WO2019184919A1 - Adamantane-containing compound and use thereof in treating cancer - Google Patents

Adamantane-containing compound and use thereof in treating cancer Download PDF

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WO2019184919A1
WO2019184919A1 PCT/CN2019/079734 CN2019079734W WO2019184919A1 WO 2019184919 A1 WO2019184919 A1 WO 2019184919A1 CN 2019079734 W CN2019079734 W CN 2019079734W WO 2019184919 A1 WO2019184919 A1 WO 2019184919A1
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compound
substituted
unsubstituted
group
synthesis
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PCT/CN2019/079734
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French (fr)
Chinese (zh)
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樊磊
王飞
吴孝泉
胥珂馨
霍永旭
李兴海
陈元伟
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成都海创药业有限公司
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Publication of WO2019184919A1 publication Critical patent/WO2019184919A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention belongs to the field of medicine and relates to a novel structural compound containing adamantane and its use in the treatment of cancer.
  • Prostate cancer is one of the common malignant tumors in older men.
  • the incidence of prostate cancer ranks second among all malignant tumors in men.
  • the incidence of prostate cancer ranks first among all male malignancies, with the second highest mortality rate.
  • China its incidence has also leapt to the third place in genitourinary malignancies in recent years.
  • the clinical symptoms of prostate cancer are few in the early stage, and most of the patients have reached the advanced stage when they are diagnosed, and they have lost the opportunity to cure the disease.
  • the treatment of castration-resistant prostate cancer is mainly based on the combination of docetaxel, mitoxantrone, prednisone and other drugs, with obvious side effects, and there is no optimal treatment.
  • New anti-tumor drugs are currently in the process of continuous development and research. Therefore, the search for an anti-tumor drug with high efficiency, safety and few side effects has broad market prospects.
  • the present invention provides a compound containing adamantane and its use in the treatment of cancer.
  • the present invention provides a compound of Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:
  • Y is selected from O, S, NR 31 , C(R 31 ) 2 ,
  • R 31 is each independently selected from the group consisting of hydrogen, hydrazine, hydrazine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
  • R 1 is selected from substituted or unsubstituted adamantyl
  • the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 , Substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 An alkynyl group, the substituents being ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
  • the two substituents on the same carbon atom are bonded to form a substituted or unsubstituted 3-6 membered cycloalkyl group, a substituted or unsubstituted 3-6 membered heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted group.
  • the substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy ;
  • R 2 to R 6 are each independently selected from the group consisting of hydrogen, hydrazine, hydrazine, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 , substituted or unsubstituted C 1 -C 4 alkyl, substituted Or unsubstituted C 1 -C 4 alkoxy group,
  • the substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ;
  • R 7 is selected from
  • R 20 is each independently selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted 3-6 membered cycloalkyl group, a substituted or unsubstituted 3-6 membered heterocyclic group, A substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, which is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 .
  • Y is selected from O, S, NR 31 ,
  • R 31 is selected from the group consisting of hydrogen, hydrazine, hydrazine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
  • R 1 is selected from substituted or unsubstituted adamantyl
  • the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 , Substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 An alkynyl group, the substituents being ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
  • the two substituents on the same carbon atom are bonded to form a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, and a heteroaryl group;
  • R 3 is selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 1 -C 4 alkoxy group,
  • the substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ;
  • R 7 is selected from
  • R 20 is each independently selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a 3 to 6 membered cycloalkyl group, a 3 to 6 membered heterocyclic group, an aryl group, a heteroaryl group,
  • the substituents are ruthenium, rhodium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 .
  • Y is selected from O, S, NR 31 ,
  • R 31 is selected from the group consisting of hydrogen, hydrazine, hydrazine, C 1 -C 2 alkyl, C 1 -C 2 alkoxy;
  • R 3 is selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 1 -C 4 alkoxy group,
  • the substituents are ruthenium, osmium, -OH, -NH 2 ;
  • R 7 is selected from
  • R 20 is each independently selected from a substituted or unsubstituted heterocyclic group selected from the group consisting of C 1 -C 4 alkyl groups and 3 to 5 membered heterocyclic rings.
  • the substituents are ruthenium, rhodium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 .
  • Y is selected from O, S, NR 31 ;
  • R 31 is selected from the group consisting of hydrogen, hydrazine and hydrazine;
  • R 3 is selected from a substituted or unsubstituted C 1 -C 2 alkyl group
  • the substituents are ruthenium and osmium
  • R 7 is selected from
  • R 20 are each independently selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a 4 membered heterocyclic ring,
  • the substituent is -CN, -COOH, -CHO, -CONH 2 .
  • Y is selected from O, NH;
  • R 3 is selected from -CH 3 or -CD 3 ;
  • R 7 is selected from
  • R 20 is independently substituted or unsubstituted, and is selected from a C 1 -C 4 alkyl group
  • the substituent is -COOH.
  • R 1 is selected from substituted or unsubstituted adamantyl
  • the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 , a substituted or unsubstituted C 1 -C 4 alkoxy group, a substituted or unsubstituted C 1 -C 4 alkyl group; the substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, - CHO, -CONH 2 ;
  • the two substituents on the same carbon atom are bonded to form a 4- to 6-membered heterocyclic group.
  • R 1 is selected from substituted or unsubstituted adamantyl
  • the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 , a C 1 -C 2 alkoxy group, a substituted or unsubstituted C 1 -C 2 alkyl group; the substituents are ruthenium, osmium, -OH, -NH 2 ;
  • the two substituents on the same carbon atom are joined to form a 5-membered heterocyclic group.
  • R 1 is selected from substituted or unsubstituted adamantyl
  • the substituent of the adamantyl group is -OH, -NH 2 , -CN, -COOH, -CONH 2 , a methoxy group, a substituted or unsubstituted methyl group; the substituent is -OH, -NH 2 ;
  • X is selected from NH, none;
  • R 3 is selected from -CH 3 , -CD 3 ;
  • R 11 is selected from the group consisting of -H, -OH, -NH 2 ;
  • the compound IIIA is one of the following structural formulas:
  • X is selected from NH, none;
  • R 3 is selected from -CH 3 , -CD 3 ;
  • R 14 is selected from -H, -OH,
  • the compound IIIB is one of the following structural formulas:
  • the compound II is as shown in formula IIIC:
  • R 3 is selected from -CH 3 or -CD 3 ;
  • R 15, R 16 are each independently selected from -H, -OH; or, R 15, R 16 connected to form
  • R 17 is selected from -H, -COOH
  • R 7 ' selected from Wherein R 20 is independently substituted or unsubstituted, and is selected from a C 1 -C 4 alkyl group, The substituent is -COOH.
  • the compound IIIC is one of the following structural formulas:
  • X is selected from NH, none;
  • R 3 is selected from -CH 3 , -CD 3 ;
  • R 18 is selected from -OH
  • the compound IIID is one of the following structural formulas:
  • the present invention also provides the above compound, or a crystalline form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof, Or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for use in the manufacture of a medicament for the treatment and/or prevention of cancer.
  • the cancer is breast cancer, brain cancer, prostate cancer, lung cancer, ovarian cancer, bone cancer, neuro-cancer, liver cancer, blood cancer, esophageal cancer, glioblastoma, multiple myeloma, mantle cell lymphoma, acute myeloid leukemia. And concurrent cancer.
  • the cancer is prostate cancer, ovarian cancer, bone cancer or neuro-cancer.
  • the present invention also provides the above compound, or a crystalline form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof, Or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for use in the manufacture of a medicament for reducing expression of a full length androgen receptor, a variant androgen receptor.
  • the present invention also provides the above compound, or a crystalline form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof, Or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for use in the preparation of a medicament for inhibiting proliferation of cancer cells.
  • the cancer cell is a prostate cancer cell, an ovarian cancer cell, a bone cancer cell, or a neural cancer cell.
  • cancer cells are cancer cells of the following cancers: breast cancer, brain cancer, prostate cancer, lung cancer, ovarian cancer, bone cancer, neuro-cancer, liver cancer, blood cancer, esophageal cancer, glioblastoma, multiple bone marrow Tumor, mantle cell lymphoma, acute myeloid leukemia and concurrent cancer.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • the structures of the compounds described in the present invention all refer to structures which are stably present.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • ⁇ refers to the isotope of hydrogen (H), also known as heavy hydrogen, and the elemental symbol is generally D or 2H.
  • ⁇ refers to the isotope of hydrogen (H), and the element symbol is generally T or 3H.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a - C b ) alkyl group indicates any alkyl group having "a" to "b" carbon atoms.
  • C 1 -C 4 alkyl means an alkyl group containing from 1 to 4 carbon atoms.
  • the C 1 -C 4 alkyl group means a straight or branched hydrocarbon chain containing one to four carbon atoms.
  • alkyl group is a hydrocarbon group in which one hydrogen atom is lost in an alkane molecule, for example, methyl-CH 3 , ethyl-CH 3 CH 2 or the like.
  • alkylene group means a hydrocarbon group in which two hydrogen atoms are absent from an alkane molecule, such as methylene-CH 2 -, ethylene-CH 2 CH 2 - or the like.
  • C 1-4 alkylene means a straight or branched hydrocarbon chain containing one to four carbon atoms.
  • alkenyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond.
  • the alkenyl group may be straight or branched.
  • C2-4 alkenyl refers to a straight or branched alkenyl group having from 2 to 4 carbon atoms.
  • Alkynyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group can be straight or branched.
  • C2-4 alkynyl refers to a straight or branched alkynyl group having from 2 to 4 carbon atoms.
  • substituted or unsubstituted C 1-4 alkyl group means that the C 1-4 alkyl group may be substituted or unsubstituted.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system, such as phenyl and naphthyl.
  • the aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but may not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be in a conjugated pi-electron system.
  • the aryl group can be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms. Containing at least one ring heteroatom selected from N, O or S, the remaining ring atoms are C, and additionally have a fully conjugated pi-electron system.
  • furyl pyrrolyl, quinolyl, thienyl, pyridyl, pyrazolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, thienopyridinyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic.
  • C 3-8 cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms.
  • Heterocyclyl means a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carries at least one cycloalkyl selected from O, S or substituted nitrogen atoms, the remainder The ring atom is carbon.
  • C 3-8 heterocyclic group means a heterocyclic group having 3 to 8 carbon atoms and a hetero atom number. The heterocyclic group may be unsubstituted or substituted with one or more substituents.
  • the "compound of the present invention” means a compound represented by the formula (I).
  • the term also includes various crystalline forms, stereoisomers, pharmaceutically acceptable salts, solvates, prodrugs, metabolites of the compounds of formula (I);
  • Stepoisomer refers to isomers resulting from the arrangement of atoms in a molecule in a spatial arrangement, such as cis-trans isomers, enantiomers, conformational isomers, and the like.
  • “Pharmaceutically acceptable” refers to an additive or composition that is physiologically tolerable when administered to an animal, such as a mammal (eg, a human), and that typically does not produce an allergic or similar adverse reaction (eg, dizziness, etc.).
  • Pharmaceutical carriers and excipients may include, but are not limited to, diluents such as lactose, glucose, mannose and/or glycerin; lubricants; polyethylene glycols; binders such as magnesium aluminum silicate, starch, gelatin, methyl Cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; and, if necessary, a disintegrant such as starch, agar, alginic acid or a salt thereof such as sodium alginate; and/or an adsorbent, coloring Agents, preservatives, stabilizers, flavoring agents and sweeteners.
  • diluents such as lactose, glucose, mannose and/or glycerin
  • lubricants such as lactose, glucose, mannose and/or glycerin
  • polyethylene glycols such as magnesium aluminum silicate, starch, gelatin, methyl Cellulose, sodium carboxymethylcellulose and/or polyvinylpyrroli
  • Salt means the above-mentioned compound or a stereoisomer thereof, an acid form and/or a base salt formed with an inorganic and/or organic acid and a base, and also a zwitterionic salt (internal salt), and also includes a quaternary ammonium salt.
  • an alkyl ammonium salt can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount).
  • the salt in the present invention may be a hydrochloride, a hydrofluoride, a sulfate, a nitrate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate or a formic acid of the compound.
  • Salt acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, lactate, citrate, picrate, A Sulfonate, ethanesulfonate, tartrate, aspartate or trifluoroacetate.
  • Solvate of the compound of the formula (I) a solvent such as ethanol, water or the like, which may contain different amounts of water such as a monohydrate, a hemihydrate, a hemihydrate, a dihydrate or a trihydrate. Things.
  • a “prodrug” is a derivative of a compound of formula I which may be less active or even inactive, but which is converted to the activity of the invention under physiological conditions (for example by metabolism, solvolysis or otherwise) a compound that exerts its pharmacological action.
  • a compound containing a carboxyl group can form a physiologically hydrolyzable ester which is prepared by hydrolysis in vivo to give the compound of formula I itself.
  • the prodrug is preferably administered orally because hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration can be used when the ester itself is active or hydrolysis occurs in the blood.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • Cancer includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, prostate cancer, cervical cancer, esophageal cancer, testicular cancer, stomach cancer, skin cancer, lung cancer, bone cancer, colon cancer, pancreatic cancer, thyroid cancer, biliary tract cancer, small intestine Cancer, colon-rectal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, neuroblastoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, epidermoid carcinoma, seminoma, melanin Tumor, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorder, lymphatic disorder, Hodgkin's disease, hair cell carcinoma and leukemia.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the "room temperature" described in the present invention is 25 ⁇ 5 °C.
  • the "overnight” as described herein is 12 ⁇ 1 hour.
  • the present invention provides a novel adamantane-containing compound and its use in the treatment of cancer.
  • the experimental results show that the compound of the present invention can significantly inhibit the proliferation of cancer cells, reduce the expression of the full-length androgen receptor (AR-FL) and the variant androgen receptor (AR-v7), inhibit the proliferation of prostate cancer cells, and cancer.
  • AR-FL full-length androgen receptor
  • AR-v7 variant androgen receptor
  • prostate cancer has a potential therapeutic effect, providing a new option for clinical screening and/or preparation of cancer drugs.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • N,N-dimethylformamide dimethyl acetal Tianjin Ruijinte Chemical Co., Ltd.
  • Lithium methoxide Tianjin Bodi Chemical Co., Ltd.
  • the synthesis method of the target compounds 101 to 117 is similar to the synthesis method of the target compound 100 in the second step of the first embodiment, and is prepared by the following steps:
  • step 1 is similar to the step 1 in the second step of the first embodiment: the compound 17 is reacted with the substituted adamantane corresponding to each product in Table 1, to prepare an intermediate similar to the compound 98;
  • step 2 is similar to the step 2 in the second step of the first embodiment: an intermediate similar to the compound 98 is reacted with the compound Int. 6 to prepare an intermediate similar to the compound 99;
  • step 3 is similar to the step 3 in the second step of the first embodiment: an intermediate similar to the compound 99 is deprotected from the Ts protecting group to prepare the corresponding target compounds 101 to 117.
  • the synthesis of the compound 110 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 111 was carried out in the same manner as the method for synthesizing the compound 100, using a reagent corresponding thereto.
  • the synthesis of the compound 117 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • reaction solution was poured into 30 mL of water, and extracted with 30 mL (10 mL ⁇ 3) of dichloromethane, and the organic phase was combined, dried over anhydrous sodium sulfate, and purified by prep-TCL to give compound Int.11 (235 mg). 43.3%.
  • the synthesis method of the target compounds 119 to 137 is similar to the synthesis method of the target compound 118 in the first step of the second embodiment, and is prepared by the following steps:
  • step 1 in the first step of Example 2 the compound 1 is reacted with the substituted adamantane corresponding to each product in Table 2 to prepare an intermediate similar to the compound Int.
  • step 2 is similar to step 2 in the first step of Example 2: an intermediate similar to compound 10 is prepared from an intermediate similar to compound Int.
  • Example 3 is similar to the step 3 in the first step of Example 2: an intermediate similar to the compound 10 is reacted with the compound Int. 6 to prepare an intermediate similar to the compound Int.
  • step 4 is similar to step 4 in the first step of Example 2: an intermediate similar to the compound Int. 11 is reacted with the corresponding sulfonyl chloride to prepare an intermediate similar to the compound Int.
  • step 5 is similar to step 5 in the first step of Example 2: the Ts protecting group is removed similarly to the intermediate of the compound Int. 12, and the corresponding target compounds 119 to 137 are obtained.
  • the synthesis of the compound 121 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis of the compound 122 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis of the compound 130 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis of the compound 132 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis of the compound 135 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis method of the target compounds 138 to 155 is similar to the synthesis method of the target compound 100 in the second step of the first embodiment, and is prepared by the following steps:
  • step 1 is similar to the step 1 in the second step of the first embodiment: the compound 17 is reacted with the substituted adamantane corresponding to each product in Table 3 to prepare an intermediate similar to the compound 98;
  • step 2 is similar to the step 2 in the second step of the first embodiment: an intermediate similar to the compound 98 is reacted with the compound Int. 8 to prepare an intermediate similar to the compound 99;
  • step 3 is similar to the step 3 in the second step of the embodiment 1.
  • the intermediates similar to the compound 99 are deprotected from the Ts protecting group to prepare the corresponding target compounds 138 to 155.
  • the synthesis of the compound 138 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 139 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 140 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 141 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 142 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 143 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 144 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 147 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 149 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 151 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 152 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 153 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 154 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis method of the target compounds 156 to 175 is similar to the synthesis method of the target compound 118 in the first step of the second embodiment, and is prepared by the following steps:
  • step 1 in the first step of Example 2 the compound 1 is reacted with the substituted adamantane corresponding to each product in Table 4 to prepare an intermediate similar to the compound Int.
  • step 2 is similar to step 2 in the first step of Example 2: an intermediate similar to compound 10 is prepared from an intermediate similar to compound Int.
  • step 3 is similar to step 3 in the first step of Example 2: an intermediate similar to compound 10 is reacted with compound Int. 8 to prepare an intermediate similar to compound Int.
  • step 4 is similar to step 4 in the first step of Example 2: an intermediate similar to the compound Int. 11 is reacted with the corresponding sulfonyl chloride to prepare an intermediate similar to the compound Int.
  • step 5 is similar to step 5 in the first step of Example 2: an intermediate similar to the compound Int. 12 is deprotected from the Ts protecting group to give the corresponding target compound 156-175.
  • the synthesis of the compound 157 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis of the compound 158 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis of the compound 161 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis of the compound 162 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis of the compound 169 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis of the compound 171 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis method of the target compound 176, 177 is similar to the synthesis method of the target compound 100 in the second step of the first embodiment, and is prepared by the following steps:
  • step 1 is similar to the step 1 in the second step of the first embodiment: the compound 17 is reacted with the substituted adamantane corresponding to each product in Table 5 to prepare an intermediate similar to the compound 98;
  • step 2 is similar to the step 2 in the second step of the first embodiment: an intermediate similar to the compound 98 is reacted with the compound Int. 6 to prepare an intermediate similar to the compound 99;
  • the synthesis method of the target compound 178-180 is similar to the synthesis method of the target compound 118 in the first step of the second embodiment, and is prepared by the following steps:
  • step 1 is similar to step 4 in the first step of Example 2: reacting the compound Int. 11 with the corresponding acid chloride to prepare an intermediate similar to the compound Int.
  • the synthesis of the compound 178 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis of the compound 180 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
  • the synthesis method of the target compound 181, 182 is similar to the synthesis method of the target compound 100 in the second step of the first embodiment, and is prepared by the following steps:
  • step 1 is similar to the step 1 in the second step of the first embodiment: the compound 17 is reacted with the substituted adamantane corresponding to each product in Table 7, to prepare an intermediate similar to the compound 98;
  • step 2 is similar to the step 2 in the second step of the first embodiment: an intermediate similar to the compound 98 is reacted with the compound Int. 8 to prepare an intermediate similar to the compound 99;
  • the synthesis of the compound 181 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 182 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis method of the target compounds 183 to 185 is similar to the synthesis method of the target compound 118 in the first step of the second embodiment, and is prepared by the following steps:
  • Example 1 is similar to step 3 in the first step of Example 2: reacting compound 10 with compound Int. 8 to prepare an intermediate similar to compound Int.
  • step 2 is similar to step 4 in the first step of Example 2: an intermediate similar to the compound Int. 11 is reacted with the corresponding acid chloride to prepare an intermediate similar to the compound Int.
  • step 3 is similar to step 5 in the first step of Example 2: an intermediate similar to the compound Int. 12 is deprotected from the Ts protecting group to prepare the corresponding target compound 183 to 185.
  • the synthesis method of the target compounds 186 to 191 is similar to the synthesis method of the target compound 100 in the second step of the first embodiment, and is prepared by the following steps:
  • step 1 is similar to the step 1 in the second step of the first embodiment: the compound 17 is reacted with the substituted adamantane corresponding to each product in Table 9, to prepare an intermediate similar to the compound 98;
  • step 2 is similar to the step 2 in the second step of the first embodiment: an intermediate similar to the compound 98 is reacted with the compound Int. 6 or Int. 8 to prepare an intermediate similar to the compound 99;
  • step 3 is similar to the step 3 in the second step of the first embodiment: an intermediate similar to the compound 99 is deprotected from the Ts protecting group to prepare the corresponding target compound 186 to 191.
  • the synthesis of the compound 186 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 187 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 188 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 190 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • the synthesis of the compound 191 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
  • Test Example 1 Biological determination of the inhibitory effect of the compound of the present invention on proliferation of CWR22RV1 cells
  • Penicillin-Streptomycin (Hyclone, Cat. No. SV30010)
  • Cell culture medium RIPM1640 medium, 10% FBS, 1% Pen Strep.
  • PBS buffer PBS powder was dissolved in 2 liters of ultrapure water and sterilized.
  • CWR22RV1 cells were subcultured with cell culture medium, and cells grown in good condition were inoculated into 96-well plates at 80 ⁇ L per well, and the number of cells per well was 1500, and cultured overnight at 37 ° C in a 5% CO 2 cell incubator.
