WO2019158025A1 - 一种三氮唑并嘧啶衍生化合物、包含其的药物组合物及其用途 - Google Patents

一种三氮唑并嘧啶衍生化合物、包含其的药物组合物及其用途 Download PDF

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WO2019158025A1
WO2019158025A1 PCT/CN2019/074755 CN2019074755W WO2019158025A1 WO 2019158025 A1 WO2019158025 A1 WO 2019158025A1 CN 2019074755 W CN2019074755 W CN 2019074755W WO 2019158025 A1 WO2019158025 A1 WO 2019158025A1
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alkyl
independently
compound
alkylene
group
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PCT/CN2019/074755
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French (fr)
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周兵
罗成
杨亚玺
张元元
杜道海
蒋华良
乔刚
王新俊
杨向波
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中国科学院上海药物研究所
苏州苏领生物医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and generally relates to a class of triazolopyrimidine compounds, pharmaceutical compositions comprising the same, and uses thereof.
  • the present invention relates to a triazolopyrimidine compound, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph , solvates or isotopically labeled compounds (including hydrazine substitutions), as well as pharmaceutical compositions and their use in the treatment of neoplastic diseases.
  • such compounds may be useful in the manufacture of a medicament for the treatment of a disease or condition mediated by PRC2.
  • Polycomb Repressive Complex 2 is a core member of the Polycomb Group, which has histone methyltransferase activity and specifically catalyzes the top three lysine of histone H3.
  • the base is modified (H3K27me3) to inhibit the expression of a specific gene.
  • the methyltransferase activity of PRC2 is derived from its catalytic member EZH2, whereas EZH2 has no catalytic activity when present alone, which requires at least a complex with the other two members of PRC2, EED and SUZ12, to catalyze methylation modification.
  • EZH2, EED and SUZ12 are considered to be core components of the PRC2 complex.
  • PRC2 is a very promising anticancer drug development target, and the discovery of inhibitors targeting PRC2 is currently a hot spot in the pharmaceutical industry.
  • Novartis and Abbott have invented a small molecule that inhibits PRC2 activity by targeting EED (Reference: Novartis EED226, US 2016/0176882, J. Med. Chem. 2017, 60, 2215-2226, J. Med. Chem. 2017, 60, 415-427, Nat. Chem. Biol. 2017, 13, 381-388; Aberdeen, A-395, Nat. Chem. Biol. 2017, 13, 389-395),
  • the compounds show strong inhibitory activity at the molecular level, at the cellular level, and in animal experiments.
  • the PRC2 complex is considered to be a key driver of the development of a variety of malignancies, and the development of inhibitors that inhibit the activity of PRC2 by targeting EED is currently highly competitive in the industry and is beneficial for use in New drug development related to it.
  • Another object of the present invention is to provide a process for the preparation of the above compounds.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more of the above compounds or a pharmaceutically acceptable salt thereof.
  • a further object of the invention is to provide the use of a compound as described above for the manufacture of a medicament for the treatment of a disease or condition mediated by PRC2.
  • a further object of the invention is to provide a method of treating a disease or condition mediated by EED and/or PRC2, characterized in that a therapeutically effective amount of one or more of the above compounds or a medicament thereof is administered to a subject Salt used.
  • the invention provides a compound of formula (I), a pharmaceutically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, polymorph, a solvate or an isotope-labeled compound (including hydrazine),
  • R 1 , R 2 and R 3 are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-(C 1 -C 4 alkyl), C 1 - C 4 haloalkoxy, or C 3 -C 6 cycloalkyl;
  • R 5 is hydrogen, halogen or C 1 -C 4 alkyl
  • A is independently specified as the following structure:
  • R Y2 is each independently hydrogen, CN, NO 2 , halogen, SCF 3 , C 1 -C 6 alkyl substituted with 0-2 R a , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G a ;
  • R Y2 and R Y3 are bonded to each other to form -R Y2' -Z 2 -R Y3' - and are respectively bonded to an atom to which they are attached, wherein Z 2 is absent, -O-, -S(O) p -, or
  • R b1 and R c1 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, G a at each occurrence.
  • R Y2′ and R Y3′ are each independently in the absence of a C 1 -C 3 alkylene group, a C 1 -C 3 haloalkylene group, or are substituted by 1-2 substituents.
  • R z1 , R z2 and R z3 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl at each occurrence;
  • R b and R c are bonded to each other to form -R b' -Z 1 -R c' - and are respectively bonded to an atom to which they are attached, wherein -Z 1 - is absent, -O-, -S(O) p -, or
  • G a and G b is independently a C6-C10 aryl group, a 5-10 membered heteroaryl group, a 3-9 membered non-aromatic heterocyclic group, a C3-C8 cycloalkyl group, or a C5-C8.
  • a cycloalkenyl group and each of them is independently unsubstituted or substituted by 1, 2, 3, 4, or 5 R v ;
  • R h , R j , R k are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl at each occurrence; and R i is independently C 1 - at each occurrence C 6 alkyl, or C 1 -C 6 haloalkyl.
  • n are each independently 0, 1, or 2;
  • p are each independently 0, 1, or 2;
  • n are each independently 0, 1, 2, 3, or 4;
  • q are each independently 0, 1, 2, or 3;
  • R 1A and R 1B , R 2A and R 2B , R 3A and R 3B , R 4A and R 4B are each independently hydrogen, hydroxy, halogen, CN, NO 2 , C 1 -C 6 alkyl , C 1 -C 6 haloalkyl, G a ;
  • R 1A and R 1B , R 2A and R 2B , R 3A and R 3B , and R 4A and R 4B on the same carbon are bonded to each other to form -R 1A' -Z 2 -R 1B' -, -R 2A' -Z 2 -R 2B' -, -R 3A' -Z 2 -R 3B' -, -R 4A' -Z 2 -R 4B' - and are bonded to the atom to which they are attached to form a spiro ring
  • Z 2 is absent, -O-, -S(O) p -, or
  • R 1A and R 2A , R 1A and R 3A , R 3A and R 4A on different carbons are bonded to each other to form -R 1A' -Z 3 -R 2A' -, -R 1A' -Z 3 - R 3A' -, -R 3A' -Z 3 -R 4A' - and are bonded to an atom to which they are attached, wherein Z 3 is absent, -O-, -S(O) p -, or
  • R 1A′ and R 1B′ , R 2A′ and R 2B′ , R 3A′ and R 3B′ , R 4A′ and R 4B′ are each independently absent, C 1 ⁇ a C 6 alkylene group, a C 1 -C 6 haloalkylene group, or a C 1 -C 3 alkylene group substituted with 1-2 substituents; the substituent is selected from CN, halogen or C 1 -C 3- alkyl;
  • R 1A and R 1B , R 4A and R 4B are each independently hydrogen, hydroxy, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, G a ;
  • substituents R 1A and R 1B and R 4A and R 4B on the same carbon are bonded to each other to form -R 1A' -Z 2 -R 1B' -, -R 4A' -Z 2 -R 4B' - and And the atomic bond to which it is attached forms a spiro ring, where Z 2 is absent, -O-, -S(O) p -, or
  • R 1A′ and R 1B′ , R 4A′ and R 4B′ are each independently absent, C 1 -C 6 alkylene, C 1 -C 6 haloalkylene Or a C 1 -C 3 alkylene group substituted by 1-2 substituents; the substituent is selected from the group consisting of CN, halogen or C 1 -C 3 alkyl;
  • M 1 is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 3-9 membered non-aromatic carbocyclic ring, a 3-9 membered non-aromatic heterocyclic ring, and M 1 is unsubstituted or 1 or 2 R 6 substitution;
  • X is C, CH or N
  • R 2A and R 2B , R 3A and R 3B , R 4A and R 4B are each independently hydrogen, hydroxy, halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl, G a ;
  • M 2 is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 3-9 membered non-aromatic carbocyclic ring, a 3-9 membered non-aromatic heterocyclic ring, and M 2 is unsubstituted or 1 or 2 R 6 substitution;
  • the compound of formula I has the formula Ia-1, Ia-2 or Ia-3:
  • R Y2 is each independently hydrogen, CN, NO 2 , halogen, C 1 -C 6 alkyl at each occurrence;
  • G a , p, R b , R c , R d , and R e are the same as described above.
  • the compound of formula I has formula Ia-4
  • R1 is hydrogen or F
  • R 1A , R 1B , R 2A , R 2B , R 3A , R 3B , R 4A or R 4B are each independently hydrogen or C 1 -C 3 alkyl;
  • R 1A and R 1B , R 2A and R 2B , R 3A and R 3B , and R 4A and R 4B on the same carbon are bonded to each other to form -R 1A' -Z 2 -R 1B' -, -R 2A' -Z 2 -R 2B' -, -R 3A' -Z 2 -R 3B' -, -R 4A' -Z 2 -R 4B' - and are bonded to the atom to which they are attached to form a spiro ring
  • Z 2 is absent, -O-;
  • substituents R 1A and R 2A , R 1A and R 3A , R 3A and R 4A on different carbons are bonded to each other to form -R 1A' -Z 3 -R 2A' -, -R 1A' -Z 3 - R 3A' -, -R 3A' -Z 3 -R 4A' - and are bonded to an atom to which they are attached, wherein Z 3 is absent, or -O-.
  • R 1A′ and R 1B′ , R 2A′ and R 2B′ , R 3A′ and R 3B′ , R 4A′ and R 4B′ are each independently absent, C 1 ⁇ C 3 alkylene;
  • the Y is O, S(O) p , NR Y1 ;
  • G a , p, R b and R c are the same as described above.
  • the compound of formula I has formula Ia-5
  • R 1 is hydrogen or F
  • R 6 is each independently halogen
  • R 1A , R 1B are each independently hydrogen or C 1 -C 3 alkyl; or R 1A , R 1B may be bonded to each other and form a 3 to 6 membered saturated cycloalkane spiro ring to the carbon to which they are attached;
  • M 1 , n, q are the same as described above.
  • the Y is O, S(O) p , NR Y1 ;
  • G a , p, R b and R c are the same as described above.
  • the compound of formula I has formula Ia-6, Ia-7, Ia-8, or Ia-9
  • R 1 is hydrogen or F; and R 6 are each independently halogen;
  • M 1 is a benzene ring or a pyridine ring
  • R 1A , R 1B are each independently hydrogen or C 1 -C 3 alkyl; or R 1A , R 1B may be bonded to each other and form a 3 to 6 membered saturated cycloalkane spiro ring to the carbon to which they are attached;
  • R 2A , R 2B are each independently hydrogen or C 1 -C 3 alkyl; or R 2A , R 2B may be bonded to each other and form a 3 to 6 membered saturated cycloalkane spiro ring with the carbon to which they are attached;
  • R Y is O, S(O) 2 , or NR Y1 ;
  • the compound of formula I has formula Ia-10, Ia-11, Ia-12 or Ia-13.
  • R 6 is each independently halogen
  • M 1 is a benzene ring or a pyridine ring
  • R 1A , R 1B are each independently hydrogen or methyl; or R 1A , R 1B may be bonded to each other and to the carbon to which they are attached to form a cyclopropane;
  • R 2A , R 2B are each independently hydrogen or methyl; or R 2A , R 2B may be bonded to each other and to the carbon to which they are attached to form a cyclopropyl spiro ring;
  • Y is O, S(O) 2 , or NR Y1 ;
  • R b is hydrogen, methyl, ethyl, isopropyl or cyclopropyl.
  • the compound of Formula I is selected from the group consisting of:
  • a pharmaceutical composition comprising the above compound, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer or a racemate thereof One or more of the following, together with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition further comprises at least one other therapeutic agent,
  • the at least one other therapeutic agent included in the pharmaceutical composition is selected from the group consisting of other anticancer agents, immunomodulators, antiallergic agents, antiemetic agents, pain relieving agents, and cell protective agents. And their combinations.
  • the disease or condition mediated by EED and/or PRC2 comprises diffuse large B-cell lymphoma, follicular lymphoma, other lymphoma, leukemia, multiple myeloma, mesothelium Tumor, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumor, including neuroblastoma, schwannomas, glioma, glial mother cells Tumor and astrocytoma; cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, deputy Thyroid tumors, uterine tumors, and soft tissue sarcomas.
  • brain tumor including neuroblastoma, schwannomas, glioma, glial mother cells
  • step 1
  • step 1 the compound of formula (I-1) is treated with hydrazine hydrate to form a compound of formula (I-2), and the compound of formula (I-2) is converted to the triazole product formula (I- with trimethyl orthoformate).
  • step 3 the triazole product of formula (I-3) is substituted with a suitable amine (I-4) to form an intermediate of formula (I-5) wherein X is a halogen and the amine compound (I-4)
  • the preparation can be carried out by referring to the literature: US 2016/0176882, or according to conventional methods known in the art.
  • the definitions of R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined above.
  • step 2 the amino group in the compound of formula (I-5) is first protected to obtain the product of formula (II-2), which is then coupled with a series of amines (II-3) to form product (II-4). Finally, the protecting group is removed by an appropriate method to prepare a compound of the formula (I).
  • the coupling reaction is effected in the presence of a palladium catalyst and a base, and optionally in the presence of a ligand, and in an elevated solvent at elevated temperatures (e.g., at about 80 to 150 degrees).
  • the reaction can be promoted by microwave radiation.
  • palladium catalysts include, but are not limited to, tris(dibenzylideneacetone)dipalladium(0), tetrakistriphenylphosphinepalladium(0), allyl palladium(II) chloride dimer, [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride ((dppf)PdCl 2 ), palladium (II) acetate.
  • Suitable ligands include, but are not limited to, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 2-dicyclohexylphosphorus-2,4,6-three Isopropylbiphenyl (X-phos), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane, 2'-bicyclo Hexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonic acid sodium hydrate and 1,1'-bis(diphenylphosphinoalkyl)ferrocene.
  • suitable bases include, but are not limited to, carbonates or phosphates of sodium, potassium and rubidium and cesium fluoride.
  • suitable solvents include toluene, acetonitrile, dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methanol And water or a mixture thereof.
  • suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples thereof are found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th Edition).
  • X is a halogen
  • PG represents a protecting group
  • the definitions of 2B , R 3A , R 3B , R 4A , R 4B , R 6 and n, m, q are as defined above.
  • a process for the preparation of a compound of formula III-2 from a compound of formula III-1 is given in Scheme 2. That is, the starting material corresponds to Y in the formula I being NH, and the amine compound (III-1) is reacted with a reagent or a compound having an R Y1 group under basic conditions to obtain the formula (III-2).
