)本申请提供了一种如式I所示的化合物或其药学上可接受的盐
(2)本申请提供了一种如式I所示的化合物用于制备预防和治疗与MLL1、MLL2、MLL融合蛋白、和/或menin蛋白活性有关的疾病的药物组合物。
在阅读并理解了详细描述后，可以明白其他方面。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
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。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
各实施例中， 1H NMR由BRUKER AVANCE NEO 400MHz型核磁共振仪记录，化学位移以δ(ppm)表示；液质联用(LCMS)由Shimadzu LC-20AD,SIL-20A，CTO-20AC，SPD-M20A，CBM-20A，LCMS-2020型质谱仪记录；制备HPLC分离使用Gilson-281型号液相色谱仪。
中间体的制备
1、中间体A的制备
Figure PCTCN2021125246-appb-000058
中间体A合成路线如下所示：
Figure PCTCN2021125246-appb-000059
(1)向化合物A-1(5.0g,28.9mmol)的二氯甲烷(25.0mL)溶液中加入三乙胺(5.84g,57.7mmol)和化合物A-2(7.27g,63.5mmol),反应液在0℃下搅拌1小时。加入饱和碳酸氢钠水溶液(40.0mL)淬灭反应,用二氯甲烷(40.0mL×3)萃取,合并有机相用饱和食盐水(30.0mL×1)洗涤,无水硫酸钠干燥,过滤, 有机相减压浓缩得到化合物A-3；
1H NMR(400MHz,CDCl 3)δ5.24-5.15(m,1H),4.31-4.23(m,2H),4.13-4.06(m,2H),3.09-3.04(m,3H),1.46-1.42(m,9H)。
(2)向化合物A-3(7.2g,28.6mmol)的N,N-二甲基甲酰胺(70.0mL)溶液中加入化合物A-4(6.54g,57.3mmol),反应液在85℃下搅拌12小时。加入水(50.0mL)淬灭反应,用乙酸乙酯(50.0mL×3)萃取,合并有机相用饱和食盐水(40.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯＝100:1到1:1)分离得到化合物A-5；
1H NMR(400MHz,MeOD)δ4.41-4.32(m,2H),4.21-4.12(m,1H),3.83-3.72(m,2H),2.34-2.31(m,3H),1.45-1.42(m,9H)。
(3)将化合物A-5(5.0g,28.9mmol)溶于乙酸(20.0mL)和水(2.0mL),加入N-氯代丁二酰亚胺(865.9mg,6.48mmol),反应液在25℃下搅拌0.5小时。加入水(10.0mL)淬灭反应,用二氯甲烷(10.0mL×2)萃取,合并有机相用饱和食盐水(10.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩得到中间体A；
1H NMR(400MHz,CDCl 3)δ4.56-4.47(m,1H),4.42-4.30(m,4H),1.48-1.44(m,9H)。
2、中间体B的制备
Figure PCTCN2021125246-appb-000060
中间体B的合成路线如下所示：
Figure PCTCN2021125246-appb-000061
(1)在30分钟内向草酰氯(5.45g,42.9mmol)的二氯甲烷(50.0mL)溶液中缓慢滴加二甲亚砜(6.10g,78.1mmol),反应液保持在-78℃。随后加入化合物B-1(5.0g,39.0mmol)的二氯甲烷溶液(50.0mL),反应液在-78℃下搅拌1小时。加入三乙胺(19.8g,195mmol)继续在-78℃下搅拌0.5小时，升温至0℃反应1小时。加入水(40.0mL)淬灭反应,用二氯甲烷(40.0mL×2)萃取,合并有机相用饱和食盐水(40.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩得到化合物B-2；
1H NMR(400MHz,CDCl 3)δ9.72(s,1H),2.67-2.71(m,2H),2.29-2.41(m,2H)。
(2)向化合物B-2(4.9g,38.8mmol)的N,N-二甲基甲酰胺(80.0mL)溶液中加入化合物B-3(3.27g,38.9mmol),三乙胺(7.87g,77.7mmol),硫(1.31g,40.8mmol),反应液在25℃下搅拌12小时。加入水(50.0mL)淬灭反应,用乙酸乙酯(50.0mL×2)萃取,合并有机相用饱和食盐水(50.0mL×4)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到化合物B-4；
MS-ESI[M+H] +,计算值225,实测值225。
(3)向化合物B-4(1.0g,4.46mmol)的乙酸(4.0mL)溶液中加入化合物 B-5(2.67g,18.0mmol),反应液在120℃下搅拌12小时。加入水(20.0mL)淬灭反应,用乙酸乙酯(20.0mL×3)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到化合物B-6。
MS-ESI[M+H] +,计算值235,实测值235。
(4)将化合物B-6(800mg,3.42mmol)溶于三氯氧磷(3.0mL)中,反应液在115℃下搅拌3小时。反应液直接减压浓缩除去三氯氧磷,加入冰和饱和碳酸氢钠溶液调节pH值至大于7,用乙酸乙酯(20.0mL×2)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到中间体B；
1H NMR(400MHz,CDCl 3)δ8.85(s,1H),7.35(s,1H),3.69-3.78(m,2H)。
3、中间体C的制备
Figure PCTCN2021125246-appb-000062
中间体C合成路线如下所示:
Figure PCTCN2021125246-appb-000063
(1)将化合物C-1(5.0g,18.6mmol)，化合物C-2(3.74g,27.9mmol)，碳酸铯(12.1g,37.2mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.36g,1.86mmol)溶于二氧六环(40.0mL)和水(40.0mL)。反应液在氮气保护下110℃搅拌1小时。加入水溶液(100mL)，用二氯甲烷(100mL×2)萃取，合并有机相用饱和食盐水(100mL×1)洗涤，无水硫酸钠干燥，过滤，有机相减压浓缩， 粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到化合物C-3。
MS-ESI[M+H] +，计算值261，实测值261。
1H NMR(400MHz,CDCl 3)δ7.36-7.42(m,1H),7.22-7.26(m,1H),6.77-6.86(m,1H),6.11-6.19(m,1H),5.44-5.51(m,1H),4.55-4.63(m,2H),3.71-3.79(m,2H),2.97-3.05(m,2H),1.50-1.51(m,9H)。
(2)将化合物C-3(1.6g，6.15mmol)，高碘酸钠(3.94g，18.4mmol)和锇酸钾(452mg，1.23mmol)溶于四氢呋喃(15.0mL)和水(24.0mL)。反应液在氮气保护加25℃下搅拌1小时。加入水(100mL)淬灭反应，用二氯甲烷(100mL×2)萃取，合并有机相用饱和食盐水(100mL×1)洗涤，无水硫酸钠干燥，过滤，有机相减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到化合物C。
1H NMR(400MHz,CDCl 3)δ10.02-10.05(m,1H),7.80-7.84(m,1H),7.58-7.63(m,1H),4.68-4.72(m,2H),3.79-3.84(m,2H),3.09-3.15(m,2H),1.51(s,9H)。
4、中间体D的制备
Figure PCTCN2021125246-appb-000064
中间体D合成路线如下所示:
Figure PCTCN2021125246-appb-000065
(1)向化合物D-1(390mg,1.40mmol)的二氯甲烷(15mL)溶液中加入1-羟基苯并***(284mg，2.1mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐 (403mg，2.10mmol)，二异丙基乙基胺(543mg，4.20mmol)和化合物D-2(205mg，2.10mmol)，反应液在25℃下搅拌16小时。加入饱和碳酸氢钠水溶液(20.0mL)，用二氯甲烷(15.0mL×3)萃取，有机相用饱和食盐水(15.0mL×1)洗涤，无水硫酸钠干燥，过滤，有机相减压浓缩，粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到化合物D-3。
MS-ESI[M+H] +，计算值322，实测值322。
1H NMR(400MHz,MeOD)δ8.64(s,1H)，7.91(s，1H)，4.68(s,2H),3.70-3.73(m,2H),3.60(s,3H),3.38(s,3H),2.91-2.94(t,J＝5.6Hz,2H),1.50(s,9H)。
(2)-78℃下向化合物D-3(400mg,1.24mmol)的四氢呋喃(15.0mL)溶液中加入二异丁基氢化铝(1.5mol/L,2.49mL,3.74mmol),反应液在氮气保护下0℃搅拌0.5小时。加入盐酸(1mol/L)淬灭反应,调节pH值至7,随后加入水(20.0mL),用乙酸乙酯(20.0mL×2)萃取,合并有机相用饱和食盐水(20.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到中间体D。
1H NMR(400MHz,MeOD)δ10.05(s,1H),8.85(s,1H),8.09(s,1H),4.72(s,2H),3.71-3.74(t,J＝5.6Hz,2H),2.95-2.98(t,J＝6.0Hz,2H)1.50(s,9H)。
5、中间体E的制备
Figure PCTCN2021125246-appb-000066
中间体E合成路线如下所示:
Figure PCTCN2021125246-appb-000067
-78℃氮气保护下向化合物E-1(1.0g,3.14mmol)的四氢呋喃(15.0mL)溶液中加入N,N-二甲基甲酰胺(344mg,4.71mmol),随后滴加正丁基锂(2.5mol/L,1.89mL,4.73mmol),反应液在氮气保护下-78℃搅拌2小时。0℃下加入饱和氯化铵水溶液(30.0mL)淬灭反应,随后加入水(40.0mL),用乙酸乙酯(40.0mL×2)萃取,合并有机相用饱和食盐水(50.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到中间体E。
1H NMR(400MHz,CDCl 3)δ9.82-9.85(m,1H),7.46-7.50(m,1H),4.52-4.57(m,2H),3.75(br t,J＝5.3Hz,2H),2.90-2.96(m,2H),1.50-1.51(m,9H)。
实施例1
本实施例提供一种式I所示的化合物1,所述化合物1的结构式如下所示：
Figure PCTCN2021125246-appb-000068
化合物1合成路线如下所示：
Figure PCTCN2021125246-appb-000069
(1)向中间体B(400mg,1.58mmol)和化合物1-1(394mg,1.74mmol)的N,N-二甲基甲酰胺(8.0mL)溶液中加入碳酸钾(437mg,3.16mmol),反应液在50℃下搅拌3小时。加入乙酸乙酯(20.0mL),用饱和食盐水(20.0mL×5)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝10:1到1:1)分离得到化合物1-2；
1H NMR(400MHz,CDCl 3)δ8.43(s,1H),7.34(s,1H),3.95(br d,J＝6.4Hz,2H),3.76(q,J＝10.8Hz,2H),3.63(q,J＝10.0Hz,2H),3.55-3.45(m,2H),3.44-3.32(m,2H),2.15-2.02(m,2H),1.96(dt,J＝6.4,12.4Hz,2H),1.46(br s,9H)。
(2)向化合物1-2(576mg,1.30mmol)的二氯甲烷(5.0mL)溶液中加入氯化氢的二氧六环溶液(4mol/L,2.0mL),反应液在20℃下搅拌2小时。反应液减压浓缩得到化合物1-3的盐酸盐；
1H NMR(400MHz,DMSO-d 6)δ9.66(br s,2H),8.59(s,1H),7.90(br s,1H),3.94(br s,6H),3.38-3.14(m,4H),2.25-1.93(m,4H)。
(3)向化合物1-3的盐酸盐(370mg,0.98mmol)的甲醇(15.0mL)溶液中加入三乙胺调节pH值到7。加入化合物1-4(255mg,0.98mmol),反应液在25℃下搅拌15分钟。随后加入氰基硼氢化钠(245mg,3.91mmol),25℃下继续搅拌12小时。加入水(20.0mL)淬灭反应,用乙酸乙酯(10.0mL×1)萃取,有机相用饱和食盐水(10.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝100:1到1:1)分离得到化合物1-5；
MS-ESI[M+H] +,计算值588,实测值588。
(4)向化合物1-5(347mg,0.59mmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物1-6的三氟乙酸盐。粗品直接用于下一步反应；
(5)向化合物1-6的三氟乙酸盐(340mg,565μmol)的N,N-二甲基甲酰胺(8.0mL)溶液中加入三乙胺调节pH值到8,随后加入中间体A(289mg,1.13mmol),反应液在25℃下搅拌0.5小时。加入水(15.0mL)淬灭反应,用乙酸乙酯(10.0mL×3)萃取,合并有机相用饱和食盐水(10.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物1-7；
MS-ESI[M+H] +,计算值707实测值707。
(6)向化合物1-7(100mg,0.14mmol)的二氯甲烷(4.0mL)溶液中加入三氟乙酸(1.5mL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物1-8的三氟乙酸盐。粗品直接用于下一步反应。
(6)向化合物1-8的三氟乙酸盐(100mg,138μmol)的N,N-二甲基甲酰胺(5.0mL)溶液中加入化合物1-9(34.5mg,208μmol)和三乙胺调节pH值到8,随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(105mg,277μmol),反应液在25℃下搅拌1小时。加入水(10.0mL)淬灭反应,用二氯甲烷(10.0mL×1)萃取,合并有机相用饱和食盐水(10.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Kromasil C18,150mm×30mm 5μm,A:水(0.2％三氟乙酸)；B:乙腈,5％-65％:20分钟；100％:5分钟)分离得到化合物1的三氟乙酸盐。
MS-ESI[M+H] +,计算值718,实测值718。
1H NMR(400MHz,MeOD)δ8.44-8.37(m,1H),7.72-7.62(m,1H),7.42-7.28(m,3H),6.79-6.69(m,1H),6.52-6.44(m,1H),4.85-4.81(m,1H),4.66-4.54(m,4H),4.45-4.35(m,3H),4.28-4.22(m,2H),4.08-3.85(m,8H),3.70-3.62(m,3H),3.52-3.36(m,2H),3.02-2.96(m,2H),2.92-2.87(m,6H),2.38-2.09(m,4H)。
实施例2
本实施例提供一种式I所示的化合物2,所述化合物2的结构式如下所示：
Figure PCTCN2021125246-appb-000070
化合物2合成路线如下所示：