  • the drug was formulated with dimethyl sulfoxide (DMSO) as a 30 mM stock solution. Dilute 3 times with DMSO before use, then dilute by 3 times to obtain 9 concentration gradients, and then dilute the compound at each concentration 200 times with the culture solution (to ensure the DMSO concentration in the culture system is 0.1%). The concentration is made to repeat 2 holes. 20 ⁇ L of the diluted compound was added to the cell culture well (final concentration of 10 ⁇ M, 3.3 ⁇ M, 1.1 ⁇ M%), and gently mixed by shaking. In addition, three cell-only negative control wells and three blank control wells (only 20 ⁇ L of culture medium diluted with 200 ⁇ L of DMSO) were placed.
  • DMSO dimethyl sulfoxide
  • the IC 50 (nM) of the activity of the compound of the present invention against CWR22RV1 was as shown in Table 10.
  • Test Example 2 Biological measurement results of the inhibitory effect of the compound 108 of the present invention on proliferation of a plurality of cancer cell lines
  • MCF ⁇ 7 cell line BT ⁇ 474 cell line, MDA ⁇ MB453 cell line, and LNCAP ⁇ AR cell line are all commercially available.
  • IC 50 (nM) of the inhibition of the activity of the compound 108 of the present invention against MCF-7, BT-474, MDA-MB453, and LNCAP-AR is shown in Table 11.
  • Cancer cell line IC 50 MCF ⁇ 7 (breast cancer cells) 47 BT-474 (breast cancer cells) 600 MDA ⁇ MB453 (breast cancer cells) 450 LNCAP ⁇ AR (prostate cancer cells) 10
  • the above experimental results indicate that the compound of the present invention can significantly inhibit the proliferation of a plurality of cancer cell lines, particularly prostate cancer cell line CWR22RV1.
  • the compounds of the invention have potential for use in the treatment of a variety of cancers, particularly prostate cancer.
  • the present invention provides a novel adamantane-containing compound and its use in the treatment of cancer.
  • the experimental results show that the compound of the present invention can significantly inhibit the proliferation of cancer cells, reduce the expression of the full-length androgen receptor (AR-FL) and the variant androgen receptor (AR-v7), inhibit the proliferation of prostate cancer cells, and cancer.
  • prostate cancer has a potential therapeutic effect, providing a new option for clinical screening and/or preparation of cancer drugs.

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Abstract

Disclosed is an adamantane-containing compound and a use thereof in treating cancer, belonging to the field of medicine. The present invention provides a compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for use as a cancer treatment. The experimental results show that the compound of the present invention can significantly inhibit the proliferation of cancer cells, reduce the expression of a full-length androgen receptor (AR-FL) and a variant androgen receptor (AR-v7), inhibit the proliferation of prostate cancer cells, has a potential therapeutic effect on cancer, especially prostate cancer, and provides a novel option for clinical screening and/or preparation of cancer drugs.

Description

一种含有金刚烷的化合物及其在治疗癌症中的用途Adamantane-containing compound and use thereof in treating cancer 技术领域Technical field
本发明属于医药领域，涉及一种含有金刚烷的结构新颖化合物及其在治疗癌症中的用途。The invention belongs to the field of medicine and relates to a novel structural compound containing adamantane and its use in the treatment of cancer.
背景技术Background technique
癌症是人类面临的最危险的疾病之一。在多数情况下癌症最终会导致病人的死亡。尽管现代医学为治疗癌症做了很大的努力，但癌症目前仍然是一个有待解决的问题。前列腺癌是老年男性常见的恶性肿瘤之一。在世界范围内，前列腺癌发病率在男性所有恶性肿瘤中位居第二。在美国，前列腺癌发病率在所有男性恶性肿瘤中居第一位，死亡率居第二位。在我国，近年来其发病率亦已跃居泌尿生殖系恶性肿瘤的第三位。前列腺癌的发病临床早期症状少，大部分患者确诊时已到晚期，失去手术根治时机。行前列腺癌根治术的患者，有27％～53％在术后10年内局部复发或远处转移。内分泌治疗是目前晚期前列腺癌的主要治疗方法，但经过中位时间14～30个月后，几乎所有前列腺癌患者最终均转为雄激素非依赖前列腺癌(androgen-independent prostate cancer,AIPC)，进而发展为激素难治性前列腺癌(hormone-refractory prostate cancer,HRPC)。此类前列腺癌统称为去势抵抗性前列腺癌(castrate-resistant prostate cancer,CRPC)。去势抵抗性前列腺癌患者生存质量差，中位生存期12～20个月。随着前列腺癌发病率、死亡率的上升，如何有效治疗去势抵抗性前列腺癌患已成为现代医学研究的热点。Cancer is one of the most dangerous diseases facing humans. In most cases, cancer can eventually lead to death. Although modern medicine has made great efforts to treat cancer, cancer is still a problem to be solved. Prostate cancer is one of the common malignant tumors in older men. Worldwide, the incidence of prostate cancer ranks second among all malignant tumors in men. In the United States, the incidence of prostate cancer ranks first among all male malignancies, with the second highest mortality rate. In China, its incidence has also leapt to the third place in genitourinary malignancies in recent years. The clinical symptoms of prostate cancer are few in the early stage, and most of the patients have reached the advanced stage when they are diagnosed, and they have lost the opportunity to cure the disease. In patients undergoing radical prostatectomy, 27% to 53% have local recurrence or distant metastasis within 10 years after surgery. Endocrine therapy is currently the main treatment for advanced prostate cancer, but after 14 to 30 months of median time, almost all patients with prostate cancer eventually turn to androgen-independent prostate cancer (AIPC). Developed as hormone-refractory prostate cancer (HRPC). Such prostate cancer is collectively referred to as castrate-resistant prostate cancer (CRPC). Patients with castration-resistant prostate cancer have poor quality of life, with a median survival of 12 to 20 months. With the increase in the incidence and mortality of prostate cancer, how to effectively treat castration-resistant prostate cancer has become a hot spot in modern medical research.
目前去势抵抗性前列腺癌的治疗手段主要是以多西紫杉醇、米托蒽醌、泼尼松等药物联合化学治疗，副作用明显，且尚无最佳治疗方案。新型抗肿瘤药物目前处于不断开发研究阶段。因此，寻找一种高效、安全、副作用少的抗肿瘤药物的研究具有广阔市场前景。At present, the treatment of castration-resistant prostate cancer is mainly based on the combination of docetaxel, mitoxantrone, prednisone and other drugs, with obvious side effects, and there is no optimal treatment. New anti-tumor drugs are currently in the process of continuous development and research. Therefore, the search for an anti-tumor drug with high efficiency, safety and few side effects has broad market prospects.
发明内容Summary of the invention
为了解决上述问题，本发明提供了一种含有金刚烷的化合物及其在治疗癌症中的用途。In order to solve the above problems, the present invention provides a compound containing adamantane and its use in the treatment of cancer.
本发明提供了式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物：The present invention provides a compound of Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:
Figure PCTCN2019079734-appb-000001
Figure PCTCN2019079734-appb-000001
式中，In the formula,
Y选自O、S、NR 31、C(R 31) 2， Y is selected from O, S, NR 31 , C(R 31 ) 2 ,
其中，R 31各自独立地选自氢、氘、氚、C 1～C 4烷基、C 1～C 4烷氧基； Wherein R 31 is each independently selected from the group consisting of hydrogen, hydrazine, hydrazine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
R 1选自取代或未取代的金刚烷基， R 1 is selected from substituted or unsubstituted adamantyl,
其中，所述金刚烷基的取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、
Figure PCTCN2019079734-appb-000002
取代或未取代的C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、取代或未取代的C 2～C 8烯基、取代或未取代的C 2～C 8炔基，所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2， Wherein the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
Figure PCTCN2019079734-appb-000002
Substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 An alkynyl group, the substituents being ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
或者，同一碳原子上的两取代基一起形成双键，所述双键为＝O、＝S、＝NR 32、＝C(R 32) 2，其中，R 32各自独立地选自氢、氘、氚、C 1～C 4烷基、C 1～C 4烷氧基， Alternatively, the two substituents on the same carbon atom together form a double bond, which is =0, =S, =NR 32 , =C(R 32 ) 2 , wherein R 32 are each independently selected from hydrogen, hydrazine , hydrazine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy,
或者，同一碳原子上的两取代基相连形成取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基，所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、C 1～C 4烷基、C 1～C 4烷氧基； Alternatively, the two substituents on the same carbon atom are bonded to form a substituted or unsubstituted 3-6 membered cycloalkyl group, a substituted or unsubstituted 3-6 membered heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted group. Heteroaryl, the substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy ;
R 2～R 6各自独立地选自氢、氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、取代或未取代的C 1～C 4烷基、取代或未取代的C 1～C 4烷氧基， R 2 to R 6 are each independently selected from the group consisting of hydrogen, hydrazine, hydrazine, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 , substituted or unsubstituted C 1 -C 4 alkyl, substituted Or unsubstituted C 1 -C 4 alkoxy group,
所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2； The substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ;
R 7选自
Figure PCTCN2019079734-appb-000003
R 7 is selected from
Figure PCTCN2019079734-appb-000003
其中，R 20各自独立地选自取代或未取代的选自C 1～C 4烷基、取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基，所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2。 Wherein R 20 is each independently selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted 3-6 membered cycloalkyl group, a substituted or unsubstituted 3-6 membered heterocyclic group, A substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, which is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 .
进一步地，further,
所述化合物Ⅰ如式Ⅱ所示：The compound I is as shown in formula II:
Figure PCTCN2019079734-appb-000004
Figure PCTCN2019079734-appb-000004
式中，In the formula,
Y选自O、S、NR 31， Y is selected from O, S, NR 31 ,
其中，R 31选自氢、氘、氚、C 1～C 4烷基、C 1～C 4烷氧基； Wherein R 31 is selected from the group consisting of hydrogen, hydrazine, hydrazine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
R 1选自取代或未取代的金刚烷基， R 1 is selected from substituted or unsubstituted adamantyl,
其中，所述金刚烷基的取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、
Figure PCTCN2019079734-appb-000005
取代或未取代的C 1～C 6烷氧基、取代或未取代的C 1～C 6烷基、取代或未取代的C 2～C 6烯基、取代或未取代的C 2～C 6炔基，所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2， Wherein the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
Figure PCTCN2019079734-appb-000005
Substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 An alkynyl group, the substituents being ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
或者，同一碳原子上的两取代基一起形成双键，所述双键为＝O、＝S、＝NR 32、＝C(R 32) 2，其中，R 32各自独立地选自氢、氘、氚， Alternatively, the two substituents on the same carbon atom together form a double bond, which is =0, =S, =NR 32 , =C(R 32 ) 2 , wherein R 32 are each independently selected from hydrogen, hydrazine ,tritium,
或者，同一碳原子上的两取代基相连形成3～6元环烷基、3～6元杂环基、芳基、杂芳基；Alternatively, the two substituents on the same carbon atom are bonded to form a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, and a heteroaryl group;
R 3选自取代或未取代的C 1～C 4烷基、取代或未取代的C 1～C 4烷氧基， R 3 is selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 1 -C 4 alkoxy group,
所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2； The substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ;
R 7选自
Figure PCTCN2019079734-appb-000006
R 7 is selected from
Figure PCTCN2019079734-appb-000006
其中，R 20各自独立地选自取代或未取代的选自C 1～C 4烷基、3～6元环烷基、3～6元杂环基、芳基、杂芳基， Wherein R 20 is each independently selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a 3 to 6 membered cycloalkyl group, a 3 to 6 membered heterocyclic group, an aryl group, a heteroaryl group,
所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2。 The substituents are ruthenium, rhodium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 .
进一步地，further,
Y选自O、S、NR 31， Y is selected from O, S, NR 31 ,
其中，R 31选自氢、氘、氚、C 1～C 2烷基、C 1～C 2烷氧基； Wherein R 31 is selected from the group consisting of hydrogen, hydrazine, hydrazine, C 1 -C 2 alkyl, C 1 -C 2 alkoxy;
R 3选自取代或未取代的C 1～C 4烷基、取代或未取代的C 1～C 4烷氧基， R 3 is selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 1 -C 4 alkoxy group,
所述取代基为氘、氚、-OH、-NH 2； The substituents are ruthenium, osmium, -OH, -NH 2 ;
R 7选自
Figure PCTCN2019079734-appb-000007
R 7 is selected from
Figure PCTCN2019079734-appb-000007
其中，R 20各自独立地选自取代或未取代的选自C 1～C 4烷基、3～5元杂环， Wherein R 20 is each independently selected from a substituted or unsubstituted heterocyclic group selected from the group consisting of C 1 -C 4 alkyl groups and 3 to 5 membered heterocyclic rings.
所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2。 The substituents are ruthenium, rhodium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 .
进一步地，further,
Y选自O、S、NR 31； Y is selected from O, S, NR 31 ;
其中，R 31选自氢、氘、氚； Wherein R 31 is selected from the group consisting of hydrogen, hydrazine and hydrazine;
R 3选自取代或未取代的C 1～C 2烷基， R 3 is selected from a substituted or unsubstituted C 1 -C 2 alkyl group,
所述取代基为氘、氚；The substituents are ruthenium and osmium;
R 7选自
Figure PCTCN2019079734-appb-000008
R 7 is selected from
Figure PCTCN2019079734-appb-000008
其中，R 20各自独立地选自取代或未取代的选自C 1～C 4烷基、4元杂环， Wherein R 20 are each independently selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a 4 membered heterocyclic ring,
所述取代基为-CN、-COOH、-CHO、-CONH 2。 The substituent is -CN, -COOH, -CHO, -CONH 2 .
进一步地，further,
Y选自O、NH；Y is selected from O, NH;
R 3选自-CH 3或-CD 3； R 3 is selected from -CH 3 or -CD 3 ;
R 7选自
Figure PCTCN2019079734-appb-000009
R 7 is selected from
Figure PCTCN2019079734-appb-000009
其中，R 20各自独立地取代或未取代的选自C 1～C 4烷基、
Figure PCTCN2019079734-appb-000010
Wherein R 20 is independently substituted or unsubstituted, and is selected from a C 1 -C 4 alkyl group,
Figure PCTCN2019079734-appb-000010
所述取代基为-COOH。The substituent is -COOH.
进一步地，further,
R 1选自取代或未取代的金刚烷基； R 1 is selected from substituted or unsubstituted adamantyl;
其中，所述金刚烷基的取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、
Figure PCTCN2019079734-appb-000011
取代或未取代的C 1～C 4烷氧基、取代或未取代的C 1～C 4烷基；所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2； Wherein the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
Figure PCTCN2019079734-appb-000011
a substituted or unsubstituted C 1 -C 4 alkoxy group, a substituted or unsubstituted C 1 -C 4 alkyl group; the substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, - CHO, -CONH 2 ;
或者，同一碳原子上的两取代基一起形成双键，所述双键为＝O、＝S、＝NH、＝CH 2； Alternatively, the two substituents on the same carbon atom together form a double bond, which is =0, =S, =NH, =CH 2 ;
或者，同一碳原子上的两取代基相连形成4～6元杂环基。Alternatively, the two substituents on the same carbon atom are bonded to form a 4- to 6-membered heterocyclic group.
进一步地，further,
R 1选自取代或未取代的金刚烷基； R 1 is selected from substituted or unsubstituted adamantyl;
其中，所述金刚烷基的取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、
Figure PCTCN2019079734-appb-000012
C 1～C 2烷氧基、取代或未取代的C 1～C 2烷基；所述取代基为氘、氚、-OH、-NH 2； Wherein the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
Figure PCTCN2019079734-appb-000012
a C 1 -C 2 alkoxy group, a substituted or unsubstituted C 1 -C 2 alkyl group; the substituents are ruthenium, osmium, -OH, -NH 2 ;
或者，同一碳原子上的两取代基一起形成双键，所述双键为＝O或＝S；Alternatively, the two substituents on the same carbon atom together form a double bond, the double bond being =O or =S;
或者，同一碳原子上的两取代基相连形成5元杂环基。Alternatively, the two substituents on the same carbon atom are joined to form a 5-membered heterocyclic group.
进一步地，further,
R 1选自取代或未取代的金刚烷基； R 1 is selected from substituted or unsubstituted adamantyl;
其中，所述金刚烷基的取代基为-OH、-NH 2、-CN、-COOH、-CONH 2、
Figure PCTCN2019079734-appb-000013
甲氧基、取代或未取代的甲基；所述取代基为-OH、-NH 2； Wherein the substituent of the adamantyl group is -OH, -NH 2 , -CN, -COOH, -CONH 2 ,
Figure PCTCN2019079734-appb-000013
a methoxy group, a substituted or unsubstituted methyl group; the substituent is -OH, -NH 2 ;
或者，同一碳原子上的两取代基一起形成＝O；Alternatively, the two substituents on the same carbon atom together form =O;
或者，同一碳原子上的两取代基相连形成
Figure PCTCN2019079734-appb-000014
Or, two substituents on the same carbon atom are connected to form
Figure PCTCN2019079734-appb-000014
进一步地，further,
所述化合物Ⅱ如式ⅢA所示：Said compound II is as shown in formula IIIA:
Figure PCTCN2019079734-appb-000015
Figure PCTCN2019079734-appb-000015
式中，In the formula,
X选自NH、无；X is selected from NH, none;
R 3选自-CH 3、-CD 3； R 3 is selected from -CH 3 , -CD 3 ;
R 11选自-H、-OH、-NH 2； R 11 is selected from the group consisting of -H, -OH, -NH 2 ;
R 12、R 13各自独立地选自-H、-OH、-NH 2、-CN、-COOH、-CONH 2、
Figure PCTCN2019079734-appb-000016
甲氧基、取代或未取代的甲基；所述取代基为-OH、-NH 2；或者，R 12、R 13一起形成＝O。 R 12 and R 13 are each independently selected from -H, -OH, -NH 2 , -CN, -COOH, -CONH 2 ,
Figure PCTCN2019079734-appb-000016
a methoxy group, a substituted or unsubstituted methyl group; the substituent is -OH, -NH 2 ; or R 12 and R 13 together form =0.
进一步地，further,
所述化合物ⅢA为下述结构式之一：The compound IIIA is one of the following structural formulas:
Figure PCTCN2019079734-appb-000017
Figure PCTCN2019079734-appb-000017
Figure PCTCN2019079734-appb-000018
Figure PCTCN2019079734-appb-000018
Figure PCTCN2019079734-appb-000019
Figure PCTCN2019079734-appb-000019
进一步地，further,
所述化合物Ⅱ如式ⅢB所示：The compound II is as shown in formula IIIB:
Figure PCTCN2019079734-appb-000020
Figure PCTCN2019079734-appb-000020
式中，In the formula,
X选自NH、无；X is selected from NH, none;
R 3选自-CH 3、-CD 3； R 3 is selected from -CH 3 , -CD 3 ;
R 14选自-H、-OH、
Figure PCTCN2019079734-appb-000021
R 14 is selected from -H, -OH,
Figure PCTCN2019079734-appb-000021
进一步地，further,
所述化合物ⅢB为下述结构式之一：The compound IIIB is one of the following structural formulas:
Figure PCTCN2019079734-appb-000022
Figure PCTCN2019079734-appb-000022
Figure PCTCN2019079734-appb-000023
Figure PCTCN2019079734-appb-000023
进一步地，further,
所述化合物Ⅱ如式ⅢC所示：The compound II is as shown in formula IIIC:
Figure PCTCN2019079734-appb-000024
Figure PCTCN2019079734-appb-000024
式中，In the formula,
R 3选自-CH 3或-CD 3； R 3 is selected from -CH 3 or -CD 3 ;
R 15、R 16各自独立地选自-H、-OH；或者，R 15、R 16相连形成
Figure PCTCN2019079734-appb-000025
R 15, R 16 are each independently selected from -H, -OH; or, R 15, R 16 connected to form
Figure PCTCN2019079734-appb-000025
R 17选自-H、-COOH； R 17 is selected from -H, -COOH;
R 7’选自
Figure PCTCN2019079734-appb-000026
其中，R 20各自独立地取代或未取代的选自C 1～C 4烷基、
Figure PCTCN2019079734-appb-000027
所述取代基为-COOH。 R 7 ' selected from
Figure PCTCN2019079734-appb-000026
Wherein R 20 is independently substituted or unsubstituted, and is selected from a C 1 -C 4 alkyl group,
Figure PCTCN2019079734-appb-000027
The substituent is -COOH.
进一步地，further,
所述化合物ⅢC为下述结构式之一：The compound IIIC is one of the following structural formulas:
Figure PCTCN2019079734-appb-000028
Figure PCTCN2019079734-appb-000028
进一步地，further,
所述化合物Ⅱ如式ⅢD所示：Said compound II is as shown in formula IIID:
Figure PCTCN2019079734-appb-000029
Figure PCTCN2019079734-appb-000029
式中，In the formula,
X选自NH、无；X is selected from NH, none;
R 3选自-CH 3、-CD 3； R 3 is selected from -CH 3 , -CD 3 ;
R 18选自-OH、
Figure PCTCN2019079734-appb-000030
R 18 is selected from -OH,
Figure PCTCN2019079734-appb-000030
进一步地，further,
所述化合物ⅢD为下述结构式之一：The compound IIID is one of the following structural formulas:
Figure PCTCN2019079734-appb-000031
Figure PCTCN2019079734-appb-000031
本发明还提供了上述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其立体化学异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗和/或预防癌症的药物中的用途。The present invention also provides the above compound, or a crystalline form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof, Or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for use in the manufacture of a medicament for the treatment and/or prevention of cancer.
进一步地，further,
所述癌症为乳腺癌、脑癌、前列腺癌，肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。The cancer is breast cancer, brain cancer, prostate cancer, lung cancer, ovarian cancer, bone cancer, neuro-cancer, liver cancer, blood cancer, esophageal cancer, glioblastoma, multiple myeloma, mantle cell lymphoma, acute myeloid leukemia. And concurrent cancer.
进一步地，further,
所述癌症为前列腺癌、卵巢癌、骨癌或神经癌。The cancer is prostate cancer, ovarian cancer, bone cancer or neuro-cancer.
本发明还提供了上述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其立体化学异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备减少全长雄激素受体、变异雄激素受体表达的药物中的用途。The present invention also provides the above compound, or a crystalline form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof, Or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for use in the manufacture of a medicament for reducing expression of a full length androgen receptor, a variant androgen receptor.