  • Examples of the compound, the reagent or compound include, but are not limited to, an acid anhydride, a sulfonic acid anhydride, an isocyanate, a thioisocyanate, an acid chloride, a sulfonyl chloride, a carbonate, a chloroformate, a carbamate, etc., examples of which include It is not limited to triethylamine, diisopropylethylamine, pyridine, DMAP, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide, NaH, and examples of the organic solvent include, but are not limited to, dichloromethane.
  • the amine compound (III-1) is subjected to condensation reaction with a carboxylic acid having an R Y1 group under a basic condition under the action of a condensing agent to obtain a formula (III-2).
  • Examples include, but are not limited to, carbonyl diimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide, 1- Hydroxybenzotriazole, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N ',N'-tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate, O-benzotriazole-N, N,N',N'-tetramethylurea tetrafluoroborate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-succinyl Amino
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 1A , R 1B , R 2A , R 2B , R 3A , R 3B , R 4A , R 4B , R b , R c , n, q, m The definition is the same as defined above.
  • a process for the preparation of a compound of formula IV-2 from a compound of formula III-1 is given in Scheme 3. That is, the raw material corresponds to Y in the formula I being NH, and the amine compound (III-1) is reductively aminated with an aldehyde or a ketone under the action of a reducing agent, or under alkaline conditions, and The halogenated compound is subjected to a substitution reaction to prepare a compound of the formula (IV-2), and examples of the reducing agent include, but are not limited to, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, and examples of the base include But not limited to triethylamine, diisopropylethylamine, pyridine, 1,5-diazabicyclo[5.4.0]undec-5-ene, DMAP, potassium carbonate, sodium hydroxide, potassium hydroxide Potassium tert-butoxide, NaH, such as, but not limited to, dichloromethane,
  • R Y1 is preferably defined as: CN, C 1 -C 6 alkyl group having 0-2 R a substitutions, C 1 -C 6 haloalkyl group, G a ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 1A , R 1B , R 2A , R 2B , R 3A , R 3B , R 4A , R 4B , R a , n, q, m, G a The definition is the same as defined above.
  • a process for the preparation of a compound of formula V-2 from a compound of formula V-1 is given in Scheme 4. That is, the starting material corresponds to Y in the formula I being NH, and the amine compound of the formula (V-1) is reacted with a reagent or a compound having an R Y1 group under basic conditions to obtain the formula (V-2).
  • Examples of the compound, the reagent or compound include, but are not limited to, an acid anhydride, a sulfonic acid anhydride, an isocyanate, a thioisocyanate, an acid chloride, a sulfonyl chloride, a carbonate, a chloroformate, a carbamate, etc., examples of which include It is not limited to triethylamine, diisopropylethylamine, pyridine, DMAP, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide, NaH, and examples of the organic solvent include, but are not limited to, dichloromethane.
  • the amine compound (V-1) is subjected to condensation reaction with a carboxylic acid having an R Y1 group under a basic condition under the action of a condensing agent to obtain a formula (V-2).
  • Examples include, but are not limited to, carbonyl diimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide, 1- Hydroxybenzotriazole, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N ',N'-tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate, O-benzotriazole-N, N,N',N'-tetramethylurea tetrafluoroborate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-succinyl Amino
  • M 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 1A , R 1B , R 4A , R 4B , R b , R c , n, q have the same meanings as defined above .
  • a process for the preparation of a compound of formula VI-2 from a compound of formula V-1 is given in Scheme 5. That is, the raw material corresponds to Y in the formula I being NH, and the amine compound (V-1) is reductively aminated with an aldehyde or a ketone under the action of a reducing agent, or under alkaline conditions, and The halogenated compound is subjected to a substitution reaction to prepare a compound of the formula (VI-2), and examples of the reducing agent include, but are not limited to, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, and examples of the base include But not limited to triethylamine, diisopropylethylamine, pyridine, 1,5-diazabicyclo[5.4.0]undec-5-ene, DMAP, potassium carbonate, sodium hydroxide, potassium hydroxide Potassium tert-butoxide, NaH, such as, but not limited to, dichloromethane,
  • R Y1 is preferably defined as: CN, C 1 -C 6 alkyl group having 0-2 R a substitutions, C 1 -C 6 haloalkyl group, G a ;
  • R 1, R 2 , R 3, the R 4, R 5, R 6 , R 1A, R 1B, R 4A, R 4B, R a, n, q, G a are as defined hereinabove defined .
  • reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and the substituents present in all of the reactants. Solvents, temperatures and other reaction conditions can be readily selected by one skilled in the art, unless otherwise specified. Specific steps are provided in the Synthesis Examples section.
  • the reaction can be further processed in a conventional manner, for example by removing the solvent from the residue and further purifying according to methods generally known in the art such as, but not limited to, crystallization, distillation, extraction, milling and chromatography. Unless otherwise stated, the starting materials and reactants are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature.
  • the starting materials can be prepared by a process selected from the group consisting of standard organic chemistry techniques, techniques similar to the synthesis of known structural analogs, or techniques similar to those described in the Schemes above or in the Synthesis Examples section. .
  • an optically active form of a compound of the invention it can be obtained by performing one of the procedures described herein using an optically active starting material (for example, prepared by asymmetric induction of a suitable reaction step), or by using standard procedures (eg, chromatographic separation). , recrystallization or enzymatic resolution) is obtained by resolution of a mixture of stereoisomers of the compound or intermediate.
  • a pure geometric isomer of a compound of the invention when desired, it can be obtained by performing one of the above steps using a pure geometric isomer as the starting material, or by using standard procedures such as chromatographic separation of the compound or intermediate A mixture of geometric isomers of the body is obtained.
  • a crystal is obtained by a recrystallization method, and its crystal structure is obtained by X-ray diffraction.
  • the reaction can be carried out using an isotope-labeled starting material as needed.
  • Step 1 10 g of substrate I-1a was dissolved in 200 mL of ethanol, and 4.4 g of hydrazine hydrate was added thereto, and the mixture was reacted at room temperature for 4 hours to obtain a suspension, which was filtered, and the filter cake was washed with n-hexane and dried under vacuum to obtain 8 g of product I-2a.
  • LC-MS: [M+H] + 235 / 237.
  • Step 1 50 g of substrate II-1a was dissolved in 200 mL of DMF, 2-bromo-1,1-diethoxyethane (70 g), and 120 g of potassium carbonate were added. Under the protection of Ar gas, the reaction was heated at 110 ° C overnight, diluted with water, diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated, and then purified by column chromatography to afford product II-2a (75 g).
  • Step 2 75 g of substrate II-2a was dissolved in 200 mL of toluene, and polyphosphoric acid (130 g) was added in portions at 95 °C, and the reaction was kept at 95 °C for 2 hours, cooled, diluted with ice water, and extracted with petroleum ether. The mixture was washed with brine, dried and concentrated, and then purified by column chromatography to give a mixture of product II-3a and II-3a' (26 g).
  • Step 3 26 g of the mixture obtained in Step 2 was dissolved in 100 mL of DMF, and zinc cyanide (20 g) and 15 g of tetratriphenylphosphine palladium were added. Under the protection of Ar gas, the reaction was heated at 100 ° C overnight, diluted with water, diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated, and then purified by column chromatography to afford product II-4a (7.2 g). In this step, the reaction product of the above II-3a' is removed by column chromatography.
  • Step 4 7.2 g of substrate II-4a, di-tert-butyl dicarbonate (22 g) was dissolved in 200 mL of methanol, and 10% Pd/C (3.5 g) was added. The mixture was subjected to H 2 reaction for 36 hours, filtered through Celite, concentrated, and purified by column chromatography to afford product II-5a (10 g).
  • Step 5 Dissolve 10 g of substrate II-5a in HCl/dioxane (4N, 50 mL), react at room temperature for 4 hours, concentrate, and then re-dissolved in MeOH (20 mL) and acetonitrile (4 mL). Potassium was reacted at 60 ° C overnight, and the solvent was concentrated to give a product II-6a (3.2 g).
  • LC-MS: [M+H] + 168.1.
  • Step 1 The substrate II-6a (12.8g) and I-3a (12.8g, 0.052mol) mixture was heated to 40 ° C overnight. Add the dichloromethane to dilute the reaction, precipitate the solid, filter, filter cake with dichloromethane Washing and drying in vacuo gave product III-1a as a white solid (10.7 g).
  • Step 2 The substrate III-1a (2.0 g) was dissolved in 20 mL of pyridine, and Boc 2 O (2.4 g) and DMAP (0.07 g) were added to react at room temperature overnight, and the solvent was concentrated to remove EA/PE (1 to 1). Beating gave product III-2a (1.6 g).
  • LC-MS: [M+H] + 464.1.
  • Compound SL-ZYE-35 was obtained in the same manner as in Example 4 except that thiomorpholine (CAS: 123-90-0) was used instead of morpholine.
  • Compound SL-ZYE-37 was obtained in the same manner as in Example 4 except that hexahydropyridine (CAS: 110-89-4) was used instead of morpholine.
  • Compound SL-ZYE-36 was obtained in the same manner as in Example 4 except that thiomorpholine-1,1-dioxide (CAS: 39093-93-1) was used instead of morpholine.
  • Compound SL-ZYE-40 was obtained in the same manner as in Example 13 except that morpholin-4-yl acetic acid (CAS: 3235-69-6) was used instead of N,N-dimethylglycine.
  • a compound was obtained in the same manner as in Example 13 except that 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (CAS: 5744-56-9) was used instead of N,N-dimethylglycine. SL-ZYE-42.
  • Compound SL-ZYE-45 was obtained in the same manner as in Example 4 except that benzomorpholine (CAS: 5735-53-5) was used instead of morpholine.
  • Compound SL-ZYE-48 was obtained in the same manner as in Example 4 except that 1,2,3,4-tetrahydroquinoxaline (CAS: 3476-89-9) was used instead of morpholine.
  • Compound SL-ZYE-50 was obtained in the same manner as in Example 4 except that Compound AN-1 (CAS: 6639-92-5) was used instead of morpholine.
  • Compound SL-ZYE-44 was obtained in the same manner as in Example 4 except that 2-piperazinone (CAS: 5625-67-2) was used instead of morpholine.
  • Compound SL-ZYE-49 was obtained in the same manner as in Example 4 except that 1-(3-pyridyl)piperazine (CAS: 67980-77-2) was used instead of morpholine.
  • Compound SL-ZYE-51 was obtained in the same manner as in Example 4 except that 2,6-dimethylmorpholine (CAS: 141-91-3) was used instead of morpholine.
  • Compound SL-ZYE-47 was obtained in the same manner as in Example 4 except that 1,4-oxazacycloheptane (CAS: 5638-60-8) was used instead of morpholine.
  • the compound SL-ZYE-41 was obtained in the same manner as in Example 4 except that hexahydropyrrolo[1,2-A]pyrazine-6-one (CAS: 117810-52-3) was used instead of morpholine. .
  • a compound was obtained in the same manner as in Example 4 except that 4,5,6,7-tetrahydropyrazole [1,5-A]pyrazine (CAS: 792163-25-8) was used instead of morpholine. SL-ZYE-56.
  • Compound SL-ZYE-61 was obtained in the same manner as in Example 29 except that the substrate SL-ZYE-61-2 prepared in Example 31 was used instead of SL-ZYE-64-2.
  • Compound SL-ZYE-62 was obtained in the same manner as in Example 10 except that the substrate SL-ZYE-61-2 prepared in Example 31 was used instead of the SL-ZYE-58 prepared in Example 7.
  • the compound SL-ZYE-63 was obtained in the same manner as in Example 29 except that the substrate SL-ZYE-63-2 prepared in Example 34 was used instead of the SL-ZYE-64-2 prepared in Example 28. .
  • Compound SL-ZYE-71 was obtained in the same manner as in Example 4 except that methyl 4-piperidinecarboxylate (CAS: 2971-79-1) was used instead of morpholine.
  • Compound SL-ZYE-88 was obtained in the same manner as in Example 4 except that 4-(azetidin-3-yl)morpholine (CAS: 302355-79-9) was used instead of morpholine.
  • the substrate SL-ZYE-64-2 (40 mg) prepared in Example 28 was dissolved in 2 mL of DCM, triethylamine (40 mg), methanesulfonyl chloride (23 mg) was added, and the mixture was stirred at room temperature for one hour and concentrated. Column chromatography gave 15 mg of white solid SL-ZYE-136.
  • Compound SL-ZYE-137 was obtained in the same manner as in Example 38 except that ethyl sulfonyl chloride was used instead of methanesulfonyl chloride.
  • the compound ZB-EED-13 was obtained in the same manner as in Example 4 except that tert-butyl 1,4-diazepane-1-carboxylate (CAS: 112275-50-0) was used instead of morpholine. .
  • LC-MS: [M+H] + 384.3.
  • Cisbio companies using homogeneous time-resolved effect of small molecule compounds with different concentrations of the fluorescent detected (the HTRF) to PRC2 activity and fitted using GraphPad Prism 5.0 software to calculate the IC 50 values of compounds (highest concentration for 50% inhibition).
  • PRC2 enzyme (purchased from Cisbio, HMT-25-114) catalyzes the cofactor S-adenosylmethionine (SAM) (purchased from Sigma, A4377) and histone polypeptide H3 (21-44) (Suzhou Qiang Yao) Biotechnology Co., Ltd., sequence: NC: ATKAARKSAPATGGVKKPHRYRPGGK (Biotin), purity ⁇ 95%) reacts to produce methylation of the 27th lysine residue of histone H3 (H3K27me1/2/3).
  • SAM cofactor S-adenosylmethionine
  • H3 (21-44) Sezhou Qiang Yao) Biotechnology Co., Ltd., sequence: NC: ATKAARKSAPATGGVKKPHRYRPGGK (Biotin), purity ⁇ 95%) reacts to produce methylation of the 27th lysine residue of histone H3 (H3K27me1/2/3).
  • the Anti-H3K27me2 antibody (available from Cell Singa
  • the distance between the Eu Cryptate and the XL665 dye on the donor and the acceptor is close to 10 nm.
  • the Eu Cryptate on the donor is excited to produce 615 nm of emitted light, which is excited by energy resonance, which in turn excites the XL665 dye on the acceptor to produce 665 nm of emitted light.
  • the ratio of double-emitting light Em665/615 is positively correlated with the methylated histone H3 polypeptide catalyzed by PRC2 enzyme, that is, the level of Em665/615 reflects the level of enzyme activity of PRC2.
  • the test system was 20 ⁇ L, in which the enzyme reaction volume was 10 ⁇ L, and the detection reaction volume was 10 ⁇ L.
  • the 4 mM or 400 ⁇ M compound is first diluted 2-fold in DMSO to 16 different concentrations, and then the compound is diluted in buffer 1 (20 mM HEPES pH 8.0, 150 mM NaCl, 1 mM DTT).