Figure PCTCN2021125246-appb-000071
向实施例1中中间体1-8的三氟乙酸盐(100mg,139μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺调节pH值到8。随后加入化合物2-1(18.8mg,208μmol,17.0μL),反应液在-78℃下搅拌0.5小时。加入水(10.0mL)淬灭反应,用二氯甲烷(10.0mL×3)萃取,合并有机相用饱和食盐水(10.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Kromasil C18,150mm×30mm 5μm,A:水(0.2％三氟乙酸)；B:乙腈,5％-65％:20分钟；100％:5分钟)分离得到化合物2的三氟乙酸盐。
MS-ESI[M+H] +,计算值661,实测值661。
1H NMR(400MHz,MeOD)δ8.49(s,1H),7.74(s,1H),7.38(d,J＝7.8Hz,1H),7.34-7.26(m,2H),6.35-6.18(m,2H),5.76(d,J＝9.6Hz,1H),4.61-4.48(m,4H),4.44-4.31(m,3H),4.20(d,J＝6.8Hz,2H),4.13-3.93(m,6H),3.67(t,J＝6.0Hz,4H),3.48(s,1H),3.12-2.89(m,3H),2.30(s,4H)。
实施例3
本实施例提供一种式I所示的化合物3,所述化合物3的结构式如下所示：
Figure PCTCN2021125246-appb-000072
化合物3合成路线如下所示：
Figure PCTCN2021125246-appb-000073
(1)向中间体B(400mg,1.58mmol)和化合物3-1(358mg,1.58mmol)的N,N-二甲基甲酰胺(10.0mL)溶液中加入碳酸钾(656mg,4.75mmol),反应液在50℃氮气保护下搅拌12小时。反应液加入水(50.0mL),用乙酸乙酯(20.0mL ×2)萃取,用饱和食盐水(20.0mL)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:1到0:1)分离得到化合物3-2；
MS-ESI[M+H] +,计算值443,实测值443。
1H NMR(400MHz,CDCl 3)δ8.44(s,1H),7.13(s,1H),4.13(br s,4H),3.64(q,J＝10.0Hz,2H),3.45(br s,4H),1.84(br t,J＝5.6Hz,4H),1.48(s,9H)。
(2)向化合物3-2(270mg,1.30mmol)的乙酸乙酯(5.0mL)溶液中加入氯化氢的二氧六环溶液(4mol/L,5.0mL),反应液在25℃下搅拌3小时。反应液减压浓缩得到化合物3-3的盐酸盐；
MS-ESI[M+H] +,计算值343,实测值343。
(3)向化合物3-3的盐酸盐(200mg,584μmol)的甲醇(10.0mL)溶液中加入三乙胺(177mg,1.75mmol),化合物3-4(153mg,584μmol)和氰基硼氢化钠(110mg,1.75mmol),25℃下搅拌12小时。加入氯化铵水溶液(50.0mL)淬灭反应,用乙酸乙酯(50.0mL×1)萃取,有机相用饱和食盐水(50.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物3-5；
MS-ESI[M+H] +,计算值588,实测值588。
(4)向化合物3-5(150mg,584μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(3.0mL),反应液在25℃下搅拌30分钟。反应液减压浓缩得到化合物3-6的三氟乙酸盐。粗品直接用于下一步反应。
(5)向化合物3-6的三氟乙酸盐(130mg,267μmol)的二氯甲烷(3.0mL)溶液中加入三乙胺(81mg,800μmol)和中间体A(82mg,320μmol),反应液在25℃下搅拌1小时。加入水(10.0mL)淬灭反应,用乙酸乙酯(20.0mL×1)萃 取,合并有机相用饱和食盐水(10.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到93:7)分离得到化合物3-7。
MS-ESI[M+H] +,计算值707,实测值707。
1H NMR(400MHz,CDCl 3)δ8.43(s,1H),7.08-7.18(m,3H),7.01-7.07(m,1H),4.48-4.57(m,2H),4.20-4.30(m,2H),4.08-4.12(m,4H),3.95(s,1H),3.62-3.69(m,4H),3.43-3.51(m,2H),2.89-2.98(m,2H),2.33-2.48(m,2H),1.82-1.98(m,4H),1.41-1.46(m,9H),1.28-1.35(m,4H)。
(6)向化合物3-7(143mg,202μmol)的二氯甲烷(8.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌30分钟。反应液减压浓缩得到化合物3-8的三氟乙酸盐。粗品直接用于下一步反应；
MS-ESI[M+H] +,计算值607,实测值607。
(7)向中间体3-8的三氟乙酸盐(60mg,99μmol)的N,N-二甲基甲酰胺(5.0mL)溶液中加入化合物3-9(16mg,99μmol),二异丙基乙基胺(13mg,99μmol),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(38mg,99μmol),反应液在25℃下搅拌1小时。加入饱和食盐水(50.0mL)淬灭反应,用二氯甲烷(50.0mL×1)萃取,合并有机相用饱和食盐水(50.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(ACQUITY C18,4.6mm×30mm 1.7μm,A:水(0.01％三氟乙酸)；B:乙腈(0.01％三氟乙酸),5％-95％:1.5分钟；95％:1分钟；5％:0.01分钟)分离得到化合物3的三氟乙酸盐。
MS-ESI[M+H] +,计算值718,实测值718。
1H NMR(400MHz,MeOD)δ8.30-8.47(m,1H),7.24-7.52(m,4H),6.62-6.89(m,1H),6.50(d,J＝15.2Hz,1H),4.55-4.67(m,4H),4.11-4.49(m,9H),3.84-3.99 (m,4H),3.67(br t,J＝6.0Hz,2H),3.45-3.55(m,2H),3.07-3.18(m,2H),3.01(br t,J＝5.2Hz,2H),2.85-2.94(m,1H),2.90(s,5H),2.32(br d,J＝14.0Hz,2H),2.07(br s,2H)。
实施例4
本实施例提供一种式I所示的化合物4,所述化合物4的结构式如下所示：
Figure PCTCN2021125246-appb-000074
化合物4合成路线如下所示：
Figure PCTCN2021125246-appb-000075
向实施例3中中间体3-8的三氟乙酸盐(60mg,99μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(10.0mg,99μmol)。随后加入化合物4-1(9mg,99μmol,8.1μL),反应液在-78℃下搅拌20分钟。加入饱和食盐水(10.0mL)淬灭反应,用二氯甲烷(20.0mL×1)萃取,合并有机相用饱和食盐水(10.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(ACQUITY C18,4.6mm×30mm 1.7μm,A:水(0.01％三氟乙酸)；B:乙腈(0.01％三氟乙酸),5％-95％:1.5分钟；95％:1分钟；5％:0.01分钟)分离得到化合物4的三氟乙酸盐；
MS-ESI[M+H] +,计算值661,实测值661。
1H NMR(400MHz,MeOD)δ8.42(s,1H),7.46(s,1H),7.29-7.38(m,3H),6.18-6.44(m,2H),5.72-5.83(m,1H),4.49-4.72(m,5H),4.14-4.41(m,8H),3.93(q,J＝10.4Hz,2H),3.64-3.71(m,2H),3.51(br d,J＝11.2Hz,2H),3.07-3.18(m,2H),3.00(br t,J＝5.6Hz,2H),2.33(br d,J＝14.4Hz,2H),2.03-2.14(m,2H)。
实施例5
本实施例提供一种式I所示的化合物5,所述化合物5的结构式如下所示：
Figure PCTCN2021125246-appb-000076
化合物5合成路线如下所示：
Figure PCTCN2021125246-appb-000077
(1)向实施例1中化合物1-3的盐酸盐(200mg,438μmol)的甲醇(5.0mL)溶液中加入三乙胺(44.3mg,438μmol),化合物5-1(115mg,438μmol)和氰基硼氢化钠(82.6mg,1.31mmol),25℃下搅拌2小时。加入饱和食盐水(50.0mL)淬灭反应,用二氯甲烷(50.0mL×1)萃取,有机相用饱和食盐水(50.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝10:1到0:1)分离得到化合物5-2；
MS-ESI[M+H] +,计算值589,实测值589。
(2)向化合物5-2(72mg,122μmol)的二氯甲烷(4.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌30分钟。反应液减压浓缩得到化合物5-3的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值489,实测值489。
(3)向化合物5-3的三氟乙酸盐(70mg,116μmol)的N,N-二甲基甲酰胺 (8.0mL)溶液中加入三乙胺(35mg,348μmol),随后加入中间体A(30mg,116μmol),反应液在25℃下搅拌5分钟。加入饱和食盐水(20.0mL)淬灭反应,用二氯甲烷(20.0mL×1)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝100:1到10:1)分离得到化合物5-4。
MS-ESI[M+H] +,计算值708实测值708。
(4)向化合物5-4(53mg,74.9μmol)的二氯甲烷(4.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌20分钟。反应液过滤,减压浓缩得到化合物5-5的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值608实测值608。
(5)向化合物5-6(50mg,69.3μmol)的二氯甲烷(5.0mL)溶液中三乙胺(7.0mg,69.3μmol),化合物5-5的三氟乙酸盐(9.0mg,69.3μmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(26.3mg,69.3μmol),反应液在25℃下搅拌0.5小时。加入饱和食盐水(20.0mL)淬灭反应,用二氯甲烷(20.0mL×1)萃取,有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Phenomenexluna C18,100mm×40mm 3μm,A:水(0.225％甲酸)；B:乙腈,0％-35％:10分钟)分离得到化合物5的甲酸盐。
MS-ESI[M+H] +,计算值719,实测值719。
1H NMR(400MHz,MeOD)δ8.40-8.33(m,1H),8.31-8.22(m,1H),7.70-7.58(m,2H),6.87-6.70(m,1H),6.33-6.20(m,1H),4.61-4.51(m,4H),4.44-4.37(m,1H),4.34-4.23(m,2H),3.95-3.79(m,5H),3.74(br s,5H),3.38-3.33(m,2H),3.01-2.94(m,2H),2.85-2.79(m,1H),2.76-2.67(m,2H),2.62-2.54(m,1H),2.47-2.37(m,6H), 2.16-2.02(m,2H),1.99-1.90(m,2H)。
实施例6
本实施例提供一种式I所示的化合物6,所述化合物6的结构式如下所示：
Figure PCTCN2021125246-appb-000078
化合物6合成路线如下所示：
Figure PCTCN2021125246-appb-000079
(1)向实施例3中化合物3-3的三氟乙酸盐(360mg,789μmol)的甲醇(15.0mL)溶液中加入三乙胺(160mg,1.58mmol),化合物6-1(247mg,947μmol),25℃下搅拌15分钟,加入氰基硼氢化钠(198mg,3.16mmol),25℃下搅 拌1小时。加入饱和食盐水(50.0mL)淬灭反应,用二氯甲烷(50.0mL×1)萃取,有机相用饱和食盐水(25.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝20:1到0:1)分离得到化合物6-2。
MS-ESI[M+H] +,计算值588,实测值588。
1H NMR(400MHz,CDCl 3)δ8.42(s,1H),7.36(s,1H),7.13-7.18(m,1H),7.06-7.12(m,2H),4.56(s,2H),3.78-3.93(m,3H),3.72-3.77(m,1H),3.59-3.69(m,6H),2.76(br s,4H),2.55-2.72(m,2H),2.06-2.17(m,2H),1.90-2.01(m,2H),1.45-1.50(m,9H)。
(2)向化合物6-2(220mg,220μmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌15分钟。反应液减压浓缩得到化合物6-3的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值488,实测值488。
(3)向化合物6-3的三氟乙酸盐(220mg,366μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺调节pH到8。加入中间体A(140mg,549μmol),反应液在25℃下搅拌0.5小时。加入水(20.0mL)淬灭反应,用二氯甲烷(20.0mL×3)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物6-4。
MS-ESI[M+H] +,计算值707,实测值707。
(4)向化合物6-4(125mg,177μmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物6-5的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值607,实测值607。
(5)向中间体6-5的三氟乙酸盐(60mg,83.2μmol)的二氯甲烷(3.0mL)溶液中加入三乙胺调节pH至7,加入化合物6-6(16mg,99μmol),反应液在-78℃下搅拌15分钟。加入水(10.0mL)淬灭反应,用二氯甲烷(20.0mL×2)萃取,合并有机相用饱和食盐水(20.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Phenomenexluna C18,100mm×40mm 3μm,A:水(0.225％甲酸)；B:乙腈,0％-50％:10分钟)分离得到化合物6的甲酸盐。
MS-ESI[M+H] +,计算值661,实测值661。
1H NMR(400MHz,MeOD)δ8.32-8.26(m,1H),7.63-7.58(m,1H),7.33-7.24(m,2H),7.22-7.14(m,1H),6.36-6.20(m,2H),5.80-5.73(m,1H),4.58-4.50(m,4H),4.37-4.29(m,1H),4.23-4.22(m,2H),4.11-4.00(m,2H),4.00-3.74(m,6H),3.70-3.60(m,2H),3.24-3.08(m,3H),3.05-2.91(m,3H),2.24-1.99(m,4H)。
实施例7
本实施例提供一种式I所示的化合物7,所述化合物7的结构式如下所示：