本发明还提供了上述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其立体化学异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备抑制癌细胞增殖的药物中的用途。The present invention also provides the above compound, or a crystalline form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a stereochemical isomer thereof, or a pharmaceutically acceptable salt thereof, Or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for use in the preparation of a medicament for inhibiting proliferation of cancer cells.
进一步地，所述癌细胞为前列腺癌细胞、卵巢癌细胞、骨癌细胞或神经癌细胞。Further, the cancer cell is a prostate cancer cell, an ovarian cancer cell, a bone cancer cell, or a neural cancer cell.
进一步地，所述癌细胞是下述癌症的癌细胞：乳腺癌、脑癌、前列腺癌，肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。Further, the cancer cells are cancer cells of the following cancers: breast cancer, brain cancer, prostate cancer, lung cancer, ovarian cancer, bone cancer, neuro-cancer, liver cancer, blood cancer, esophageal cancer, glioblastoma, multiple bone marrow Tumor, mantle cell lymphoma, acute myeloid leukemia and concurrent cancer.
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。The compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。Definitions of terms of use in connection with the present invention: Unless otherwise stated, the initial definitions provided herein by the group or term apply to the group or term of the entire specification; for terms not specifically defined herein, it should be based on the disclosure and context. Given the meanings that those skilled in the art can give to them.
本发明中所述化合物的结构均是指能够稳定存在的结构。The structures of the compounds described in the present invention all refer to structures which are stably present.
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
“氘”是指氢(H)的同位素，也被称为重氢，元素符号一般为D或2H。"氘" refers to the isotope of hydrogen (H), also known as heavy hydrogen, and the elemental symbol is generally D or 2H.
“氚”是指氢(H)的同位素，元素符号一般为T或3H。"氚" refers to the isotope of hydrogen (H), and the element symbol is generally T or 3H.
“卤素”为氟、氯、溴或碘。"Halogen" is fluorine, chlorine, bromine or iodine.
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀(C a～C b)烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，C 1～C 4烷基是指包含1～4个碳原子的烷基。C 1～C 4烷基是指含有一个至四个碳原子的直链或支链的烃链。 The minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a - C b ) alkyl group indicates any alkyl group having "a" to "b" carbon atoms. Thus, for example, C 1 -C 4 alkyl means an alkyl group containing from 1 to 4 carbon atoms. The C 1 -C 4 alkyl group means a straight or branched hydrocarbon chain containing one to four carbon atoms.
“烷基”是烷烃分子中少掉一个氢原子而成的烃基，例如，甲基-CH 3,乙基-CH 3CH 2等。 The "alkyl group" is a hydrocarbon group in which one hydrogen atom is lost in an alkane molecule, for example, methyl-CH 3 , ethyl-CH 3 CH 2 or the like.
“亚烷基”是指烷烃分子中少掉两个氢原子而成的烃基，例如亚甲基-CH 2-,亚乙基-CH 2CH 2-等。“C 1-4亚烷基”是指含有一个至四个碳原子的直链或支链的烃链。 The "alkylene group" means a hydrocarbon group in which two hydrogen atoms are absent from an alkane molecule, such as methylene-CH 2 -, ethylene-CH 2 CH 2 - or the like. "C 1-4 alkylene" means a straight or branched hydrocarbon chain containing one to four carbon atoms.
“烯基”是指具有至少一个碳-碳双键的脂肪族碳氢基团。所述的烯基可以是直链或支链的。例如，术语“C 2-4烯基”指具有2-4个碳原子的直链或支链烯基。 "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group may be straight or branched. For example, the term " C2-4 alkenyl" refers to a straight or branched alkenyl group having from 2 to 4 carbon atoms.
“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的。例如，术语“C 2-4炔基”指具有2-4个碳原子的直链或支链炔基。 "Alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be straight or branched. For example, the term " C2-4 alkynyl" refers to a straight or branched alkynyl group having from 2 to 4 carbon atoms.
“取代或未取代的C 1-4烷基”是指C 1-4烷基可以是被取代的，也可以没有取代基的。 The "substituted or unsubstituted C 1-4 alkyl group" means that the C 1-4 alkyl group may be substituted or unsubstituted.
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。"Aryl" means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but may not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be in a conjugated pi-electron system. On the ring of carbon atoms. The aryl group can be substituted or unsubstituted.
“杂芳基”指包含一个到多个杂原子的杂芳族基团。含有至少一个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。例如呋喃基、吡咯基、喹啉基、噻吩基、吡啶基、吡唑基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基、噻吩并吡啶基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。"Heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. Containing at least one ring heteroatom selected from N, O or S, the remaining ring atoms are C, and additionally have a fully conjugated pi-electron system. For example, furyl, pyrrolyl, quinolyl, thienyl, pyridyl, pyrazolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, thienopyridinyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.
“环烷基”指饱和或不饱和的环状烃取代基；环状烃可以是单环也可以是多环。例如，“C 3-8环烷基”指碳原子数为3～8的环烷基。 "Cycloalkyl" means a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic. For example, "C 3-8 cycloalkyl" means a cycloalkyl group having 3 to 8 carbon atoms.
“杂环基”指饱和或不饱和的环状烃取代基；环状烃可以是单环也可以是多环，且携带至少一个选自O、S或取代的氮原子的环烷基，其余环原子为碳，例如，“C 3-8杂环基”指碳原子数和杂原子数共为3～8的杂环基。杂环基可以是非取代的，也可以被一个或多个取代基取代。 "Heterocyclyl" means a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carries at least one cycloalkyl selected from O, S or substituted nitrogen atoms, the remainder The ring atom is carbon. For example, "C 3-8 heterocyclic group" means a heterocyclic group having 3 to 8 carbon atoms and a hetero atom number. The heterocyclic group may be unsubstituted or substituted with one or more substituents.
“本发明化合物”指式(I)所示的化合物。该术语还包括式(I)化合物的各种晶型形式、立体异构体、药学上可接受的盐、溶剂合物、前体药物、代谢产物；The "compound of the present invention" means a compound represented by the formula (I). The term also includes various crystalline forms, stereoisomers, pharmaceutically acceptable salts, solvates, prodrugs, metabolites of the compounds of formula (I);
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，例如：顺反异构体、对映异构体、构象异构体等。"Stereoisomer" refers to isomers resulting from the arrangement of atoms in a molecule in a spatial arrangement, such as cis-trans isomers, enantiomers, conformational isomers, and the like.
“药学上可接受的”是指当给药至动物例如哺乳动物(例如人类)时生理学上可耐受且通常不会产生过敏或类似的不良反应(例如头晕等)的添加剂或组合物。药物载体和赋形剂可以包括但不限于稀释剂，例如乳糖、葡萄糖、甘露糖和/或甘油；润滑剂；聚乙二醇；粘合剂，例如硅酸铝镁、淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮；并且，如果需要的话，还包括崩解剂，例如淀粉、琼脂、海藻酸或其盐如海藻酸钠；和/或吸附剂、着色剂、防腐剂、稳定剂、矫味剂和甜味剂。"Pharmaceutically acceptable" refers to an additive or composition that is physiologically tolerable when administered to an animal, such as a mammal (eg, a human), and that typically does not produce an allergic or similar adverse reaction (eg, dizziness, etc.). Pharmaceutical carriers and excipients may include, but are not limited to, diluents such as lactose, glucose, mannose and/or glycerin; lubricants; polyethylene glycols; binders such as magnesium aluminum silicate, starch, gelatin, methyl Cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; and, if necessary, a disintegrant such as starch, agar, alginic acid or a salt thereof such as sodium alginate; and/or an adsorbent, coloring Agents, preservatives, stabilizers, flavoring agents and sweeteners.
“盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、氢氟酸盐、硫酸盐、硝酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、 磷酸盐、甲酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、乙磺酸盐、酒石酸盐、天冬氨酸盐或三氟乙酸盐。"Salt" means the above-mentioned compound or a stereoisomer thereof, an acid form and/or a base salt formed with an inorganic and/or organic acid and a base, and also a zwitterionic salt (internal salt), and also includes a quaternary ammonium salt. For example, an alkyl ammonium salt. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount). These salts may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent, or may be obtained by lyophilization after reaction in an aqueous medium. The salt in the present invention may be a hydrochloride, a hydrofluoride, a sulfate, a nitrate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate or a formic acid of the compound. Salt, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, lactate, citrate, picrate, A Sulfonate, ethanesulfonate, tartrate, aspartate or trifluoroacetate.
“式(I)所示的化合物的溶剂合物”，溶剂如乙醇、水等，其中，可含有不同量的水，如一水合物、半水合物、一个半水合物、二水合物或者三水合物。"Solvate of the compound of the formula (I)", a solvent such as ethanol, water or the like, which may contain different amounts of water such as a monohydrate, a hemihydrate, a hemihydrate, a dihydrate or a trihydrate. Things.
“前体药物”是通式Ⅰ化合物的衍生物，其在可能具有较弱的活性或甚至没有活性，但在生理条件下(例如通过代谢、溶剂分解或另外的方式)转化为本发明的活性成分，从而发挥其药理作用的化合物。例如，含有羧基的化合物可形成生理上可水解的酯，其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药，这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时，可使用肠胃外给药。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。A "prodrug" is a derivative of a compound of formula I which may be less active or even inactive, but which is converted to the activity of the invention under physiological conditions (for example by metabolism, solvolysis or otherwise) a compound that exerts its pharmacological action. For example, a compound containing a carboxyl group can form a physiologically hydrolyzable ester which is prepared by hydrolysis in vivo to give the compound of formula I itself. The prodrug is preferably administered orally because hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration can be used when the ester itself is active or hydrolysis occurs in the blood. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolic product" refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
癌症包括但不限于下列癌症：乳腺癌、卵巢癌、前列腺癌、子宫颈癌、食道癌、睾丸癌、胃癌、皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑与中枢神经系统的癌症、神经母细胞瘤、大细胞癌、腺癌、腺瘤、滤泡癌、表皮样癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、何杰金氏病、毛发细胞癌和白血病。Cancer includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, prostate cancer, cervical cancer, esophageal cancer, testicular cancer, stomach cancer, skin cancer, lung cancer, bone cancer, colon cancer, pancreatic cancer, thyroid cancer, biliary tract cancer, small intestine Cancer, colon-rectal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, neuroblastoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, epidermoid carcinoma, seminoma, melanin Tumor, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorder, lymphatic disorder, Hodgkin's disease, hair cell carcinoma and leukemia.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
本发明所述“室温”为25±5℃。The "room temperature" described in the present invention is 25 ± 5 °C.
本发明所述“过夜”为12±1小时。The "overnight" as described herein is 12 ± 1 hour.
本发明提供了一种结构新颖的含有金刚烷的化合物及其在治疗癌症中的用途。实验结果表明，本发明化合物能够显著抑制癌细胞的增殖，减少全长雄激素受体(AR-FL)和变异雄激素受体(AR-v7)的表达，抑制前列腺癌细胞的增殖，对癌症，尤其是前列腺癌具有潜在的治疗作用，为临床上筛选和/或制备癌症药物提供了一种新的选择。The present invention provides a novel adamantane-containing compound and its use in the treatment of cancer. The experimental results show that the compound of the present invention can significantly inhibit the proliferation of cancer cells, reduce the expression of the full-length androgen receptor (AR-FL) and the variant androgen receptor (AR-v7), inhibit the proliferation of prostate cancer cells, and cancer. In particular, prostate cancer has a potential therapeutic effect, providing a new option for clinical screening and/or preparation of cancer drugs.
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发 明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention without departing from the spirit and scope of the invention.
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.
具体实施方式detailed description
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。The raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
5-溴-2-甲氧基-4-甲基-3-硝基吡啶、甲磺酰氯、乙磺酰氯、丁磺酰氯：上海毕得医药科技有限公司5-Bromo-2-methoxy-4-methyl-3-nitropyridine, methanesulfonyl chloride, ethanesulfonyl chloride, butylsulfonyl chloride: Shanghai Bied Pharmaceutical Technology Co., Ltd.
N,N-二甲基甲酰胺二甲基缩醛：天津市瑞金特化学品有限公司N,N-dimethylformamide dimethyl acetal: Tianjin Ruijinte Chemical Co., Ltd.
甲醇锂：天津博迪化工股份有限公司Lithium methoxide: Tianjin Bodi Chemical Co., Ltd.
联硼酸频哪醇酯：上海泽信化工科技有限公司Boronic acid pinacol ester: Shanghai Zexin Chemical Technology Co., Ltd.
四三苯基磷钯、氘代碘甲烷、2-羟基金刚烷、1-羟基金刚烷、1-氨基金刚烷、：百灵威科技有限公司Tetrakistriphenylphosphine palladium, deuterated methyl iodide, 2-hydroxyadamantane, 1-hydroxyadamantane, 1-aminoadamantane: Bailingwei Technology Co., Ltd.
N,N-二甲胺甲酰胺、乙酸乙酯、二氯甲烷、还原铁粉、DIPEA、乙酸、乙醇、氢化钠、对甲苯磺酰氯、正己烷、1,4-二氧六环、甲醇、乙酰氯、甲基叔丁基醚、碳酸铯、碘甲烷、醋酸钾、无水硫酸钠、碳酸钠、氢氧化钾、四氢呋喃、均购买自成都市科龙化工试剂厂；N,N-dimethylamine formamide, ethyl acetate, dichloromethane, reduced iron powder, DIPEA, acetic acid, ethanol, sodium hydride, p-toluenesulfonyl chloride, n-hexane, 1,4-dioxane, methanol, Acetyl chloride, methyl tert-butyl ether, cesium carbonate, methyl iodide, potassium acetate, anhydrous sodium sulfate, sodium carbonate, potassium hydroxide, tetrahydrofuran, all purchased from Chengdu Kelong Chemical Reagent Factory;
1，4-二羟基金刚烷，2-甲基-1，4-二羟基金刚烷、4-氰基-1-羟基金刚、4-甲酸-1-羟基金刚烷、4-羟甲基-1-羟基金刚烷、1-羟基-3-氨基金刚烷、4-胺甲基-1-羟基金刚烷、4-羟基-1-甲酸金刚烷、1-羟基-4-氨基金刚烷、1-羟基-4-羰基金刚烷、1-氨基-3-磷酸酯金刚烷、4-氨基-1-磷酸酯金刚烷、1-羟基-4-磷酸酯金刚烷、6-羟基-2,2'-[1,3]二氧戊环金刚烷、2，6-二羟基金刚烷、1-羟基-4-甲氧基金刚烷、1-羟基-4-甲酰胺金刚烷、1-氧杂环丁烷-3-磺酰氯、丁二酸单酰氯均购自成都普康生物科技有限公司1,4-Dihydroxyadamantane, 2-methyl-1,4-dihydroxyadamantane, 4-cyano-1-hydroxymethyl, 4-carboxylic acid-1-hydroxyadamantane, 4-hydroxymethyl-1 -hydroxyadamantane, 1-hydroxy-3-aminoadamantane, 4-aminomethyl-1-hydroxyadamantane, 4-hydroxy-1-carboxylic acid adamantane, 1-hydroxy-4-aminoadamantane, 1-hydroxyl -4-carbonyl adamantane, 1-amino-3-phosphate adamantane, 4-amino-1-phosphate adamantane, 1-hydroxy-4-phosphate adamantane, 6-hydroxy-2,2'-[ 1,3] dioxolane adamantane, 2,6-dihydroxyadamantane, 1-hydroxy-4-methoxyadamantane, 1-hydroxy-4-carboxamide adamantane, 1-oxetane Benzene sulfonyl chloride and succinic acid monochloride were purchased from Chengdu Pukang Biotechnology Co., Ltd.
实施例1 本发明化合物100～117的合成Example 1 Synthesis of Compounds 100 to 117 of the Invention
一、Int 1～Int 8的合成First, the synthesis of Int 1 ~ Int 8
1、(E)-2-(5-溴-2-甲氧基-3-硝基吡啶-4-基)-N,N-二甲基乙胺(Int 1)的合成1. Synthesis of (E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethylamine (Int 1)
Figure PCTCN2019079734-appb-000032
Figure PCTCN2019079734-appb-000032
向装有N,N-二甲基甲酰胺(4L)的10L的反应瓶中加入5-溴-2-甲氧基-4-甲基-3-硝基吡 啶(200g，0.8mol)，N,N-二甲基甲酰胺二甲基缩醛(571.2g，4.8mol)，甲醇锂(0.9g,0.024mol)，加热到110℃搅拌反应3个小时。待反应液冷却至室温后，将其缓慢倒入加入冰水(12L)中，充分析出固体后，抽滤，水(1L)洗，烘干。得棕红色固体粉末中间体1(240g)，收率98％。To a 10 L reaction flask containing N,N-dimethylformamide (4 L) was added 5-bromo-2-methoxy-4-methyl-3-nitropyridine (200 g, 0.8 mol), N N-dimethylformamide dimethyl acetal (571.2 g, 4.8 mol), lithium methoxide (0.9 g, 0.024 mol), and the mixture was stirred at 110 ° C for 3 hours. After the reaction solution was cooled to room temperature, it was slowly poured into ice water (12 L), and the solid was analyzed, filtered, washed with water (1 L), and dried. A brownish red solid powder intermediate 1 (240 g) was obtained in a yield of 98%.
2、4-溴-7-甲氧基-1H-吡咯并[2,3-c]吡啶(Int.2)的合成2. Synthesis of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (Int. 2)
Figure PCTCN2019079734-appb-000033
Figure PCTCN2019079734-appb-000033
向10L的反应瓶中加入溶剂乙酸乙酯(5L)，还原铁粉(223g,3.97mol)，乙酸(2.3L,39.7mol)，升温至80℃后，分批加入中间体化合物1(240g,0.79mol)。加完后继续于该温度下反应30分钟。冷却，抽滤，旋干，用乙醇(1L)和水(1L)的混合溶剂打浆。抽滤烘干后得中间体化合物2(140g)，收率78％。Ethyl acetate (5 L) was added to a 10 L reaction flask, iron powder (223 g, 3.97 mol), acetic acid (2.3 L, 39.7 mol), and the mixture was heated to 80 ° C, and then intermediate compound 1 (240 g, 0.79 mol). After the addition was completed, the reaction was continued at this temperature for 30 minutes. Cool, filter by suction, spin dry, and beat with a mixed solvent of ethanol (1 L) and water (1 L). After suction filtration and drying, Intermediate Compound 2 (140 g) was obtained in a yield of 78%.
3、4-溴-7-甲氧基-1-对甲苯磺酰基-1H-吡咯并[2,3-c]吡啶(Int.3)的合成Synthesis of 4-bromo-7-methoxy-1-p-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine (Int.3)
Figure PCTCN2019079734-appb-000034
Figure PCTCN2019079734-appb-000034
向5L的反应瓶中加入N,N-二甲基甲酰胺(2L)，中间体化合物2(140g,0.62mol)。溶清后，冰水浴下冷却至0℃，并分批向反应液中加入NaH(40g，60％，0.99mol)，控制反应升温不超过10℃。加完NaH停止冒出气泡后，分批加入对甲苯磺酰氯(177g,0.93mol)，室温下搅拌过夜。反应完全后，将反应液倒入6L水中，析出固体，抽滤，固体用200mL乙酸乙酯加热溶解，加入600mL正己烷，析出固体，抽滤后得中间体化合物3(188g)，收率80％。N,N-dimethylformamide (2 L), Intermediate Compound 2 (140 g, 0.62 mol) was added to a 5 L reaction flask. After dissolving, it was cooled to 0 ° C in an ice water bath, and NaH (40 g, 60%, 0.99 mol) was added to the reaction mixture in portions, and the temperature of the reaction was controlled to not exceed 10 °C. After the addition of NaH to stop bubbling, p-toluenesulfonyl chloride (177 g, 0.93 mol) was added portionwise and stirred at room temperature overnight. After the reaction was completed, the reaction mixture was poured into 6 L of water, and a solid was precipitated. The solid was filtered, and the solid was dissolved in ethyl acetate (200 mL), and then 600 mL of n-hexane was added to precipitate a solid, which was filtered to give intermediate compound 3 (188 g). %.
4、4-溴-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(Int.4)的合成Synthesis of 4-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one (Int.4)
Figure PCTCN2019079734-appb-000035
Figure PCTCN2019079734-appb-000035
向5L的反应瓶中加入2L 1,4-二氧六环，甲醇(78g,2.45mol)。室温下，向反应瓶中滴加乙酰氯(154g,1.96mol)。滴加完毕后，继续搅拌1个小时。加入中间体化合物3(188g,0.49mol)，并升温至80℃，搅拌过夜。反应完全后，旋干，用300mL甲基叔丁基醚打浆，抽滤后得中间体化合物4(139g)，收率77％。To a 5 L reaction vial was added 2 L of 1,4-dioxane, methanol (78 g, 2.45 mol). Acetyl chloride (154 g, 1.96 mol) was added dropwise to the reaction flask at room temperature. After the addition was completed, stirring was continued for 1 hour. Intermediate compound 3 (188 g, 0.49 mol) was added, and the mixture was warmed to 80 ° C and stirred overnight. After completion of the reaction, the mixture was dried, and then pulverized with 300 mL of methyl tert-butyl ether and filtered to give Intermediate Compound 4 (139 g).
5、4-溴-6-甲基-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(Int.5)的合成Synthesis of 4-bromo-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one (Int.5)
Figure PCTCN2019079734-appb-000036
Figure PCTCN2019079734-appb-000036
向5L的反应瓶中加入2L 1,4-二氧六环，中间体化合物4(79g,0.21mol)、碳酸铯(118g,0.32mol)、碘甲烷(92g,0.64mol)室温下，搅拌过夜。反应完全后，过滤，旋干，得中间体化合物5(75g)，收率94％。2 L of 1,4-dioxane was added to a 5 L reaction flask, intermediate compound 4 (79 g, 0.21 mol), cesium carbonate (118 g, 0.32 mol), and iodomethane (92 g, 0.64 mol) were stirred at room temperature overnight. . After completion of the reaction, the mixture was filtered and dried to give Intermediate Compound 5 (75 g).