  • the compound was transferred to a 384-well plate at 2.5 ⁇ L/well (OptiPlate-384, available from PerkinElmer, 6007299); the latter reagent was all from buffer 2 (20 mM HEPES pH 8.0, 150 mM NaCl, 0.01% Triton).
  • the detection reaction system first add 5 ⁇ L of a mixture containing 200 ⁇ M S-adenosyl homocysteine (SAH), 1000-fold diluted antibody and 100-fold diluted receptor to each well in a 384-well reaction plate, incubate at room temperature. For 15 minutes, 5 ⁇ L of a mixture containing 1.6 M potassium fluoride KF and 100-fold diluted donor was added to each well and incubated for 30 minutes at room temperature. The 384-well plate was placed in a multi-plate reader EnVision (PerkinElmer) to read the fluorescence signal value. Data analysis software by GraphPad Prism5.0 obtained 50 values IC.
  • SAH S-adenosyl homocysteine
  • Compound Enzyme activity IC 50 ( ⁇ M) Compound Enzyme activity IC 50 ( ⁇ M) SL-ZYE-31 0.029 SL-ZYE-35 0.101 SL-ZYE-02 0.018 SL-ZYE-58 0.012 SL-ZYE-37 0.581 SL-ZYE-36 0.003 SL-ZYE-01 0.006 SL-ZYE-32 0.026 SL-ZYE-03 0.025 SL-ZYE-33 0.014 SL-ZYE-39 0.013 SL-ZYE-40 0.010 SL-ZYE-42 0.016 SL-ZYE-45 0.027 SL-ZYE-48 0.010 SL-ZYE-50 0.007 SL-ZYE-44 0.070 SL-ZYE-49 0.065 SL-ZYE-51 0.069 SL-ZYE-47 0.031
  • DLBCL Human diffuse large B-cell lymphoma (DLBCL) cell line SU-DHL-4 (from ATCC, CRL-2957) containing 10% fetal bovine serum (Gibco, purchased from Life Technologies, 10099-141) and 1% antibiotic RPMI 1640 medium (Gibco, purchased from Life Technologies, Inc., 22400-089) (penicillin and streptomycin, purchased from Life Technologies, Inc., 10378016) was cultured in a CO 2 cell incubator (37 ° C, 5% CO 2 ). .
  • SU-DHL-4 cells in the exponential growth phase were plated in 24-well plates (purchased from Corning, 3524) in a volume of 1 mL/well with a cell density of 1*10E5 cells. /hole. The cells were seeded and placed in a CO 2 incubator for 1 hour. Different concentrations of 3-fold gradient dilutions of compounds were added to 24-well plates containing cells at concentrations ranging from 0.03 nM to 20 [mu]M.
  • the cold luminescence signal was detected using a multi-plate reader EnVision (available from PerkinElmer) at a wavelength of 400-700 nm. Data was analyzed using GraphPad Prism 5.0 software, the value of 50 obtained IC.
  • the compound according to the present disclosure can have significant activity for inhibiting PRC2, particularly among SL-ZYE-01, SL-ZYE-36, SL-ZYE-40, SL-ZYE-50, SL.
  • Compounds such as -ZYE-62, SL-ZYE-65, SL-ZYE-66, ZB-EED-09, ZB-EED-10 and ZB-EED-11 have an IC50 of less than 10 nM and have particularly excellent effects.
  • the compounds According to the long-term growth inhibition test results of the cells, it can be seen that the compounds have significant activity in inhibiting SU-DHL-4 cells, and particularly SL-ZYE-62 and SL-ZYE-36 have very potent cell activities.
  • the cellular activity of the positive compounds was increased by nearly 100-fold.

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Abstract

本公开涉及一种由以下通式表示的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体，包含其的药物组合物及其用途。该类化合物可用于制备用于治疗由PRC2介导的疾病或病症的药物。

Description

一种三氮唑并嘧啶衍生化合物、包含其的药物组合物及其用途 技术领域
本发明涉及药物化学和药物治疗学领域，总体上涉及一类三氮唑并嘧啶化合物、包含其的药物组合物及其用途。具体而言，本发明涉及一种三氮唑并嘧啶化合物、其可药用的盐、对映异构体、非对映异构体、阻转异构体、外消旋体、多晶型物、溶剂合物或经同位素标记的化合物(包括氘取代)，以及药物组合物及其在肿瘤疾病治疗中的应用。特别地，该类化合物可制备用于治疗由PRC2介导的疾病或病症的药物。
背景技术
多梳抑制复合物PRC2(Polycomb Repressive Complex 2)是多梳家族蛋白(Polycomb Group)的核心成员，具有组蛋白甲基转移酶活性，可特异性催化组蛋白H3第27位赖氨酸的三甲基化修饰(H3K27me3)，从而抑制特定基因的表达。PRC2的甲基转移酶活性来源于其催化成员EZH2，然而EZH2在单独存在时并没有催化活性，其至少需要与PRC2的另外两个成员EED和SUZ12形成复合物后才能催化甲基化修饰。因而，EZH2，EED和SUZ12被认为是PRC2复合物的核心组分。近来研究发现，PRC2的核心组分在多种肿瘤细胞中过表达，其活性异常是导致多种恶性肿瘤发病及恶化的直接原因。同时，最近对淋巴瘤病人的基因测序结果表明，EZH2在生发中心B细胞淋巴瘤(GCB-DLBCL)病人中出现激活性突变，突变后的EZH2改变PRC2的底物特异性，从而提高细胞中H3K27me3水平。通过siRNA方法下调EZH2或其他核心组分的表达，将显著抑制淋巴瘤细胞的增殖，这表明GCB-DLBCL的发生发展与PRC2的过度激活密切相关。因而，PRC2是一个非常有前景的抗癌药物开发靶标，靶向PRC2的抑制剂发现是目前制药界研究的热点。近期，诺华及艾伯维两大制药公司发明了一类通过借助靶向EED来抑制PRC2活性的小分子(参考文献：诺华的EED226，US 2016/0176882，J.Med.Chem.2017,60,2215–2226，J.Med.Chem.2017,60,415–427，Nat.Chem.Biol.2017,13,381–388；艾伯维的A-395，Nat.Chem.Biol.2017,13,389–395)，该类化合物在分子水平、细胞水平以及动物实验上都显示极强的抑制活性。综上所述，PRC2复合物被认为是导致多种恶性肿瘤发生发展的关键驱动因子，而借助靶向EED来抑制PRC2活性的抑制剂的开发目前在业界具有很高的热度，有利于用于与之相关的新药研发。
发明内容
本发明的一个目的是提供一种三氮唑并嘧啶化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体、多晶型物、溶剂合物或经同位素标记的化合物。
本发明的另一个目的在于提供一种上述化合物的制备方法。
本发明的再一个目的在于提供一种包含治疗有效量的一种或多种上述化合物或其可药用的盐的药物组合物。
本发明的又一个目的在于提供上述化合物在制备用于治疗由PRC2介导的疾病或病症的药物中的用途。
本发明的又一个目的在于提供一种治疗由EED和/或PRC2介导的疾病或病症的方法，其特征在于，向受试者施用治疗有效量的一种或多种上述化合物或其可药用的盐。
在一个方面，本发明提供通式(I)化合物、其可药用的盐、对映异构体、非对映异构体、阻转异构体、外消旋体、多晶型物、溶剂合物或经同位素标记的化合物(包括氘取代)，
Figure PCTCN2019074755-appb-000001
其中，
1)
Figure PCTCN2019074755-appb-000002
为单键或双键；
2)R 1、R 2及R 3各自独立地为氢、卤素、C 1-C 4烷基、C 1-C 4卤代烷基、-O-(C 1-C 4烷基)、C 1-C 4卤代烷氧基、或C 3-C 6环烷基；
R 4各自独立地为氢、OH、＝O、或C 1-C 4烷基；
R 5为氢、卤素或C 1-C 4烷基；
3)A独立地指定为以下结构：
Figure PCTCN2019074755-appb-000003
Figure PCTCN2019074755-appb-000004
Y为不存在、O、S(O) p、NR Y1、C＝O、C＝S、C(R Y2)R Y3；其中，
R Y1为氢、CN、氧代、含0-2个R a取代的C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、-C(＝O)R b、-C(＝O)OR b、-C(＝S)R b、-C(＝S)OR b、-C(＝S)SR b、-C(＝O)SR b、-C(＝NH)SR b、-C(＝NH)OR b、-C(＝NH)R b、-S(＝O)R b、-S(＝O) 2R b、-S(＝O) 2NR bR c、-S(＝O) 2OR b、-C(＝O)NR bR c、-C(＝S)NR bR c、-C(＝NH)NR bR c；
R Y2在每次出现时各自独立地为氢、CN、NO 2、卤素、SCF 3、含0-2个R a取代的C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a；
R Y3在每次出现时各自独立地为氢、CN、NO 2、卤素、SCF 3、含0-2个R a取代的C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、-(OCH 2CH 2) mOR d、-(OCH 2CH 2) mNR bR c、-OC(＝O)R b、-OC(＝O)NR bR c、-OC(＝O)SR b、-SR d、-SC(＝O)R b、-SC(＝O)OR b、-SC(＝O)NR bR c、-S(＝O) 2R b、-S(＝O) 2NR bR c、-S(＝O) 2OR b、-S(＝O)R b、-N(R e)C(＝O)R b、-N(R e)C(＝O)OR b、-N(R e)C(＝O)NR bR c、-N(R e)C(＝O)SR b、-N(R e)C(＝S)R b、-N(R e)C(＝S)OR b、-N(R e)C(＝S)SR b、-N(R e)C(＝S)NR bR c、-N(R e)C(＝NH)R b、-N(R e)C(＝NH)OR b、-N(R e)C(＝NH)NR bR c、-N(R e)S(＝O) 2R b、-N(R e)S(＝O) 2OR b、-N(R e)S(＝O) 2NR bR c、-C(＝O)R b、-C(＝O)NR bR c、-C(＝O)OR b、-C(＝O)SR b、-C(＝S)R b、-C(＝S)NR bR c；
或者，R Y2与R Y3彼此连接以形成-R Y2’-Z 2-R Y3’-并分别和与之相连的原子键结，其中Z 2为不存在、-O-、-S(O) p-、或者
Figure PCTCN2019074755-appb-000005
其中R w为氢、含0-2个R a取代的C 1-C 6烷基、G a、-C(＝O)R b1-、-C(＝O)OR b1、-NC(＝S)R b1、-C(＝S)OR b1、-C(＝S)SR b1、-C(＝O)SR b1、-C(＝NH)SR b1、-C(＝NH)OR b1、-C(＝NH)R b1、-S(＝O) 2R b1、-S(＝O) 2NR b1R c1、-C(＝O)NR b1R c1、-C(＝S)NR b1R c1、-C(＝NH)NR b1R c1；
R b1与R c1在每次出现时各自独立地为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、或者被1-2个取代基取代的C 1-C 6烷基，所述取代基选自CN、SCF 3、-(OCH 2CH 2) mOR z1、-(OCH 2CH 2) mNR z1R z2、N(R z3)C(＝O)R z1、-N(R z3)C(＝O)OR z1、-N(R z3)C(＝O)NR z1R z2、-N(R z3)C(＝NH)NR z1R z2、-N(R z3)S(＝O) 2R z1、-N(R z3)S(＝O) 2NR z1R z2、-OC(＝O)NR z1R z2、-C(＝O)NR z1R z2、-S(＝O) 2R z1、-S(O) 2NR z1R z2、-S(＝O)R z1、C 1-C 6卤代烷基、和G b；
其中，R Y2’和R Y3’在每次出现时各自独立地为不存在、C 1-C 3亚烷基、C 1-C 3卤代亚烷基、或者被1-2个取代基取代的C 1-C 3亚烷基；所述取代基选自CN、-(OCH 2CH 2) mOR z1、-(OCH 2CH 2) mNR z1R z2、N(R z3)C(＝O)R z1、-N(R z3)C(＝O)OR z1、-N(R z3)C(＝O)NR z1R z2、-N(R z3)C(＝NH)NR z1R z2、-N(R z3)S(＝O) 2R z1、-N(R z3)S(＝O) 2NR z1R z2、-OC(＝O)NR z1R z2、-C(＝O)NR z1R z2、-S(＝O) 2R z1、-S(O) 2NR z1R z2、C 1-C 3烷基、C 1-C 6卤代烷基、和G b；