Figure PCTCN2021125246-appb-000080
化合物7合成路线如下所示：
Figure PCTCN2021125246-appb-000081
向实施例6中化合物6-5的三氟乙酸盐(60mg,83.3μmol)的二氯甲烷(3.0mL)溶液中三乙胺(8.4mg,83.3μmol),化合物7-1(27.6mg,167μmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(63.3mg,167μmol),反应液在25℃下搅拌0.5小时。加入水(20.0mL)淬灭反应,用二氯甲烷(20.0mL×3)萃取,有机相用饱和食盐水(20.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(1_Welch Xtimate,70mm×40mm 3μm,A:水(0.225％甲酸)；B:乙腈,10％-40％:10分钟)分离得到化合物7的甲酸盐。
MS-ESI[M+H] +,计算值719,实测值719。
1H NMR(400MHz,MeOD)δ8.32-8.25(m,1H),7.63-7.56(m,1H),7.36-7.25(m,2H),7.23-7.16(m,1H),6.82-6.71(m,1H),6.42-6.31(m,1H),4.62-4.50(m,4H),4.40-4.32(m,1H),4.28-4.21(m,2H),4.18-4.08(m,2H),3.99-3.78(m,6H),3.73-3.59(m,4H),3.28-3.05(m,4H),3.00-2.91(m,2H),2.73-2.60(m,6H),2.26-2.04(m,4H)。
实施例8
本实施例提供一种式I所示的化合物8,所述化合物8的结构式如下所示：
Figure PCTCN2021125246-appb-000082
化合物8合成路线如下所示：
Figure PCTCN2021125246-appb-000083
(1)向中间体B(200mg,792μmol)和化合物8-1(179mg,792μmol)的N,N-二甲基甲酰胺(8.0mL)溶液中加入碳酸钾(219mg,1.58mmol),反应液在 80℃下搅拌2小时。加入饱和氯化铵水溶液(20.0mL),用二氯甲烷(50.0mL)萃取,随后有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝50:1到1:1)分离得到化合物8-2。
MS-ESI[M+H] +,计算值443,实测值443。
(2)向化合物8-2(218mg,493μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌1小时。反应液减压浓缩得到化合物8-3的三氟乙酸盐。
MS-ESI[M+H] +,计算值343,实测值343。
(3)向化合物8-3的三氟乙酸盐(224mg,491μmol)的甲醇(10.0mL)溶液中加入三乙胺(149mg,1.47mmol)。随后加入化合物8-4(129mg,494μmol)和氰基硼氢化钠(308mg,4.90mmol),反应液在25℃下搅拌2小时。加入乙酸乙酯(20.0mL),有机相用水(20.0mL)饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物8-5。
MS-ESI[M+H] +,计算值588,实测值588。
1H NMR(400MHz,MeOD)δ8.35(s,1H),7.51(s,1H),7.17-7.24(m,3H),4.61(s,2H),4.56(br s,2H),4.00(br s,2H),3.85-3.91(m,6H),3.63(br d,J＝5.2Hz,2H),3.59(br s,2H),2.86(t,J＝5.6Hz,2H),1.95-1.99(m,4H),1.49(s,9H)。
(4)向化合物8-5(94.3mg,160μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌1小时。反应液过滤,减压浓缩得到化合物8-6的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值488,实测值488。
(5)向化合物8-6的三氟乙酸盐(96.5mg,160μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(81.1mg,801μmol),随后加入中间体A(61.7mg,241μmol),反应液在25℃下搅拌2小时。加入水(15.0mL)淬灭反应,加入二氯甲烷(20.0mL)萃取,有机相用水(20.0mL)饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝10:1)分离得到化合物8-7。
MS-ESI[M+H] +,计算值707实测值707。
1H NMR(400MHz,MeOD)δ8.33(s,1H),7.51(s,1H),7.15(dt,J＝16.0,8.0Hz,3H),4.49(s,2H),4.19-4.33(m,1H),4.09-4.16(m,4H),3.90-3.94(m,1H),3.85-3.89(m,5H),3.70(s,2H),3.62(t,J＝6.0Hz,2H),3.24(s,4H),2.94(t,J＝5.6Hz,2H),1.89-1.93(m,4H),1.43(s,9H)。
(6)向化合物8-7(56.0mg,79.2μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌1小时。反应液过滤,减压浓缩得到化合物8-8的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值607实测值607。
(7)向化合物8-8的三氟乙酸盐(57.1mg,79.2μmol)的二氯甲烷(3.0mL)溶液中加入化合物8-9(10.7mg,118μmol)和三乙胺(40.0mg,395μmol),反应液在-78℃下搅拌1小时。加入二氯甲烷(20.0mL),有机相用水(20.0mL)和饱和食盐水(20.0mL×2)依次洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18,100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,15％-45％:10分钟)分离得到化合物8的甲酸盐。
MS-ESI[M+H] +,计算值661,实测值661。
1H NMR(400MHz,MeOD)δ8.35(s,1H),7.50(s,1H),7.24-7.30(m,2H), 7.18-7.22(m,1H),6.21-6.36(m,2H),5.74-5.80(m,1H),4.49-4.56(m,4H),4.31-4.37(m,1H),4.24(d,J＝7.2Hz,2H),4.09(s,2H),3.85-3.93(m,6H),3.70(s,4H),3.65(td,J＝6.0,2.4Hz,2H),2.98(br t,J＝6.0Hz,2H),1.94-2.02(m,4H)。
实施例9
本实施例提供一种式I所示的化合物9,所述化合物9的结构式如下所示：
Figure PCTCN2021125246-appb-000084
化合物9合成路线如下所示：
Figure PCTCN2021125246-appb-000085
(1)向中间体B(200mg,792μmol)和化合物9-1(188mg,950μmol)的N,N-二甲基甲酰胺(10.0mL)溶液中加入碳酸钾(219mg,1.58mmol),反应液在25℃下搅拌2小时。加入饱和食盐水(50.0mL),用二氯甲烷(50.0mL)萃取,随后有机相用饱和食盐水(50.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝50:1到1:1)分离得到化合物9-2。
MS-ESI[M+H] +,计算值415,实测值415。
(2)向化合物9-2(274mg,661μmol)的二氯甲烷(4.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌0.5小时。反应液减压浓缩得到化合物9-3的三氟乙酸盐。
MS-ESI[M+H] +,计算值315,实测值315。
(3)向化合物9-3的三氟乙酸盐(280mg,891μmol)的甲醇(10.0mL)溶液中加入三乙胺(90.1mg,891μmol)。随后加入化合物9-4(349mg,1.34mmol)和氰基硼氢化钠(55.9mg,891μmol),反应液在25℃下搅拌1小时。加入乙酸乙酯(40.0mL),有机相用水(20.0mL)和饱和食盐水(20.0mL×2)依次洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝100:1到10:1)分离得到化合物9-5。
MS-ESI[M+H] +,计算值560,实测值560。
1H NMR(400MHz,MeOD)δ8.43-8.47(m,1H),7.08-7.13(m,4H),4.56-4.60(m,2H),4.42-4.54(m,4H),3.60-3.69(m,6H),3.46-3.57(m,4H),2.82-2.87(m,2H),1.51(s,9H)。
(4)向化合物9-5(100mg,179μmol)的二氯甲烷(10.0mL)溶液中加入三氟乙酸(2.5mL),反应液在25℃下搅拌0.5小时。反应液过滤,减压浓缩得到化合物9-6的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值460,实测值460。
(5)向化合物9-6的三氟乙酸盐(100mg,174μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(70.6mg,697μmol),随后加入中间体A(66.9mg,262μmol),反应液在25℃下搅拌5分钟。加入水(30.0mL)淬灭反应,加入二氯甲烷(40.0mL)萃取,有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝100:1到10:1)分离 得到化合物9-7。
MS-ESI[M+H] +,计算值679实测值679。
(6)向化合物9-7(77.0mg,113μmol)的二氯甲烷(4.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌1小时。反应液过滤,减压浓缩得到化合物9-8的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值579实测值579。
(7)向化合物9-8的三氟乙酸盐(75.0mg,108μmol)的二氯甲烷(5.0mL)溶液中加入化合物9-9(9.8mg,108μmol)和三乙胺(32.9mg,325μmol),反应液在-78℃下搅拌5分钟。加入二氯甲烷(50.0mL),有机相用饱和食盐水(50.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18,100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,10％-40％:10分钟)分离得到化合物9的甲酸盐。
MS-ESI[M+H] +,计算值633,实测值633。
1H NMR(400MHz,MeOD)δ8.24-8.31(m,1H),7.32-7.42(m,1H),7.15-7.26(m,3H),6.19-6.38(m,2H),5.71-5.81(m,1H),4.49-4.64(m,8H),4.29-4.36(m,1H),4.20-4.27(m,2H),3.83-3.97(m,8H),3.61-3.69(m,2H),2.92-3.01(m,2H)。
实施例10
本实施例提供一种式I所示的化合物10,所述化合物10的结构式如下所示：
Figure PCTCN2021125246-appb-000086
化合物10合成路线如下所示：
Figure PCTCN2021125246-appb-000087
(1)向实施例1中化合物1-3的三氟乙酸盐(500mg,1.10mmol)的甲醇(15.0mL)溶液中加入三乙胺(221.7mg,2.19mmol)。随后加入化合物10-1(343mg,1.31mmol)和氰基硼氢化钠(275mg,4.38mmol),反应液在25℃下搅拌1小时。加入水(20.0mL),用二氯甲烷(20.0mL×2)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物10-2。
MS-ESI[M+H] +,计算值588,实测值588。
(2)向化合物10-2(330mg,561μmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物10-3的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值488实测值488。
(3)向化合物10-2的三氟乙酸盐(330mg,548μmol)的二氯甲烷(5.0mL) 溶液中加入三乙胺(111mg,1.1mmol,153μL),随后加入中间体A(210mg,823μmol),反应液在25℃下搅拌10分钟。加入水(20.0mL)淬灭反应,用二氯甲烷(20.0mL×2)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到9:1)分离得到化合物10-4。
MS-ESI[M+H] +,计算值707实测值707。
(4)向化合物10-4(120mg,170μmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌10分钟。反应液过滤,减压浓缩得到化合物10-5的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值607实测值607。
(5)向化合物10-5的三氟乙酸盐(60.0mg,83.3μmol)的二氯甲烷(3.0mL)溶液中加入三乙胺(8.42mg,83.3μmol,11.6μL)。随后加入化合物10-6(11.3mg,125μmol,10.2μL),反应液在-78℃下搅拌5分钟。加入水(20.0mL)淬灭反应,用二氯甲烷(20.0mL×2)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Welch Xtimate,75mm×40mm 3μm,A:水(0.225％甲酸)；B:乙腈,10％-40％:10分钟)分离得到化合物10的甲酸盐。
MS-ESI[M+H] +,计算值661实测值661。
1H NMR(400MHz,MeOD)δ8.25-8.33(m,1H),7.36-7.45(m,1H),7.22-7.30(m,2H),7.16-7.21(m,1H),6.21-6.37(m,2H),5.73-5.80(m,1H),4.48-4.61(m,3H),4.31-4.40(m,2H),4.04-4.30(m,6H),3.79-3.93(m,4H),3.61-3.73(m,2H),2.93-3.02(m,2H),2.62-2.92(m,4H),1.96-2.10(m,4H)。
实施例11
本实施例提供一种式I所示的化合物11,所述化合物11的结构式如下所示：
Figure PCTCN2021125246-appb-000088
化合物11合成路线如下所示：
Figure PCTCN2021125246-appb-000089
(1)向实施例10中化合物10-5的三氟乙酸盐(60.0mg,83.3μmol)的二氯甲烷(3.0mL)溶液中加入三乙胺(8.42mg,83.3μmol,11.6μL),随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(63.3mg,166μmol)和化合物11-1的盐酸盐(27.6mg,166μmol),反应液在25℃下搅拌0.5小时。加入水(20.0mL)淬灭反应,用二氯甲烷(20.0mL×2)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Welch Xtimate,75mm×40mm 3μm,A:水(0.225％甲酸)；B:乙腈,5％-35％:10分钟)分离得到化合物11的甲酸盐。
MS-ESI[M+H]+,计算值718,实测值718。