6、6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(Int.6)的合成6,6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrole Synthesis of [2,3-c]pyridine-7(6H)-one (Int.6)
Figure PCTCN2019079734-appb-000037
Figure PCTCN2019079734-appb-000037
向2L的反应瓶中加入800mL 1,4-二氧六环，中间体化合物5(40g,0.1mol)、联硼酸频哪醇酯(105g,0.4mol)、醋酸钾(20.4g,0.2mol)，氮气置换三次后加入四三苯基磷钯(12g,0.01mol)，氮气置换三次，升温至110℃，搅拌过夜。反应完全后，过滤，柱层析得中间体化合物6(40g)，收率93％。To a 2 L reaction flask was added 800 mL of 1,4-dioxane, intermediate compound 5 (40 g, 0.1 mol), diboronic acid pinacol ester (105 g, 0.4 mol), potassium acetate (20.4 g, 0.2 mol) After replacing three times with nitrogen, tetrakistriphenylphosphine palladium (12 g, 0.01 mol) was added, and the mixture was replaced with nitrogen three times, heated to 110 ° C, and stirred overnight. After completion of the reaction, filtration and column chromatography gave Intermediate Compound 6 (40 g).
7、4-溴-6-氘代甲基-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(Int.5)的合成Synthesis of 4-bromo-6-deuterated methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine-7(6H)-one (Int.5)
Figure PCTCN2019079734-appb-000038
Figure PCTCN2019079734-appb-000038
向5L的反应瓶中加入2L 1,4-二氧六环，中间体化合物4(79g,0.21mol)、碳酸铯(118g,0.32mol)、氘代碘甲烷(92g,0.64mol)室温下，搅拌过夜。反应完全后，过滤，旋干，得中间体化合物7(75g)，收率94％。2 L of 1,4-dioxane, intermediate compound 4 (79 g, 0.21 mol), cesium carbonate (118 g, 0.32 mol), deuterated iodomethane (92 g, 0.64 mol) were added to a 5 L reaction flask at room temperature. Stir overnight. After completion of the reaction, the mixture was filtered and dried to give Intermediate Compound 7 (75 g).
8、6-氘代甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(Int.6)的合成8,6-Deuterated methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H Synthesis of pyrrolo[2,3-c]pyridine-7(6H)-one (Int.6)
Figure PCTCN2019079734-appb-000039
Figure PCTCN2019079734-appb-000039
向2L的反应瓶中加入800mL 1,4-二氧六环，中间体化合物7(40g,0.1mol)、联硼酸频哪醇酯(105g,0.4mol)、醋酸钾(20.4g,0.2mol)，氮气置换三次后加入四三苯基磷钯(12g,0.01mol)，氮气置换三次，升温至110℃，搅拌过夜。反应完全后，过滤，柱层析得中间体化合物8(40g)，收率93％。To a 2 L reaction flask was added 800 mL of 1,4-dioxane, intermediate compound 7 (40 g, 0.1 mol), diboronic acid pinacol ester (105 g, 0.4 mol), potassium acetate (20.4 g, 0.2 mol) After replacing three times with nitrogen, tetrakistriphenylphosphine palladium (12 g, 0.01 mol) was added, and the mixture was replaced with nitrogen three times, heated to 110 ° C, and stirred overnight. After completion of the reaction, filtration and column chromatography gave Intermediate Compound 8 (40 g).
二、目标化合物100的合成Second, the synthesis of target compound 100
Figure PCTCN2019079734-appb-000040
Figure PCTCN2019079734-appb-000040
1、2-(2-溴-4-(甲基磺酰基)苯氧基)金刚烷的合成(98)Synthesis of 2-(2-bromo-4-(methylsulfonyl)phenoxy)adamantane (98)
Figure PCTCN2019079734-appb-000041
Figure PCTCN2019079734-appb-000041
向50mL的反应瓶中加入化合物21(1.26g，5mmol)，2-羟基金刚烷(912mg，6mmol)，碳酸铯(3.9g，12mmol),DMSO(20mL)，体系在100℃下反应10小时。反应完毕后，将反应液倒入50mL水中，用30mL(15mL×3)二氯甲烷萃取，合并有机相，无水硫酸钠干燥，柱层析纯化后得化合物98(1.5g)，收率78％。质谱:384(M+H +)。 Compound 21 (1.26 g, 5 mmol), 2-hydroxyadamantane (912 mg, 6 mmol), cesium carbonate (3.9 g, 12 mmol), DMSO (20 mL) was added to a 50 mL reaction flask, and the system was reacted at 100 ° C for 10 hours. After the reaction was completed, the reaction solution was poured into 50 mL of water, and extracted with 30 mL (15 mL × 3) dichloromethane, and the organic phase was combined, dried over anhydrous sodium sulfate and purified by column chromatography to give compound 98 (1.5 g), yield 78 %. Mass spectrum: 384 (M+H + ).
2、4-(2-((金刚烷-2-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1-对甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(99)的合成2. 4-(2-((Adamantyl-2-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1-p-toluenesulfonyl-1,6-dihydro Synthesis of -7H-pyrrolo[2,3-c]pyridine-7-one (99)
Figure PCTCN2019079734-appb-000042
Figure PCTCN2019079734-appb-000042
向30mL的反应瓶中加入化合物98(384mg，1mmol)，化合物Int.6(556mg，1.3mmol)，Pd(PPh 3) 4(69.2mg，0.06mmol)，Na 2CO 3(212mg，2mmol),DMF/H 2O(5mL/0.3mL)，体系在氮气保护下100℃反应10小时。反应完毕后，将反应液倒入30mL水中，用30mL(10mL×3)二氯甲烷萃取，合并有机相，无水硫酸钠干燥，prep-TCL纯化后得化合物99(278mg)，收率45.9％。 Compound 98 (384 mg, 1 mmol), compound Int. 6 (556 mg, 1.3 mmol), Pd (PPh 3 ) 4 (69.2 mg, 0.06 mmol), Na 2 CO 3 (212 mg, 2 mmol), DMF/H 2 O (5 mL / 0.3 mL), the system was reacted at 100 ° C for 10 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into 30 mL of water, and extracted with 30 mL (10 mL×3) of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate and purified by prep-TCL to give compound 99 (278 mg). .
质谱:607(M+H +)。 Mass Spectrum: 607 (M+H + ).
3、4-(2-((金刚烷-2-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(100)的合成3, 4-(2-((Adamantyl-2-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 Synthesis of 3-c]pyridine-7-one (100)
Figure PCTCN2019079734-appb-000043
Figure PCTCN2019079734-appb-000043
向30mL的反应瓶中加入化合物99(80mg，0.132mmol)，THF(1mL)，KOH(4mL，4M)，体系在80℃下反应3小时。反应完毕后，将反应液倒入30mL水中，用30mL(10mL×3)二氯甲烷萃取，合并有机相，无水硫酸钠干燥，prep-TCL纯化后得化合物100(51mg)，收率85.5％。质谱:453(M+H +)。 1H NMR(400MHz,DMSO)δ12.07(s,1H),7.89(m,1H),7.85-7.40(m,1H),7.4(s,1H),7.37(m,1H),7.30(m,1H),6.20(s,1H),4.72(s,1H),3.57(s,3H),3.22(s,3H),2.07(s,2H),1.81(m,7H),1.63(s,3H),1.25(s,2H). To a 30 mL reaction flask was added compound 99 (80 mg, 0.132 mmol), THF (1 mL), EtOAc (4mL, 4M), and the system was reacted at 80 ° C for 3 hours. After the reaction was completed, the reaction solution was poured into 30 mL of water, and extracted with 30 mL (10 mL×3) of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, and purified by prep-TCL to give compound 100 (51 mg). . Mass Spectrum: 453 (M+H + ). 1 H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 7.89 (m, 1H), 7.85-7.40 (m, 1H), 7.4 (s, 1H), 7.37 (m, 1H), 7.30 (m) , 1H), 6.20 (s, 1H), 4.72 (s, 1H), 3.57 (s, 3H), 3.22 (s, 3H), 2.07 (s, 2H), 1.81 (m, 7H), 1.63 (s, 3H), 1.25 (s, 2H).
三、目标化合物101～117的合成。3. Synthesis of target compounds 101 to 117.
目标化合物101～117的合成方法与实施例1步骤二中目标化合物100的合成方法相似，都是通过以下步骤制备得到：The synthesis method of the target compounds 101 to 117 is similar to the synthesis method of the target compound 100 in the second step of the first embodiment, and is prepared by the following steps:
①与实施例1步骤二中的步骤1类似：将化合物21与表1中各产物对应的取代的金刚烷进行反应，制备得到类似于化合物98的中间体；1 is similar to the step 1 in the second step of the first embodiment: the compound 17 is reacted with the substituted adamantane corresponding to each product in Table 1, to prepare an intermediate similar to the compound 98;
②与实施例1步骤二中的步骤2类似：将类似于化合物98的中间体与化合物Int.6反应，制备得到类似于化合物99的中间体；2 is similar to the step 2 in the second step of the first embodiment: an intermediate similar to the compound 98 is reacted with the compound Int. 6 to prepare an intermediate similar to the compound 99;
③与实施例1步骤二中的步骤3类似：类似于化合物99的中间体脱出Ts保护基，制备得到对应的目标化合物101～117。3 is similar to the step 3 in the second step of the first embodiment: an intermediate similar to the compound 99 is deprotected from the Ts protecting group to prepare the corresponding target compounds 101 to 117.
表1 产物101～117对应的原料取代金刚烷的结构Table 1 Structure of the raw materials corresponding to the products 101 to 117 instead of adamantane
Figure PCTCN2019079734-appb-000044
Figure PCTCN2019079734-appb-000044
Figure PCTCN2019079734-appb-000045
Figure PCTCN2019079734-appb-000045
2、4-(2-((金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3c]吡啶-7-酮(101)的合成2. 4-(2-((Adamantyl-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2 Synthesis of 3c]pyridine-7-one (101)
Figure PCTCN2019079734-appb-000046
Figure PCTCN2019079734-appb-000046
化合物101的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 101 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:453(M+H +)。 1H NMR(400MHz,DMSO)δ12.05(s,1H),7.88(d,J＝2.4Hz,1H),7.83(d,J＝8.8Hz,1H),7.41–7.33(m,2H),7.29(s,1H),6.19(s,1H),4.71(s,1H),3.56(s,3H),3.21(s,3H),3.02(s,2H),2.1-1.9(m,4H),1.80(m,5H),1.62(m,3H) Mass Spectrum: 453 (M+H + ). 1 H NMR (400MHz, DMSO) δ12.05 (s, 1H), 7.88 (d, J = 2.4Hz, 1H), 7.83 (d, J = 8.8Hz, 1H), 7.41-7.33 (m, 2H), 7.29 (s, 1H), 6.19 (s, 1H), 4.71 (s, 1H), 3.56 (s, 3H), 3.21 (s, 3H), 3.02 (s, 2H), 2.1-1.9 (m, 4H) , 1.80 (m, 5H), 1.62 (m, 3H)
3、4-(2-((金刚烷-1-基)氨基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3c]吡啶-7-酮(102)的合成3, 4-(2-((Adamantyl-1-yl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2, Synthesis of 3c]pyridine-7-one (102)
Figure PCTCN2019079734-appb-000047
Figure PCTCN2019079734-appb-000047
化合物102的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 102 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:452(M+H +)。 Mass Spectrum: 452 (M+H + ).
4、4-(2-((3-羟基金刚烷-1-基)氨基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,13-c]吡啶-7-酮(103)的合成4-(2-((3-Hydroxyadamantan-1-yl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole Synthesis of [2,13-c]pyridine-7-one (103)
Figure PCTCN2019079734-appb-000048
Figure PCTCN2019079734-appb-000048
化合物103的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 103 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:468(M+H +)。 1H NMR(400MHz,DMSO)δ12.24(s,1H),7.75(m,1H),7.55(m,1H),7.31(s,1H),7.38(s,1H),7.15(d,J＝8.6Hz,1H),6.02(s,1H),4.54(s,1H),4.48(s,1H),3.58(s,3H),3.13(s,3H),2.16(s,2H),1.74(m,5H),1.50(m,6H),1.25(s,1H). Mass Spectrum: 468 (M+H + ). 1 H NMR (400MHz, DMSO) δ12.24 (s, 1H), 7.75 (m, 1H), 7.55 (m, 1H), 7.31 (s, 1H), 7.38 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.02 (s, 1H), 4.54 (s, 1H), 4.48 (s, 1H), 3.58 (s, 3H), 3.13 (s, 3H), 2.16 (s, 2H), 1.74 (m, 5H), 1.50 (m, 6H), 1.25 (s, 1H).
5、4-(2-(((1R，3S，5S)-3-氨基-金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,13-c]吡啶-7-酮(104)的合成5. 4-(2-((1R,3S,5S)-3-Amino-adamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1 Synthesis of 6-dihydro-7H-pyrrolo[2,13-c]pyridin-7-one (104)
Figure PCTCN2019079734-appb-000049
Figure PCTCN2019079734-appb-000049
化合物104的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 104 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:468(M+H +)。 Mass Spectrum: 468 (M+H + ).
6、4-(2-(((反式-4-氨基金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(105)的合成6, 4-(2-((trans-4-Aminoadamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-dihydro Synthesis of -7H-pyrrolo[2,3-c]pyridin-7-one (105)
Figure PCTCN2019079734-appb-000050
Figure PCTCN2019079734-appb-000050
化合物105的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 105 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:468(M+H +)。 Mass Spectrum: 468 (M+H + ).
7、4-(2-((反式-5-羟基金刚烷-2-基)氨基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(106)的合成7, 4-(2-((trans-5-hydroxyadamantan-2-yl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-dihydro-7H Synthesis of pyrrolo[2,3-c]pyridin-7-one (106)
Figure PCTCN2019079734-appb-000051
Figure PCTCN2019079734-appb-000051
化合物106的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 106 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:468(M+H +)。 1H NMR(400MHz,DMSO)δ12.22(s,1H),7.77(m,1H),7.56(m,1H),7.33–7.32(m,2H),6.8(m,1H),6.01(s,1H),4.78(m,1H),4.46(s,1H),3.58(m,4H),3.11(s,3H),2.01(s,2H),1.84-1.74(m,3H),1.60-1.54(m,4H),1.30-1.22(m,4H) Mass Spectrum: 468 (M+H + ). 1 H NMR (400MHz, DMSO) δ12.22 (s, 1H), 7.77 (m, 1H), 7.56 (m, 1H), 7.33-7.32 (m, 2H), 6.8 (m, 1H), 6.01 (s , 1H), 4.78 (m, 1H), 4.46 (s, 1H), 3.58 (m, 4H), 3.11 (s, 3H), 2.01 (s, 2H), 1.84-1.74 (m, 3H), 1.60- 1.54 (m, 4H), 1.30-1.22 (m, 4H)
8、6-甲基-4-(5-(甲基磺酰基)-2-(((4-氧代金刚烷-1-基)氧基)苯基)-1,6-二氢-7H-吡咯并[2，3-c]吡啶-7-酮(107)的合成8,6-Methyl-4-(5-(methylsulfonyl)-2-(((4-oxoadamantan-1-yl)oxy)phenyl)-1,6-dihydro-7H Synthesis of pyrrolo[2,3-c]pyridin-7-one (107)
Figure PCTCN2019079734-appb-000052
Figure PCTCN2019079734-appb-000052
化合物107的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 107 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:467(M+H +)。 1H NMR(400MHz,DMSO)δ12.09(s,1H),7.93(d,J＝2.4Hz,1H),7.83(dd,J＝8.6,2.5Hz,1H),7.53(d,J＝8.6Hz,1H),7.37(s,1H),7.32(t,J＝2.7Hz,1H),6.22–6.14(m,1H),3.60(s,3H),3.26(s,3H),2.66(s,1H),2.41(s,2H),2.19(s,1H),1.97(s,4H),1.85(d,J＝12.1Hz,2H),1.74(d,J＝12.4Hz,2H). Mass Spectrum: 467 (M+H + ). 1 H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.83 (dd, J = 8.6, 2.5 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.37 (s, 1H), 7.32 (t, J = 2.7 Hz, 1H), 6.22 - 6.14 (m, 1H), 3.60 (s, 3H), 3.26 (s, 3H), 2.66 (s) , 1H), 2.41 (s, 2H), 2.19 (s, 1H), 1.97 (s, 4H), 1.85 (d, J = 12.1 Hz, 2H), 1.74 (d, J = 12.4 Hz, 2H).
9、4-(2-((4-羟基金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,13-c]吡啶-7-酮9, 4-(2-((4-Hydroxyadamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole And [2,13-c]pyridine-7-one
Figure PCTCN2019079734-appb-000053
Figure PCTCN2019079734-appb-000053
化合物108的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 108 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:469(M+H +)。 1H NMR(400MHz,DMSO)δ12.17–11.94(m,1H),7.91(d,J＝2.5Hz,1H),7.86–7.76(m,1H),7.47(d,J＝8.6Hz,1H),7.36(s,1H),7.31(s,1H),6.17(d,J＝2.7Hz,1H),4.70–4.57(m,1H),3.58(d,J＝13.3Hz,3H),3.25(s,3H),2.19–2.07(m,1H),1.98–1.63(m,8H),1.53–1.38(m,2H),1.05(d,J＝6.1Hz,2H). Mass Spectrum: 469 (M+H + ). 1 H NMR (400 MHz, DMSO) δ 12.17 - 11.94 (m, 1H), 7.91 (d, J = 2.5 Hz, 1H), 7.86 - 7.76 (m, 1H), 7.47 (d, J = 8.6 Hz, 1H) ), 7.36 (s, 1H), 7.31 (s, 1H), 6.17 (d, J = 2.7 Hz, 1H), 4.70 - 4.57 (m, 1H), 3.58 (d, J = 13.3 Hz, 3H), 3.25 (s, 3H), 2.19–2.07 (m, 1H), 1.98–1.63 (m, 8H), 1.53–1.38 (m, 2H), 1.05 (d, J=6.1 Hz, 2H).
10、4-(2-((4-羟基-4-甲基金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(109)的合成10, 4-(2-((4-Hydroxy-4-methyladamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-di Synthesis of Hydrogen-7H-pyrrolo[2,3-c]pyridin-7-one (109)
Figure PCTCN2019079734-appb-000054
Figure PCTCN2019079734-appb-000054
化合物109的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 109 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:483(M+H +)。 Mass spectrum: 483 (M+H + ).
11、5-(2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯氧基)金刚烷-2-腈(110)的合成11, 5-(2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl) Synthesis of phenoxy)adamantan-2-carbonitrile (110)
Figure PCTCN2019079734-appb-000055
Figure PCTCN2019079734-appb-000055
化合物110的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 110 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:478(M+H +)。 Mass Spectrum: 478 (M+H + ).
12、5-(2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯氧基)金刚烷-2-甲酸(111)的合成12,5-(2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl) Synthesis of phenoxy)adamantane-2-carboxylic acid (111)
Figure PCTCN2019079734-appb-000056
Figure PCTCN2019079734-appb-000056
化合物111的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 111 was carried out in the same manner as the method for synthesizing the compound 100, using a reagent corresponding thereto.
质谱:497(M+H +)。 Mass Spectrum: 497 (M+H + ).
13、4-(2-((4-(羟甲基)金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并并[2,3-c]吡啶-7-酮(112)的合成13. 4-(2-((4-(Hydroxymethyl)adamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-dihydro Synthesis of -7H-pyrrolo[2,3-c]pyridin-7-one (112)
Figure PCTCN2019079734-appb-000057
Figure PCTCN2019079734-appb-000057
化合物112的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 112 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:483(M+H +)。 Mass spectrum: 483 (M+H + ).
14、4-(2-((4-(胺甲基)金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并并[2,3-c]吡啶-7-酮(113)的合成14. 4-(2-((4-(Aminomethyl)adamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-dihydro Synthesis of -7H-pyrrolo[2,3-c]pyridin-7-one (113)
Figure PCTCN2019079734-appb-000058
Figure PCTCN2019079734-appb-000058
化合物113的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 113 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:482(M+H +)。 Mass Spectrum: 482 (M+H + ).
15、4-(2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯氧基)金刚烷-1-羧酸(114)的合成15-(2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl) Synthesis of phenoxy)adamantane-1-carboxylic acid (114)
Figure PCTCN2019079734-appb-000059
Figure PCTCN2019079734-appb-000059
化合物114的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 114 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:497(M+H +)。 Mass Spectrum: 497 (M+H + ).
16、3-((2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯基)氨基)金刚烷-1-基磷酸二氢盐(115)的合成16. 3-((2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonate) Synthesis of acyl)phenyl)amino)adamantan-1-ylphosphonic acid dihydrogen salt (115)
Figure PCTCN2019079734-appb-000060
Figure PCTCN2019079734-appb-000060
化合物115的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 115 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:548(M+H +)。 Mass spectrum: 548 (M+H + ).
17、4-((2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯基)氨基)金刚烷-1-基磷酸二氢盐(116)的合成17. 4-((2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonate) Synthesis of acyl)phenyl)amino)adamantan-1-ylphosphonic acid dihydrogen salt (116)
Figure PCTCN2019079734-appb-000061
Figure PCTCN2019079734-appb-000061
化合物116的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 116 was carried out in the same manner as in the synthesis of Compound 100 using the corresponding reagent.
质谱:548(M+H +)。 Mass spectrum: 548 (M+H + ).
18、5-(2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯氧基)金刚烷-2-基二氢磷酸酯(117)的合成18,5-(2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl) Synthesis of phenoxy)adamantan-2-yldihydrophosphate (117)
Figure PCTCN2019079734-appb-000062
Figure PCTCN2019079734-appb-000062
化合物117的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 117 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:549(M+H +)。 Mass spectrum: 549 (M+H + ).