R a在每次出现时各自独立地为卤素、CN、SCF 3、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、-(OCH 2CH 2) mOR d、-(OCH 2CH 2) mNR bR c、-OC(＝O)R b、-OC(＝O)NR bR c、-OC(＝O)SR b、-SR d、-SC(＝O)R b、-SC(＝O)OR b、-SC(＝O)NR bR c、-S(＝O) 2R b、-S(＝O) 2NR bR c、-S(＝O) 2OR b、-S(＝O)R b、-N(R e)C(＝O)R b、-N(R e)C(＝O)OR b、-N(R e)C(＝O)NR bR c、-N(R e)C(＝O)SR b、-N(R e)C(＝S)R b、-N(R e)C(＝S)OR b、-N(R e)C(＝S)SR b、-N(R e)C(＝S)NR bR c、-N(R e)C(＝NH)R b、-N(R e)C(＝NH)OR b、-N(R e)C(＝NH)NR bR c、-N(R e)S(＝O) 2R b、-N(R e)S(＝O) 2OR b、-N(R e)S(＝O) 2NR bR c、-C(＝O)R b、-C(＝O)NR bR c、-C(＝O)OR b、-C(＝O)SR b、-C(＝S)R b、-C(＝S)NR bR c；
R b、R c、R d及R e在每次出现时各自独立地为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、或者被1-2个取代基取代的C 1-C 6烷基，所述取代基选自CN、SCF 3、-(OCH 2CH 2) mOR z1、-(OCH 2CH 2) mNR z1R z2、N(R z3)C(＝O)R z1、-N(R z3)C(＝O)OR z1、 -N(R z3)C(＝O)NR z1R z2、-N(R z3)C(＝NH)NR z1R z2、-N(R z3)S(＝O) 2R z1、-N(R z3)S(＝O) 2NR z1R z2、-OC(＝O)NR z1R z2、-C(＝O)NR z1R z2、-S(＝O) 2R z1、-S(O) 2NR z1R z2、-S(＝O)R z1、C 1-C 6卤代烷基、和G b；
R z1、R z2和R z3在每次出现时各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、或C 1-C 6卤代烷基；
或者，R b与R c彼此连接以形成-R b’-Z 1-R c’-并分别和与之相连的原子键结，其中，所述-Z 1-为不存在、-O-、-S(O) p-、或者
Figure PCTCN2019074755-appb-000006
其中，R b’和R c’在每次出现时各自独立地为不存在、C 1-C 6亚烷基、C 1-C 3卤代亚烷基、或者被1-2个取代基取代的C 1-C 6亚烷基；所述取代基选自CN、-(OCH 2CH 2) mOR z1、-(OCH 2CH 2) mNR z1R z2、N(R z3)C(＝O)R z1、-N(R z3)C(＝O)OR z1、-N(R z3)C(＝O)NR z1R z2、-N(R z3)C(＝NH)NR z1R z2、-N(R z3)S(＝O) 2R z1、-N(R z3)S(＝O) 2NR z1R z2、-OC(＝O)NR z1R z2、-C(＝O)NR z1R z2、-S(＝O) 2R z1、-S(O) 2NR z1R z2、C 1-C 3烷基、C 1-C 6卤代烷基、和G b；
G a和G b在每次出现时各自独立地为C6-C10芳基、5-10元杂芳基、3-9元非芳族杂环基、C3-C8环烷基、或C5-C8环烯基，并且其各自独立地为未取代的或被1、2、3、4、或5个R v取代；
R v在每次出现时各自独立地为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、C 1-C 6卤代烷基、NO 2、CN、SCF 3、氧代、-OR h、-OC(＝O)R i、-OC(＝O)NR jR k、-SR h、-S(＝O) 2R h、-S(＝O) 2NR jR k、-C(＝O)R h、-C(＝O)OR h、-C(＝O)NR jR k、-NR jR k、-N(R h)C(＝O)R i、-N(R h)S(＝O) 2R i、-N(R h)C(＝O)OR i、-N(R h)C(＝O)NR jR k、-(C 1-C 6亚烷基)-OR h、-(C 1-C 6亚烷基)-OC(＝O)R i、-(C 1-C 6亚烷基)-OC(＝O)NR jR k、-(C 1-C 6亚烷基)-S(＝O) 2R h、-(C 1-C 6亚烷基)-S(＝O) 2NR jR k、-(C 1-C 6亚烷基)-C(＝O)R h、-(C 1-C 6亚烷基)-C(＝O)OR h、-(C 1-C 6亚烷基)-C(＝O)NR jR k、-(C 1-C 6亚烷基)-NR jR k、-(C 1-C 6亚烷基)-N(R h)C(＝O)R i、-(C 1-C 6亚烷基)-N(R h)S(＝O) 2R i、-(C 1-C 6亚烷基)-N(R h)C(＝O)OR i、-(C 1-C 6亚烷基)-N(R h)C(＝O)NR jR k、或-(C 1-C 6亚烷基)-CN；
R h、R j、R k在每次出现时各自独立地为氢、C 1-C 6烷基、或C 1-C 6卤代烷基；和R i在每次出现时独立地为C 1-C 6烷基、或C 1-C 6卤代烷基。
n各自独立地为0、1、或2；
p各自独立地为0、1、或2；
m各自独立地为0、1、2、3、或4；
q各自独立地为0、1、2、或3；
3a)当A为
Figure PCTCN2019074755-appb-000007
时，
R 1A及R 1B、R 2A及R 2B、R 3A及R 3B、R 4A及R 4B在每次出现时各自独立地为氢、羟基、卤素、CN、NO 2、C 1-C 6烷基、C 1-C 6卤代烷基、G a；
或者，R 1A与R 1B、R 2A与R 2B可和与之连接的碳原子形成羰基(＝O)或硫羰基(＝S)；
或者，同碳上的取代基R 1A与R 1B、R 2A与R 2B、R 3A与R 3B以及R 4A与R 4B彼此连接以形成-R 1A’-Z 2-R 1B’-、-R 2A’-Z 2-R 2B’-、-R 3A’-Z 2-R 3B’-、-R 4A’-Z 2-R 4B’-并分别和与之相连的原子键结形成一个螺环，其中Z 2为不存在、-O-、-S(O) p-、或者
Figure PCTCN2019074755-appb-000008
或者，不同碳上的取代基R 1A及R 2A、R 1A及R 3A、R 3A及R 4A彼此连接以形成-R 1A’-Z 3-R 2A’-、-R 1A’-Z 3-R 3A’-、-R 3A’-Z 3-R 4A’-并分别和与之相连的原子键结，其中Z 3为不存在、-O-、-S(O) p-、或者
Figure PCTCN2019074755-appb-000009
其中，所述R 1A’及R 1B’、R 2A’及R 2B’、R 3A’及R 3B’、R 4A’及R 4B’在每次出现时各自独立地为不存在、C 1-C 6亚烷基、C 1-C 6卤代亚烷基、或者被1-2个取代基取代的C 1-C 3亚烷基；所述取代基选自CN、卤素或者C 1-C 3烷基；
3b)当A为
Figure PCTCN2019074755-appb-000010
时，
R 1A及R 1B、R 4A及R 4B在每次出现时各自独立地为氢、羟基、卤素、CN、NO 2、C 1-C 6烷基、C 1-C 6卤代烷基、G a；
或者，R 1A与R 1B可和与之连接的碳原子形成羰基(＝O)或者硫羰基(＝S)；
或者，同碳上的取代基R 1A与R 1B及R 4A与R 4B彼此连接以形成-R 1A’-Z 2-R 1B’-、-R 4A’-Z 2-R 4B’-并分别和与之相连的原子键结形成一个螺环，其中Z 2为不存在、-O-、-S(O) p-、或者
Figure PCTCN2019074755-appb-000011
其中，所述R 1A’及R 1B’、R 4A’及R 4B’在每次出现时各自独立地为不存在、C 1-C 6亚烷基、C 1-C 6卤代亚烷基、或者被1-2个取代基取代的C 1-C 3亚烷基；所述取代基选自CN、卤素或者C 1-C 3烷基；
M 1为6-10元芳环、5-10元杂芳环、3-9元非芳族碳环、3-9元非芳族杂环，并且M 1为未取代的或被1或2个R 6取代；
R 6在每次出现时各自独立地为C 1-C 6烷基、卤素、C 1-C 6卤代烷基、NO 2、CN、SCF 3、氧代、-OR h、-OC(＝O)NR jR k、-S(＝O) 2R h、-(C 1-C 6亚烷基)S(＝O) 2R h、-S(＝O) 2NR jR k、-C(＝O)R h、-C(＝O)OR h、-C(＝O)NR jR k、-NR jR k、-N(R h)C(＝O)R i、-N(R h)S(＝O) 2R i、-N(R h)C(＝O)OR i、-N(R h)C(＝O)NR jR k；
3c)当A为
Figure PCTCN2019074755-appb-000012
时，
X为C、CH或者N
R 2A及R 2B、R 3A及R 3B、R 4A及R 4B在每次出现时各自独立地为氢、羟基、卤素、CN、NO 2、C 1-C 6烷基、C 1-C 6卤代烷基、G a；
或者，R 2A与R 2B可和与之连接的碳原子形成羰基(＝O)或者硫羰基(＝S)；
M 2为6-10元芳环、5-10元杂芳环、3-9元非芳族碳环、3-9元非芳族杂环，并且M 2为未取代的或被1或2个R 6取代；
R 6在每次出现时各自独立地为C 1-C 6烷基、卤素、C 1-C 6卤代烷基、NO 2、CN、SCF 3、氧代、-OR h、-OC(＝O)NR jR k、-S(＝O) 2R h、-(C 1-C 6亚烷基)S(＝O) 2R h、-S(＝O) 2NR jR k、-C(＝O)R h、-C(＝O)OR h、-C(＝O)NR jR k、-NR jR k、-N(R h)C(＝O)R i、-N(R h)S(＝O) 2R i、-N(R h)C(＝O)OR i、-N(R h)C(＝O)NR jR k。
根据本发明的另一个实施方式，所述通式I所述的化合物具有式Ia-1、Ia-2或Ia-3：
Figure PCTCN2019074755-appb-000013
其中，
Figure PCTCN2019074755-appb-000014
为单键或双键；
所述X、M 1、M 2、R 1、R 2、R 3、R 4、R 5、R 6、R 1A、R 1B、R 2A、R 2B、R 3A、R 3B、R 4A、R 4B和n、m、q的定义与上文所述相同，且所述Y为不存在、O、S(O) p、NR Y1、C(R Y2)R Y3；
R Y1为氢、CN、氧代、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、-C(＝O)R b、-C(＝O)OR b、-C(＝S)R b、-C(＝S)OR b、-C(＝S)SR b、-C(＝O)SR b、-C(＝NH)SR b、-C(＝NH)OR b、-C(＝NH)R b、-S(＝O)R b、-S(＝O) 2R b、-S(＝O) 2NR bR c、-S(＝O) 2OR b、-C(＝O)NR bR c、-C(＝S)NR bR c、-C(＝NH)NR bR c；
R Y2在每次出现时各自独立地为氢、CN、NO 2、卤素、C 1-C 6烷基；
R Y3在每次出现时各自独立地为氢、CN、NO 2、卤素、C 1-C 6烷基、G a、-C(＝O)OR b；-(OCH 2CH 2) mOR d、-(OCH 2CH 2) mNR bR c、-N(R e)C(＝O)R b、-N(R e)C(＝O)OR b、-N(R e)C(＝O)NR bR c、-N(R e)C(＝O)SR b、-N(R e)C(＝S)R b、-N(R e)C(＝S)OR b、-N(R e)C(＝S)SR b、 -N(R e)C(＝S)NR bR c、-N(R e)C(＝NH)R b、-N(R e)C(＝NH)OR b、-N(R e)C(＝NH)NR bR c、-N(R e)S(＝O) 2R b、-N(R e)S(＝O) 2OR b、-N(R e)S(＝O) 2NR bR c；
G a、p、R b、R c、R d、和R e的定义与上文所述的相同。
根据本发明的另一个实施方式，所述通式I所述的化合物具有式Ia-4
Figure PCTCN2019074755-appb-000015
其中，R1为氢或F；
m、q的定义与上文所述相同，
R 1A、R 1B、R 2A、R 2B、R 3A、R 3B、R 4A或R 4B各自独立地为氢或者C 1-C 3烷基；
或者，R 1A与R 1B、R 2A与R 2B可和与之连接的碳原子形成羰基(＝O)、硫羰基(＝S)；
或者，同碳上的取代基R 1A与R 1B、R 2A与R 2B、R 3A与R 3B以及R 4A与R 4B彼此连接以形成-R 1A’-Z 2-R 1B’-、-R 2A’-Z 2-R 2B’-、-R 3A’-Z 2-R 3B’-、-R 4A’-Z 2-R 4B’-并分别和与之相连的原子键结形成一个螺环，其中Z 2为不存在、-O-；
或者，不同碳上的取代基R 1A及R 2A、R 1A及R 3A、R 3A及R 4A彼此连接以形成-R 1A’-Z 3-R 2A’-、-R 1A’-Z 3-R 3A’-、-R 3A’-Z 3-R 4A’-并分别和与之相连的原子键结，其中Z 3为不存在、或者-O-。
其中，所述R 1A’及R 1B’、R 2A’及R 2B’、R 3A’及R 3B’、R 4A’及R 4B’在每次出现时各自独立地为不存在、C 1-C 3亚烷基；
所述Y为O、S(O) p、NR Y1；
R Y1为氢、CN、氧代、C 1-C 6烷基、G a、-C(＝O)R b、-C(＝O)OR b、-C(＝S)R b、-S(＝O) 2R b、-S(＝O) 2NR bR c、-C(＝O)NR bR c、-C(＝NH)NR bR c；
G a、p、R b和R c的定义与上文所述的相同。
根据本发明的另一个实施方式，所述通式I所述的化合物具有式Ia-5
Figure PCTCN2019074755-appb-000016
其中，R 1为氢或F；
R 6各自独立地为卤素；
R 1A、R 1B各自独立地为氢或者C 1-C 3烷基；或者R 1A、R 1B可彼此连接并和与之相连的碳形成3至6元饱和环烷烃螺环；
M 1、n、q的定义与上文所述相同。
所述Y为O、S(O) p、NR Y1；
R Y1为氢、CN、氧代、C 1-C 6烷基、G a、-C(＝O)R b、-C(＝O)OR b、-C(＝S)R b、-S(＝O) 2R b、-S(＝O) 2NR bR c、-C(＝O)NR bR c、-C(＝NH)NR bR c；
G a、p、R b和R c的定义与上文所述的相同。
根据本发明的另一个实施方式，所述通式I所述的化合物具有式Ia-6、Ia-7、Ia-8、或者Ia-9
Figure PCTCN2019074755-appb-000017
其中，R 1为氢或F；R 6各自独立地为卤素；
M 1为苯环或者吡啶环；
q各自独立地为1或者2；n各自独立地为0、1、或2；
R 1A、R 1B各自独立地为氢或者C 1-C 3烷基；或者R 1A、R 1B可彼此连接并和与之相连的碳形成3至6元饱和环烷烃螺环；
R 2A、R 2B各自独立地为氢或者C 1-C 3烷基；或者R 2A、R 2B可彼此连接并和与之相连的碳形成3至6元饱和环烷烃螺环；