1H NMR(400MHz,MeOD)δ8.26-8.31(m,1H),7.38-7.42(m,1H),7.24-7.31(m,2H),7.17-7.22(m,1H),6.70-6.85(m,1H),6.27-6.41(m,1H),4.57-4.62(m,2H),4.32-4.42(m,2H),4.06-4.30(m,6H),3.83-3.93(m,4H),3.64-3.70(m,2H),3.57-3.62(m,2H),2.94-3.02(m,3H),2.77-2.93(m,4H),2.59-2.65(m,6H), 1.96-2.12(m,4H)。
实施例12
本实施例提供一种式I所示的化合物12,所述化合物12的结构式如下所示：
Figure PCTCN2021125246-appb-000090
化合物12合成路线如下所示：
Figure PCTCN2021125246-appb-000091
(1)向实施例1中化合物1-3的三氟乙酸盐(150mg,329μmol)的甲醇(5.0mL)溶液中加入三乙胺(33.3mg,329μmol,45.74μL)。加入化合物E(132mg,493μmol),反应液在25℃下搅拌15分钟。随后加入氰基硼氢化钠(82.6mg,1.31mmol),25℃下继续搅拌12小时。加入水(30.0mL)淬灭反应,用乙酸乙酯(30.0mL×3)萃取,有机相用饱和食盐水(30.0mL×2)洗涤,无水硫酸钠干燥, 过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到化合物12-1；
MS-ESI[M+H] +,计算值594,实测值594。
(2)向化合物12-1(190mg,320μmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌10分钟。反应液过滤,减压浓缩得到化合物12-2的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值494实测值494。
(3)向化合物12-2的三氟乙酸盐(190mg,313μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(31.6mg,313μmol,43.5μL),随后加入中间体A(80.0mg,313μmol),反应液在25℃下搅拌30分钟。加入水(30.0mL)淬灭反应,用二氯甲烷(30.0mL×2)萃取,合并有机相用饱和食盐水(30.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到9:1)分离得到化合物12-3。
MS-ESI[M+H] +,计算值713实测值713。
(4)向化合物12-3(76.0mg,107μmol)的二氯甲烷(4.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌10分钟。反应液过滤,减压浓缩得到化合物12-4的三氟乙酸盐。粗品直接用于下一步反应；MS-ESI[M+2H] 2+,计算值307实测值307。
(5)向化合物12-5的盐酸盐(17.3mg,104μmol)的二氯甲烷(3.0mL)溶液中加入三乙胺(5.29mg,52.3μmol,7.28μL),随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(39.8mg,105μmol)和化合物12-4的三氟乙酸盐(38.0mg,52.3μmol),反应液在25℃下搅拌0.5小时。加入水(30.0mL)淬灭反应,用二氯甲烷(30.0mL×2)萃取,合并有机相用饱和食盐水(30.0mL× 2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,0％-30％:10分钟)分离得到化合物12的甲酸盐。
MS-ESI[M+H] +,计算值724,实测值724。
1H NMR(400MHz,MeOD)δ8.18(s,1H),7.51(s,1H),6.74(s,1H),6.61-6.70(m,1H),6.23-6.32(m,1H),4.38-4.52(m,2H),4.28-4.34(m,2H),4.17-4.27(m,1H),4.06-4.15(m,2H),3.93-4.05(m,2H),3.66-3.91(m,6H),3.54-3.65(m,4H),2.74-3.04(m,6H),2.55-2.65(m,6H),1.89-2.13(m,4H)。
实施例13
本实施例提供一种式I所示的化合物13,所述化合物13的结构式如下所示：
Figure PCTCN2021125246-appb-000092
化合物13合成路线如下所示：
Figure PCTCN2021125246-appb-000093
(1)向实施例12中化合物12-5的三氟乙酸盐(38.0mg,52.3μmol)的二氯甲烷(3.0mL)溶液中加入三乙胺(5.29mg,52.3μmol)。随后加入化合物13-1 (7.10mg,78.4μmol),反应液在-78℃下搅拌5分钟。加入水(30.0mL)淬灭反应,用二氯甲烷(30.0mL×2)萃取,合并有机相用饱和食盐水(30.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm，A:水(0.225％甲酸)；B:乙腈,15％-35％:10分钟)分离得到化合物13的甲酸盐。
MS-ESI[M+H] +,计算值667实测值667。
1H NMR(400MHz,MeOD)δ8.18(s,1H),7.51(s,1H),6.68(s,1H),6.09-6.25(m,2H),5.61-5.69(m,1H),4.35-4.47(m,2H),4.30(s,2H),4.15-4.25(m,1H),4.06-4.14(m,2H),3.67-3.93(m,8H),3.50-3.60(m,2H),2.63-2.92(m,6H),1.85-2.10(m,4H)。
实施例14
本实施例提供一种式I所示的化合物14,所述化合物14的结构式如下所示：
Figure PCTCN2021125246-appb-000094
化合物14合成路线如下所示：
Figure PCTCN2021125246-appb-000095
(1)向实施例1中化合物1-3的三氟乙酸盐(176mg,386μmol)的甲醇(5.0mL)溶液中加入三乙胺(130mg,1.29mmol,179μL)。然后加入化合物C(101mg,386μmol)和氰基硼氢化钠(162mg,2.57mmol),25℃下继续搅拌12小时。将反应液减压浓缩,溶于乙酸乙酯(150mL)，饱和食盐水(120.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到16:1)分离得到化合物14-1；
MS-ESI[M+H] +,计算值589,实测值589。
(2)向化合物14-1(70.0mg,119μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(441mg,3.87mmol,287μL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物14-2的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值489实测值489。
(3)向化合物14-2的三氟乙酸盐(70.0mg,116μmol)的二氯甲烷(3.0mL)溶液中加入三乙胺(353mg,3.48mmol,485μL),随后加入中间体A(44.6mg,174μmol),反应液在25℃下搅拌1小时。加入水(50.0mL)淬灭反应,用二氯甲烷(40.0mL)萃取，有机相用饱和食盐水(30.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝10:1)分离得到化合物14-3。
MS-ESI[M+H] +,计算值708实测值708。
1H NMR(400MHz,CDCl 3)δ8.22-8.27(m,1H),7.52-7.62(m,2H),7.36(d,J＝8.0Hz,1H),4.51(s,2H),4.22-4.30(m,1H),4.14(br s,4H),3.86(q,J＝10.8Hz,4H),3.76(s,2H),3.69(br t,J＝6.0Hz,2H),3.01(br t,J＝6.0Hz,2H),2.80-2.88(m,1H),2.73(br d,J＝9.6Hz,2H),2.59(br d,J＝9.6Hz,1H),2.00-2.13(m,2H),1.88-1.98(m,2H),1.42(s,9H),1.27-1.34(m,2H)
(4)向化合物14-3(39.0mg,55.1μmol)的二氯甲烷(2.0mL)溶液中加入三氟乙酸(353mg,3.10mmol,229μL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物14-4的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值608实测值608。
(5)向化合物14-6的盐酸盐(17.9mg,108μmol)的二氯甲烷(2.0mL)溶液中加入三乙胺(16.4mg,162μmol,22.6μL),随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(41.1mg,108μmol)，反应液在25℃下搅拌0.5小时。然后加入化合物14-4的三氟乙酸盐(39.0mg,54.0μmol)、三乙胺(8.20mg,81.1μmol,11.3μL)的二氯甲烷溶液(2.0mL),反应液在25℃下搅拌0.5小时。加入水(50.0mL)淬灭反应,用二氯甲烷(60.0mL)萃取，有机相用饱和食盐水(30.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,15％-45％:10分钟)分离得到化合物14的甲酸盐。
MS-ESI[M+H]+,计算值719,实测值719。
1H NMR(400MHz,MeOD)δ8.29(s,1H),7.63(br s,2H),7.38(br s,1H),6.77(br s,1H),6.33(br d,J＝14.0Hz,1H),4.58-4.68(m,2H),4.24-4.41(m,3H),4.00-4.08(m,2H),3.82-3.96(m,6H),3.75(br s,2H),3.55(m,2H),2.88-3.19(m,7H),2.59(br s,6H),1.79-2.41(m,5H)。
实施例15
本实施例提供一种式I所示的化合物15,所述化合物15的结构式如下所示：
Figure PCTCN2021125246-appb-000096
化合物15合成路线如下所示：
Figure PCTCN2021125246-appb-000097
(1)向实施例14中化合物14-4的三氟乙酸盐(17.0mg,23.6μmol)的二氯甲烷(2.0mL)溶液中加入三乙胺(1.96mg,19.4μmol,2.70μL)和化合物15-1(3.51mg,38.8μmol,3.16μL),反应液在-78℃下搅拌3小时。加入水(25.0mL)淬灭反应,用二氯甲烷(30.0mL)萃取，有机相用饱和食盐水(30.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,15％-35％:10分钟)分离得到化合物15的甲酸盐。
MS-ESI[M+H] +,计算值662实测值662。
1H NMR(400MHz,MeOD)δ8.30(s,1H),7.60-7.65(m,2H),7.33-7.38(m,1H),6.26-6.32(m,1H),5.77(dd,J＝9.6,2.5Hz,1H),4.61-4.66(m,2H),4.49-4.56(m,2H),4.38(ddd,J＝13.7,8.0,5.7Hz,1H),4.22-4.32(m,2H),4.13-4.19(m,2H),3.88(q,J＝10.6Hz,6H),3.80(br t,J＝6.1Hz,1H),3.74-3.77(m,2H),3.13-3.26(m,3H),3.07(br t,J＝5.7Hz,3H),2.18(br d,J＝5.6Hz,2H),2.07-2.13(m,2H)。
实施例16
本实施例提供一种式I所示的化合物16,所述化合物16的结构式如下所示：
Figure PCTCN2021125246-appb-000098
化合物16合成路线如下所示：
Figure PCTCN2021125246-appb-000099
(1)向实施例1中化合物1-3的三氟乙酸盐(310mg,679μmol)的甲醇(5.0mL)溶液中加入三乙胺(68.7mg,679μmol,94.5μL)。然后加入化合物16-1(272mg,1.02mmol)和氰基硼氢化钠(171mg,2.72mmol),25℃下继续搅拌12小时。将反应液倒入水(40.0mL)中,乙酸乙酯(40mL×3)萃取,合并有机相,用饱和食盐水(40.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到9:1)分离得到化合物16-2；
MS-ESI[M+H] +,计算值594,实测值594。
(2)向化合物16-2(350mg,589μmol)的二氯甲烷(8.0mL)溶液中加入 三氟乙酸(3.08g,27.0mmol,2mL),反应液在25℃下搅拌10分钟。反应液过滤,减压浓缩得到化合物16-3的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值494实测值494。
(3)向化合物16-3的三氟乙酸盐(350mg,576μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(58.3mg,576μmol,80.2μL),随后加入中间体A(221mg,864μmol),反应液在25℃下搅拌0.5小时。加入水(30.0mL)淬灭反应,用二氯甲烷(30.0mL×3)萃取,合并有机相,用饱和食盐水(30.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1：0到9:1)分离得到化合物16-4。
MS-ESI[M+H] +,计算值713实测值713。
(4)向化合物16-4(210mg,295μmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(3.08g,27.0mmol,2mL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物16-5的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+2H] 2+,计算值307实测值307。
(5)向化合物16-6的盐酸盐(47.9mg,289μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(14.6mg,144μmol,20.11μL),随后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(110mg,289μmol)和化合物16-5的三氟乙酸盐(105mg,144μmol),反应液在25℃下搅拌0.5小时。加入水(20.0mL)淬灭反应,用二氯甲烷(20.0mL×2)萃取,有机相用饱和食盐水(20.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,0％-30％:10分钟)分离得到化合物16的甲酸盐。
MS-ESI[M+H] +,计算值724,实测值724。
1H NMR(400MHz,MeOD)δ8.28(s,1H),7.61(s,1H),6.71-6.84(m,2H),6.25-6.38(m,1H),4.53-4.56(m,2H),4.27-4.35(m,1H),4.18-4.24(m,2H),3.98-4.04(m,2H),3.59-3.91(m,12H),2.73-3.07(m,6H),2.65-2.67(m,6H),1.93-2.21(m,4H)。
实施例17
本实施例提供一种式I所示的化合物17,所述化合物17的结构式如下所示：
Figure PCTCN2021125246-appb-000100
化合物17合成路线如下所示：
Figure PCTCN2021125246-appb-000101