实施例2 化合物118～137的合成Example 2 Synthesis of Compounds 118 to 137
一、化合物118的合成I. Synthesis of Compound 118
Figure PCTCN2019079734-appb-000063
Figure PCTCN2019079734-appb-000063
1、2-(2-溴-4-硝基苯氧基)金刚烷(Int.9)的合成Synthesis of 2-(2-bromo-4-nitrophenoxy)adamantane (Int.9)
Figure PCTCN2019079734-appb-000064
Figure PCTCN2019079734-appb-000064
向50mL的反应瓶中加入化合物1(1.1g，5mmol)，2-羟基金刚烷(912mg，6mmol)，碳酸铯(3.91g，12mmol),DMSO(25mL)，体系在100℃下反应10小时。反应完毕后，将反应液倒入50mL水中，用30mL(15mL×3)二氯甲烷萃取，合并有机相，无水硫酸钠干燥， 柱层析纯化后得化合物Int.9(1.5g)，收率85.2％。质谱:353(M+H +)。 Compound 1 (1.1 g, 5 mmol), 2-hydroxyadamantane (912 mg, 6 mmol), cesium carbonate (3.91 g, 12 mmol), DMSO (25 mL) was added to a 50 mL reaction flask, and the system was reacted at 100 ° C for 10 hours. After the reaction was completed, the reaction solution was poured into 50 mL of water, and extracted with 30 mL (15 mL × 3) of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate and purified by column chromatography to give compound Int.9 (1.5 g). The rate is 85.2%. Mass Spectrum: 353 (M+H + ).
2、4-((金刚烷-2-基)氧基)-3-溴苯胺(Int.10)的合成2. Synthesis of 4-((adamantan-2-yl)oxy)-3-bromoaniline (Int. 10)
Figure PCTCN2019079734-appb-000065
Figure PCTCN2019079734-appb-000065
向50mL的反应瓶中加入化合物Int.9(1.06g,3mmol)，甲醇(20mL)，雷尼镍(50mg)，在0℃下加入水合肼(3mL)，体系在20℃下反应3小时。反应完毕后，将反应液倒入50mL水中，用30mL(15mL×3)二氯甲烷萃取，合并有机相，无水硫酸钠干燥，柱层析纯化后得化合物Int.10(850mg),收率87.7％。质谱:323(M+H +)。 To a 50 mL reaction flask was added Compound Int. 9 (1.06 g, 3 mmol), methanol (20 mL), Raney nickel (50 mg), and hydrazine hydrate (3 mL) was added at 0 ° C, and the system was reacted at 20 ° C for 3 hours. After completion of the reaction, the reaction solution was poured into 50 mL of water, and extracted with 30 mL (15 mL × 3) of dichloromethane, and the organic phase was combined, dried over anhydrous sodium sulfate and purified by column chromatography to give compound Int. 10 (850 mg). 87.7%. Mass Spectrum: 323 (M+H + ).
3、4-(2-((金刚烷-2-基)氧基)-5-氨基苯基)-6-甲基-1-对甲苯磺酰-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(Int.11)的合成3, 4-(2-((Adamantyl-2-yl)oxy)-5-aminophenyl)-6-methyl-1-p-toluenesulfonyl-1,6-dihydro-7H-pyrrole Synthesis of [2,3-c]pyridine-7-one (Int. 11)
Figure PCTCN2019079734-appb-000066
Figure PCTCN2019079734-appb-000066
向30mL的反应瓶中加入化合物Int.10(323mg，1mmol)，化合物Int.6(556mg，1.3mmol)，Pd(PPh 3) 4(69.2mg，0.06mmol)，Na 2CO 3(212mg，2mmol),DMF/H 2O(5mL/0.3mL)，体系在氮气保护下100℃反应10小时。反应完毕后，将反应液倒入30mL水中，用30mL(10mL×3)二氯甲烷萃取，合并有机相，无水硫酸钠干燥，prep-TCL纯化后得化合物Int.11(235mg)，收率43.3％。 To a 30 mL reaction flask was added compound Int. 10 (323 mg, 1 mmol), compound Int. 6 (556 mg, 1.3 mmol), Pd(PPh 3 ) 4 (69.2 mg, 0.06 mmol), Na 2 CO 3 (212 mg, 2 mmol) ), DMF/H 2 O (5 mL / 0.3 mL), and the system was reacted at 100 ° C for 10 hours under nitrogen atmosphere. After completion of the reaction, the reaction solution was poured into 30 mL of water, and extracted with 30 mL (10 mL×3) of dichloromethane, and the organic phase was combined, dried over anhydrous sodium sulfate, and purified by prep-TCL to give compound Int.11 (235 mg). 43.3%.
质谱:544(M+H +)。 Mass spectrum: 544 (M+H + ).
4、N-(4-((金刚烷-2-基)氧基)-3-(6-甲基-7-氧代-1-对甲苯磺酰-6,7-二氢-1H-吡咯并[2,1，3-c]吡啶-4-基)苯基)-N-(甲基磺酰基)甲磺酰胺(Int.12)的合成4. N-(4-((Adamantyl-2-yl)oxy)-3-(6-methyl-7-oxo-1-p-toluenesulfonyl-6,7-dihydro-1H-pyrrole Synthesis of [2,1,3-c]pyridin-4-yl)phenyl)-N-(methylsulfonyl)methanesulfonamide (Int.12)
Figure PCTCN2019079734-appb-000067
Figure PCTCN2019079734-appb-000067
向30mL的反应瓶中加入化合物Int.11(239mg，0.3mmol)，二氯甲烷(5mL)，DIPEA(143mg，1.2mmol)，在0℃下甲磺酰氯(80mg，0.7mmol)，体系在20℃下反应3小时。反应完毕后，将反应液倒入30mL水中，用30mL(10mL×3)二氯甲烷萃取，合并有机相，无水硫酸钠干燥，prep-TCL纯化后得化合物Int.12(156mg)，收率74％。质谱:700(M+H +)。 Compound 30. The reaction was carried out at ° C for 3 hours. After the reaction was completed, the reaction solution was poured into 30 mL of water, and extracted with 30 mL (10 mL×3) of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, and purified by prep-TCL to give compound Int.12 (156 mg). 74%. Mass Spectrum: 700 (M+H + ).
5、N-(4-((金刚烷-2-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)甲磺酰胺(118)的合成5. N-(4-((Adamantyl-2-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-C Synthesis of pyridin-4-yl)phenyl)methanesulfonamide (118)
Figure PCTCN2019079734-appb-000068
Figure PCTCN2019079734-appb-000068
向30mL的反应瓶中加入化合物Int.12(126mg，0.18mmol)，THF(1mL)，KOH(4mL，4M)，体系在80℃下反应3小时。反应完毕后，将反应液倒入30mL水中，用30mL(10mL×3)二氯甲烷萃取，合并有机相，无水硫酸钠干燥，prep-TCL纯化后得化合物118(59mg)，收率70％。质谱:468(M+H +)。 1H-NMR(400MHz,DMSO)δ12.01(s,1H),9.41(s,1H),7.36(s,1H),7.33–7.26(m,2H),7.16–7.06(m,2H),6.29–6.22(m,1H),4.43(s,1H),3.54(s,3H),2.93(s,3H),1.99(s,2H),1.75(m,7H),1.62(m,3H),1.40–1.15(m,2H). To a 30 mL reaction flask was added Compound Int. 12 (126 mg, 0.18 mmol), THF (1 mL), KOH (4 mL, 4M), and the system was reacted at 80 ° C for 3 hours. After completion of the reaction, the reaction solution was poured into 30 mL of water, and extracted with 30 mL (10 mL × 3) of dichloromethane, and the organic phase was combined, dried over anhydrous sodium sulfate, and purified by prep-TCL to give compound 118 (59 mg), yield 70% . Mass Spectrum: 468 (M+H + ). 1 H-NMR (400 MHz, DMSO) δ 12.01 (s, 1H), 9.41 (s, 1H), 7.36 (s, 1H), 7.33 - 7.26 (m, 2H), 7.16 - 7.06 (m, 2H), 6.29–6.22(m,1H),4.43(s,1H),3.54(s,3H),2.93(s,3H),1.99(s,2H),1.75(m,7H),1.62(m,3H) , 1.40–1.15 (m, 2H).
二、化合物119～137的合成2. Synthesis of compounds 119-137
目标化合物119～137的合成方法与实施例2步骤一中目标化合物118的合成方法相似，都是通过以下步骤制备得到：The synthesis method of the target compounds 119 to 137 is similar to the synthesis method of the target compound 118 in the first step of the second embodiment, and is prepared by the following steps:
①与实施例2步骤一中的步骤1类似：将化合物1与表2中各产物对应的取代的金刚烷进行反应，制备得到类似于化合物Int.9的中间体；1 is similar to step 1 in the first step of Example 2: the compound 1 is reacted with the substituted adamantane corresponding to each product in Table 2 to prepare an intermediate similar to the compound Int.
②与实施例2步骤一中的步骤2类似：由类似于化合物Int.9的中间体制得类似于化合物 10的中间体；2 is similar to step 2 in the first step of Example 2: an intermediate similar to compound 10 is prepared from an intermediate similar to compound Int.
③与实施例2步骤一中的步骤3类似：由类似于化合物10的中间体与化合物Int.6反应，制备得到类似于化合物Int.11的中间体；3 is similar to the step 3 in the first step of Example 2: an intermediate similar to the compound 10 is reacted with the compound Int. 6 to prepare an intermediate similar to the compound Int.
④与实施例2步骤一中的步骤4类似：将类似于化合物Int.11的中间体与对应的磺酰氯进行反应，制备得到类似于化合物Int.12的中间体；4 is similar to step 4 in the first step of Example 2: an intermediate similar to the compound Int. 11 is reacted with the corresponding sulfonyl chloride to prepare an intermediate similar to the compound Int.
⑤与实施例2步骤一中的步骤5类似：类似于化合物Int.12的中间体脱出Ts保护基，制备得到对应的目标化合物119～137。5 is similar to step 5 in the first step of Example 2: the Ts protecting group is removed similarly to the intermediate of the compound Int. 12, and the corresponding target compounds 119 to 137 are obtained.
表2 产物118～137对应的原料取代金刚烷和磺酰氯Table 2 The corresponding raw materials of products 118-137 replace adamantane and sulfonyl chloride
Figure PCTCN2019079734-appb-000069
Figure PCTCN2019079734-appb-000069
Figure PCTCN2019079734-appb-000070
Figure PCTCN2019079734-appb-000070
1、N-(4-((金刚烷-2-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)乙磺酰胺(119)的合成1, N-(4-((adamantan-2-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-C Synthesis of pyridin-4-yl)phenyl)ethanesulfonamide (119)
Figure PCTCN2019079734-appb-000071
Figure PCTCN2019079734-appb-000071
化合物119的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 119 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:482(M+H +)。 1H NMR(400MHz,DMSO)δ12.02(s,1H),9.51(s,1H),7.36(s,1H),7.32(d,J＝2.5Hz,1H),7.29(s,1H),7.14(dd,J＝8.8,2.5Hz,1H),7.10(s,1H),6.24(s,1H),4.42(s,1H),3.54(s,3H),3.03(d,J＝7.4Hz,2H),1.99(s,2H),1.75(m,7H),1.62(s,3H),1.35(d,J＝12.1Hz,2H),1.22(m,3H). Mass Spectrum: 482 (M+H + ). 1 H NMR (400 MHz, DMSO) δ 12.02 (s, 1 H), 9.51 (s, 1H), 7.36 (s, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.29 (s, 1H), 7.14 (dd, J=8.8, 2.5 Hz, 1H), 7.10 (s, 1H), 6.24 (s, 1H), 4.42 (s, 1H), 3.54 (s, 3H), 3.03 (d, J = 7.4 Hz) , 2H), 1.99 (s, 2H), 1.75 (m, 7H), 1.62 (s, 3H), 1.35 (d, J = 12.1 Hz, 2H), 1.22 (m, 3H).
2、N-(4-((金刚烷-2-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)氧杂环丁烷-3-磺酰胺(120)的合成2. N-(4-((Adamantyl-2-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-C Synthesis of pyridin-4-yl)phenyl)oxetane-3-sulfonamide (120)
Figure PCTCN2019079734-appb-000072
Figure PCTCN2019079734-appb-000072
化合物120的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 120 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:510(M+H +)。 1H NMR(400MHz,DMSO)δ12.02(s,1H),9.73(s,1H),7.35(s,1H),7.29(dd,J＝7.2,4.4Hz,2H),7.09(s,2H),6.25(s,1H),4.77(m,2H),4.70–4.54(m,3H),4.44(s,1H),3.54(s,3H),1.99(s,2H),1.74(m,7H),1.62(s,3H),1.35(d,J＝12.5Hz,2H). Mass spectrum: 510 (M+H + ). 1 H NMR (400 MHz, DMSO) δ 12.02 (s, 1 H), 9.73 (s, 1H), 7.35 (s, 1H), 7.29 (dd, J = 7.2, 4.4 Hz, 2H), 7.09 (s, 2H) ), 6.25 (s, 1H), 4.77 (m, 2H), 4.70 - 4.54 (m, 3H), 4.44 (s, 1H), 3.54 (s, 3H), 1.99 (s, 2H), 1.74 (m, 7H), 1.62 (s, 3H), 1.35 (d, J = 12.5 Hz, 2H).
3、N-(4-((金刚烷-1-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)甲磺酰胺(121)的合成3, N-(4-((adamantan-1-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-C Synthesis of pyridin-4-yl)phenyl)methanesulfonamide (121)
Figure PCTCN2019079734-appb-000073
Figure PCTCN2019079734-appb-000073
化合物121的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 121 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:468(M+H +)。 Mass Spectrum: 468 (M+H + ).
4、N-(4-((金刚烷-1-基)氨基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)甲磺酰胺(122)的合成4. N-(4-((Adamantyl-1-yl)amino)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-C] Synthesis of pyridin-4-yl)phenyl)methanesulfonamide (122)
Figure PCTCN2019079734-appb-000074
Figure PCTCN2019079734-appb-000074
化合物122的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 122 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:467(M+H +)。 Mass Spectrum: 467 (M+H + ).
5、N-(4-((3-羟基金刚烷-1-基)氨基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(123)的合成5. N-(4-((3-Hydroxyadamantan-1-yl)amino)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3 Synthesis of -c]pyridin-4-yl)phenyl)methanesulfonamide (123)
Figure PCTCN2019079734-appb-000075
Figure PCTCN2019079734-appb-000075
化合物123的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 123 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:483(M+H +)。 Mass spectrum: 483 (M+H + ).
6、N-(4-((3-氨基-金刚烷-1-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(124)的合成6, N-(4-((3-Amino-adamantan-1-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2 Synthesis of 3-(3-pyridin-4-yl)phenyl)methanesulfonamide (124)
Figure PCTCN2019079734-appb-000076
Figure PCTCN2019079734-appb-000076
化合物124的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 124 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:483(M+H +)。 Mass spectrum: 483 (M+H + ).
7、N-(4-((反式-4-氨基金刚烷-1-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,1，3-c]吡啶-4-基)苯基)甲磺酰胺(125)的合成7. N-(4-((trans-4-Aminoadamantan-1-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrole Synthesis of [2,1,3-c]pyridin-4-yl)phenyl)methanesulfonamide (125)
Figure PCTCN2019079734-appb-000077
Figure PCTCN2019079734-appb-000077
化合物125的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 125 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:483(M+H +)。 Mass spectrum: 483 (M+H + ).
8、N-(4-((反式-5-羟基金刚烷-2-基)氨基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,1， 3-c]吡啶-4-基)苯基)甲磺酰胺(126)的合成8. N-(4-((trans-5-hydroxyadamantan-2-yl)amino)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[ Synthesis of 2,1,3-c]pyridin-4-yl)phenyl)methanesulfonamide (126)
Figure PCTCN2019079734-appb-000078
Figure PCTCN2019079734-appb-000078
化合物126的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 126 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:483(M+H +)。 Mass spectrum: 483 (M+H + ).
9、N-(3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-((4—氧代金刚烷-1-基)氧基)苯基)甲磺酰胺(127)的合成9, N-(3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((4-oxo) Synthesis of adamantane-1-yl)oxy)phenyl)methanesulfonamide (127)
Figure PCTCN2019079734-appb-000079
Figure PCTCN2019079734-appb-000079
化合物127的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 127 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:482(M+H +)。 Mass Spectrum: 482 (M+H + ).
10、N-(4-((4-羟基金刚烷-1-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(128)的合成10. N-(4-((4-Hydroxyadamantan-1-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2, Synthesis of 3-c]pyridin-4-yl)phenyl)methanesulfonamide (128)
Figure PCTCN2019079734-appb-000080
Figure PCTCN2019079734-appb-000080
化合物128的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 128 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:484(M+H +)。 Mass Spectrum: 484 (M+H + ).
11、N-(4-((4-羟基-4-甲基金刚烷-1-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(129)的合成11. N-(4-((4-Hydroxy-4-methyladamantan-1-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H- Synthesis of pyrrolo[2,3-c]pyridin-4-yl)phenyl)methanesulfonamide (129)
Figure PCTCN2019079734-appb-000081
Figure PCTCN2019079734-appb-000081
化合物129的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 129 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:498(M+H +)。 Mass Spectrum: 498 (M+H + ).
12、N-(4-((4-氰基金刚烷-1-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(130)的合成12. N-(4-((4-Cyanoxanthyl-1-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2 Synthesis of 3-(3-pyridin-4-yl)phenyl)methanesulfonamide (130)
Figure PCTCN2019079734-appb-000082
Figure PCTCN2019079734-appb-000082
化合物130的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 130 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:493(M+H +)。 Mass spectrum: 493 (M+H + ).
13、5-(2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰氨基)苯氧基)金刚烷-2-羧酸(131)的合成13, 5-(2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl) Synthesis of Amino)phenoxy)adamantane-2-carboxylic Acid (131)
Figure PCTCN2019079734-appb-000083
Figure PCTCN2019079734-appb-000083
化合物131的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 131 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:512(M+H +)。 Mass spectrum: 512 (M+H + ).
14、N-(4-((4-(羟甲基)金刚烷-1-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(132)的合成14. N-(4-((4-(Hydroxymethyl)adamantan-1-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrole Synthesis of [2,3-c]pyridin-4-yl)phenyl)methanesulfonamide (132)
Figure PCTCN2019079734-appb-000084
Figure PCTCN2019079734-appb-000084
化合物132的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 132 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:498(M+H +)。 Mass Spectrum: 498 (M+H + ).
15、N-(4-((4-(氨基甲基)金刚烷-1-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(133)的合成15. N-(4-((4-(Aminomethyl)adamantan-1-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrole Synthesis of [2,3-c]pyridin-4-yl)phenyl)methanesulfonamide (133)
Figure PCTCN2019079734-appb-000085
Figure PCTCN2019079734-appb-000085
化合物133的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 133 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:497(M+H +)。 Mass Spectrum: 497 (M+H + ).
16、4-(2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰氨基)苯氧基)金刚烷-1-羧酸(134)的合成16. 4-(2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl) Synthesis of Amino)phenoxy)adamantane-1-carboxylic Acid (134)
Figure PCTCN2019079734-appb-000086
Figure PCTCN2019079734-appb-000086
化合物134的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 134 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:512(M+H +)。 Mass spectrum: 512 (M+H + ).
17、3-((2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰氨基)苯基)氨基)金刚烷-1-基磷酸二氢盐(135)的合成17. 3-((2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonate) Synthesis of Amidoamino)phenyl)amino)adamantan-1-ylphosphonic Dihydrogen Salt (135)
Figure PCTCN2019079734-appb-000087
Figure PCTCN2019079734-appb-000087
化合物135的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 135 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:563(M+H +)。 Mass Spectrum: 563 (M+H + ).
18、4-((2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰氨基)苯基)氨基)金刚烷-1-基酯(136)的合成18, 4-((2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonate) Synthesis of Amidoamino)phenyl)amino)adamantan-1-yl Ester (136)
Figure PCTCN2019079734-appb-000088
Figure PCTCN2019079734-appb-000088
化合物136的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 136 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:563(M+H +)。 Mass Spectrum: 563 (M+H + ).
19、5-(2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰氨基)苯氧基)金刚烷-2-基二氢磷酸酯(137)的合成19-(2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl) Synthesis of Amino)phenoxy)adamantan-2-yldihydrophosphate (137)
Figure PCTCN2019079734-appb-000089
Figure PCTCN2019079734-appb-000089
化合物137的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 137 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:563(M+H +)。 Mass Spectrum: 563 (M+H + ).
实施例3 目标化合物138～155的合成Example 3 Synthesis of target compounds 138-155
目标化合物138～155的合成方法与实施例1步骤二中目标化合物100的合成方法相似，都是通过以下步骤制备得到：The synthesis method of the target compounds 138 to 155 is similar to the synthesis method of the target compound 100 in the second step of the first embodiment, and is prepared by the following steps:
①与实施例1步骤二中的步骤1类似：将化合物21与表3中各产物对应的取代的金刚烷进行反应，制备得到类似于化合物98的中间体；1 is similar to the step 1 in the second step of the first embodiment: the compound 17 is reacted with the substituted adamantane corresponding to each product in Table 3 to prepare an intermediate similar to the compound 98;
②与实施例1步骤二中的步骤2类似：将类似于化合物98的中间体与化合物Int.8反应，制备得到类似于化合物99的中间体；2 is similar to the step 2 in the second step of the first embodiment: an intermediate similar to the compound 98 is reacted with the compound Int. 8 to prepare an intermediate similar to the compound 99;
③与实施例1步骤二中的步骤3类似：类似于化合物99的中间体脱出Ts保护基，制备得到对应的目标化合物138～155。3 is similar to the step 3 in the second step of the embodiment 1. The intermediates similar to the compound 99 are deprotected from the Ts protecting group to prepare the corresponding target compounds 138 to 155.