Y为O、S(O) 2、或者NR Y1；R Y1为氢、CN、C 1-C 3烷基、环丙基、-C(＝S)R b、-C(＝O)R b、-C(＝O)OR b、-S(＝O) 2R b、-C(＝O)NR bR c、-C(＝NH)NR bR c、-S(＝O) 2NR bR c；R b和R c的定义与上文所述相同。
根据本发明的另一个实施方式，所述通式I所述的化合物具有式Ia-10、Ia-11、Ia-12或者Ia-13。
Figure PCTCN2019074755-appb-000018
R 6各自独立地为卤素；
M 1为苯环或者吡啶环；
q各自独立地为1或者2；n各自独立地为0、1、或2；
R 1A、R 1B各自独立地为氢或者甲基；或者R 1A、R 1B可彼此连接并和与之相连的碳形成环丙螺环；
R 2A、R 2B各自独立地为氢或者甲基；或者R 2A、R 2B可彼此连接并和与之相连的碳形成环丙螺环；
Y为O、S(O) 2、或者NR Y1；R Y1为氢、CN、C 1-C 3烷基、环丙基、-C(＝O)R b、-C(＝O)OR b、-S(＝O) 2R b、-C(＝O)NHR b；R b为氢、甲基、乙基、异丙基或者环丙基。
根据本公开的另一方面，所述通式I所述的化合物选自如下化合物：
Figure PCTCN2019074755-appb-000019
Figure PCTCN2019074755-appb-000020
Figure PCTCN2019074755-appb-000021
Figure PCTCN2019074755-appb-000022
根据本公开的另一方面，其提供了一种药物组合物，该药物组合物包含上述的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体中的一种或多种，以及至少一种药学上可接受的载体、稀释剂或赋形剂。
根据本公开的另一方面，所述药物组合物进一步包含至少一种其他治疗剂，
根据本公开的另一方面，所述药物组合物中包含的所述至少一种其他治疗剂选自其他抗癌剂、免疫调节剂、抗过敏剂、止吐剂、疼痛缓解剂、细胞保护剂及其组合。
根据本公开的另一方面，其提供了上述的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体或药物组合物在制备用于治疗由EED和/或PRC2介导的疾病或病症的药物中的用途。
根据本公开的另一方面，所述由EED和/或PRC2介导的疾病或病症包括弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、其他淋巴瘤、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、肝细胞癌、前列腺癌、乳腺癌、胆管及胆囊癌、膀胱癌；脑瘤、包括神经母细胞瘤、神经鞘瘤、神经胶质瘤、神经胶质母细胞瘤及星细胞瘤；子宫颈癌、结肠癌、黑色素瘤、子宫内膜癌、食道癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾细胞癌、直肠癌、甲状腺癌、副甲状腺肿瘤、子宫肿瘤及软组织肉瘤。
根据本发明的另一方面，提供了用于制备本发明化合物的方法，其中，所述方法如下所示：
方案一：
步骤1：
Figure PCTCN2019074755-appb-000023
在步骤1中，用水合肼处理式(I-1)，生成式(I-2)化合物，再用原甲酸三甲酯将式(I-2)化合物转化为三氮唑产物式(I-3)，将三氮唑产物式(I-3)与适合的胺式(I-4)发生取代反应生成式(I-5)中间体，其中X为卤素，胺类化合物式(I-4)的制备可以参见文献：US 2016/0176882，或根据本领域已知的常规方法制备而得。R 1、R 2、R 3、R 4、R 5和n的定义与前文一致。
步骤2：
Figure PCTCN2019074755-appb-000024
在步骤2中，首先将式(I-5)化合物中的氨基进行保护得到式(II-2)产物，再与一系列胺(II-3)发生偶联反应生成产物式(II-4)，最后采用适当的方法去除保护基团，制备得到通式(I)化合物。所述偶联反应在钯催化剂和碱的存在下，并且任选在配体存在下，和在适当溶剂中在升高温度下(例如在约80度至150度)实现。反应可以通过微波辐射促进。钯催化剂的实例包括但不限于三(二亚苄基丙酮)二钯(0)、四三苯基膦钯(0)、氯化烯丙基钯(II)二聚物、[1,1'-双(二苯基膦基)二茂铁]二氯化钯((dppf)PdCl 2)、醋酸钯(II)。 适当的配体的实例包括但不限于4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos)、2-二环己基磷-2,4,6-三异丙基联苯(X-phos)、1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷、2′-二环己基膦基-2,6-二甲氧基-1,1′-联苯基-3-磺酸钠水合物和1,1’-双(二苯基磷烷基)二茂铁。可以使用的适当的碱的实例包括但不限于钠、钾和铯的碳酸盐或磷酸盐和氟化铯。适当溶剂的非限制性实例包括甲苯、乙腈、二甲氧基乙烷、N,N-二甲基甲酰胺、二甲基亚砜、二氧六环、四氢呋喃、乙二醇二甲醚、甲醇和水或其混合物。适当保护基和使用这样的适当保护基进行保护和脱保护不同取代基的方法是本领域技术人员熟知的；其实例发现在T.Greene and P.Wuts,Protecting Groups in Organic Synthesis(第4版)，John Wiley&Sons,(2007)，其以整体并入本文作为参考。在步骤2中，X为卤素，PG表示保护基团，A、X、Y、M、N、R 1、R 2、R 3、R 4、R 5、R 1A、R 1B、R 2A、R 2B、R 3A、R 3B、R 4A、R 4B、R 6和n、m、q的定义与前文一致。
方案二：
Figure PCTCN2019074755-appb-000025
在方案二中给出了由式III-1的化合物制备式III-2的化合物的方法。即，原料对应于通式I中的Y为NH，将此胺基化合物式(III-1)在碱性条件下，与带有R Y1基团的试剂或化合物反应得到式(III-2)化合物，所述试剂或化合物的实例包括但不限于酸酐、磺酸酐、异氰酸酯、硫代异氰酸酯、酰氯、磺酰氯、碳酸酯、氯甲酸酯、氨基甲酸酯等，所述碱的实例包括但不限于三乙胺、二异丙基乙基胺、吡啶、DMAP、碳酸钾、氢氧化钠、氢氧化钾、叔丁醇钾、NaH，所述有机溶剂的实例包括但不限于二氯甲烷、四氢呋喃、乙腈、1，4-二氧六环。或者将此胺基化合物式(III-1)在碱性条件下，与带有R Y1基团的羧酸在缩合剂的作用下发生缩合反应得到式(III-2)，所述缩合剂的实例包括但不限于羰基二咪唑、二环己基碳二亚胺、二异丙基碳二亚胺、1-(-3-二甲氨基丙基)-3-乙基碳二亚胺、1-羟基苯并三唑、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸盐、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、6-氯苯并三氮唑-1,1,3,3-四甲基脲四氟硼酸酯、2- 琥珀酰亚胺基-1,1,3,3-四甲基脲四氟硼酸酯和2-(5-降冰片烯-2,3-二甲酰亚胺基)-1,1,3,3-四甲基脲四氟硼酸季铵盐，所述缩合反应可以在碱存在下在有机溶剂中进行，所述碱的实例包括但不限于三乙胺、二异丙基乙基胺、1,5-二氮杂二环[5.4.0]十一-5-烯，所述有机溶剂的实例包括但不限于二氯甲烷、氯仿、N,N-二甲基甲酰胺、四氢呋喃。其中，R Y1优选地定义为：-C(＝O)R b、-C(＝O)OR b、-S(＝O) 2R b、-S(＝O) 2NR bR c、-C(＝O)NR bR c、-C(＝S)NR bR c；
R 1、R 2、R 3、R 4、R 5、R 1A、R 1B、R 2A、R 2B、R 3A、R 3B、R 4A、R 4B、R b、R c、n、q、m的定义与上文中定义的相同。
方案三：
Figure PCTCN2019074755-appb-000026
在方案三中给出了由式III-1的化合物制备式IV-2的化合物的方法。即，原料对应于通式I中的Y为NH，将此胺基化合物式(III-1)在还原剂的作用下与醛或酮发生还原胺化反应，或在碱性条件下，与各类卤代物发生取代反应制备得到式(IV-2)化合物，所述还原剂的实例包括但不限于氰基硼氢化钠、三乙酰氧基硼氢化钠、硼氢化钠，所述碱的实例包括但不限于三乙胺、二异丙基乙基胺、吡啶、1,5-二氮杂二环[5.4.0]十一-5-烯，DMAP、碳酸钾、氢氧化钠、氢氧化钾、叔丁醇钾、NaH，所述有机溶剂例如但不限于二氯甲烷、二氯乙烷、氯仿、N,N-二甲基甲酰胺、四氢呋喃。
其中，R Y1优选地定义为：CN、含0-2个R a取代的C 1-C 6烷基、C 1-C 6卤代烷基、G a；
R 1、R 2、R 3、R 4、R 5、R 1A、R 1B、R 2A、R 2B、R 3A、R 3B、R 4A、R 4B、R a、n、q、m、G a的定义与上文中定义的相同。
方案四：
Figure PCTCN2019074755-appb-000027
在方案四中给出了由式V-1的化合物制备式V-2的化合物的方法。即，原料对应于通式I中的Y为NH，将此胺基化合物式(V-1)在碱性条件下，与带有R Y1基团的试剂或化合物反应得到式(V-2)化合物，所述试剂或化合物的实例包括但不限于酸酐、磺酸酐、异氰酸酯、硫代异氰酸酯、酰氯、磺酰氯、碳酸酯、氯甲酸酯、氨基甲酸酯等，所述碱的实例包括但不限于三乙胺、二异丙基乙基胺、吡啶、DMAP、碳酸钾、氢氧化钠、氢氧化钾、叔丁醇钾、NaH，所述有机溶剂的实例包括但不限于二氯甲烷、四氢呋喃、乙腈、1，4-二氧六环。或者将此胺基化合物式(V-1)在碱性条件下，与带有R Y1基团的羧酸在缩合剂的作用下发生缩合反应得到式(V-2)，所述缩合剂的实例包括但不限于羰基二咪唑、二环己基碳二亚胺、二异丙基碳二亚胺、1-(-3-二甲氨基丙基)-3-乙基碳二亚胺、1-羟基苯并三唑、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸盐、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、6-氯苯并三氮唑-1,1,3,3-四甲基脲四氟硼酸酯、2-琥珀酰亚胺基-1,1,3,3-四甲基脲四氟硼酸酯和2-(5-降冰片烯-2,3-二甲酰亚胺基)-1,1,3,3-四甲基脲四氟硼酸季铵盐，所述缩合反应可以在碱存在下在有机溶剂中进行，所述碱的实例包括但不限于三乙胺、二异丙基乙基胺、1,5-二氮杂二环[5.4.0]十一-5-烯，所述有机溶剂的实例包括但不限于二氯甲烷、氯仿、N,N-二甲基甲酰胺、四氢呋喃。其中，R Y1优选地定义为：-C(＝O)R b、-C(＝O)OR b、-S(＝O) 2R b、-S(＝O) 2NR bR c、-C(＝O)NR bR c、-C(＝S)NR bR c；
M 1、R 1、R 2、R 3、R 4、R 5、R 6、R 1A、R 1B、R 4A、R 4B、R b、R c、n、q的定义与上文中定义的相同。
方案五：
Figure PCTCN2019074755-appb-000028
在方案五中给出了由式V-1的化合物制备式VI-2的化合物的方法。即，原料对应于通式I中的Y为NH，将此胺基化合物式(V-1)在还原剂的作用下与醛或酮发生还原胺化反应，或在碱性条件下，与各类卤代物发生取代反应制备得到式(VI-2)化合物，所述还原剂的实例包括但不限于氰基硼氢化钠、三乙酰氧基硼氢化钠、硼氢化钠，所述碱的实例包括但不限于三乙胺、二异丙基乙基胺、吡啶、1,5-二氮杂二环[5.4.0]十一-5-烯，DMAP、碳酸钾、氢氧化钠、氢氧化钾、叔丁醇钾、NaH，所述有机溶剂例如但不限于二氯甲烷、二氯乙烷、氯仿、N,N-二甲基甲酰胺、四氢呋喃。
其中，R Y1优选地定义为：CN、含0-2个R a取代的C 1-C 6烷基、C 1-C 6卤代烷基、G a；
M 1、R 1、R 2、R 3、R 4、R 5、R 6、R 1A、R 1B、R 4A、R 4B、R a、n、q、G a的定义与上文中定义的相同。
每一独立步骤的最佳反应条件和反应时间可以根据所用特定反应物和所有反应物中存在的取代基改变。除非另外规定，溶剂、温度和其他反应条件可以由本领域技术人员容易选择。具体步骤提供在合成实施例部分。反应可以常规方式进一步处理，例如通过从残留物除去溶剂并根据本领域通常已知的方法例如但不限于结晶、蒸馏、萃取、研磨和色谱进一步纯化。除非另外说明起始原料和反应剂是可商业购买的或者可以由本领域技术人员从可购买的材料使用化学文献描述的方法制备。
起始材料如果不可从商业渠道购买，可以由选自下列的步骤制备：标准有机化学技术、类似于合成已知结构类似物的技术、或类似于上述方案或合成实施例部分描述的步骤的技术。当需要本发明化合物的光学活性形式时，其可以由进行本文所述步骤之一使用光学活性起始材料(例如通过适当反应步骤的不对称诱导制备)获得，或者通过使用标准步骤(例如色谱分离、重结晶或酶拆分)拆分化合物或中间体的立体异构体混合物获得。
类似地，当需要本发明化合物的纯几何异构体时，其可以由使用纯几何异构体作为起始材料进行上述步骤之一获得，或者通过使用标准步骤，例如色谱分离拆分化合物或中间体的几何异构体混合物获得。
制备本发明化合物的多晶型物时，通过采用重结晶方法得到晶体，并根据X射线衍射得到其晶体结构。
制备本发明化合物的经同位素标记的化合物时，可根据需要采用经同位素标记的原料进行反应。
具体实施方式
本说明书中公开的所有特征，或公开的所有方法或过程中的步骤，除了互相排斥的特征和/或步骤以外，均可以以任何方式组合。以下实施例证实本发明的部分范围，且并非特意限制本发明的保护范围。
除非另有说明，否则本发明实施例中的原料或中间体均来自商业购买或者按照文献(例如但不限于：US 2016/0176882，J.Med.Chem.2017,60,2215–2226)中记载的方法制备。
实施例1：中间体I-3a的合成
Figure PCTCN2019074755-appb-000029
步骤1：将10g底物I-1a溶于200mL乙醇，加入4.4g水合肼，室温下反应4小时，得到悬浊液，过滤，滤饼用正己烷洗涤，真空干燥得8g产物I-2a，LC-MS:[M+H] +＝235/237。
步骤2：将8g底物I-2a溶于40mL原甲酸三乙酯，加热回流反应2小时，减压浓缩后，经柱层析分离得到产物I-3a(7.2g)，为白色固体，LC-MS:[M+H] +＝245/247。
实施例2：中间体II-6a的合成
Figure PCTCN2019074755-appb-000030
步骤1：将50g底物II-1a溶于200mL DMF，加入2-溴-1,1-二乙氧基乙烷(70g)，以及120g碳酸钾。在Ar气保护下，110度加热反应过夜，冷却后加水稀释，乙酸乙酯萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物II-2a(75g)。
步骤2：将75g底物II-2a溶于200mL甲苯中，在95度下分批加入多聚磷酸(130g)， 保持在95度下反应2小时，冷却后加冰水稀释，石油醚萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物II-3a和II-3a’的混合物(26g)。
步骤3：将26g步骤2中所得混合物溶于100mL DMF，加入氰化锌(20g)，以及15g四三苯基膦钯。在Ar气保护下，100度加热反应过夜，冷却后加水稀释，乙酸乙酯萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物II-4a(7.2g)。在此步骤中，上述II-3a’的反应产物经过柱层析被除去。
1H NMR(400MHz,MeOD)δ8.09(d,J＝2.2Hz,1H),7.87(ddd,J＝9.1,4.0,0.9Hz,1H),7.29(t,J＝9.4Hz,1H),7.06(dd,J＝2.2,0.9Hz,1H).