(1)向实施例16中化合物16-5的三氟乙酸盐(105mg,144μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(14.6mg,144μmol,20.1μL),再加入化合物17-1(19.6mg,217μmol,17.7μL),反应液在-78℃下搅拌5分钟。加入水(20.0mL)淬灭反应,用二氯甲烷(20.0mL×2)萃取，有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,10％-40％:10分钟)分离得到化合物17的甲酸盐。
MS-ESI[M+H] +,计算值667实测值667。
1H NMR(400MHz,MeOD)δ8.27(s,1H),7.59(s,1H),6.84(s,1H),6.18-6.33(m,2H),5.71-5.79(m,1H),4.43-4.61(m,2H),4.25-4.34(m,1H),4.18-4.24(m,2H),4.03-4.12(m,2H),3.74-3.97(m,7H),3.52-3.72(m,3H),2.96-3.16(m,3H),2.84-2.91(m,1H),2.71-2.79(m,2H),1.96-2.22(m,4H)。
实施例18
本实施例提供一种式I所示的化合物18，所述化合物18的结构式如下所示：
Figure PCTCN2021125246-appb-000102
化合物18合成路线如下所示：
Figure PCTCN2021125246-appb-000103
(1)向实施例3中化合物3-3的三氟乙酸盐(95.0mg,250μmol)的甲醇(5.0mL)溶液中加入三乙胺(76.1mg,752μmol),化合物D(65.7mg,250μmol),加入氰基硼氢化钠(63.0mg,1.0mmol),25℃下搅拌16小时。加入氯化铵(10.0mL),用二氯甲烷(10.0mL×2)萃取,有机相用饱和食盐水(10.0mL× 2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝20:1到1：0)分离得到化合物18-1。
MS-ESI[M+H] +,计算值589,实测值589。
(2)向化合物18-1(89mg,151μmol)的二氯甲烷(4.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌20分钟。反应液减压浓缩得到化合物18-2的三氟乙酸盐。粗品直接用于下一步反应。
(3)向化合物18-2的三氟乙酸盐(73.0mg,149μmol)的N,N-二甲基甲酰胺(2.0mL)溶液中加入三乙胺(15.1mg,149μmol)。加入中间体A(38.2mg,149μmol),反应液在25℃下搅拌1小时。将反应液倒入水中(30.0mL),用二氯甲烷(15.0mL×2)萃取,合并有机相用饱和食盐水(10.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝50:1到10:1)分离得到化合物18-3。
MS-ESI[M+H] +,计算值708,实测值708。
(4)向化合物18-3(98mg,138μmol)的二氯甲烷(4.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物18-4的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值608,实测值608。
(5)向中间体18-4的三氟乙酸盐(84mg,116μmol)的二氯甲烷(2.0mL)溶液中加入N,N-二异丙基乙胺(45.1mg,349μmol),N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(88.5mg，232μmol)加入化合物19-6(15.0mg,99μmol),反应液在25℃下搅拌30分钟。向反应液中加入水(30.0mL),用二氯甲烷(50.0mL)萃取,合并有机相用饱和食盐水(50.0mL)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Kromasil C18,150mm×30mm 5 μm,A:水(0.2％三氟乙酸)；B:乙腈,5％-65％:20分钟；100％:5分钟)分离得到化合物18的三氟乙酸盐。
MS-ESI[M+H] +,计算值719，实测值719。
1H NMR(400MHz,MeOD)δ8.29-8.24(m,1H),8.20-8.16(m,1H),7.63-7.54(m,1H),7.33-7.27(m,1H),6.76-6.60(m,1H),6.33-6.20(m,1H),5.31-5.19(m,1H),4.54-4.50(m,1H),4.35-4.30(m,1H),4.23-4.17(m,2H),3.82-3.74(m,2H),3.60-3.50(m,5H),2.94-2.89(m,2H),2.55-2.46(m,8H),2.12-2.07(m,1H),1.96-1.83(m,5H),1.55-1.46(m,1H),1.23(br s,7H)。
实施例19
本实施例提供一种式I所示的化合物19，所述化合物19的结构式如下所示：
Figure PCTCN2021125246-appb-000104
化合物19合成路线如下所示：
Figure PCTCN2021125246-appb-000105
(1)向化合物B-4(17.5g,78.1mmol)的四氢呋喃(100mL)溶液中加入N,N'-羰基二咪唑(37.9g,234mmol)和1,8-二氮杂二环[5.4.0]十一碳-7-烯(35.7g,234mmol),反应液在70℃下搅拌4小时。加入水(50.0mL)淬灭反应,用乙酸乙酯(50.0mL×1)萃取,水相减压浓缩。得到化合物19-1。
MS-ESI[M+H] +,计算值251,实测值251。
(2)将化合物19-1(9.12g,36.45mmol)溶于三氯氧磷(34.0mL)中,反应液在115℃下搅拌8小时。反应液直接减压浓缩除去三氯氧磷,加入冰和饱和碳酸氢钠溶液调节pH值至大于7,用二氯甲烷(30.0mL×2)萃取,合并有机相用饱和食盐水(30.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到化合物19-2。
(3)向中间体19-2(2.15g,4.51mmol)和化合物19-3(2.01mg,7.66mmol)的N,N-二甲基甲酰胺(20.0mL)溶液中加入碳酸钾(2.89g,20.9mmol),反应液 在50℃下搅拌3小时。加入饱和食盐水(50.0mL),用乙酸乙酯(50.0mL)萃取,随后有机相用饱和食盐水(50.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,得到化合物19-4。
MS-ESI[M+H] +,计算值477,实测值477。
(4)向化合物19-4(2.0g,6.97mmol)的四氢呋喃(20.0mL)溶液中加入甲胺(21.5mL,2mol/L,四氢呋喃溶液),反应液在50℃下搅拌12小时。过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到化合物19-5。
1H NMR(400MHz,DMSO-d6)δ7.01-7.25(s,1H),6.51-6.66(m,1H),3.80-3.88(m,2H),3.36(m,4H),3.28-3.33(m,4H),2.69-2.84(m,3H),1.65-1.78(m,4H),1.34-1.43(m,9H)。
(5)向化合物19-5(1.26g,2.67mmol)的二氯甲烷(15.0mL)溶液中加入三氟乙酸(3.0mL),反应液在25℃下搅拌1小时。反应液减压浓缩得到化合物19-6的三氟乙酸盐。
MS-ESI[M+H] +,计算值372,实测值372。
(6)向化合物19-6的三氟乙酸盐(950mg,2.56mmol)的甲醇(20.0mL)溶液中加入三乙胺(3.45mg,3.41mmol)。随后加入化合物19-7(534mg,2.05mmol)和氰基硼氢化钠(642mg,10.2mmol),反应液在25℃下搅拌12小时。加入乙酸乙酯(40.0mL),有机相用水(20.0mL)和饱和食盐水(20.0mL×2)依次洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝100:1到10:1)分离得到化合物19-8。
1H NMR(400MHz,DMSO-d6)δ7.13(s,4H),6.61(d,J＝4.4Hz,1H),4.50(s,2H),4.08-4.11(m,2H),3.85(q,J＝10.8Hz,3H),3.55(s,3H),3.17(d,J＝5.2Hz, 4H),3.07-3.12(m,2H),2.78(s,2H),2.76(d,J＝4.4Hz,3H),1.43(s,9H),1.14-1.25(m,4H)。
(7)向化合物19-8(700mg,1.14mmol)的二氯甲烷(15.0mL)溶液中加入三氟乙酸(3.0mL),反应液在25℃下搅拌1小时。反应液过滤,减压浓缩得到化合物19-9的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值517,实测值517。
(8)向化合物19-9的三氟乙酸盐(480mg,929μmol)的N,N-二甲基甲酰胺(10.0mL)溶液中加入三乙胺(1.74g,17.2mmol),随后加入中间体A(475mg,1.86mmol),反应液在25℃下搅拌30分钟。加入水(30.0mL)淬灭反应,加入二氯甲烷(40.0mL)萃取,有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,得到化合物19-10。
MS-ESI[M+H] +,计算值736实测值736。
(9)向化合物19-10(100mg,135μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌1小时。反应液过滤,减压浓缩得到化合物19-11的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值636实测值636。
(10)向中间体19-11的三氟乙酸盐(19.5mg,117μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(363mg,3.59mmol),N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(59.8mg，157μmol)和化合物19-12(50.0mg,78.6μmol),反应液在25℃下搅拌0.5小时。向反应液中加入水(30.0mL),用二氯甲烷(50.0mL)萃取,合并有机相用饱和食盐水(50.0mL)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,0％-30％:10分钟)分离得到化合物19的甲酸盐。。
MS-ESI[M+H] +,计算值747，实测值747。
1H NMR(400MHz,MeOD)δ7.25-7.31(m,2H),7.20(d,J＝8.0Hz,1H),7.10(s,1H),6.73-6.82(m,1H),6.35(d,J＝15.2Hz,1H),4.51-4.60(m,4H),4.32-4.39(m,1H),4.26(d,J＝6.8Hz,2H),4.09(s,4H),3.94(s,2H),3.64-3.74(m,4H),3.61(d,J＝6.8Hz,2H),2.98(t,J＝5.6Hz,3H),2.85(s,6H),2.63(s,6H),2.02(s,4H)。
实施例20
本实施例提供一种式I所示的化合物20，所述化合物20的结构式如下所示：
Figure PCTCN2021125246-appb-000106
化合物20合成路线如下所示：
Figure PCTCN2021125246-appb-000107
向实施例19中中间体19-11的三氟乙酸盐(50.0mg,78.6μmol)的乙酸乙酯(5.0mL)溶液中加入三乙胺(23.8mg,235μmol),丙基磷酸酐(200mg,314μmol,50％乙酸乙酯溶液),4A分子筛(50.0mg)和化合物20-1(21.2mg,235μmol),反应液在25℃下搅拌0.5小时。加入水(50.0mL),用乙酸乙酯(50.0mL)萃取,合并有机相用饱和食盐水(50.0mL)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,15％-35％:10分钟)分离得到化合物20的甲酸盐。。
MS-ESI[M+H] +,计算值708，实测值708。
1H NMR(400MHz,MeOD)δ7.18-7.28(m,3H),7.09-7.12(s,1H),5.47-5.64(m,1H),5.19-5.26(m,1H),4.58-4.70(m,3H),4.54-4.56(m,2H),4.33-4.39(m,1H),4.24-4.31(m,2H),3.97-4.15(s,4H),3.79-3.86(s,2H),3.64-3.73(m,4H),2.95-3.00(m,2H),2.89-2.91(s,3H),2.74-2.87(s,3H),1.99(br s,4H))。
实施例21
本实施例提供一种式I所示的化合物21，所述化合物21的结构式如下所示：
Figure PCTCN2021125246-appb-000108
化合物21合成路线如下所示：
Figure PCTCN2021125246-appb-000109
向实施例19中中间体19-11的三氟乙酸盐(50.0mg,78.7μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(363mg,3.59mmol),加入化合物21-1(14.2mg,157μmol),反应液在-78℃下搅拌30分钟。将反应液减压浓缩得到粗品，粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,10％-40％:10分钟)分离得到化合物21的甲酸盐。
MS-ESI[M+H] +,计算值690，实测值690。
1H NMR(400MHz,MeOD)δ7.37-7.42(m,2H),7.25-7.32(m,2H),6.19-6.36(m,2H),5.72-5.82(m,1H),4.61-4.58(m,3H),4.46-4.57(m,2H),4.35-4.44(m,2H),4.29-4.35(m,3H),4.21-4.29(m,3H),3.81(m,J＝10.8Hz,2H),3.63-3.71(m,2H), 3.37-3.54(m,2H),3.07-3.24(m,2H),2.99-3.04(m,2H),2.94-2.99(m,3H),2.07-2.34(m,4H)。
实施例22
本实施例提供一种式I所示的化合物22，所述化合物22的结构式如下所示：
Figure PCTCN2021125246-appb-000110
化合物22合成路线如下所示：
Figure PCTCN2021125246-appb-000111
(1)向实施例3中化合物3-3的三氟乙酸盐(102.0mg,223μmol)的甲醇(2.0mL)溶液中加入三乙胺(24.9mg,246μmol),化合物22-1(59.8mg,223μmol),加入氰基硼氢化钠(70.2mg,1.12mmol),25℃下搅拌12小时。加入水(3.0mL),用二氯甲烷(10.0mL)萃取，无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝10:1)分离得到化合物22-2。
MS-ESI[M+H] +,计算值594,实测值594。
(2)向化合物22-2(90mg,152μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌30分钟。反应液减压浓缩得到化合物 22-3的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值494,实测值494。
(3)向化合物22-3的三氟乙酸盐(90mg,148μmol)的二氯甲烷(3.0mL)溶液中加入三乙胺(45.0mg,444μmol)。加入中间体A(56.8mg,222μmol),反应液在25℃下搅拌10分钟。加入水(2.0mL)淬灭反应,用二氯甲烷(10.0mL×2)萃取,合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝100:1到10:1)分离得到化合物22-4。
MS-ESI[M+H] +,计算值713,实测值713。