表3 产物138～155对应的原料取代金刚烷的结构Table 3 Structure of the raw materials corresponding to the products 138-155 substituted adamantane
Figure PCTCN2019079734-appb-000090
Figure PCTCN2019079734-appb-000090
Figure PCTCN2019079734-appb-000091
Figure PCTCN2019079734-appb-000091
1、4-(2-((金刚烷-2-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(138)的合成1, 4-(2-((Adamantyl-2-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1,6-dihydro-7H- Synthesis of pyrrolo[2,3-c]pyridin-7-one (138)
Figure PCTCN2019079734-appb-000092
Figure PCTCN2019079734-appb-000092
化合物138的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 138 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:456(M+H +)。 1H NMR(400MHz,DMSO)δ12.07(s,1H),7.75(m,1H),7.55(m,1H),7.31(s,1H),7.38(s,1H),7.15(d,J＝8.6Hz,1H),6.20(s,1H),4.72(s,1H),3.20(s,3H),2.42(s,1H),2.07(s,1H),1.81(m,5H),1.63(m,5H),1.36(m,2H). Mass Spectrum: 456 (M+H + ). 1 H NMR (400MHz, DMSO) δ12.07 (s, 1H), 7.75 (m, 1H), 7.55 (m, 1H), 7.31 (s, 1H), 7.38 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.20 (s, 1H), 4.72 (s, 1H), 3.20 (s, 3H), 2.42 (s, 1H), 2.07 (s, 1H), 1.81 (m, 5H), 1.63 (m, 5H), 1.36 (m, 2H).
2、4-(2-((金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,3c]吡啶-7-酮(139)的合成2. 4-(2-((Adamantyl-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1,6-dihydro-7H- Synthesis of pyrrolo[2,3c]pyridine-7-one (139)
Figure PCTCN2019079734-appb-000093
Figure PCTCN2019079734-appb-000093
化合物139的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 139 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:456(M+H +)。 Mass Spectrum: 456 (M+H + ).
3、4-(2-((金刚烷-1-基)氨基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,3c]吡啶-7-酮(140)的合成3, 4-(2-((Adamantyl-1-yl)amino)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1,6-dihydro-7H-pyrrole Synthesis of [2,3c]pyridine-7-one (140)
Figure PCTCN2019079734-appb-000094
Figure PCTCN2019079734-appb-000094
化合物140的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 140 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:455(M+H +)。 Mass Spectrum: 455 (M+H + ).
4、4-(2-((3-羟基金刚烷-1-基)氨基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,13-c]吡啶-7-酮(141)的合成4-(2-((3-Hydroxyadamantan-1-yl)amino)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1,6-dihydro- Synthesis of 7H-pyrrolo[2,13-c]pyridine-7-one (141)
Figure PCTCN2019079734-appb-000095
Figure PCTCN2019079734-appb-000095
化合物141的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 141 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:471(M+H +)。 Mass Spectrum: 471 (M+H + ).
5、4-(2-((3-氨基-金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,13-c]吡啶-7-酮(142)的合成5. 4-(2-((3-Amino-adamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1,6-di Synthesis of Hydrogen-7H-pyrrolo[2,13-c]pyridine-7-one (142)
Figure PCTCN2019079734-appb-000096
Figure PCTCN2019079734-appb-000096
化合物142的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 142 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:471(M+H +)。 Mass Spectrum: 471 (M+H + ).
6、4-(2-(((反式-4-氨基金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(143)的合成6, 4-(2-((trans-4-Aminoadamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1, Synthesis of 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (143)
Figure PCTCN2019079734-appb-000097
Figure PCTCN2019079734-appb-000097
化合物143的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 143 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:471(M+H +)。 Mass Spectrum: 471 (M+H + ).
7、4-(2-((反式-5-羟基金刚烷-2-基)氨基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(144)的合成7, 4-(2-((trans-5-hydroxyadamantan-2-yl)amino)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1,6- Synthesis of Dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (144)
Figure PCTCN2019079734-appb-000098
Figure PCTCN2019079734-appb-000098
化合物144的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 144 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:471(M+H +)。 Mass Spectrum: 471 (M+H + ).
8、6-(甲基-D3)-4-(5-(甲基磺酰基)-2-(((4-氧代金刚烷8,6-(Methyl-D3)-4-(5-(methylsulfonyl)-2-(((4-oxoadamantane)
-1-基)氧基)苯基)-1,6-二氢-7H-吡咯并[2，3-c]吡啶-7-酮(145)的合成Synthesis of -1-yl)oxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (145)
Figure PCTCN2019079734-appb-000099
Figure PCTCN2019079734-appb-000099
化合物145的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 145 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:470(M+H +)。 Mass Spectrum: 470 (M+H + ).
9、4-(2-((4-羟基金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,13-c]吡啶-7-酮(146)的合成9. 4-(2-((4-Hydroxyadamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1,6-dihydro Synthesis of -7H-pyrrolo[2,13-c]pyridine-7-one (146)
Figure PCTCN2019079734-appb-000100
Figure PCTCN2019079734-appb-000100
化合物146的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 146 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:472(M+H +)。 Mass Spectrum: 472 (M+H + ).
10、4-(2-((4-羟基-4-甲基金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(147)的合成10, 4-(2-((4-Hydroxy-4-methyladamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1 Synthesis of 6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (147)
Figure PCTCN2019079734-appb-000101
Figure PCTCN2019079734-appb-000101
化合物147的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 147 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:486(M+H +)。 Mass spectrum: 486 (M+H + ).
11、5-(2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯氧基)金刚烷-2-腈(148)的合成11, 5-(2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-( Synthesis of Methylsulfonyl)phenoxy)adamantan-2-carbonitrile (148)
Figure PCTCN2019079734-appb-000102
Figure PCTCN2019079734-appb-000102
化合物148的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 148 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:481(M+H +)。 Mass Spectrum: 481 (M+H + ).
12、5-(2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯氧基)金刚烷-2-甲酸(149)的合成12, 5-(2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-( Synthesis of Methylsulfonyl)phenoxy)adamantane-2-carboxylic Acid (149)
Figure PCTCN2019079734-appb-000103
Figure PCTCN2019079734-appb-000103
化合物149的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 149 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:500(M+H +)。 Mass spectrum: 500 (M+H + ).
13、4-(2-((4-(羟甲基)金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并并[2,3-c]吡啶-7-酮(150)的合成13. 4-(2-((4-(Hydroxymethyl)adamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1, Synthesis of 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (150)
Figure PCTCN2019079734-appb-000104
Figure PCTCN2019079734-appb-000104
化合物150的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 150 was carried out in the same manner as in the synthesis of Compound 100, using a reagent corresponding thereto.
质谱:486(M+H +)。 Mass spectrum: 486 (M+H + ).
14、4-(2-((4-(胺甲基)金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并并[2,3-c]吡啶-7-酮(151)的合成4-(2-((4-(Aminomethyl)adamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1, Synthesis of 6-Dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (151)
Figure PCTCN2019079734-appb-000105
Figure PCTCN2019079734-appb-000105
化合物151的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 151 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:485(M+H +)。 Mass Spectrum: 485 (M+H + ).
15、4-(2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯氧基)金刚烷-1-羧酸(152)的合成15. 4-(2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-( Synthesis of Methylsulfonyl)phenoxy)adamantane-1-carboxylic acid (152)
Figure PCTCN2019079734-appb-000106
Figure PCTCN2019079734-appb-000106
化合物152的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 152 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:500(M+H +)。 Mass spectrum: 500 (M+H + ).
16、3-((2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯基)氨基)金刚烷-1-基磷酸二氢盐(153)的合成3-((2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4- Synthesis of (Methylsulfonyl)phenyl)amino)adamantan-1-ylphosphonic acid dihydrogen salt (153)
Figure PCTCN2019079734-appb-000107
Figure PCTCN2019079734-appb-000107
化合物153的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 153 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:551(M+H +)。 Mass spectrum: 551 (M+H + ).
17、4-((2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯基)氨基)金刚烷-1-基磷酸二氢盐(154)的合成17. 4-((2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4- Synthesis of (Methylsulfonyl)phenyl)amino)adamantan-1-ylphosphonic acid dihydrogen salt (154)
Figure PCTCN2019079734-appb-000108
Figure PCTCN2019079734-appb-000108
化合物154的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 154 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:551(M+H +)。 Mass spectrum: 551 (M+H + ).
18、5-(2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯氧基)金刚烷-2-基二氢磷酸酯(155)的合成18,5-(2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-( Synthesis of Methylsulfonyl)phenoxy)adamantan-2-yldihydrophosphate (155)
Figure PCTCN2019079734-appb-000109
Figure PCTCN2019079734-appb-000109
化合物155的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 155 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:552(M+H +)。 Mass spectrum: 552 (M+H + ).
实施例4 目标化合物156～175的合成Example 4 Synthesis of target compounds 156 to 175
目标化合物156～175的合成方法与实施例2步骤一中目标化合物118的合成方法相似，都是通过以下步骤制备得到：The synthesis method of the target compounds 156 to 175 is similar to the synthesis method of the target compound 118 in the first step of the second embodiment, and is prepared by the following steps:
①与实施例2步骤一中的步骤1类似：将化合物1与表4中各产物对应的取代的金刚烷进行反应，制备得到类似于化合物Int.9的中间体；1 is similar to step 1 in the first step of Example 2: the compound 1 is reacted with the substituted adamantane corresponding to each product in Table 4 to prepare an intermediate similar to the compound Int.
②与实施例2步骤一中的步骤2类似：由类似于化合物Int.9的中间体制得类似于化合物10的中间体；2 is similar to step 2 in the first step of Example 2: an intermediate similar to compound 10 is prepared from an intermediate similar to compound Int.
③与实施例2步骤一中的步骤3类似：由类似于化合物10的中间体与化合物Int.8反应，制备得到类似于化合物Int.11的中间体；3 is similar to step 3 in the first step of Example 2: an intermediate similar to compound 10 is reacted with compound Int. 8 to prepare an intermediate similar to compound Int.
④与实施例2步骤一中的步骤4类似：将类似于化合物Int.11的中间体与对应的磺酰氯进行反应，制备得到类似于化合物Int.12的中间体；4 is similar to step 4 in the first step of Example 2: an intermediate similar to the compound Int. 11 is reacted with the corresponding sulfonyl chloride to prepare an intermediate similar to the compound Int.
⑤与实施例2步骤一中的步骤5类似：类似于化合物Int.12的中间体脱出Ts保护基，制备得到对应的目标化合物156～175。5 is similar to step 5 in the first step of Example 2: an intermediate similar to the compound Int. 12 is deprotected from the Ts protecting group to give the corresponding target compound 156-175.
表4 产物156～175对应的原料取代金刚烷和磺酰氯Table 4 The corresponding raw materials of products 156-175 replace adamantane and sulfonyl chloride
Figure PCTCN2019079734-appb-000110
Figure PCTCN2019079734-appb-000110
Figure PCTCN2019079734-appb-000111
Figure PCTCN2019079734-appb-000111
1、N-(4-((金刚烷-2-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)甲磺酰胺(156)的合成1, N-(4-((adamantan-2-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2 Synthesis of 3-C]pyridin-4-yl)phenyl)methanesulfonamide (156)
Figure PCTCN2019079734-appb-000112
Figure PCTCN2019079734-appb-000112
化合物156的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 156 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:471(M+H +)。 Mass Spectrum: 471 (M+H + ).
2、N-(4-((金刚烷-2-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)乙磺酰胺(157)的合成2. N-(4-((Adamantyl-2-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2 Synthesis of 3-C]pyridin-4-yl)phenyl)ethanesulfonamide (157)
Figure PCTCN2019079734-appb-000113
Figure PCTCN2019079734-appb-000113
化合物157的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 157 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:485(M+H +)。 Mass Spectrum: 485 (M+H + ).
3、N-(4-((金刚烷-2-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)氧杂环丁烷-3-磺酰胺(158)的合成3. N-(4-((Adamantyl-2-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2 Synthesis of 3-C]pyridin-4-yl)phenyl)oxetane-3-sulfonamide (158)
Figure PCTCN2019079734-appb-000114
Figure PCTCN2019079734-appb-000114
化合物158的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 158 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:513(M+H +)。 Mass Spectrum: 513 (M+H + ).
4、N-(4-((金刚烷-1-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)甲磺酰胺(159)的合成4. N-(4-((Adamantyl-1-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2 Synthesis of 3-C]pyridin-4-yl)phenyl)methanesulfonamide (159)
Figure PCTCN2019079734-appb-000115
Figure PCTCN2019079734-appb-000115
化合物159的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 159 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:471(M+H +)。 Mass Spectrum: 471 (M+H + ).
5、N-(4-((金刚烷-1-基)氨基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)甲磺酰胺(160)的合成5. N-(4-((Adamantyl-1-yl)amino)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2, Synthesis of 3-C]pyridin-4-yl)phenyl)methanesulfonamide (160)
Figure PCTCN2019079734-appb-000116
Figure PCTCN2019079734-appb-000116
化合物160的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 160 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:470(M+H +)。 Mass Spectrum: 470 (M+H + ).
6、N-(4-((3-羟基金刚烷-1-基)氨基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(161)的合成6. N-(4-((3-Hydroxyadamantan-1-yl)amino)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrole Synthesis of [2,3-c]pyridin-4-yl)phenyl)methanesulfonamide (161)
Figure PCTCN2019079734-appb-000117
Figure PCTCN2019079734-appb-000117
化合物161的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 161 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:486(M+H +)。 Mass spectrum: 486 (M+H + ).
7、N-(4-((3-氨基-金刚烷-1-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(162)的合成7. N-(4-((3-Amino-adamantan-1-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H- Synthesis of pyrrolo[2,3-c]pyridin-4-yl)phenyl)methanesulfonamide (162)
Figure PCTCN2019079734-appb-000118
Figure PCTCN2019079734-appb-000118
化合物162的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 162 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:486(M+H +)。 Mass spectrum: 486 (M+H + ).
8、N-(4-((反式-4-氨基金刚烷-1-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,1，3-c]吡啶-4-基)苯基)甲磺酰胺(163)的合成8. N-(4-((trans-4-Aminoadamantan-1-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro- Synthesis of 1H-pyrrolo[2,1,3-c]pyridin-4-yl)phenyl)methanesulfonamide (163)
Figure PCTCN2019079734-appb-000119
Figure PCTCN2019079734-appb-000119
化合物163的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 163 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:486(M+H +)。 Mass spectrum: 486 (M+H + ).
9、N-(4-((反式-5-羟基金刚烷-2-基)氨基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并 [2,1，3-c]吡啶-4-基)苯基)甲磺酰胺(164)的合成9. N-(4-((trans-5-hydroxyadamantan-2-yl)amino)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H Synthesis of pyrrolo[2,1,3-c]pyridin-4-yl)phenyl)methanesulfonamide (164)
Figure PCTCN2019079734-appb-000120
Figure PCTCN2019079734-appb-000120
化合物164的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 164 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:486(M+H +)。 Mass spectrum: 486 (M+H + ).
10、N-(3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-((4—氧代金刚烷-1-基)氧基)苯基)甲磺酰胺(165)的合成10. N-(3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-( Synthesis of (4-oxoadamantan-1-yl)oxy)phenyl)methanesulfonamide (165)
Figure PCTCN2019079734-appb-000121
Figure PCTCN2019079734-appb-000121
化合物165的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 165 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:485(M+H +)。 Mass Spectrum: 485 (M+H + ).
11、N-(4-((4-羟基金刚烷-1-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(166)的合成11. N-(4-((4-Hydroxyadamantan-1-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrole Synthesis of [2,3-c]pyridin-4-yl)phenyl)methanesulfonamide (166)
Figure PCTCN2019079734-appb-000122
Figure PCTCN2019079734-appb-000122
化合物166的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 166 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:487(M+H +)。 Mass Spectrum: 487 (M+H + ).
12、N-(4-((4-羟基-4-甲基金刚烷-1-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(167)的合成12. N-(4-((4-Hydroxy-4-methyladamantan-1-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-di Synthesis of Hydrogen-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)methanesulfonamide (167)
Figure PCTCN2019079734-appb-000123
Figure PCTCN2019079734-appb-000123
化合物167的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 167 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:501(M+H +)。 Mass Spectrum: 501 (M+H + ).
13、N-(4-((4-氰基金刚烷-1-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(168)的合成13. N-(4-((4-Cyanoxanthyl-1-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H- Synthesis of pyrrolo[2,3-c]pyridin-4-yl)phenyl)methanesulfonamide (168)
Figure PCTCN2019079734-appb-000124
Figure PCTCN2019079734-appb-000124
化合物168的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 168 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:496(M+H +)。 Mass Spectrum: 496 (M+H + ).
14、5-(2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰氨基)苯氧基)金刚烷-2-羧酸(169)的合成14, 5-(2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-( Synthesis of Methylsulfonylamino)phenoxy)adamantane-2-carboxylic Acid (169)
Figure PCTCN2019079734-appb-000125
Figure PCTCN2019079734-appb-000125
化合物169的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 169 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:515(M+H +)。 Mass Spectrum: 515 (M+H + ).
15、N-(4-((4-(羟甲基)金刚烷-1-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(170)的合成15. N-(4-((4-(Hydroxymethyl)adamantan-1-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydrol Synthesis of -1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)methanesulfonamide (170)
Figure PCTCN2019079734-appb-000126
Figure PCTCN2019079734-appb-000126
化合物170的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 170 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:501(M+H +)。 Mass Spectrum: 501 (M+H + ).
16、N-(4-((4-(氨基甲基)金刚烷-1-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)甲磺酰胺(171)的合成16. N-(4-((4-(Aminomethyl)adamantan-1-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydrol Synthesis of -1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)methanesulfonamide (171)
Figure PCTCN2019079734-appb-000127
Figure PCTCN2019079734-appb-000127
化合物171的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 171 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:500(M+H +)。 Mass spectrum: 500 (M+H + ).
17、4-(2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰氨基)苯氧基)金刚烷-1-羧酸(172)的合成17. 4-(2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-( Synthesis of Methylsulfonylamino)phenoxy)adamantane-1-carboxylic Acid (172)
Figure PCTCN2019079734-appb-000128
Figure PCTCN2019079734-appb-000128
化合物172的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 172 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:515(M+H +)。 Mass Spectrum: 515 (M+H + ).
18、3-((2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰氨基)苯基)氨基)金刚烷-1-基磷酸二氢盐(173)的合成18, 3-((2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4- Synthesis of (Methylsulfonylamino)phenyl)amino)adamantan-1-ylphosphonic acid dihydrogen salt (173)
Figure PCTCN2019079734-appb-000129
Figure PCTCN2019079734-appb-000129
化合物173的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 173 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:566(M+H +)。 Mass spectrum: 566 (M+H + ).
19、4-((2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰氨基)苯基)氨基)金刚烷-1-基酯(174)的合成19, 4-((2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4- Synthesis of (Methylsulfonylamino)phenyl)amino)adamantan-1-yl ester (174)
Figure PCTCN2019079734-appb-000130
Figure PCTCN2019079734-appb-000130
化合物174的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 174 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:566(M+H +)。 Mass spectrum: 566 (M+H + ).
20、5-(2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰氨基)苯氧基)金刚烷-2-基二氢磷酸酯(175)的合成20,5-(2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-( Synthesis of Methylsulfonylamino)phenoxy)adamantan-2-yldihydrophosphate (175)
Figure PCTCN2019079734-appb-000131
Figure PCTCN2019079734-appb-000131
化合物175的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 175 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:566(M+H +)。 Mass spectrum: 566 (M+H + ).
实施例5 本发明化合物176、177的合成Example 5 Synthesis of Compounds 176 and 177 of the Invention
目标化合物176、177的合成方法与实施例1步骤二中目标化合物100的合成方法相似，都是通过以下步骤制备得到：The synthesis method of the target compound 176, 177 is similar to the synthesis method of the target compound 100 in the second step of the first embodiment, and is prepared by the following steps:
①与实施例1步骤二中的步骤1类似：将化合物21与表5中各产物对应的取代的金刚烷进行反应，制备得到类似于化合物98的中间体；1 is similar to the step 1 in the second step of the first embodiment: the compound 17 is reacted with the substituted adamantane corresponding to each product in Table 5 to prepare an intermediate similar to the compound 98;
②与实施例1步骤二中的步骤2类似：将类似于化合物98的中间体与化合物Int.6反应，制备得到类似于化合物99的中间体；2 is similar to the step 2 in the second step of the first embodiment: an intermediate similar to the compound 98 is reacted with the compound Int. 6 to prepare an intermediate similar to the compound 99;
③与实施例1步骤二中的步骤3类似：类似于化合物99的中间体脱出Ts保护基，制备得到对应的目标化合物176、177。3 Similar to Step 3 in Step 2 of Example 1, the Ts protecting group was removed from the intermediate of Compound 99 to give the corresponding target compound 176, 177.
表5 产物176、177对应的原料取代金刚烷的结构Table 5 Structure of the raw materials corresponding to the products 176, 177 substituted adamantane
Figure PCTCN2019079734-appb-000132
Figure PCTCN2019079734-appb-000132
1、6-甲基-4-(5-(甲基磺酰基)-2-(((1R，5R，7S)-螺[金刚烷-2,2'-[1,3]二氧戊环]-6-基)氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(176)的合成1,6-Methyl-4-(5-(methylsulfonyl)-2-(((1R,5R,7S)-spiro[adamantane-2,2'-[1,3]dioxolane Synthesis of ]-6-yl)oxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (176)
Figure PCTCN2019079734-appb-000133
Figure PCTCN2019079734-appb-000133
化合物176的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 176 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:511(M+H +)。 1H NMR(400MHz,DMSO)δ12.07(s,1H),7.89(d,J＝2.4Hz,1H),7.84(dd,J＝8.7,2.4Hz,1H),7.38(d,J＝8.6Hz,2H),7.31(t,J＝2.6Hz,1H),6.19(d,J＝2.1Hz,1H),4.65(s,1H),3.84(d,J＝8.3Hz,4H),3.34(s,3H),3.23(s,3H),1.95(m,4H),1.74(m,3H),1.55(m,5H),1,24(s,1H). Mass spectrum: 511 (M+H + ). 1 H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.7, 2.4 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.31 (t, J = 2.6 Hz, 1H), 6.19 (d, J = 2.1 Hz, 1H), 4.65 (s, 1H), 3.84 (d, J = 8.3 Hz, 4H), 3.34 ( s, 3H), 3.23 (s, 3H), 1.95 (m, 4H), 1.74 (m, 3H), 1.55 (m, 5H), 1, 24 (s, 1H).