步骤4：将7.2g底物II-4a，二碳酸二叔丁酯(22g)溶于200mL甲醇，加入10％Pd/C(3.5g)。通入H 2反应36小时，硅藻土过滤，浓缩，经柱层析分离得到产物II-5a(10g)。 1H NMR(400MHz,DMSO-d 6)δ7.25(t,J＝5.3Hz,1H),6.89–6.82(m,1H),6.63(dd,J＝8.6,3.9Hz,1H),4.53(t,J＝8.7Hz,2H),4.12(d,J＝5.6Hz,2H),3.22(t,J＝8.7Hz,2H),1.38(s,9H).
步骤5：将10g底物II-5a溶于HCl/二氧六环(4N,50mL)，室温下反应4小时，浓缩，粗品再溶于甲醇(20mL)和乙腈(4mL)中，加入6g碳酸钾，60度下反应过夜，浓缩除去溶剂，经柱层析分离得到产物II-6a(3.2g)。LC-MS:[M+H] +＝168.1。
实施例3：中间体III-2a的合成
Figure PCTCN2019074755-appb-000031
步骤1：将底物II-6a(12.8g)和I-3a(12.8g,0.052mol)混合物加热至40℃反应过夜.加入二氯甲烷稀释反应，析出固体，过滤，滤饼用二氯甲烷洗涤，真空干燥，得产物III-1a为白色固体(10.7g)。 1H NMR(400MHz,DMSO-d 6)δ9.49(s,1H),8.76(s,1H),7.86(s,1H),6.98–6.91(m,1H),6.71(dd,J＝8.6,3.9Hz,1H),4.66(d,J＝3.9Hz,2H),4.54(t,J＝8.7Hz,2H),3.28(t,J＝8.7Hz,2H).LC-MS:[M+H] +＝364.1。
步骤2：将底物III-1a(2.0g)溶于20mL吡啶，加入Boc 2O(2.4g)和DMAP(0.07g)室温下反应过夜，浓缩除去溶剂，加入EA/PE(1比1)打浆得到产物III-2a(1.6g)。LC-MS:[M+H] +＝464.1。
实施例4：化合物SL-ZYE-31的合成
Figure PCTCN2019074755-appb-000032
在Ar气保护下，将底物III-2a(20.0mg)，吗啉(12mg，CAS：110-91-8)，三(二 亚苄基丙酮)二钯(Pd 2(dba) 3，4mg，CAS：51364-51-3)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(XantPhos，5mg，CAS：161265-03-8)，碳酸铯(28mg)溶于10mL甲苯中，加热至80℃反应两个小时，浓缩除去溶剂，经柱层析分离得到中间体SL-ZYE-31-1(15mg)。LC-MS:[M+H] +＝471.2。
将中间体SL-ZYE-31-1(15mg)3mL溶于二氯甲烷，加入2mL三氟乙酸，室温反应2小时，浓缩除去溶剂，乙酸乙酯溶解，用饱和碳酸氢钠水溶液和饱和食盐水洗涤数次，经柱层析分离得到产物SL-ZYE-31(5mg)。 1H NMR(400MHz,CDCl 3)δ8.84(s,1H),7.08(s,1H),6.87–6.71(m,1H),6.62(dd,J＝8.7,4.0Hz,1H),5.81(m,1H),4.73(d,J＝5.4Hz,2H),4.62(t,J＝8.7Hz,2H),3.99–3.81(m,4H),3.38(m,6H).LC-MS:[M+H] +＝371.1。
实施例5：化合物SL-ZYE-35的合成
Figure PCTCN2019074755-appb-000033
除了采用硫代吗啉(CAS：123-90-0)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-35。
1H NMR(400MHz,CD 3OD)δ9.49(s,1H),8.07(s,1H),6.93–6.81(m,1H),6.67(dd,J＝8.7,3.9Hz,1H),4.81(s,2H),4.61(t,J＝8.7Hz,2H),3.46–3.34(m,6H),2.94–2.85(m,4H).LC-MS:[M+H] +＝387.1。
实施例6：化合物SL-ZYE-02的合成
Figure PCTCN2019074755-appb-000034
除了采用N-甲基哌嗪(CAS：109-01-3)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-02。
1H NMR(400MHz,DMSO-d 6)δ9.44(s,1H),8.20(m,1H),7.10(s,1H),7.00–6.82(m,1H),6.69(dd,J＝8.7,3.8Hz,1H),4.60(d,J＝5.1Hz,2H),4.53(t,J＝8.7Hz,2H),3.30(m,8H),2.92(brs,3H),2.52(m,2H).LC-MS:[M+H] +＝384.2。
实施例7：化合物SL-ZYE-58的合成
Figure PCTCN2019074755-appb-000035
除了采用N-叔丁氧羰基哌嗪(CAS：143238-38-4)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-58。
1H NMR(400MHz,DMSO-d 6)δ9.48(s,1H),8.31(t,J＝5.0Hz,1H),7.17(s,1H),6.97–6.88(m,1H),6.69(dd,J＝8.6,3.8Hz,1H),4.61(d,J＝5.0Hz,2H),4.54(t,J＝8.8Hz,2H),3.48(m,4H),3.28(m,4H),3.17(m,2H).LC-MS:[M+H] +＝370.2。
实施例8：化合物SL-ZYE-37的合成
Figure PCTCN2019074755-appb-000036
除了采用六氢吡啶(CAS：110-89-4)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-37。
1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.48(s,1H),7.69(s,1H),6.89–6.76(m,1H),6.65(dd,J＝8.6,4.0Hz,1H),4.77(s,2H),4.61(t,J＝8.7Hz,2H),3.76(m,4H),3.40(t,J＝8.8Hz,2H),2.07(m,4H),1.81(m,2H).LC-MS:[M+H] +＝369.1。
实施例9：化合物SL-ZYE-36的合成
Figure PCTCN2019074755-appb-000037
除了采用硫代吗啉-1,1-二氧化物(CAS：39093-93-1)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-36。
1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.31(s,1H),7.41(s,1H),6.86–6.79(m,1H),6.63(dd,J＝8.6,3.9Hz,1H),4.70(s,2H),4.59(t,J＝8.7Hz,2H),3.80–3.73(m,4H),3.42–3.33(m,6H).LC-MS:[M-H] +＝417.1。
实施例10：化合物SL-ZYE-01的合成
Figure PCTCN2019074755-appb-000038
将实施例7中制备的产物SL-ZYE-58(10mg)溶解于2mL二氯甲烷(DCM)中，加入三乙胺(7mg)，乙酸酐(4mg)，室温下反应1小时，加二氯甲烷稀释，水洗，干燥浓缩，经柱层析分离得到产物SL-ZYE-01(6mg)。
1H NMR(400MHz,DMSO-d 6)δ9.40(s,1H),8.13(t,J＝5.0Hz,1H),7.08(s,1H),6.98–6.88(m,1H),6.69(dd,J＝8.6,3.9Hz,1H),4.60(d,J＝4.8Hz,2H),4.53(t,J＝8.7Hz,2H),3.62(m,4H),3.30-3.19(m,6H),2.05(s,3H).LC-MS:[M+H] +＝412.2。
实施例11：化合物SL-ZYE-32的合成
Figure PCTCN2019074755-appb-000039
将实施例7中制备的产物SL-ZYE-58(10mg)溶解于2mL二氯甲烷中，加入三乙胺(7mg)，异氰酸乙酯(3.4mg)，室温下反应1小时，加二氯甲烷稀释，水洗，干燥浓缩，经柱层析分离得到产物SL-ZYE-32(1.5mg)。LC-MS:[M+H] +＝441.2。
实施例12：化合物SL-ZYE-03的合成
Figure PCTCN2019074755-appb-000040
将实施例7中制备的产物SL-ZYE-58(10mg)溶解于2mL二氯甲烷中，加入三乙胺(7mg)，甲基磺酸酐(4.5mg)，室温下反应1小时，加二氯甲烷稀释，水洗，干燥浓缩，经柱层析分离得到产物SL-ZYE-03(2mg)。
1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.06(s,1H),7.11(s,1H),6.85–6.76(m,1H),6.64(dd,J＝8.6,3.8Hz,1H),4.66(s,2H),4.60(t,J＝8.7Hz,2H),3.51–3.43(m,4H),3.39(m,4H),3.35(m,2H),2.85(s,3H).LC-MS:[M+H] +＝448.2。
实施例13：化合物SL-ZYE-33的合成
Figure PCTCN2019074755-appb-000041
将实施例7中制备的产物SL-ZYE-58(20mg)溶解于5mL DMF中，加入三乙胺(13mg)，室温下反应5分钟，然后加入N,N-二甲基甘氨酸(6.6mg，CAS：1118-68-9)以及HATU(32.6mg)，室温下反应1小时，加水稀释，乙酸乙酯萃取，水洗，干燥浓缩，经柱层析分离得到产物SL-ZYE-33(8mg)。
1H NMR(400MHz,CD 3OD)δ9.26(s,1H),7.24(s,1H),6.93–6.79(m,1H),6.63(dd,J＝8.6,3.8Hz,1H),4.71(s,2H),4.57(t,J＝8.7Hz,2H),3.81(m,4H),3.42(s,2H),3.36(m,2H),3.29(m,2H),3.24(m,2H),2.42(s,6H).LC-MS:[M+H] +＝455.2。
实施例14：化合物SL-ZYE-39的合成
Figure PCTCN2019074755-appb-000042
将实施例7中制备的化合物SL-ZYE-58(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(187mg),随后滴加丙烯酰氯(6.1mg溶于1mL DCM)，反应液保持在0℃搅拌10分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物SL-ZYE-39(8mg)。
1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.07(s,1H),7.05(s,1H),6.76(t,J＝9.3Hz,1H),6.65–6.49(m,2H),6.23(m,1H),5.71(m,1H),4.61(s,2H),4.54(t,J＝8.7Hz,2H),3.86(m,2H),3.76(m,2H),3.35–3.27(m,4H),3.21(m,2H).LC-MS:[M+H] +＝424.2。
实施例15：化合物SL-ZYE-40的合成
Figure PCTCN2019074755-appb-000043
除了采用吗啉-4-基乙酸(CAS：3235-69-6)代替N,N-二甲基甘氨酸以外，采用与实施例13中相同的方法，得到化合物SL-ZYE-40。
1H NMR(400MHz,CD 3OD)δ9.28(s,1H),7.25(s,1H),6.89–6.79(m,1H),6.63(dd,J＝8.7,3.8Hz,1H),4.71(s,2H),4.58(t,J＝8.7Hz,2H),3.89–3.80(m,4H),3.80–3.71(m, 4H),3.52(s,2H),3.37(m,2H),3.26–3.20(m,4H),2.72(m,4H).LC-MS:[M+H] +＝497.2。
实施例16：化合物SL-ZYE-42的合成
Figure PCTCN2019074755-appb-000044
除了采用1,3-二甲基-1H-吡唑-5-甲酸(CAS：5744-56-9)代替N,N-二甲基甘氨酸以外，采用与实施例13中相同的方法，得到化合物SL-ZYE-42。
1H NMR(400MHz,CDCl 3)δ9.01(s,1H),7.11(s,1H),6.83–6.70(m,1H),6.60(dd,J＝8.7,3.9Hz,1H),6.44(m,1H),6.12(s,1H),4.71(d,J＝4.8Hz,2H),4.60(t,J＝8.7Hz,2H),4.05–3.76(m,7H),3.36(m,6H),2.28(s,3H).LC-MS:[M+H] +＝492.3。
实施例17：化合物SL-ZYE-45的合成
Figure PCTCN2019074755-appb-000045
除了采用苯并吗啉(CAS：5735-53-5)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-45。
1H NMR(400MHz,CD 3OD)δ9.52(s,1H),8.26(s,1H),6.95–6.82(m,2H),6.81–6.64(m,3H),6.49(dd,J＝7.8,1.7Hz,1H),4.87(s,2H),4.62(t,J＝8.7Hz,2H),4.49–4.37(m,2H),3.79–3.70(m,2H),3.44(t,J＝8.7Hz,2H).LC-MS:[M+H] +＝419.2。
实施例18：化合物SL-ZYE-48的合成
Figure PCTCN2019074755-appb-000046
除了采用1,2,3,4-四氢喹喔啉(CAS：3476-89-9)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-48。
1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.30(s,1H),7.55(s,1H),6.84(t,J＝9.3Hz,1H),6.65(m,3H),6.45(m,2H),4.74(s,2H),4.59(t,J＝8.6Hz,2H),3.76(m,2H),3.46(m,2H),3.38(t,J＝8.6Hz,2H).LC-MS:[M+H] +＝418.2。
实施例19：化合物SL-ZYE-50的合成
Figure PCTCN2019074755-appb-000047
除了采用化合物AN-1(CAS：6639-92-5)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-50。
1H NMR(400MHz,CDCl 3)δ9.21(s,1H),7.75(s,1H),7.07(m,1H),6.89(m,1H),6.79(t,J＝9.5Hz,1H),6.71(m,1H),6.64(dd,J＝8.7,3.7Hz,1H),6.55(d,J＝8.1Hz,1H),4.76(s,2H),4.60(t,J＝8.2Hz,2H),4.08(m,2H),3.80(m,2H),3.41(m,2H),2.31(s,3H).LC-MS:[M+H] +＝460.2。
实施例20：化合物SL-ZYE-44的合成
Figure PCTCN2019074755-appb-000048
除了采用2-哌嗪酮(CAS：5625-67-2)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-44。
1H NMR(400MHz,CD 3OD)δ9.52(s,1H),8.05(s,1H),6.91–6.80(m,1H),6.66(dd,J＝8.7,3.9Hz,1H),4.81(s,2H),4.60(t,J＝8.6Hz,2H),3.77(m,2H),3.52(m,2H),3.41(m,4H).LC-MS:[M+H] +＝384.2。
实施例21：化合物SL-ZYE-49的合成
Figure PCTCN2019074755-appb-000049
除了采用1-(3-吡啶基)哌嗪(CAS：67980-77-2)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-49。
1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.19(s,1H),8.28(m,1H),8.01(m,1H),7.39(m,1H),7.31(m,1H),7.15(s,1H),6.80(t,J＝9.3Hz,1H),6.63(m,1H),4.66(s,2H),4.59(t,J＝8.6Hz,2H),3.45(m,8H),3.35(m,2H).LC-MS:[M+H] +＝447.2。
实施例22：化合物SL-ZYE-51的合成
Figure PCTCN2019074755-appb-000050
除了采用2,6-二甲基吗啉(CAS：141-91-3)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-51。
1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.26(s,1H),7.85(s,1H),6.89–6.77(m,1H),6.63(dd,J＝8.6,3.8Hz,1H),4.69(s,2H),4.59(t,J＝8.7Hz,3H),3.97(m,2H),3.67(m,2H),3.37(m,2H),3.33(m,2H),1.25(s,3H),1.23(s,3H).LC-MS:[M+H] +＝399.2。
实施例23：化合物SL-ZYE-47的合成
Figure PCTCN2019074755-appb-000051
除了采用1,4-氧杂氮杂环庚烷(CAS：5638-60-8)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-47。
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),6.99(s,1H),6.83(t,J＝9.4Hz,1H),6.65(dd,J＝8.6,3.8Hz,1H),5.22(m,1H),4.70(d,J＝5.4Hz,2H),4.63(t,J＝8.7Hz,2H),3.93(m,4H),3.81(m,4H),3.38(t,J＝8.7Hz,2H),2.20–2.05(m,2H).LC-MS:[M+H] +＝385.2。