(4)向化合物22-4(90mg,126μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物22-5的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值613,实测值613。
(5)向中间体22-5的三氟乙酸盐(40.0mg,55μmol)的二氯甲烷(2.0mL)溶液中加入三乙胺(8.35mg,82.6μmol),N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(27.21mg，71.55μmol)加入化合物24-6(27.4mg,165μmol),反应液在25℃下搅拌3小时。向反应液中加入水(30.0mL),用二氯甲烷(50.0mL)萃取,合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Phenomenex Luna C18 100mm×30mm 3μm,A:水(0.225％甲酸)；B:乙腈,0％-30％:8分钟)分离得到化合物22的甲酸盐。
MS-ESI[M+H] +,计算值724，实测值724。
1H NMR(400MHz,MeOD)δ8.26-8.32(m,1H),7.37-7.44(m,1H),6.70-6.85(m,2H),6.33-6.44(m,1H),4.50-4.63(m,4H),4.05-4.39(m,6H),3.84-3.93(m,4H), 3.62-3.74(m,4H),3.32(br s,2H),2.74-2.84(m,3H),2.60-2.72(m,8H),1.95-2.05(m,4H)。
实施例23
本实施例提供一种式I所示的化合物23，所述化合物23的结构式如下所示：
Figure PCTCN2021125246-appb-000112
化合物23合成路线如下所示：
Figure PCTCN2021125246-appb-000113
向中间体22-5的三氟乙酸盐(57.0mg,78.4μmol)的二氯甲烷(3.0mL)溶液中加入三乙胺(15.9mg,157μmol),加入化合物23-1(7.95mg,87.8μmol),反应液在-78℃下搅拌10分钟。将反应液减压浓缩，粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,10％-40％:10分钟)分离得到化合物23的甲酸盐。
MS-ESI[M+H] +,计算值667，实测值667。
1H NMR(400MHz,MeOD)δ8.25-8.28(m,1H),7.37-7.44(m,1H),6.76-6.81(m,1H),6.20-6.36(m,2H),5.72-5.79(m,1H),4.58-4.69(m,8H),4.46-4.55(m,2H),4.26-4.35(m,1H),4.17-4.25(m,2H),3.80-3.94(m,4H),3.61-3.72(m,2H),2.73-2.82(m,2H),2.49-2.72(m,2H),1.88-2.01(m,4H)
实施例24
本实施例提供一种式I所示的化合物24，所述化合物24的结构式如下所示：
Figure PCTCN2021125246-appb-000114
化合物24合成路线如下所示：
Figure PCTCN2021125246-appb-000115
(1)向实施例3中化合物3-3的三氟乙酸盐(100.0mg,219μmol)的甲醇(5.0mL)溶液中加入三乙胺(44.3mg,438μmol),化合物E(87.8mg,328μmol),加入氰基硼氢化钠(55.1mg,876μmol),25℃下搅拌12小时。加入水(40.0mL),用乙酸乙酯(40.0mL×2)萃取,有机相用饱和食盐水(40.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1：0到0：1)分离得到化合物24-1。
MS-ESI[M+H] +,计算值594,实测值594。
(2)向化合物24-1(120mg,202μmol)的二氯甲烷(4.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌10分钟。反应液减压浓缩得到化合物24-2的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值494,实测值494。
(3)向化合物24-2的三氟乙酸盐(120.0mg,198μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(20.0mg,198μmol)。加入中间体A(101mg,395μmol),反应液在25℃下搅拌30分钟。加入水(20.0mL)淬灭反应,用乙酸乙酯(20.0mL×3)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物24-3。
MS-ESI[M+H] +,计算值713,实测值713。
(4)向化合物24-3(80.0mg,112μmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物24-4的三氟乙酸盐。粗品直接用于下一步反应。
(5)向中间体24-4的三氟乙酸盐(34.2mg,206μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(10.4mg,103μmol),N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(78.5mg，206μmol)加入化合物24-5(75.0mg,103μmol),反应液在25℃下搅拌30分钟。向反应液中加入水(30.0mL),用乙酸乙酯(20.0mL×3)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,10％-40％:10分钟)分离得到化合物24的甲酸盐。
MS-ESI[M+H] +,计算值724，实测值724。
1H NMR(400MHz,MeOD)δ8.27(s,1H),7.40(s,1H),6.69-6.89(m,2H),6.29-6.41(m,1H),5.49(s,1H),4.48-4.62(m,2H),4.40-4.47(m,2H),4.29-4.38(m,2H),4.06-4.27(m,6H),3.81-3.94(m,4H),3.56-3.76(m,4H),2.93(s,2H),2.63(s,9H),2.01(s,4H)
实施例25
本实施例提供一种式I所示的化合物25，所述化合物25的结构式如下所示：
Figure PCTCN2021125246-appb-000116
化合物25合成路线如下所示：
Figure PCTCN2021125246-appb-000117
(1)向实施例3中化合物3-3的三氟乙酸盐(300.0mg,657μmol)的甲醇(5.0mL)溶液中加入三乙胺(66.5mg,657μmol),化合物C(344mg,1.31mmol),加入氰基硼氢化钠(165mg,2.63mmol),25℃下搅拌12小时。加入水(40.0mL),用乙酸乙酯(40.0mL×2)萃取,有机相用饱和食盐水(40.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1：0到0：1)分离得到化合物25-1。
MS-ESI[M+H] +,计算值589,实测值589。
(2)向化合物25-1(383mg,651μmol)的二氯甲烷(4.0mL)溶液中加入三氟乙酸(2.5mL),反应液在25℃下搅拌30分钟。反应液减压浓缩得到化合物25-2的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值489,实测值489。
(3)向化合物25-2的三氟乙酸盐(200mg,332μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(33.6mg,332μmol)。加入中间体A(127mg,498μmol),反应液在25℃下搅拌1小时。向反应液中加入水(30.0mL),加入乙酸乙酯(50.0mL)萃取,合并有机相用饱和食盐水(30.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到45:1)分离得到化合物25-3。
MS-ESI[M+H] +,计算值708,实测值708。
(4)向化合物25-3(125mg,177μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(0.5mL),反应液在25℃下搅拌30分钟。反应液过滤,减压浓缩得到化合物25-4的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值608,实测值608。
(5)向中间体25-4的三氟乙酸盐(60.0mg,83.1μmol)的二氯甲烷(2.0mL)溶液中加入三乙胺(25.3mg,250μmol),N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(63.2mg,166μmol)加入化合物25-5(27.6mg,167μmol),反应液在25℃下搅拌30分钟。向反应液中加入水(30.0mL),用二氯甲烷(50.0mL)萃取,合并有机相用饱和食盐水(30mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,10％-40％:10分钟)分离得到化合物25的甲酸盐。
MS-ESI[M+H] +,计算值719,实测值719。
1H NMR(400MHz,MeOD)δ8.28(s,1H),7.64(br d,J＝7.6Hz,1H),7.36-7.45(m,2H),6.70-6.86(m,1H),6.40(br d,J＝15.6Hz,1H),4.55-4.66(m,4H),4.38-4.45(m,1H),4.24-4.36(m,3H),4.05-4.24(m,3H),3.96(s,2H),3.88(q,J＝ 10.8Hz,2H),3.77(br t,J＝5.6Hz,2H),3.71(br d,J＝6.4Hz,2H),3.09(br t,J＝5.6Hz,2H),2.87(br s,4H),2.71(s,6H),1.99-2.10(m,4H)。
实施例26
本实施例提供一种式I所示的化合物26，所述化合物26的结构式如下所示：
Figure PCTCN2021125246-appb-000118
化合物26合成路线如下所示：
Figure PCTCN2021125246-appb-000119
(1)向实施例25中化合物25-4的三氟乙酸盐(60.0mg,83.1μmol)的二氯甲烷(2.0mL)溶液中加入三乙胺(25.2mg,249μmol),加入化合物26-1(15.1mg,166μmol),反应液在-78℃下搅拌1小时。向反应液中加入水(30.0mL),用二氯甲烷(50.0mL)萃取,合并有机相用饱和食盐水(30.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,2％-25％:10分钟)分离得到化合物26的甲酸盐。
MS-ESI[M+H] +,计算值662,实测值662。
1H NMR(400MHz,MeOD)δ8.29(s,1H),7.65(br d,J＝8.0Hz,1H),7.37-7.41(m,2H),6.22-6.38(m,2H),5.77(dd,J＝9.6,2.4Hz,1H),4.50-4.59(m, 2H),4.38-4.43(m,1H),4.25-4.33(m,3H),4.23(br d,J＝11.6Hz,3H),4.02(s,2H),3.88(q,J＝10.8Hz,3H),3.76(br d,J＝8.8Hz,2H),3.10(br t,J＝5.6Hz,2H),2.98-3.04(m,1H),2.94(br s,4H),2.07(br s,4H)
实施例27
本实施例提供一种式I所示的化合物27，所述化合物27的结构式如下所示：
Figure PCTCN2021125246-appb-000120
化合物27合成路线如下所示：
Figure PCTCN2021125246-appb-000121
(1)向实施例3中化合物3-3的三氟乙酸盐(200.0mg,438μmol)的二氯甲烷(10.0mL)溶液中加入三乙胺(177mg,1.75mmol),化合物27-1(112mg,525μmol),加入氰基硼氢化钠(55.0mg,876μmol),25℃下搅拌12小时。加入水(10.0mL),用乙酸乙酯(10.0mL×2)萃取,有机相用饱和食盐水(10.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到0：1)分离得到化合物27-2。
MS-ESI[M+H] +,计算值540,实测值540。
(2)向化合物27-2(200mg,370μmol)的二氯甲烷(9.0mL)溶液中加入三氟乙酸(3.0mL),反应液在25℃下搅拌1小时。反应液减压浓缩得到化合物27-3的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值440,实测值440。
(3)向化合物27-3的三氟乙酸盐(200.0mg,361μmol)的二氯甲烷(6.0mL)溶液中加入三乙胺(73.1mg,722μmol)。加入中间体A(184mg,722μmol),反应液在25℃下搅拌1小时。加入水(10.0mL)淬灭反应,用二氯甲烷(10.0mL×2)萃取,合并有机相用饱和食盐水(10.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到0:1)分离得到化合物27-4。
MS-ESI[M+H] +,计算值659,实测值659。
(4)向化合物27-4(143mg,217μmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌1小时。反应液过滤,减压浓缩得到化合物27-5的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值559,实测值559。
(5)向化合物27-5的三氟乙酸盐(70.0mg,104μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(21.0mg,208μmol),N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(79.1mg，208μmol)加入化合物27-6(51.7mg,312μmol),反应液在25℃下搅拌1小时。加水(10.0mL),用二氯甲烷(10.0mL×2)萃取,合并有机相用饱和食盐水(10.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,10％-40％:10分钟)分离得到化合物27的甲酸盐。
MS-ESI[M+H] +,计算值670，实测值670。
1H NMR(400MHz,MeOD)δ8.29-8.31(m,1H),7.38-7.41(m,1H),6.73-6.83(m,1H),6.35-6.47(m,1H),4.58-4.67(m,1H),4.19-4.38(m,6H),3.66-3.96(m,7H),2.97-3.16(m,4H),2.76-2.96(m,5H),2.70-2.76(m,6H),2.07-2.20(m,4H),1.88-2.02(m,3H),1.27-1.36(m,2H)。
实施例28
本实施例提供一种式I所示的化合物28，所述化合物28的结构式如下所示：
Figure PCTCN2021125246-appb-000122
化合物28合成路线如下所示：
Figure PCTCN2021125246-appb-000123
(1)向实施例27中化合物27-5的三氟乙酸盐(70.0mg,104μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(21.0mg,208μmol)和化合物28-1(14.1mg,156μmol),反应液在-78℃下搅拌1小时。向反应液中加水(10.0mL),用二氯甲烷(10mL×2)萃取,合并有机相用饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18 100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,5％-35％:10分钟)分离得到化合物28的甲酸盐。
MS-ESI[M+H] +,计算值613，实测值613。