2、4-(2-((6-羟基金刚烷-2-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,13-c]吡啶-7-酮(177)的合成2, 4-(2-((6-Hydroxyadamantan-2-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrole Synthesis of [2,13-c]pyridine-7-one (177)
Figure PCTCN2019079734-appb-000134
Figure PCTCN2019079734-appb-000134
化合物177的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 177 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:569(M+H +)。 1H NMR(400MHz,DMSO)δ12.07(s,1H),7.89(d,J＝2.4Hz,1H),7.84(dd,J＝8.7,2.5Hz,1H),7.40(s,1H),7.36(d,J＝8.8Hz,1H),7.31(t,J＝2.7Hz,1H),6.22–6.17(m,1H),5.33(m,1H),4.64(s,1H),3.57(s,3H),3.22(s,3H),1.98(m,4H),1.77–1.61(m,3H),1.48(m,5H),1.24(s,1H). Mass spectrum: 569 (M+H + ). 1 H NMR (400MHz, DMSO) δ12.07 (s, 1H), 7.89 (d, J = 2.4Hz, 1H), 7.84 (dd, J = 8.7,2.5Hz, 1H), 7.40 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.31 (t, J = 2.7 Hz, 1H), 6.22 - 6.17 (m, 1H), 5.33 (m, 1H), 4.64 (s, 1H), 3.57 (s) , 3H), 3.22 (s, 3H), 1.98 (m, 4H), 1.77 - 1.61 (m, 3H), 1.48 (m, 5H), 1.24 (s, 1H).
实施例6 化合物178～180的合成Example 6 Synthesis of Compounds 178-180
目标化合物178～180的合成方法与实施例2步骤一中目标化合物118的合成方法相似，都是通过以下步骤制备得到：The synthesis method of the target compound 178-180 is similar to the synthesis method of the target compound 118 in the first step of the second embodiment, and is prepared by the following steps:
①与实施例2步骤一中的步骤4类似：将化合物Int.11与对应的酰氯进行反应，制备得到类似于化合物Int.12的中间体；1 is similar to step 4 in the first step of Example 2: reacting the compound Int. 11 with the corresponding acid chloride to prepare an intermediate similar to the compound Int.
②与实施例2步骤一中的步骤5类似：类似于化合物Int.12的中间体脱出Ts保护基，制备得到对应的目标化合物178～180。2 Similar to step 5 in the first step of Example 2: an intermediate similar to the compound Int. 12 was deprotected from the Ts protecting group to prepare the corresponding target compound 178-180.
表6 产物178～180对应的原料：酰氯Table 6 Raw materials corresponding to products 178-180: acid chloride
Figure PCTCN2019079734-appb-000135
Figure PCTCN2019079734-appb-000135
1、N-(4-((金刚烷-2-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)丁烷-1-磺酰胺(178)的合成1, N-(4-((adamantan-2-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-C Synthesis of pyridin-4-yl)phenyl)butane-1-sulfonamide (178)
Figure PCTCN2019079734-appb-000136
Figure PCTCN2019079734-appb-000136
化合物178的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 178 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:510(M+H +)。1H NMR(400MHz,DMSO)δ12.06(s,1H),9.51(s,1H),7.35(m,4H),7.12(d,J＝6.0Hz,1H),6.25(s,1H),4.44(s,1H),3.56(s,3H),3.04(m,2H),2.01(s,2H),1.70(m,10H),1.32(m,6H),0.86(t,J＝6.9Hz,3H). Mass spectrum: 510 (M+H + ). 1H NMR (400MHz, DMSO) δ 12.06 (s, 1H), 9.51 (s, 1H), 7.35 (m, 4H), 7.12 (d, J = 6.0 Hz, 1H), 6.25 (s, 1H), 4.44 (s, 1H), 3.56 (s, 3H), 3.04 (m, 2H), 2.01 (s, 2H), 1.70 (m, 10H), 1.32 (m, 6H), 0.86 (t, J = 6.9 Hz, 3H).
2、N-(4-(((1R，3S，5R)-金刚烷-2-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-C]吡啶-4-基)苯基)乙酰胺(179)的合成2. N-(4-((1R,3S,5R)-adamantan-2-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H- Synthesis of pyrrolo[2,3-C]pyridin-4-yl)phenyl)acetamide (179)
Figure PCTCN2019079734-appb-000137
Figure PCTCN2019079734-appb-000137
化合物179的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 179 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:510(M+H +)。1H NMR(400MHz,DMSO)δ12.06(s,1H),7.23(s,1H),7.35(d,J＝17.7Hz,3H),7.12(d,J＝6.0Hz,1H),6.25(s,1H),4.44(s,1H),3.56(s,3H),2.04(s,3H),2.01(s,2H),1.70(m,9H),1.32(m,4H). Mass spectrum: 510 (M+H + ). 1H NMR (400MHz, DMSO) δ 12.06 (s, 1H), 7.23 (s, 1H), 7.35 (d, J = 17.7 Hz, 3H), 7.12 (d, J = 6.0 Hz, 1H), 6.25 (s) , 1H), 4.44 (s, 1H), 3.56 (s, 3H), 2.04 (s, 3H), 2.01 (s, 2H), 1.70 (m, 9H), 1.32 (m, 4H).
3、4-((4-((金刚烷-2-基)氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3c]吡啶-4- 基)苯基)氨基)-4-氧代丁酸(180)的合成3, 4-((4-((Adamantyl-2-yl)oxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3c]] Synthesis of pyridin-4-yl)phenyl)amino)-4-oxobutanoic acid (180)
Figure PCTCN2019079734-appb-000138
Figure PCTCN2019079734-appb-000138
化合物180的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of the compound 180 was carried out in the same manner as in the synthesis of the compound 118 by using a reagent corresponding thereto.
质谱:490(M+H +)。1H NMR(400MHz,DMSO)δ12.06(s,1H),11.0(s,1H),7.23(s,1H),7.35(d,J＝17.7Hz,3H),7.12(d,J＝6.0Hz,1H),6.25(s,1H),4.44(s,1H),3.56(s,3H),2.82(t,2H),2.45(t,2H)2.01(s,2H),1.70(m,9H),1.32(m,4H). Mass spectrum: 490 (M+H + ). 1H NMR (400MHz, DMSO) δ 12.06 (s, 1H), 11.0 (s, 1H), 7.23 (s, 1H), 7.35 (d, J = 17.7 Hz, 3H), 7.12 (d, J = 6.0 Hz) , 1H), 6.25 (s, 1H), 4.44 (s, 1H), 3.56 (s, 3H), 2.82 (t, 2H), 2.45 (t, 2H) 2.01 (s, 2H), 1.70 (m, 9H) ), 1.32 (m, 4H).
实施例7 化合物181、182的合成Example 7 Synthesis of Compounds 181 and 182
目标化合物181、182的合成方法与实施例1步骤二中目标化合物100的合成方法相似，都是通过以下步骤制备得到：The synthesis method of the target compound 181, 182 is similar to the synthesis method of the target compound 100 in the second step of the first embodiment, and is prepared by the following steps:
①与实施例1步骤二中的步骤1类似：将化合物21与表7中各产物对应的取代的金刚烷进行反应，制备得到类似于化合物98的中间体；1 is similar to the step 1 in the second step of the first embodiment: the compound 17 is reacted with the substituted adamantane corresponding to each product in Table 7, to prepare an intermediate similar to the compound 98;
②与实施例1步骤二中的步骤2类似：将类似于化合物98的中间体与化合物Int.8反应，制备得到类似于化合物99的中间体；2 is similar to the step 2 in the second step of the first embodiment: an intermediate similar to the compound 98 is reacted with the compound Int. 8 to prepare an intermediate similar to the compound 99;
③与实施例1步骤二中的步骤3类似：类似于化合物99的中间体脱出Ts保护基，制备得到对应的目标化合物181、182。3 Similar to Step 3 in Step 2 of Example 1, the intermediates similar to Compound 99 were deprotected from the Ts protecting group to give the corresponding target compounds 181, 182.
表7 产物181、182对应的原料取代金刚烷的结构Table 7 Structure of the substituted adamantane corresponding to the starting materials of products 181 and 182
Figure PCTCN2019079734-appb-000139
Figure PCTCN2019079734-appb-000139
1、6-(甲基-D3)-4-(5-(甲基磺酰基)-2-(((1R，5R，7S)-螺[金刚烷-2,2'-[1,3]二氧戊环]-6-基)氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(181)的合成1,6-(Methyl-D3)-4-(5-(methylsulfonyl)-2-(((1R,5R,7S)-spiro[adamantane-2,2'-[1,3] Synthesis of Dioxolane]-6-yl)oxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (181)
Figure PCTCN2019079734-appb-000140
Figure PCTCN2019079734-appb-000140
化合物181的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 181 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:514(M+H +)。 Mass Spectrum: 514 (M+H + ).
2、4-(2-((6-羟基金刚烷-2-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(182)的合成2. 4-(2-((6-Hydroxyadamantan-2-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1,6-dihydro Synthesis of -7H-pyrrolo[2,3-c]pyridin-7-one (182)
Figure PCTCN2019079734-appb-000141
Figure PCTCN2019079734-appb-000141
化合物182的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 182 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:472(M+H +)。 Mass Spectrum: 472 (M+H + ).
实施例8 化合物183～185的合成Example 8 Synthesis of Compounds 183-185
目标化合物183～185的合成方法与实施例2步骤一中目标化合物118的合成方法相似，都是通过以下步骤制备得到：The synthesis method of the target compounds 183 to 185 is similar to the synthesis method of the target compound 118 in the first step of the second embodiment, and is prepared by the following steps:
①与实施例2步骤一中的步骤3类似：由化合物10与化合物Int.8反应，制备得到类似于化合物Int.11的中间体；1 is similar to step 3 in the first step of Example 2: reacting compound 10 with compound Int. 8 to prepare an intermediate similar to compound Int.
②与实施例2步骤一中的步骤4类似：将类似于化合物Int.11的中间体与对应的酰氯进行反应，制备得到类似于化合物Int.12的中间体；2 is similar to step 4 in the first step of Example 2: an intermediate similar to the compound Int. 11 is reacted with the corresponding acid chloride to prepare an intermediate similar to the compound Int.
③与实施例2步骤一中的步骤5类似：类似于化合物Int.12的中间体脱出Ts保护基，制备得到对应的目标化合物183～185。3 is similar to step 5 in the first step of Example 2: an intermediate similar to the compound Int. 12 is deprotected from the Ts protecting group to prepare the corresponding target compound 183 to 185.
表8 产物183～185对应的原料：酰氯Table 8 Raw materials corresponding to products 183 to 185: acid chloride
Figure PCTCN2019079734-appb-000142
Figure PCTCN2019079734-appb-000142
1、N-(4-((金刚烷-2-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,1，3-c]吡啶-4-基)苯基)丁烷-1-磺酰胺(183)的合成1, N-(4-((adamantan-2-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2 Synthesis of 1,1,3-c]pyridin-4-yl)phenyl)butane-1-sulfonamide (183)
Figure PCTCN2019079734-appb-000143
Figure PCTCN2019079734-appb-000143
化合物183的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 183 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:513(M+H +)。 Mass Spectrum: 513 (M+H + ).
2、N-(4-((金刚烷-2-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,1，3-c]吡啶-4-基)苯基)乙酰胺(184)的合成2. N-(4-((Adamantyl-2-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2 Synthesis of 1,1,3-c]pyridin-4-yl)phenyl)acetamide (184)
Figure PCTCN2019079734-appb-000144
Figure PCTCN2019079734-appb-000144
化合物184的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 184 was carried out in the same manner as in the synthesis of Compound 118 using the corresponding reagent.
质谱:435(M+H +)。 Mass Spectrum: 435 (M+H + ).
3、4-((4-((金刚烷-2-基)氧基)-3-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)氨基)-4-氧代丁酸(185)的合成3, 4-((4-((Adamantyl-2-yl)oxy)-3-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[ Synthesis of 2,3-c]pyridin-4-yl)phenyl)amino)-4-oxobutanoic acid (185)
Figure PCTCN2019079734-appb-000145
Figure PCTCN2019079734-appb-000145
化合物185的合成与合成化合物118的方法一样，用与之相对应的试剂合成。The synthesis of Compound 185 was carried out in the same manner as in the synthesis of Compound 118 using a reagent corresponding thereto.
质谱:493(M+H +)。 Mass spectrum: 493 (M+H + ).
实施例9 目标化合物186～191的制备Example 9 Preparation of target compounds 186-191
目标化合物186～191的合成方法与实施例1步骤二中目标化合物100的合成方法相似，都是通过以下步骤制备得到：The synthesis method of the target compounds 186 to 191 is similar to the synthesis method of the target compound 100 in the second step of the first embodiment, and is prepared by the following steps:
①与实施例1步骤二中的步骤1类似：将化合物21与表9中各产物对应的取代的金刚烷进行反应，制备得到类似于化合物98的中间体；1 is similar to the step 1 in the second step of the first embodiment: the compound 17 is reacted with the substituted adamantane corresponding to each product in Table 9, to prepare an intermediate similar to the compound 98;
②与实施例1步骤二中的步骤2类似：将类似于化合物98的中间体与化合物Int.6或Int.8反应，制备得到类似于化合物99的中间体；2 is similar to the step 2 in the second step of the first embodiment: an intermediate similar to the compound 98 is reacted with the compound Int. 6 or Int. 8 to prepare an intermediate similar to the compound 99;
③与实施例1步骤二中的步骤3类似：类似于化合物99的中间体脱出Ts保护基，制备得到对应的目标化合物186～191。3 is similar to the step 3 in the second step of the first embodiment: an intermediate similar to the compound 99 is deprotected from the Ts protecting group to prepare the corresponding target compound 186 to 191.
表9 产物186～191对应的原料取代金刚烷的结构Table 9 Structure of the substituted adamantane corresponding to the starting materials of products 186-191
Figure PCTCN2019079734-appb-000146
Figure PCTCN2019079734-appb-000146
1、反式-4-(2-((4-羟甲基金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢 -7H-吡咯并[2,13-c]吡啶-7-酮1, trans-4-(2-((4-hydroxymethyladamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-di Hydrogen-7H-pyrrolo[2,13-c]pyridine-7-one
Figure PCTCN2019079734-appb-000147
Figure PCTCN2019079734-appb-000147
化合物186的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 186 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:483(M+H +)。 Mass spectrum: 483 (M+H + ).
2、顺式-4-(2-((4-羟甲基金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-甲基-1,6-二氢-7H-吡咯并[2,13-c]吡啶-7-酮2, cis-4-(2-((4-hydroxymethyladamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-methyl-1,6-di Hydrogen-7H-pyrrolo[2,13-c]pyridine-7-one
Figure PCTCN2019079734-appb-000148
Figure PCTCN2019079734-appb-000148
化合物187的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 187 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:483(M+H +)。 Mass spectrum: 483 (M+H + ).
3、5-(2-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯氧基)金刚烷-2-甲酰胺的合成3,5-(2-(6-Methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl) Synthesis of phenoxy)adamantane-2-carboxamide
Figure PCTCN2019079734-appb-000149
Figure PCTCN2019079734-appb-000149
化合物188的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 188 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:496(M+H +)。 Mass Spectrum: 496 (M+H + ).
4、反式-4-(2-((4-羟甲基金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,13-c]吡啶-7-酮4, trans-4-(2-((4-hydroxymethyladamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1 ,6-Dihydro-7H-pyrrolo[2,13-c]pyridine-7-one
Figure PCTCN2019079734-appb-000150
Figure PCTCN2019079734-appb-000150
化合物189的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of Compound 189 was carried out in the same manner as in the synthesis of Compound 100 using a reagent corresponding thereto.
质谱:486(M+H +)。 Mass spectrum: 486 (M+H + ).
5、顺式-4-(2-((4-羟甲基金刚烷-1-基)氧基)-5-(甲基磺酰基)苯基)-6-(甲基-D3)-1,6-二氢-7H-吡咯并[2,13-c]吡啶-7-酮5. cis-4-(2-((4-Hydroxymethyladamantan-1-yl)oxy)-5-(methylsulfonyl)phenyl)-6-(methyl-D3)-1 ,6-Dihydro-7H-pyrrolo[2,13-c]pyridine-7-one
Figure PCTCN2019079734-appb-000151
Figure PCTCN2019079734-appb-000151
化合物190的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 190 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:486(M+H +)。 Mass spectrum: 486 (M+H + ).
6、5-(2-(6-(甲基-D3)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-4-(甲基磺酰基)苯氧基)金刚烷-2-甲酰胺的合成6, 5-(2-(6-(methyl-D3)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-( Synthesis of Methylsulfonyl)phenoxy)adamantane-2-carboxamide
Figure PCTCN2019079734-appb-000152
Figure PCTCN2019079734-appb-000152
化合物191的合成与合成化合物100的方法一样，用与之相对应的试剂合成。The synthesis of the compound 191 was carried out in the same manner as in the synthesis of the compound 100 by using a reagent corresponding thereto.
质谱:499(M+H +)。 Mass Spectrum: 499 (M+H + ).
以下通过试验例的形式说明本发明的有益效果。The beneficial effects of the present invention will be described below by way of test examples.
试验例1 本发明化合物对CWR22RV1细胞增殖抑制作用的生物学测定Test Example 1 Biological determination of the inhibitory effect of the compound of the present invention on proliferation of CWR22RV1 cells
一、实验材料：First, the experimental materials:
CWR22RV1 cell line(中国科学院细胞库，TCHu100)CWR22RV1 cell line (Chinese Academy of Sciences Cell Bank, TCHu100)
FBS(Gibco,Cat.No.10099-141)FBS (Gibco, Cat. No. 10099-141)
0.01M PBS(Biosharp,Cat.No.162262)0.01M PBS (Biosharp, Cat. No. 162262)
RIPM1640(Hyclone,Cat.No.308090.01)RIPM1640 (Hyclone, Cat. No. 308090.01)
Penicillin-Streptomycin(Hyclone,Cat.No.SV30010)Penicillin-Streptomycin (Hyclone, Cat. No. SV30010)
Cell counting kit-8(Signalway Antibody,Cat.No.CP002)Cell counting kit-8 (Signalway Antibody, Cat. No.CP002)
DMSO(Sigma,Cat.No.D5879)DMSO (Sigma, Cat. No. D5879)
Centrifuge Tube,15ml(Excell Bio,Cat.No.CS015-0001)Centrifuge Tube, 15ml (Excell Bio, Cat. No. CS015-0001)
Cell Culture Dish,(Excell Bio,Cat.No.CS016-0128)Cell Culture Dish, (Excell Bio, Cat. No. CS016-0128)
96-well cell culture cluster(Corning,Cat.No.3599)96-well cell culture cluster (Corning, Cat. No. 3599)
二、实验方法：Second, the experimental method:
1.缓冲液配制：1. Buffer preparation:
细胞培养液：RIPM1640培养基，10％FBS，1％Pen Strep。Cell culture medium: RIPM1640 medium, 10% FBS, 1% Pen Strep.
PBS缓冲液：PBS粉剂溶于2升超纯水中，灭菌。PBS buffer: PBS powder was dissolved in 2 liters of ultrapure water and sterilized.
2.实验步骤：2. Experimental steps:
(1)CWR22RV1细胞用细胞培养液传代培养，取生长状态良好的细胞接种于96孔板，每孔80μL，每孔细胞数为1500，于37℃，5％CO 2细胞孵育箱中培养过夜。 (1) CWR22RV1 cells were subcultured with cell culture medium, and cells grown in good condition were inoculated into 96-well plates at 80 μL per well, and the number of cells per well was 1500, and cultured overnight at 37 ° C in a 5% CO 2 cell incubator.
(2)将药物用二甲基亚砜(DMSO)配置成30mM的储存液。临用前再用DMSO稀释3倍，再按3倍梯度稀释，得到9个浓度梯度，再用培养液将各浓度的化合物稀释200倍(以此保证培养体系中DMSO浓度为0.1％)，每个浓度做2个孔重复。取20μL稀释好的化合物加到细胞培养孔(终浓度为10μM,3.3μM,1.1μM…)，轻轻振荡混匀。另外设置3个只加细胞的阴性对照孔和3个只加培养液的空白对照孔(6孔各加20μL培养液稀释200倍的DMSO)。(2) The drug was formulated with dimethyl sulfoxide (DMSO) as a 30 mM stock solution. Dilute 3 times with DMSO before use, then dilute by 3 times to obtain 9 concentration gradients, and then dilute the compound at each concentration 200 times with the culture solution (to ensure the DMSO concentration in the culture system is 0.1%). The concentration is made to repeat 2 holes. 20 μL of the diluted compound was added to the cell culture well (final concentration of 10 μM, 3.3 μM, 1.1 μM...), and gently mixed by shaking. In addition, three cell-only negative control wells and three blank control wells (only 20 μL of culture medium diluted with 200 μL of DMSO) were placed.
3.结果检测：3. Results detection:
(1)培养6天后，每孔加10μL CCK-8，于37℃，5％CO 2细胞孵育箱中继续培养2.5小时。 (1) After 6 days of culture, 10 μL of CCK-8 was added to each well, and incubation was continued for 2.5 hours at 37 ° C in a 5% CO 2 cell incubator.
(2)用多功能酶标仪在450nm处测定吸光度(OD值)。(2) The absorbance (OD value) was measured at 450 nm using a multi-function microplate reader.
(3)数据用软件GraphPad Prism6中Dose-response-inhibition方程分析，得出IC 50值。 (3) The data was analyzed by the Dose-response-inhibition equation in the software GraphPad Prism6, and the IC 50 value was obtained.
本发明化合物对CWR22RV1的活性抑制的IC 50(nM)，结果如表10所示。 The IC 50 (nM) of the activity of the compound of the present invention against CWR22RV1 was as shown in Table 10.
表10 本发明化合物对CWR22RV1的活性抑制的IC 50(nM) Table 10 IC 50 (nM) of inhibition of CWR22RV1 activity by the compounds of the present invention
Figure PCTCN2019079734-appb-000153
Figure PCTCN2019079734-appb-000153
Figure PCTCN2019079734-appb-000154
Figure PCTCN2019079734-appb-000154
试验例2 本发明化合物108对多个癌细胞系增殖抑制作用的生物学测定结果Test Example 2 Biological measurement results of the inhibitory effect of the compound 108 of the present invention on proliferation of a plurality of cancer cell lines
一、试验材料：First, the test materials:
MCF‐7 cell line、BT‐474 cell line、MDA‐MB453 cell line、LNCAP‐AR cell line均为市售所得。MCF‐7 cell line, BT‐474 cell line, MDA‐MB453 cell line, and LNCAP‐AR cell line are all commercially available.