实施例24：化合物SL-ZYE-41的合成
Figure PCTCN2019074755-appb-000052
除了采用六氢吡咯并[1,2-A]吡嗪-6-酮(CAS：117810-52-3)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-41。
1H NMR(400MHz,CDCl 3)δ9.01(s,1H),7.14(s,1H),6.87–6.76(m,1H),6.64(dd,J＝8.7,4.0Hz,1H),6.23(brs,1H),4.73(s,2H),4.63(t,J＝8.6Hz,2H),4.16(m,2H),3.95(m,1H),3.82(m,1H),3.39(m,2H),3.17(m,1H),2.75(m,1H),2.44(m,3H),2.25(m,1H).LC-MS:[M+H] +＝424.2。
实施例25：化合物SL-ZYE-56的合成
Figure PCTCN2019074755-appb-000053
除了采用4,5,6,7-四氢吡唑[1,5-A]并吡嗪(CAS：792163-25-8)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-56。
1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.21(s,1H),7.47(d,J＝1.7Hz,1H),7.18(s,1H),6.80(t,J＝9.4Hz,1H),6.62(dd,J＝8.6,3.8Hz,1H),6.12(s,1H),4.65(s,2H),4.58(t,J＝8.7Hz,2H),4.52(s,2H),4.32(t,J＝5.4Hz,2H),3.93(t,J＝5.3Hz,2H),3.36–3.33(m,2H).LC-MS:[M+H] +＝407.2。
实施例26：化合物SL-ZYE-57的合成
Figure PCTCN2019074755-appb-000054
除了采用3-甲基-5,6,7,8-四氢咪唑[1,5A]吡嗪(CAS：734531-00-1)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-57。
1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.61(s,1H),7.83(s,1H),7.25(s,1H),6.82(t,J＝9.3Hz,1H),6.64(dd,J＝8.5,3.6Hz,1H),4.77(s,2H),4.62(m,2H),4.51(m,2H),4.35(m,2H),3.82(m,2H),3.41(m,2H),2.68(s,3H).LC-MS:[M+H] +＝421.2。
实施例27：化合物SL-ZYE-66的合成
Figure PCTCN2019074755-appb-000055
将实施例7中制备的化合物SL-ZYE-58(30.0mg)溶解于THF(10mL)中，加入三乙胺(20.0mg),搅拌5分钟后，加入溴化腈(13.6mg)，继续反应过夜。浓缩除去溶剂，加入乙酸乙酯稀释，水洗干燥，经柱层析分离得到SL-ZYE-66(15mg)。
1H NMR(400MHz,CDCl 3)δ8.90(s,1H),7.09(s,1H),6.77(t,J＝9.4Hz,1H),6.67–6.55(m,1H),6.15(m,1H),4.70(d,J＝5.2Hz,2H),4.60(t,J＝8.7Hz,2H),3.49-3.33(m,10H).LC-MS:[M+H] +＝395.2。
实施例28：化合物SL-ZYE-64-2的合成
Figure PCTCN2019074755-appb-000056
除了采用4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯(CAS：674792-08-6)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-64-2。LC-MS:[M+H] +＝396.2。
实施例29：化合物SL-ZYE-64的合成
Figure PCTCN2019074755-appb-000057
将实施例28中制备的化合物SL-ZYE-64-2(10.0mg),多聚甲醛(15.0mg)和氰基硼氢化钠(15.0mg)溶于甲醇中(5mL)，加入微量醋酸(0.1mL)加热至回流反应3小时，浓缩除去溶剂，经柱层析分离得到产物SL-ZYE-64(8.0mg)。
1H NMR(400MHz,CD 3OD)δ9.26(s,1H),7.27(s,1H),6.84(m,1H),6.64(dd,J＝8.6,3.9Hz,1H),4.72(s,2H),4.58(t,J＝8.7Hz,2H),3.51(m,2H),3.43(m,2H),3.34(m,4H),2.76(s,3H),1.06(m,2H),0.94(m,2H).LC-MS:[M+H] +＝410.2。
实施例30：化合物SL-ZYE-65的合成
Figure PCTCN2019074755-appb-000058
除了采用实施例28中制备的底物SL-ZYE-64-2代替实施例7中制备的SL-ZYE-58以外，采用与实施例10中相同的方法，得到化合物SL-ZYE-65。LC-MS:[M+H] +＝438.2。
实施例31：化合物SL-ZYE-61-2的合成
Figure PCTCN2019074755-appb-000059
除了采用3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(CAS：149771-44-8)代替吗啉以 外，采用与实施例4中相同的方法，得到化合物SL-ZYE-61-2。LC-MS:[M+H] +＝396.2。
实施例32：化合物SL-ZYE-61的合成
Figure PCTCN2019074755-appb-000060
除了采用实施例31中制备的底物SL-ZYE-61-2代替SL-ZYE-64-2以外，采用与实施例29中相同的方法，得到化合物SL-ZYE-61。
1H NMR(400MHz,CD 3OD)δ9.27(s,1H),7.19(s,1H),6.90–6.80(m,1H),6.64(dd,J＝8.6,3.9Hz,1H),4.71(s,2H),4.57(t,J＝8.7Hz,2H),3.86(m,4H),3.36(m,2H),3.21(m,2H),2.75(s,3H),2.37–2.25(m,4H).LC-MS:[M+H] +＝410.2。
实施例33：化合物SL-ZYE-62的合成
Figure PCTCN2019074755-appb-000061
除了采用实施例31中制备的底物SL-ZYE-61-2代替实施例7中制备的SL-ZYE-58以外，采用与实施例10中相同的方法，得到化合物SL-ZYE-62。
1H NMR(400MHz,CD 3OD)δ9.25(s,1H),7.13(s,1H),6.89–6.79(m,1H),6.64(dd,J＝8.7,3.8Hz,1H),4.75-4.66(m,3H),4.57(t,J＝8.7Hz,2H),4.43(m,1H),3.87(d,J＝9.2Hz,1H),3.72(d,J＝9.0Hz,1H),3.36(m,2H),2.96(m,2H),2.23(m,2H),2.16(s,3H),2.08(m,2H).LC-MS:[M+H] +＝438.2。
实施例34：化合物SL-ZYE-63-2的合成
Figure PCTCN2019074755-appb-000062
除了采用2,5-二氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯(CAS：858671-91-7)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-63-2。LC-MS:[M+H] +＝396.2。
实施例35：化合物SL-ZYE-63的合成
Figure PCTCN2019074755-appb-000063
除了采用实施例34中制备的底物SL-ZYE-63-2代替实施例28中制备的SL-ZYE-64-2以外，采用与实施例29中相同的方法，得到化合物SL-ZYE-63。
1H NMR(400MHz,CD 3OD)δ9.28(s,1H),7.17(s,1H),6.90–6.79(m,1H),6.64(dd,J＝8.6,3.7Hz,1H),4.76(m,1H),4.71(s,2H),4.58(t,J＝8.7Hz,2H),3.94(m,1H),3.77(m,2H),3.61(m,1H),3.40(m,3H),3.04(s,3H),2.21(m,4H),.LC-MS:[M+H] +＝410.2。
实施例36：化合物SL-ZYE-71的合成
Figure PCTCN2019074755-appb-000064
除了采用4-哌啶甲酸甲酯(CAS：2971-79-1)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-71。
1H NMR(400MHz,CD 3OD)δ9.44(s,1H),7.95(s,1H),6.90–6.81(m,1H),6.65(dd,J＝8.6,3.9Hz,1H),4.78(s,2H),4.59(t,J＝8.7Hz,2H),3.73(s,3H),3.47(m,2H),3.39(t,J＝8.7Hz,2H),3.13(m,2H),2.63(m,1H),2.13(m,2H),2.09–1.95(m,2H).LC-MS:[M+H] +＝427.2。
实施例37：化合物SL-ZYE-88的合成
Figure PCTCN2019074755-appb-000065
除了采用4-(氮杂环丁-3-基)吗啉(CAS：302355-79-9)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-88。
1H NMR(400MHz,CDCl 3)δ8.83(s,1H),6.79(t,J＝9.6Hz,1H),6.71(s,1H),6.65–6.56(m,1H),5.69(s,1H),4.68(d,J＝5.6Hz,2H),4.60(t,J＝8.7Hz,2H),4.24(d,J＝6.9Hz,2H),3.92(d,J＝6.3Hz,2H),3.75(m,4H),3.35(m,3H),2.44(m,4H).LC-MS:[M+H] +＝426.2。
实施例38：化合物SL-ZYE-136的合成
Figure PCTCN2019074755-appb-000066
将实施例28中制备的底物SL-ZYE-64-2(40mg)，溶于2mL DCM中，加入三乙胺(40mg)，甲基磺酰氯(23mg)，室温下搅拌反应一小时，浓缩，柱层析得15mg白色固体SL-ZYE-136。
1H NMR(400MHz,CDCl 3)δ8.86(s,1H),7.04(s,1H),6.84–6.72(m,1H),6.61(dd,J＝8.6,3.8Hz,1H),5.91(m,1H),4.72(d,J＝4.8Hz,2H),4.61(t,J＝8.8Hz,2H),3.81(m,2H),3.47(m,2H),3.41–3.27(m,4H),2.96(s,3H),1.16(m,2H),1.07(m,2H).LC-MS:[M+H] +＝474.2。
实施例39：化合物SL-ZYE-137的合成
Figure PCTCN2019074755-appb-000067
除了采用乙基磺酰氯代替甲基磺酰氯以外，采用与实施例38中相同的方法，得到化合物SL-ZYE-137。
1H NMR(400MHz,CDCl 3)δ8.86(s,1H),7.05(s,1H),6.84–6.74(m,1H),6.62(dd,J＝8.6,3.7Hz,1H),5.86(m,1H),4.71(m,2H),4.61(t,J＝8.7Hz,2H),3.75(m,2H),3.49(m,2H),3.42–3.30(m,4H),2.99(q,J＝7.5Hz,2H),1.31(t,J＝7.3Hz,3H),1.08(brs,4H).LC-MS:[M+H] +＝488.1。
实施例40：化合物SL-ZYE-89-2的合成
Figure PCTCN2019074755-appb-000068
除了采用4-(氮杂环丁烷-3-基)哌嗪-1-羧酸叔丁酯(CAS：219725-67-4)代替吗啉以外，采用与实施例4中相同的方法，得到化合物SL-ZYE-89-2。LC-MS:[M+H] +＝425.2。
实施例41：化合物SL-ZYE-89的合成
Figure PCTCN2019074755-appb-000069
除了采用实施例40中制备的底物SL-ZYE-89-2代替SL-ZYE-58以外，采用与实施例10中相同的方法，得到化合物SL-ZYE-89。LC-MS:[M+H] +＝467.2。
实施例42：化合物ZB-EED-01的合成
Figure PCTCN2019074755-appb-000070
将实施例7中制备的化合物SL-ZYE-58(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(150mg),随后滴加异丁酰氯(7.1mg溶于1mL DCM中)，反应液保持在0℃搅拌10分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-01(8mg)。 1H NMR(400MHz,CDCl 3)δ9.09(s,1H),7.09(s,1H),6.81–6.70(m,1H),6.66–6.54(m,2H),4.72(d,J＝5.2Hz,2H),4.59(t,J＝8.7Hz,2H),3.82(m,2H),3.73(m,2H),3.41(m,2H),3.36(t,J＝8.8Hz,2H),3.25(m,2H),2.84(m,1H),1.15(d,J＝6.7Hz,6H).LC-MS:[M+H] +＝440.2。
实施例43：化合物ZB-EED-02的合成
Figure PCTCN2019074755-appb-000071
将实施例7中制备的化合物SL-ZYE-58(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(100mg),随后滴加环丙基甲酰氯(CAS号：4023-34-1)(7.1mg溶于1mL DCM中)，反应液保持在0℃搅拌10分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-02(8mg)。 1H NMR(400MHz,CDCl 3)δ8.96(s,1H),7.10(s,1H),6.79(t,J＝9.4Hz,1H),6.62(dd,J＝8.6,3.9Hz,1H),6.19(m,1H),4.73(d,J＝5.2Hz,2H),4.61(t,J＝8.7Hz,2H),3.88(m,4H),3.47(m,2H),3.37(t,J＝8.7Hz,2H),3.28(m,2H),1.79(m,1H),1.01(m,2H),0.81(m,2H).LC-MS:[M+H] +＝438.2。
实施例44：化合物ZB-EED-03的合成
Figure PCTCN2019074755-appb-000072
将实施例7中制备的化合物SL-ZYE-58(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(100mg),随后滴加丙酰氯(7mg溶于1mL DCM中)，反应液保持在0℃搅拌10分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-03(6mg)。 1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.26(s,1H),7.15(s,1H),6.81(t,J＝9.3Hz,1H),6.62(dd,J＝8.7,3.8Hz,1H),4.66(d,J＝5.2Hz,2H),4.59(t,J＝8.7Hz,2H),3.83(m,2H),3.74(m,2H),3.33(m,4H),3.22(m,2H),2.44(q,J＝7.4Hz,2H),1.16(t,J＝7.5Hz,3H).LC-MS:[M+H] +＝426.2。
实施例45：化合物ZB-EED-04的合成
Figure PCTCN2019074755-appb-000073
将实施例7中制备的化合物SL-ZYE-58(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(150mg),随后滴加环丙磺酰氯(CAS号：139631-62-2)(9.5mg溶于1mL DCM中)，反应液保持在0℃搅拌10分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-04(8mg)。LC-MS:[M+H] +＝474.2。
实施例46：化合物ZB-EED-05的合成
Figure PCTCN2019074755-appb-000074
将实施例7中制备的化合物SL-ZYE-58(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(150mg),随后滴加异丙基磺酰氯(9.5mg溶于1mL DCM中)，反应液保持在0℃搅拌10分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物 ZB-EED-05(8mg)。LC-MS:[M+H] +＝476.2。
实施例47：化合物ZB-EED-06的合成
Figure PCTCN2019074755-appb-000075
将实施例7中制备的化合物SL-ZYE-58(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(50mg),随后滴加乙基磺酰氯(8.5mg溶于1mL DCM中)，反应液保持在0℃搅拌10分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-06(5mg)。 1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.16(s,1H),7.12(s,1H),6.79(t,J＝9.4Hz,1H),6.62(dd,J＝8.7,3.9Hz,1H),4.64(s,2H),4.58(t,J＝8.7Hz,2H),4.08(m,4H),3.57–3.43(m,4H),3.35(m,2H),3.03(q,J＝7.4Hz,2H),1.39(t,J＝7.4Hz,3H).LC-MS:[M+H] +＝462.2。