1H NMR(400MHz,MeOD)δ8.28-8.30(m,1H),7.39-7.40(m,1H),6.25-6.36 (m,2H),5.76-5.81(m,1H),4.58-4.62(m,1H),4.47-4.51(m,1H),4.19-4.37(m,6H),3.76-3.94(m,5H),2.84-2.98(m,6H),2.66-2.70(m,2H),2.05-2.10(m,4H),1.86-1.93(m,3H),1.22-1.31(m,2H)
实施例29
本实施例提供一种式I所示的化合物29,所述化合物29的结构式如下所示：
Figure PCTCN2021125246-appb-000124
化合物29合成路线如下所示：
Figure PCTCN2021125246-appb-000125
(1)向中间体B(200mg,792μmol)和化合物29-1(185mg,871μmol)的N,N-二甲基甲酰胺(5.0mL)溶液中加入碳酸钾(219mg,1.58mmol),反应液在80℃下搅拌12小时。加入水(20.0mL),用乙酸乙酯(20.0mL×2)萃取,合并有机相用饱和食盐水(20.0mL×3)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到0:1)分离得到化合物29-2。
MS-ESI[M+H] +,计算值429,实测值429。
(2)向化合物29-2(258mg,602μmol)的二氯甲烷(6.0mL)溶液中加入 三氟乙酸(2.0mL),反应液在25℃下搅拌0.5小时。反应液减压浓缩得到化合物29-3的三氟乙酸盐。
MS-ESI[M+H] +,计算值329,实测值329。
(3)向化合物29-3的三氟乙酸盐(190mg,430μmol)的甲醇(5.0mL)溶液中加入三乙胺(86.9mg,859μmol)。随后加入化合物30-4(148mg,568μmol)和氰基硼氢化钠(108mg,1.72mmol),反应液在25℃下搅拌1小时。加入水(20.0mL),用二氯甲烷(20.0mL×2)萃取,合并有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物29-5。
MS-ESI[M+H] +,计算值574,实测值574。
(4)向化合物29-5(210mg,366μmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌0.5小时。反应液过滤,减压浓缩得到化合物29-6的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值474,实测值474。
(5)向化合物29-6的三氟乙酸盐(210mg,357μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(36.2mg,357μmol),随后加入中间体A(183mg,715μmol),反应液在25℃下搅拌30分钟。加入水(20.0mL)淬灭反应,加入二氯甲烷(20.0mL×2)萃取,有机相用饱和食盐水(20.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物29-7。
MS-ESI[M+H] +,计算值693实测值693。
(6)向化合物29-7(195mg,274μmol)的二氯甲烷(6.0mL)溶液中加入三氟乙酸(2.0mL),反应液在25℃下搅拌1小时。反应液过滤,减压浓缩得到化 合物29-8的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值593实测值593。
(7)向化合物29-8的三氟乙酸盐(95.0mg,134μmol)的二氯甲烷(5.0mL)溶液中加入化合物29-9(18.3mg,202μmol)和三乙胺(13.6mg,134μmol),反应液在-78℃下搅拌5分钟。加入二氯甲烷(50.0mL),有机相用饱和食盐水(50.0mL×2)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18,100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,10％-40％:10分钟)分离得到化合物29的甲酸盐。
MS-ESI[M+H] +,计算值647,实测值647。
1H NMR(400MHz,MeOD)δ8.27(s,1H),7.36(s,1H),7.19-7.27(m,2H),7.12-7.17(m,1H),6.19-6.34(m,2H),5.71-5.78(m,1H),4.49-4.55(m,4H),4.28-4.47(m,5H),4.20-4.25(m,2H),3.83-3.91(m,2H),3.72-3.78(m,2H),3.62-3.68(m,2H),2.93-3.03(m,4H),2.76-2.85(m,2H),2.24-2.32(m,2H)。
实施例30
本实施例提供一种式I所示的化合物30,所述化合物30的结构式如下所示：
Figure PCTCN2021125246-appb-000126
化合物30合成路线如下所示：
Figure PCTCN2021125246-appb-000127
(1)向中间体B(317mg,1.42mmol)和化合物30-1(220mg,1.18mmol)的N,N-二甲基甲酰胺(5.0mL)溶液中加入碳酸钾(328mg,2.37mmol),反应液在80℃下搅拌2小时。加入水(40.0mL),用乙酸乙酯(40.0mL×2)萃取,合并有机相用饱和食盐水(50.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物30-2。
MS-ESI[M+H] +,计算值403,实测值403。
(2)向化合物30-2(470mg,1.17μmol)的二氯甲烷(15.0mL)溶液中加入三氟乙酸(5.0mL),反应液在25℃下搅拌0.5小时。反应液减压浓缩得到化合物30-3的三氟乙酸盐。
MS-ESI[M+H] +,计算值303,实测值303。
(3)向化合物30-3的三氟乙酸盐(100mg,240μmol)的甲醇(5.0mL)溶液中加入三乙胺(48.6mg,480μmol)。随后加入化合物30-4(79.4mg,288μmol)和氰基硼氢化钠(60.3mg,960μmol),反应液在25℃下搅拌12小时。加入水(40.0mL),用乙酸乙酯(40.0mL×2)萃取,合并有机相用饱和食盐水(50.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物30-5。
MS-ESI[M+H] +,计算值554,实测值554。
(4)向化合物30-5(78.0mg,140μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌0.5小时。反应液过滤,减压浓缩得到化合物30-6的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值454,实测值454。
(5)向化合物30-6的三氟乙酸盐(78.0mg,137μmol)的二氯甲烷(3.0mL)溶液中加入三乙胺(13.9mg,137μmol),随后加入中间体A(70.2mg,274μmol),反应液在25℃下搅拌30分钟。加入水(40.0mL)淬灭反应,加入乙酸乙酯(40.0mL×2)萃取,有机相用饱和食盐水(50.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物30-7。
MS-ESI[M+H] +,计算值673实测值673。
(6)向化合物30-7(57.0mg,84.7μmol)的二氯甲烷(3.0mL)溶液中加入 三氟乙酸(1.0mL),反应液在25℃下搅拌1小时。反应液过滤,减压浓缩得到化合物30-8的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值573实测值573。
(7)向化合物30-8的三氟乙酸盐(58.0mg,84.4μmol)的二氯甲烷(3.0mL)溶液中三乙胺(8.55mg,84.4μmol),化合物30-9(41.9mg,253μmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(64.2mg,168μmol),反应液在25℃下搅拌1小时。加入水(40.0mL)淬灭反应,用乙酸乙酯(40.0mL×2)萃取,有机相用饱和食盐水(50.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18,100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,15％-45％:10分钟)分离得到化合物30的甲酸盐。
MS-ESI[M+H] +,计算值684,实测值684。
1H NMR(400MHz,MeOD)δ8.34-8.38(m,1H),7.50-7.57(m,1H),6.70-6.82(m,2H),6.32-6.43(m,1H),4.50-4.62(m,4H),4.28-4.36(m,1H),4.19-4.26(m,2H),3.94-4.03(m,4H),3.85-3.93(m,2H),3.74-3.79(m,2H),3.61-3.73(m,4H),2.64-2.79(m,12H)。
实施例31
本实施例提供一种式I所示的化合物31,所述化合物31的结构式如下所示：
Figure PCTCN2021125246-appb-000128
化合物31合成路线如下所示：
Figure PCTCN2021125246-appb-000129
(1)向实施例30中化合物30-3的三氟乙酸盐(100mg,240μmol)的甲醇(5.0mL)溶液中加入三乙胺(48.6mg,480μmol)。随后加入化合物E(79.4mg,288μmol)和氰基硼氢化钠(60.3mg,960μmol),反应液在25℃下搅拌12小时。加入水(40.0mL),用乙酸乙酯(40.0mL×2)萃取,合并有机相用饱和食盐水(50.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物31-1。
MS-ESI[M+H] +,计算值554,实测值554。
(2)向化合物31-1(72.0mg,130μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌0.5小时。反应液过滤,减压浓缩得到化合物31-2的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值454,实测值454。
(3)向化合物31-2的三氟乙酸盐(70.0mg,123μmol)的二氯甲烷(5.0mL)溶液中加入三乙胺(12.4mg,123μmol),随后加入中间体A(63.0mg,246μmol),反应液在25℃下搅拌60分钟。加入水(40.0mL)淬灭反应,加入乙酸乙酯(40.0mL×2)萃取,有机相用饱和食盐水(50.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分 离得到化合物31-3。
MS-ESI[M+H] +,计算值673实测值673。
(4)向化合物31-3(46.0mg,68.3μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(1.0mL),反应液在25℃下搅拌1小时。反应液过滤,减压浓缩得到化合物31-4的三氟乙酸盐。粗品直接用于下一步反应。
MS-ESI[M+H] +,计算值573实测值573。
(5)向化合物31-4的三氟乙酸盐(46.0mg,66.9μmol)的二氯甲烷(3.0mL)溶液中三乙胺(6.78mg,66.9μmol),化合物31-5(33.2mg,200μmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(50.9mg,133μmol),反应液在25℃下搅拌1小时。加入水(40.0mL)淬灭反应,用乙酸乙酯(40.0mL×2)萃取,有机相用饱和食盐水(50.0mL×1)洗涤,无水硫酸钠干燥,过滤,有机相减压浓缩。粗品制备高效液相色谱法(Xtimate C18,100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,15％-45％:10分钟)分离得到化合物31的甲酸盐。
MS-ESI[M+H] +,计算值684,实测值684。
1H NMR(400MHz,MeOD)δ8.32-8.39(m,1H),7.49-7.58(m,1H),6.63-6.85(m,2H),6.29-6.48(m,1H),4.50-4.65(m,2H),4.37-4.47(m,2H),4.21-4.37(m,3H),3.93-4.05(m,4H),3.85-3.93(m,2H),3.60-3.82(m,6H),2.86-2.96(m,2H),2.56-2.81(m,10H)。
试验例
化合物对MV-4-11细胞抗增殖作用的测定：
1、实验原理：MV-4-11为一种人类白血病细胞株,带有MLL易位并且表达MLL融合蛋白MLL-AF4。本申请所涉及的化合物通过干扰menin/MLL蛋白/蛋白相互作用,抑制MV-4-11的增殖。
2、实验材料：Cell Counting Kit-8购自上海李记生物技术有限公司(货号D3100L4057)；96孔透明底白色细胞培养板购自Corning Costar(货号3610)；胎牛血清购自GIBCO(货号#10099-141)；伊思柯夫改良培养液(IMDM)培养基购自Invitrogen(货号为12440046)；台式酶标仪SpectraMax i3X购自Molecular Devices；
3、实验方法：将处于对数生长期的细胞重新悬浮于完全培养基
(IMDM+10％胎牛血清(FBS))中,接种至96孔板中(每孔加100μL细胞悬液,即每孔接种15000细胞)。细胞在37℃,100％相对湿度,5％CO 2培养箱中孵育24小时。
将待测化合物溶解在二甲亚砜(DMSO)中,配制成浓度为10mM的储备液,用DMSO按4倍梯度逐级稀释8次。再用培养基稀释20倍。按25μL/孔加入接种细胞的96孔板中,使化合物终浓度依次为:100μM、25μM、6.25μM、1.56μM、0.39μM、0.098μM、0.024μM、0.006μM、0.0015μM(4倍稀释,9个浓度)。
加入待测化合物的细胞置于37℃,100％相对湿度,5％CO 2培养箱中分别孵育72小时；使用CCK-8方法检测细胞活力:每孔中加入10μL CCK-8检测试剂,置于培养箱中继续孵育约4小时。使用台式酶标仪读取波长450nM(参比波长650nM)。
4、数据处理：
按下式计算药物对肿瘤细胞生长的抑制率：
肿瘤细胞生长抑制率％＝[(ODc-ODs)/(ODc-ODb)]×100％
其中,ODs:样品的OD(细胞+CCK-8+待测化合物),ODc:阴性对照的OD(细胞+CCK-8+DMSO),ODb:空白对照的OD(培养基+CCK-8+ DMSO)。
并用Graphpad软件计算化合物的IC 50。
具体测试方法如表1所示：
表1
Figure PCTCN2021125246-appb-000130
由表1测试数据可知，本申请所述式I所示化合物对人髓性单核细胞白血病MV-4-11细胞的生长具有较佳的抑制作用，具有用于制备治疗和预防白血病药物 的潜力。
试验例2
化合物对MV-4-11细胞抗增殖作用的测定(CTG方法):
1、实验原理:MV-4-11为一种人类白血病细胞株，带有MLL易位并且表达MLL融合蛋白MLL-AF4。本申请所涉及的化合物通过干扰menin/MLL蛋白/蛋白相互作用，抑制MV-4-11的增殖。
2、实验材料:CellTiter-Glo购自Promega(货号#G7571)；IMDM培养基购自Gibco(货号#12440061)；胎牛血清购自Excell(货号#FND500)；二甲亚砜(DMSO)购自Sigma(货号#D2650)；384孔细胞培养板购自Corning(货号#3756)；自动细胞计数器购自Life technologies(型号为Countess II)；酶标仪购自PerkinElmer(型号为EnVisionMultilabel Reader)。
3、实验方法:将处于对数生长期的细胞重新悬浮于生长培养基(IMDM+10％FBS)并稀释至目标密度(50000/mL)。将上述细胞悬浮液按照每孔50μL接种至384孔板中；在37℃，5％CO 2培养箱中孵育过夜。