其它材料来源与试验例1相同。The other material sources were the same as in Test Example 1.
二、试验方法：Second, the test method:
与试验例1相同。The same as Test Example 1.
本发明化合物108对MCF‐7、BT‐474、MDA‐MB453、LNCAP‐AR的活性抑制的IC 50(nM)，结果如表11所示。 The IC 50 (nM) of the inhibition of the activity of the compound 108 of the present invention against MCF-7, BT-474, MDA-MB453, and LNCAP-AR is shown in Table 11.
表11 本发明化合物对多个癌细胞系的活性抑制的IC 50(nM) Table 11 IC 50 (nM) of inhibition of activity of compounds of the invention against multiple cancer cell lines
癌细胞系Cancer cell line IC 50(nM) IC 50 (nM)
MCF‐7(乳腺癌细胞)MCF‐7 (breast cancer cells) 4747
BT‐474(乳腺癌细胞)BT-474 (breast cancer cells) 600600
MDA‐MB453(乳腺癌细胞)MDA‐MB453 (breast cancer cells) 450450
LNCAP‐AR(前列腺癌细胞)LNCAP‐AR (prostate cancer cells) 1010
上述实验结果表明，本发明的化合物能够显著抑制多个癌细胞系，尤其是前列腺癌细胞CWR22RV1的增殖。本发明的化合物有潜力应用于各种癌症，特别是前列腺癌的治疗。The above experimental results indicate that the compound of the present invention can significantly inhibit the proliferation of a plurality of cancer cell lines, particularly prostate cancer cell line CWR22RV1. The compounds of the invention have potential for use in the treatment of a variety of cancers, particularly prostate cancer.
综上，本发明提供了一种结构新颖的含有金刚烷的化合物及其在治疗癌症中的用途。实验结果表明，本发明化合物能够显著抑制癌细胞的增殖，减少全长雄激素受体(AR-FL)和变异雄激素受体(AR-v7)的表达，抑制前列腺癌细胞的增殖，对癌症，尤其是前列腺癌具有潜在的治疗作用，为临床上筛选和/或制备癌症药物提供了一种新的选择。In summary, the present invention provides a novel adamantane-containing compound and its use in the treatment of cancer. The experimental results show that the compound of the present invention can significantly inhibit the proliferation of cancer cells, reduce the expression of the full-length androgen receptor (AR-FL) and the variant androgen receptor (AR-v7), inhibit the proliferation of prostate cancer cells, and cancer. In particular, prostate cancer has a potential therapeutic effect, providing a new option for clinical screening and/or preparation of cancer drugs.

Claims (23)

  1. 式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物：a compound of Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:
    Figure PCTCN2019079734-appb-100001
    Figure PCTCN2019079734-appb-100001
    式中，In the formula,
    Y选自O、S、NR 31、C(R 31) 2， Y is selected from O, S, NR 31 , C(R 31 ) 2 ,
    其中，R 31各自独立地选自氢、氘、氚、C 1～C 4烷基、C 1～C 4烷氧基； Wherein R 31 is each independently selected from the group consisting of hydrogen, hydrazine, hydrazine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
    R 1选自取代或未取代的金刚烷基， R 1 is selected from substituted or unsubstituted adamantyl,
    其中，所述金刚烷基的取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、
    Figure PCTCN2019079734-appb-100002
    取代或未取代的C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、取代或未取代的C 2～C 8烯基、取代或未取代的C 2～C 8炔基，所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2，     Wherein the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
    Figure PCTCN2019079734-appb-100002
    Substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 An alkynyl group, the substituents being ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
    或者，同一碳原子上的两取代基一起形成双键，所述双键为＝O、＝S、＝NR 32、＝C(R 32) 2，其中，R 32各自独立地选自氢、氘、氚、C 1～C 4烷基、C 1～C 4烷氧基， Alternatively, the two substituents on the same carbon atom together form a double bond, which is =0, =S, =NR 32 , =C(R 32 ) 2 , wherein R 32 are each independently selected from hydrogen, hydrazine , hydrazine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy,
    或者，同一碳原子上的两取代基相连形成取代或未取代的3～6元环烷基、取代或未取代的3～6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基，所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、C 1～C 4烷基、C 1～C 4烷氧基； Alternatively, the two substituents on the same carbon atom are bonded to form a substituted or unsubstituted 3-6 membered cycloalkyl group, a substituted or unsubstituted 3-6 membered heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted group. Heteroaryl, the substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy ;
    R 2～R 6各自独立地选自氢、氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、取代或未取代的C 1～C 4烷基、取代或未取代的C 1～C 4烷氧基， R 2 to R 6 are each independently selected from the group consisting of hydrogen, hydrazine, hydrazine, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 , substituted or unsubstituted C 1 -C 4 alkyl, substituted Or unsubstituted C 1 -C 4 alkoxy group,
    所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2； The substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ;
    R 7选自
    Figure PCTCN2019079734-appb-100003
    R 7 is selected from
    Figure PCTCN2019079734-appb-100003
    其中，R 20各自独立地选自取代或未取代的选自C 1～C 4烷基、取代或未取代的3～6元环烷 基、取代或未取代的3～6元杂环基、取代或未取代的芳基、取代或未取代的杂芳基， Wherein R 20 is each independently selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted 3-6 membered cycloalkyl group, a substituted or unsubstituted 3-6 membered heterocyclic group, a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,
    所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2。 The substituents are ruthenium, rhodium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 .
  2. 根据权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅰ如式Ⅱ所示：The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein the compound I As shown in Equation II:
    Figure PCTCN2019079734-appb-100004
    Figure PCTCN2019079734-appb-100004
    式中，In the formula,
    Y选自O、S、NR 31， Y is selected from O, S, NR 31 ,
    其中，R 31选自氢、氘、氚、C 1～C 4烷基、C 1～C 4烷氧基； Wherein R 31 is selected from the group consisting of hydrogen, hydrazine, hydrazine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
    R 1选自取代或未取代的金刚烷基， R 1 is selected from substituted or unsubstituted adamantyl,
    其中，所述金刚烷基的取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、
    Figure PCTCN2019079734-appb-100005
    取代或未取代的C 1～C 6烷氧基、取代或未取代的C 1～C 6烷基、取代或未取代的C 2～C 6烯基、取代或未取代的C 2～C 6炔基，所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2，     Wherein the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
    Figure PCTCN2019079734-appb-100005
    Substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 An alkynyl group, the substituents being ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
    或者，同一碳原子上的两取代基一起形成双键，所述双键为＝O、＝S、＝NR 32、＝C(R 32) 2，其中，R 32各自独立地选自氢、氘、氚， Alternatively, the two substituents on the same carbon atom together form a double bond, which is =0, =S, =NR 32 , =C(R 32 ) 2 , wherein R 32 are each independently selected from hydrogen, hydrazine ,tritium,
    或者，同一碳原子上的两取代基相连形成3～6元环烷基、3～6元杂环基、芳基、杂芳基；Alternatively, the two substituents on the same carbon atom are bonded to form a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, and a heteroaryl group;
    R 3选自取代或未取代的C 1～C 4烷基、取代或未取代的C 1～C 4烷氧基， R 3 is selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 1 -C 4 alkoxy group,
    所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2； The substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ;
    R 7选自
    Figure PCTCN2019079734-appb-100006
    R 7 is selected from
    Figure PCTCN2019079734-appb-100006
    其中，R 20各自独立地选自取代或未取代的选自C 1～C 4烷基、3～6元环烷基、3～6元杂环基、芳基、杂芳基， Wherein R 20 is each independently selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a 3 to 6 membered cycloalkyl group, a 3 to 6 membered heterocyclic group, an aryl group, a heteroaryl group,
    所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2。 The substituents are ruthenium, rhodium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 .
  3. 根据权利要求2所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂 合物、或其前体药物、或其代谢产物，其特征在于：The compound according to claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, which is characterized by:
    Y选自O、S、NR 31， Y is selected from O, S, NR 31 ,
    其中，R 31选自氢、氘、氚、C 1～C 2烷基、C 1～C 2烷氧基； Wherein R 31 is selected from the group consisting of hydrogen, hydrazine, hydrazine, C 1 -C 2 alkyl, C 1 -C 2 alkoxy;
    R 3选自取代或未取代的C 1～C 4烷基、取代或未取代的C 1～C 4烷氧基， R 3 is selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 1 -C 4 alkoxy group,
    所述取代基为氘、氚、-OH、-NH 2； The substituents are ruthenium, osmium, -OH, -NH 2 ;
    R 7选自
    Figure PCTCN2019079734-appb-100007
    R 7 is selected from
    Figure PCTCN2019079734-appb-100007
    其中，R 20各自独立地选自取代或未取代的选自C 1～C 4烷基、3～5元杂环， Wherein R 20 is each independently selected from a substituted or unsubstituted heterocyclic group selected from the group consisting of C 1 -C 4 alkyl groups and 3 to 5 membered heterocyclic rings.
    所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2。 The substituents are ruthenium, rhodium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 .
  4. 根据权利要求3所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：The compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, which is characterized by:
    Y选自O、S、NR 31； Y is selected from O, S, NR 31 ;
    其中，R 31选自氢、氘、氚； Wherein R 31 is selected from the group consisting of hydrogen, hydrazine and hydrazine;
    R 3选自取代或未取代的C 1～C 2烷基， R 3 is selected from a substituted or unsubstituted C 1 -C 2 alkyl group,
    所述取代基为氘、氚；The substituents are ruthenium and osmium;
    R 7选自
    Figure PCTCN2019079734-appb-100008
    R 7 is selected from
    Figure PCTCN2019079734-appb-100008
    其中，R 20各自独立地选自取代或未取代的选自C 1～C 4烷基、4元杂环， Wherein R 20 are each independently selected from a substituted or unsubstituted C 1 -C 4 alkyl group, a 4 membered heterocyclic ring,
    所述取代基为-CN、-COOH、-CHO、-CONH 2。 The substituent is -CN, -COOH, -CHO, -CONH 2 .
  5. 根据权利要求4所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：The compound according to claim 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, characterized by:
    Y选自O、NH；Y is selected from O, NH;
    R 3选自-CH 3或-CD 3； R 3 is selected from -CH 3 or -CD 3 ;
    R 7选自
    Figure PCTCN2019079734-appb-100009
    R 7 is selected from
    Figure PCTCN2019079734-appb-100009
    其中，R 20各自独立地取代或未取代的选自C 1～C 4烷基、
    Figure PCTCN2019079734-appb-100010
    Wherein R 20 is independently substituted or unsubstituted, and is selected from a C 1 -C 4 alkyl group,
    Figure PCTCN2019079734-appb-100010
    所述取代基为-COOH。The substituent is -COOH.
  6. 根据权利要求1～5任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：The compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, characterized in that :
    R 1选自取代或未取代的金刚烷基； R 1 is selected from substituted or unsubstituted adamantyl;
    其中，所述金刚烷基的取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、
    Figure PCTCN2019079734-appb-100011
    取代或未取代的C 1～C 4烷氧基、取代或未取代的C 1～C 4烷基；所述取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2；     Wherein the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
    Figure PCTCN2019079734-appb-100011
    a substituted or unsubstituted C 1 -C 4 alkoxy group, a substituted or unsubstituted C 1 -C 4 alkyl group; the substituents are ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, - CHO, -CONH 2 ;
    或者，同一碳原子上的两取代基一起形成双键，所述双键为＝O、＝S、＝NH、＝CH 2； Alternatively, the two substituents on the same carbon atom together form a double bond, which is =0, =S, =NH, =CH 2 ;
    或者，同一碳原子上的两取代基相连形成4～6元杂环基。Alternatively, the two substituents on the same carbon atom are bonded to form a 4- to 6-membered heterocyclic group.
  7. 根据权利要求6所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：The compound according to claim 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein:
    R 1选自取代或未取代的金刚烷基； R 1 is selected from substituted or unsubstituted adamantyl;
    其中，所述金刚烷基的取代基为氘、氚、-OH、-NH 2、-CN、-COOH、-CHO、-CONH 2、
    Figure PCTCN2019079734-appb-100012
    C 1～C 2烷氧基、取代或未取代的C 1～C 2烷基；所述取代基为氘、氚、-OH、-NH 2；     Wherein the substituent of the adamantyl group is ruthenium, osmium, -OH, -NH 2 , -CN, -COOH, -CHO, -CONH 2 ,
    Figure PCTCN2019079734-appb-100012
    a C 1 -C 2 alkoxy group, a substituted or unsubstituted C 1 -C 2 alkyl group; the substituents are ruthenium, osmium, -OH, -NH 2 ;
    或者，同一碳原子上的两取代基一起形成双键，所述双键为＝O或＝S；Alternatively, the two substituents on the same carbon atom together form a double bond, the double bond being =O or =S;
    或者，同一碳原子上的两取代基相连形成5元杂环基。Alternatively, the two substituents on the same carbon atom are joined to form a 5-membered heterocyclic group.
  8. 根据权利要求7所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：The compound according to claim 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein:
    R 1选自取代或未取代的金刚烷基； R 1 is selected from substituted or unsubstituted adamantyl;
    其中，所述金刚烷基的取代基为-OH、-NH 2、-CN、-COOH、-CONH 2、
    Figure PCTCN2019079734-appb-100013
    甲氧基、取代或未取代的甲基；所述取代基为-OH、-NH 2；     Wherein the substituent of the adamantyl group is -OH, -NH 2 , -CN, -COOH, -CONH 2 ,
    Figure PCTCN2019079734-appb-100013
    a methoxy group, a substituted or unsubstituted methyl group; the substituent is -OH, -NH 2 ;
    或者，同一碳原子上的两取代基一起形成＝O；Alternatively, the two substituents on the same carbon atom together form =O;
    或者，同一碳原子上的两取代基相连形成
    Figure PCTCN2019079734-appb-100014
    Or, two substituents on the same carbon atom are connected to form
    Figure PCTCN2019079734-appb-100014
  9. 根据权利要求2～8任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅱ如式ⅢA所示：The compound according to any one of claims 2 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, characterized in that : The compound II is as shown in formula IIIA:
    Figure PCTCN2019079734-appb-100015
    Figure PCTCN2019079734-appb-100015
    式中，In the formula,
    X选自NH、无；X is selected from NH, none;
    R 3选自-CH 3、-CD 3； R 3 is selected from -CH 3 , -CD 3 ;
    R 11选自-H、-OH、-NH 2； R 11 is selected from the group consisting of -H, -OH, -NH 2 ;
    R 12、R 13各自独立地选自-H、-OH、-NH 2、-CN、-COOH、-CONH 2、
    Figure PCTCN2019079734-appb-100016
    甲氧基、取代或未取代的甲基；所述取代基为-OH、-NH 2；或者，R 12、R 13一起形成＝O。     R 12 and R 13 are each independently selected from -H, -OH, -NH 2 , -CN, -COOH, -CONH 2 ,
    Figure PCTCN2019079734-appb-100016
    a methoxy group, a substituted or unsubstituted methyl group; the substituent is -OH, -NH 2 ; or R 12 and R 13 together form =0.
  10. 根据权利要求9所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢA为下述结构式之一：The compound according to claim 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein the compound IIIA Is one of the following structural formulas:
    Figure PCTCN2019079734-appb-100017
    Figure PCTCN2019079734-appb-100017
    Figure PCTCN2019079734-appb-100018
    Figure PCTCN2019079734-appb-100018
    Figure PCTCN2019079734-appb-100019
    Figure PCTCN2019079734-appb-100019
  11. 根据权利要求2～8任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅱ如式ⅢB所示：The compound according to any one of claims 2 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, characterized in that : The compound II is as shown in formula IIIB:
    Figure PCTCN2019079734-appb-100020
    Figure PCTCN2019079734-appb-100020
    式中，In the formula,
    X选自NH、无；X is selected from NH, none;
    R 3选自-CH 3、-CD 3； R 3 is selected from -CH 3 , -CD 3 ;
    R 14选自-H、-OH、
    Figure PCTCN2019079734-appb-100021
    R 14 is selected from -H, -OH,
    Figure PCTCN2019079734-appb-100021
  12. 根据权利要求11所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢB为下述结构式之一：The compound according to claim 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein the compound IIIB Is one of the following structural formulas:
    Figure PCTCN2019079734-appb-100022
    Figure PCTCN2019079734-appb-100022
  13. 根据权利要求2～8任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅱ如式ⅢC所示：The compound according to any one of claims 2 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, characterized in that : The compound II is as shown in formula IIIC:
    Figure PCTCN2019079734-appb-100023
    Figure PCTCN2019079734-appb-100023
    式中，In the formula,
    R 3选自-CH 3或-CD 3； R 3 is selected from -CH 3 or -CD 3 ;
    R 15、R 16各自独立地选自-H、-OH；或者，R 15、R 16相连形成
    Figure PCTCN2019079734-appb-100024
    R 15, R 16 are each independently selected from -H, -OH; or, R 15, R 16 connected to form
    Figure PCTCN2019079734-appb-100024
    R 17选自-H、-COOH； R 17 is selected from -H, -COOH;
    R 7’选自
    Figure PCTCN2019079734-appb-100025
    其中，R 20各自独立地取代或未取代的选自C 1～C 4烷基、
    Figure PCTCN2019079734-appb-100026
    所述取代基为-COOH。     R 7 ' selected from
    Figure PCTCN2019079734-appb-100025
    Wherein R 20 is independently substituted or unsubstituted, and is selected from a C 1 -C 4 alkyl group,
    Figure PCTCN2019079734-appb-100026
    The substituent is -COOH.
  14. 根据权利要求13所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢC为下述结构式之一：The compound according to claim 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein the compound IIIC Is one of the following structural formulas:
    Figure PCTCN2019079734-appb-100027
    Figure PCTCN2019079734-appb-100027
    Figure PCTCN2019079734-appb-100028
    Figure PCTCN2019079734-appb-100028
  15. 根据权利要求2～8任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物Ⅱ如式ⅢD所示：The compound according to any one of claims 2 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, characterized in that : The compound II is as shown in formula IIID:
    Figure PCTCN2019079734-appb-100029
    Figure PCTCN2019079734-appb-100029
    式中，In the formula,
    X选自NH、无；X is selected from NH, none;
    R 3选自-CH 3、-CD 3； R 3 is selected from -CH 3 , -CD 3 ;
    R 18选自-OH、
    Figure PCTCN2019079734-appb-100030
    R 18 is selected from -OH,
    Figure PCTCN2019079734-appb-100030
  16. 根据权利要求15所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：所述化合物ⅢD为下述结构式之一：The compound according to claim 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, wherein the compound IIID Is one of the following structural formulas:
    Figure PCTCN2019079734-appb-100031
    Figure PCTCN2019079734-appb-100031
    Figure PCTCN2019079734-appb-100032
    Figure PCTCN2019079734-appb-100032
  17. 权利要求1～16任意一项所述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其立体化学异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗和/或预防癌症的药物中的用途。The compound according to any one of claims 1 to 16, or a crystal form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a stereochemical isomer thereof, or a pharmaceutically acceptable compound thereof Use of an acceptable salt, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for the manufacture of a medicament for the treatment and/or prevention of cancer.
  18. 根据权利要求17所述的用途，其特征在于：所述癌症为乳腺癌、脑癌、前列腺癌，肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。The use according to claim 17, wherein the cancer is breast cancer, brain cancer, prostate cancer, lung cancer, ovarian cancer, bone cancer, neuro-cancer, liver cancer, blood cancer, esophageal cancer, glioblastoma, multiple Sexual myeloma, mantle cell lymphoma, acute myeloid leukemia and concurrent cancer.
  19. 根据权利要求18所述的用途，其特征在于：所述癌症为前列腺癌、卵巢癌、骨癌或神经癌。The use according to claim 18, characterized in that the cancer is prostate cancer, ovarian cancer, bone cancer or neuro-cancer.
  20. 权利要求1～16任意一项所述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其立体化学异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备减少全长雄激素受体、变异雄激素受体表达的药物中的用途。The compound according to any one of claims 1 to 16, or a crystal form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a stereochemical isomer thereof, or a pharmaceutically acceptable compound thereof Use of a salt, or a solvate thereof, or a prodrug thereof, or a metabolite thereof thereof, for the manufacture of a medicament for reducing expression of a full length androgen receptor, a variant androgen receptor.
  21. 权利要求1～16任意一项所述化合物、或其晶型、或其立体异构体、或其同位素体、或其互变异构体、或其立体化学异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备抑制癌细胞增殖的药物中的用途。The compound according to any one of claims 1 to 16, or a crystal form thereof, or a stereoisomer thereof, or a isotope thereof, or a tautomer thereof, or a stereochemical isomer thereof, or a pharmaceutically acceptable compound thereof The use of a salt, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for the preparation of a medicament for inhibiting proliferation of cancer cells.
  22. 根据权利要求21所述的用途，其特征在于：所述癌细胞为前列腺癌细胞、卵巢癌细胞、骨癌细胞或神经癌细胞。The use according to claim 21, wherein the cancer cells are prostate cancer cells, ovarian cancer cells, bone cancer cells or nerve cancer cells.
  23. 根据权利要求22所述的用途，其特征在于：所述癌细胞是下述癌症的癌细胞：乳腺癌、脑癌、前列腺癌，肺癌、卵巢癌、骨癌、神经癌、肝癌、血癌、食道癌、恶性胶质瘤、多发性骨髓瘤、套细胞淋巴瘤、急性骨髓性白血病及并发的癌症。The use according to claim 22, wherein the cancer cells are cancer cells of the following cancers: breast cancer, brain cancer, prostate cancer, lung cancer, ovarian cancer, bone cancer, neurocarcinoma, liver cancer, blood cancer, esophagus Cancer, malignant glioma, multiple myeloma, mantle cell lymphoma, acute myeloid leukemia and concurrent cancer.
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