将待测化合物溶解在DMSO中，配制成浓度为10mM的储备液。首先用DMSO将储备液稀释至2mmol/L，再3倍梯度稀释，共10个浓度。取各浓度的上述溶液5.5μL，分别用94.5μL生长培养基稀释。然后按5μL/孔加入接种细胞的384孔板中。
将加入待测化合物的细胞置于37℃，5％CO 2培养箱中孵育72小时。室温下平衡384孔板，每孔中加入15μL CellTiter-Glo试剂，涡旋器上混合2分钟，室温孵育60分钟，EnVisionMultilabel Reader读取发光值，用GraphPad Prism 5.0 software软件计算化合物的IC 50。
4、实验数据:
具体测试结果如表2所示:
表2
Figure PCTCN2021125246-appb-000131
Figure PCTCN2021125246-appb-000132
由表2测试数据可知，本申请所述式I所示的螺环类化合物对人髓性单核细胞白血病MV-4-11细胞的生长具有较佳的抑制作用，具有用于制备治疗和预防白血病药物的潜力。
申请人声明，本申请通过上述实施例来说明所述噻吩并嘧啶类化合物、包含其药物组合物及其应用，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。

Claims (12)

  1. 一种噻吩并嘧啶类化合物，其特征在于，所述噻吩并嘧啶类化合物的结构式如下式I所示：
    Figure PCTCN2021125246-appb-100001
    其中，
    R 1选自H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基、取代或未取代的C1-C6烷基羰基、取代或未取代的
    Figure PCTCN2021125246-appb-100002
    取代或未取代的C2-C8烯基、取代或未取代的C2-C8炔基、取代或未取代的C1-C6烷基砜基、取代或未取代的C1-C6烷基亚砜基、
    Figure PCTCN2021125246-appb-100003
    其中，R a、R b各自独立地选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基、或R a与R b与N相连形成的取代或未取代的4-8元杂环，其中，R a与R b与N相连形成杂环包含1-3个选自N、O、S、P的杂原子，
    Figure PCTCN2021125246-appb-100004
    表示基团的连接位置；
    R 2选自H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C16芳基、取代或未取代的5-16元杂芳基、取代或未取代的4-8元杂环基、取代或未取代的C1-C6烷基羰基、取代或未取代的
    Figure PCTCN2021125246-appb-100005
    取代或未取代的C2-C8烯基、取代或未取代的C2-C8炔基、 取代或未取代的C1-C6烷基砜基、取代或未取代的C1-C6烷基亚砜基、
    Figure PCTCN2021125246-appb-100006
    其中，R c、R d各自独立地选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基、或R c与R d与N相连形成的取代或未取代的4-8元杂环，其中，R c与R d与N相连形成的杂环包含1-3个选自N、O、S、P的杂原子，
    Figure PCTCN2021125246-appb-100007
    表示基团的连接位置；
    R 3分别独立地选自H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C1-C4烷氨基、-NH 2、-NO 2、-COOH、-CN、-OH、取代或未取代的C1-C6烷基砜基、取代或未取代的C1-C6烷基亚砜基、取代或未取代的C1-C6烷基硫基、
    Figure PCTCN2021125246-appb-100008
    Figure PCTCN2021125246-appb-100009
    其中，R 3'选自H、甲基或氟；R 3”选自氯或溴，
    Figure PCTCN2021125246-appb-100010
    表示基团的连接位置；
    Y、Z分别独立地选自N或CH，且Y和Z中至少有一个为N；
    W选自N或C；
    U 1、U 2、U 3、U 4、U 5、U 6、U 7、U 8分别独立地选自
    Figure PCTCN2021125246-appb-100011
    Figure PCTCN2021125246-appb-100012
    且U 1、U 2、U 3、U 4中至多有一个为
    Figure PCTCN2021125246-appb-100013
    Figure PCTCN2021125246-appb-100014
    U 5、U 6中至多有一个为
    Figure PCTCN2021125246-appb-100015
    Figure PCTCN2021125246-appb-100016
    U 7、U 8中至多有一个为
    Figure PCTCN2021125246-appb-100017
    Figure PCTCN2021125246-appb-100018
    其中，
    Figure PCTCN2021125246-appb-100019
    表示基团的连接位置，
    每一个R'分别独立地选自：H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
    每一个R”分别独立地选自：H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
    每一个R”'分别独立地选自：H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
    每一个R””分别独立地选自：H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
    A选自取代或未取代的C6-C16芳基、取代或未取代的5-16元杂芳基，其中，所述的杂芳基包含1-3个选自N、O、S、P的杂原子；
    L 1为不存在、
    Figure PCTCN2021125246-appb-100020
    其中，
    Figure PCTCN2021125246-appb-100021
    表示基团的连接位置，R L1'、R L1”分别独立地选自H、卤素、取代或未取代的C1-C4烷基，或R L1'与R L1”与相连的碳原子形成取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环，其中，R L1'与R L1”与相连的碳原子形成的杂环包含1-3个选自N、O、S、P的杂原子；
    L 2选自
    Figure PCTCN2021125246-appb-100022
    其中，
    Figure PCTCN2021125246-appb-100023
    表示基团的连接位置；
    X选自碳原子或
    Figure PCTCN2021125246-appb-100024
    其中，
    Figure PCTCN2021125246-appb-100025
    表示基团的连接位置；
    R 4选自
    Figure PCTCN2021125246-appb-100026
    其中，R4'选自氟或氯，R4”选自H、甲基或氟，R 4”'选自H、取代或未取代的C1-C4烷基、取代或未取代的的C1-C4烷氧基、取代或未取代的C1-C4烷氨基、取代或未取代的(C1-C4烷基) 2 氨基、取代或未取代的C1-C4烷硫基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基、取代或未取代的C2-C4酰基，所述杂环基包含1-3个选自N、O、S、P的杂原子，其中，
    Figure PCTCN2021125246-appb-100027
    表示基团的连接位置。
  2. 根据权利要求1所述的噻吩并嘧啶类化合物，其特征在于，所述R 1选自H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基，其中，所述杂环基包含1-3个选自N、O、S、P的杂原子。
  3. 根据权利要求2所述的噻吩并嘧啶类化合物，其特征在于，所述R 1选自取代或未取代的C1-C6烷基。
  4. 根据权利要求3所述的噻吩并嘧啶类化合物，其特征在于，所述R 1为卤素取代的C1-C6烷基，更进一步优选为三氟乙基；
    优选地，所述R 2选自H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C16芳基、取代或未取代的5-16元杂芳基、取代或未取代的4-8元杂环基，其中，所述杂芳基或杂环基包含1-3个选自N、O、S、P的杂原子，进一步优选地，所述R 2为H；
    优选地，所述R 3为H、取代或未取代的C1-C6烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C1-C4烷氨基、-NH 2或-CN；
    优选地，所述Y、Z分别选自N；
    优选地，所述W为C；
    优选地，所述U 1、U 2、U 3、U 4、U 5、U 6、U 7、U 8分别独立地选自
    Figure PCTCN2021125246-appb-100028
    Figure PCTCN2021125246-appb-100029
    且U 1、U 2、U 3、U 4中至多有一个为
    Figure PCTCN2021125246-appb-100030
    中至多有一个为
    Figure PCTCN2021125246-appb-100031
    U 7、U 8中至多有一个为
    Figure PCTCN2021125246-appb-100032
    其中，
    Figure PCTCN2021125246-appb-100033
    表示基团的连接位置，
    每一个R'分别独立地选自H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
    每一个R”分别独立地选自H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
    每一个R”'分别独立地选自H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
    每一个R””分别独立地选自H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、氰基；
    优选地，所述A选自取代或未取代的C6-C10芳基、取代或未取代的5-12元杂芳基，其中，所述的杂芳基包含1-3个选自N、O、S、P的杂原子；
    优选地，A为取代或未取代的苯环、取代或未取代的吡啶环、取代或未取代的哒嗪环、取代或未取代的嘧啶环、取代或未取代的三氮嗪环、取代或未取代的噻吩环、取代或未取代的噻唑环、取代或未取代的咪唑环、取代或未取代的吡咯环、取代或未取代的吡唑环、取代或未取代的噁唑环、取代或未取代的异噁唑环、取代或未取代的三氮唑环；
    优选地，所述L 1为不存在或-CH 2-，优选为-CH 2-；
    优选地，所述L 2选自
    Figure PCTCN2021125246-appb-100034
    优选为
    Figure PCTCN2021125246-appb-100035
    其中，
    Figure PCTCN2021125246-appb-100036
    表示基团的连接位置；
    优选地，所述X选自碳原子；
    优选地，所述R 4选自
    Figure PCTCN2021125246-appb-100037
    其中，R4'选自氟或氯，R4”选自H、甲基或氟，R4”'选自H、取代或未取代的C1-C4烷基，
    Figure PCTCN2021125246-appb-100038
    表示基团的连接位置。
  5. 根据权利要求1-4中任一项所述的噻吩并嘧啶类化合物，其特征在于，所述式I所示的化合物中螺环部分结构式为
    Figure PCTCN2021125246-appb-100039
    其中
    Figure PCTCN2021125246-appb-100040
    表示基团的连接位置，选自如下基团中的任意一种：
    Figure PCTCN2021125246-appb-100041
    优选地，所述式I所示的化合物中螺环部分结构式为
    Figure PCTCN2021125246-appb-100042
    其中，
    Figure PCTCN2021125246-appb-100043
    表示基团的连接位置，选自如下基团中的任意一种：
    Figure PCTCN2021125246-appb-100044
  6. 根据权利要求1-5中任一项所述的噻吩并嘧啶类化合物，其特征在于，所述式I中结构式为
    Figure PCTCN2021125246-appb-100045
    所示的并环部分，其中
    Figure PCTCN2021125246-appb-100046
    表示基团的连接位置，选自如下基团中的任意一种：
    Figure PCTCN2021125246-appb-100047
    Figure PCTCN2021125246-appb-100048
    其中，R e、R f分别独立地选自H、甲基、三氟甲基、二氟甲基、甲氧基、乙氧基、三氟甲氧基、卤素、羟基、氨基、氰基、甲氨基、二甲氨基、乙氨基、甲乙氨基、二乙氨基、三氟乙氨基、羧基、甲氧基羰基、乙氧基羰基、氨基甲酰基、甲氨基甲酰基、二甲氨基甲酰基、甲乙氨基甲酰基或二乙氨基甲酰基。
  7. 根据权利要求1-6中任一项所述的噻吩并嘧啶类化合物，其特征在于，所述式I中结构式为
    Figure PCTCN2021125246-appb-100049
    所示的环状部分，其中，
    Figure PCTCN2021125246-appb-100050
    表示基团的连接位置，选自如下基团中的任意一种：
    Figure PCTCN2021125246-appb-100051
  8. 根据权利要求1-7中任一项所述的噻吩并嘧啶类化合物，其特征在于，所述R 4选自-CH 2F、-CH 2Cl、
    Figure PCTCN2021125246-appb-100052
    Figure PCTCN2021125246-appb-100053
  9. 根据权利要求1-8中任一项所述的噻吩并嘧啶类化合物，其特征在于，所述式I所示的化合物选自下述化合物中的任意一种：
    Figure PCTCN2021125246-appb-100054
    Figure PCTCN2021125246-appb-100055
    Figure PCTCN2021125246-appb-100056
    Figure PCTCN2021125246-appb-100057
    Figure PCTCN2021125246-appb-100058
  10. 根据权利要求1-9中任一项所述的噻吩并嘧啶类化合物，其特征在于，所述噻吩并嘧啶类化合物还包括式I所示的化合物的药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物或多晶型物或氘代物中的任意一种。
  11. 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1-10中任一项所述的噻吩并嘧啶类化合物和药学上可接受的载体。
  12. 根据权利要求1-10中任一项所述的噻吩并嘧啶类化合物或权利要求11所述的药物组合物的用途，其特征在于，所述用途选自下述(a)-(c)中的任意一种：
    (a)制备用于预防或治疗与MLL1、MLL2、MLL融合蛋白、和/或menin蛋白活性有关的肿瘤、糖尿病和其他疾病的药物；
    (b)制备用于体外非治疗性与MLL1、MLL2、MLL融合蛋白、和/或menin蛋白的活性有关的抑制剂；
    (c)制备用于体外非治疗性肿瘤细胞的增殖抑制剂。
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