实施例48：化合物ZB-EED-07的合成
Figure PCTCN2019074755-appb-000076
将实施例31中制备的化合物SL-ZYE-61-2(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(150mg),随后滴加异丁酰氯(7.1mg溶于1mL DCM中)，反应液保持在0℃搅拌60分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-07。 1H NMR(400MHz,CDCl 3)δ8.90(s,1H),6.97(s,1H),6.80(m,1H),6.62(dd,J＝8.7,4.0Hz,1H),5.99(m,1H),4.85(d,J＝6.0Hz,1H),4.72(d,J＝5.4Hz,2H),4.61(t,J＝8.7Hz,2H),4.34(m,1H),4.25(d,J＝11.2Hz,1H),3.64(d,J＝9.9Hz,1H),3.37(t,J＝8.7Hz,2H),3.05(d,J＝10.3Hz,1H),2.89(d,J＝10.2Hz,1H),2.75(m,1H),2.27(m,1H),2.10-1.90(m,3H),1.19(d,J＝6.7Hz,3H),1.16(d,J＝6.8Hz,3H).LC-MS:[M+H] +＝466.2。
实施例49：化合物ZB-EED-08的合成
Figure PCTCN2019074755-appb-000077
将实施例31中制备的化合物SL-ZYE-61-2(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(50mg),随后滴加环丙基甲酰氯(CAS号：4023-34-1)(7.0mg溶于1mL DCM中)，反应液保持在0℃搅拌60分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-08。 1H NMR(400MHz,CDCl 3)δ8.82(s,1H),6.98(s,1H),6.84–6.79(m,1H),6.64(dd,J＝8.6,3.9Hz,1H),5.73(m,1H),4.82(d,J＝6.1Hz,1H),4.71(d,J＝5.5Hz,2H),4.62(t,J＝8.7Hz,2H),4.55(d,J＝6.1Hz,1H),4.28(d,J＝10.8Hz,1H),3.62(d,J＝11.0Hz,1H),3.37(t,J＝8.7Hz,2H),3.09(d,J＝11.2Hz,1H),3.00(d,J＝10.3Hz,1H),2.33(m,1H),2.11(m,2H),1.97(m,1H),1.78–1.69(m,1H),1.03(m,2H),0.79(m,2H).LC-MS:[M+H] +＝464.2。
实施例50：化合物ZB-EED-09的合成
Figure PCTCN2019074755-appb-000078
将实施例31中制备的化合物SL-ZYE-61-2(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(50mg),随后滴加丙酰氯(7.0mg溶于1mL DCM中)，反应液保持在0℃搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-09。 1H NMR(400MHz,CDCl 3)δ9.11(s,1H),6.97(s,1H),6.79–6.67(m,2H),6.58(dd,J＝8.7,3.9Hz,1H),4.79(d,J＝6.6Hz,1H),4.70(d,J＝5.2Hz,2H),4.58(t,J＝8.7Hz,2H),4.25(d,J＝5.9Hz,1H),4.17(d,J＝10.9Hz,1H),3.60(d,J＝9.1Hz,1H),3.34(t,J＝8.7Hz,2H),3.03(d,J＝10.4Hz,1H),2.86(d,J＝10.7Hz,1H),2.43–1.85(m,6H),1.16(t,J＝7.5Hz,3H).LC-MS:[M+H] +＝452.2。
实施例51：化合物ZB-EED-10的合成
Figure PCTCN2019074755-appb-000079
将实施例31中制备的化合物SL-ZYE-61-2(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(150mg),随后加入甲基磺酸酐(10mg)，反应液保持在室温搅拌60分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-10(10mg)。
1H NMR(400MHz,CDCl 3)δ8.69(s,1H),6.97(s,1H),6.87–6.77(m,1H),6.64(dd,J＝8.7,3.9Hz,1H),5.33(t,J＝5.7Hz,1H),4.70(d,J＝5.5Hz,2H),4.61(t,J＝8.7Hz,2H),4.33(brs,2H),3.96(dd,J＝11.2,2.7Hz,2H),3.37(t,J＝8.7Hz,2H),3.08(d,J＝10.8Hz,2H),2.96(s,3H),2.25–2.16(m,2H),2.11–2.02(m,2H).LC-MS:[M+H] +＝474.2。
实施例52：化合物ZB-EED-11的合成
Figure PCTCN2019074755-appb-000080
将实施例31中制备的化合物SL-ZYE-61-2(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(50mg),随后滴加乙基磺酰氯(8.5mg溶于1mL DCM中)，反应液保持在0℃搅拌10分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-11(5mg)。 1H NMR(400MHz,CDCl 3和CD 3OD的混合物)δ9.24(s,1H),7.08(s,1H),6.89–6.76(m,1H),6.63(dd,J＝8.6,3.8Hz,1H),4.68(s,2H),4.58(t,J＝8.7Hz,2H),4.30(brs,2H),3.82(d,J＝8.5Hz,2H),3.36(m,2H),3.14(q,J＝7.3Hz,2H),3.03(d,J＝10.8Hz,2H),2.21(m,2H),2.06(m,2H),1.40(t,J＝7.3Hz,3H).LC-MS:[M+H] +＝488.2。
实施例53：化合物ZB-EED-12的合成
Figure PCTCN2019074755-appb-000081
将实施例28中制备的化合物SL-ZYE-64-2(25.0mg)溶于DCM(5mL)中，0℃下 加入三乙胺(50mg),随后滴加丙酰氯(7.0mg溶于1mL DCM中)，反应液保持在0℃搅拌10分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-12(5mg)。LC-MS:[M+H] +＝452.2。
实施例54：化合物ZB-EED-13的合成
Figure PCTCN2019074755-appb-000082
除了采用1,4-二氮杂环庚烷-1-甲酸叔丁酯(CAS:112275-50-0)代替吗啉以外，采用与实施例4中相同的方法，得到化合物ZB-EED-13。LC-MS:[M+H] +＝384.3。
实施例55：化合物ZB-EED-14的合成
Figure PCTCN2019074755-appb-000083
将实施例54中制备的化合物ZB-EED-13(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(40mg),随后滴加乙酰氯(5.0mg溶于1mL DCM中)，反应液保持在0℃搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-14。 1H NMR(400MHz,CDCl 3)δ8.80(d,J＝12.8Hz,1H),7.00(d,J＝9.0Hz,1H),6.83(t,J＝9.3Hz,1H),6.68–6.63(m,1H),5.54(m,1H),4.71-4.67(m,2H),4.63(t,J＝8.7Hz,2H),4.11-4.07(m,1H),3.87–3.74(m,3H),3.70–3.60(m,3H),3.55(t,J＝6.3Hz,1H),3.38(t,J＝8.6Hz,2H),2.13-2.03(m,5H).LC-MS:[M+H] +＝426.2。
实施例56：化合物ZB-EED-15的合成
Figure PCTCN2019074755-appb-000084
将实施例54中制备的化合物ZB-EED-13(25.0mg)溶于DCM(5mL)中，0℃下加 入三乙胺(40mg),随后滴加丙酰氯(6.0mg溶于1mL DCM中)，反应液保持在0℃搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-15。LC-MS:[M+H] +＝440.2。
实施例57：化合物ZB-EED-16的合成
Figure PCTCN2019074755-appb-000085
将实施例54中制备的化合物ZB-EED-13(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(40mg),随后滴加异丁酰氯(7.0mg溶于1mL DCM中)，反应液保持在0℃搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-16。LC-MS:[M+H] +＝454.2。
实施例58：化合物ZB-EED-17的合成
Figure PCTCN2019074755-appb-000086
将实施例54中制备的化合物ZB-EED-13(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(40mg),随后滴加环丙基甲酰氯(7.0mg溶于1mL DCM中)，反应液保持在0℃搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-17。LC-MS:[M+H] +＝452.2。
实施例59：化合物ZB-EED-18的合成
Figure PCTCN2019074755-appb-000087
将实施例54中制备的化合物ZB-EED-13(25.0mg)溶于DCM(5mL)中，0℃下加 入三乙胺(40mg),随后滴加甲基磺酸酐(8mg)，反应液保持在室温搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-18。 1H NMR(400MHz,CDCl 3)δ8.71(s,1H),7.01(s,1H),6.85(m,1H),6.68(m,1H),5.20(m,1H),4.70(d,J＝5.5Hz,2H),4.64(t,J＝8.6Hz,2H),4.00(m,2H),3.78(m,2H),3.62(m,2H),3.48–3.35(m,4H),2.84(s,3H),2.18(m,2H).LC-MS:[M+H] +＝462.2。
实施例60：化合物ZB-EED-19的合成
Figure PCTCN2019074755-appb-000088
将实施例54中制备的化合物ZB-EED-13(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(40mg),随后滴加乙基磺酰氯(8.5mg溶于1mL DCM中)，反应液保持在0℃搅拌10分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-19。LC-MS:[M+H] +＝476.2。
实施例61：化合物ZB-EED-20的合成
Figure PCTCN2019074755-appb-000089
将实施例54中制备的化合物ZB-EED-13(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(40mg)，随后滴加氯甲酸甲酯(6mg溶于1mL DCM中)，反应液保持在0℃搅拌50分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-20。LC-MS:[M+H] +＝442.2。
实施例62：化合物ZB-EED-21的合成
Figure PCTCN2019074755-appb-000090
将实施例54中制备的化合物ZB-EED-13(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(40mg)，随后滴加氯甲酸乙酯(6.5mg溶于1mL DCM中)，反应液保持在0℃搅拌50分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-21。LC-MS:[M+H] +＝456.2。
实施例63：化合物ZB-EED-22的合成
Figure PCTCN2019074755-appb-000091
将实施例31中制备的化合物SL-ZYE-61-2(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(30mg),随后滴加氯甲酸甲酯(7.0mg溶于1mL DCM中)，反应液保持在0℃搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-22。LC-MS:[M+H] +＝454.2。
实施例64：化合物ZB-EED-23的合成
Figure PCTCN2019074755-appb-000092
将实施例31中制备的化合物SL-ZYE-61-2(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(30mg),随后滴加氯甲酸乙酯(7.0mg溶于1mL DCM中)，反应液保持在0℃搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-23。LC-MS:[M+H] +＝468.2。
实施例65：化合物ZB-EED-24的合成
Figure PCTCN2019074755-appb-000093
将实施例31中制备的化合物SL-ZYE-61-2(25.0mg)溶于DCM(5mL)中，加入三乙胺(20mg),随后滴加异氰酸乙酯(7mg)，反应液保持在室温搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-24。LC-MS:[M+H] +＝467.2。
实施例66：化合物ZB-EED-25的合成
Figure PCTCN2019074755-appb-000094
将实施例7中制备的化合物SL-ZYE-58(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(100mg),随后滴加氯甲酸甲酯(7mg溶于1mL DCM中)，反应液保持在0℃搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-25。LC-MS:[M+H] +＝428.2。
实施例67：化合物ZB-EED-26的合成
Figure PCTCN2019074755-appb-000095
将实施例7中制备的化合物SL-ZYE-58(25.0mg)溶于DCM(5mL)中，0℃下加入三乙胺(100mg),随后滴加氯甲酸乙酯(7mg溶于1mL DCM中)，反应液保持在0℃搅拌30分钟，加水淬灭，二氯甲烷萃取，食盐水洗，干燥浓缩，经柱层析分离得到产物ZB-EED-26。LC-MS:[M+H] +＝442.2。
实验实施例：多梳抑制复合物2(PRC2)酶活性测定实验
利用Cisbio公司的均相时间分辨荧光(HTRF)技术检测不同浓度的小分子化合物对PRC2酶活性的影响，并用GraphPad Prism 5.0软件拟合计算出化合物的IC 50值(最高抑 制浓度的50％)。PRC2酶(购自Cisbio公司，HMT-25-114)催化辅因子S-腺苷甲硫氨酸(SAM)(购自Sigma公司，A4377)和组蛋白多肽H3(21-44)(苏州强耀生物科技有限公司，序列为N-C：ATKAARKSAPATGGVKKPHRYRPGGK(Biotin)，纯度≥95％)反应产生组蛋白H3第27位赖氨酸残基的甲基化(H3K27me1/2/3)。Anti-H3K27me2抗体(购自Cell Singaling Technology公司，9728S)能够特异性识别并结合甲基化的组蛋白H3多肽产物。购自Cisbio公司的供体ProteinA-Eu Cryptate(Cat#61PRAKLA)和受体Streptavidin-XL665(Cat#610SAXLA)分别特异性识别并结合anti-H3K27me2抗体和组蛋白H3多肽C端标记的生物素，导致供体和受体上的Eu Cryptate铕穴状化合物和XL665染料距离接近10nm以内。在激发光激发下，供体上的Eu Cryptate被激发产生615nm的发射光，通过能量共振转移，进而激发受体上的XL665染料产生665nm的发射光。双发射光的比值Em665/615与PRC2酶催化产生的甲基化组蛋白H3多肽呈正相关关系，即Em665/615的高低反应了PRC2的酶活性水平。
在本实验中，测试体系为20μL，其中酶反应体积为10μL，检测反应体积为10μL。在酶反应体系中，首先需要将4mM或400μM化合物在DMSO中2倍梯度稀释成16种不同的浓度，然后将化合物在缓冲液1(20mM HEPES pH8.0，150mM NaCl，1mM DTT)中稀释50倍，再将化合物以2.5μL/孔转移到384孔板中(OptiPlate-384，购自PerkinElmer公司，6007299)；后面的试剂全部由缓冲液2(20mM HEPES pH8.0，150mM NaCl，0.01％Triton X-100，0.1％BSA(w/v，购自Sigma公司)，1mM DTT)稀释；384孔板中加入5μL/孔5ng/μL的PRC2酶，与化合物在室温孵育30分钟；加入2.5μL/孔的底物混合液(12μM SAM和2μM组蛋白H3多肽)，启动酶催化反应，在室温孵育4小时。在检测反应体系中，首先在384孔反应板中每孔加入5μL含有200μM S-腺苷同型半胱氨酸(SAH)、1000倍稀释的抗体和100倍稀释的受体的混合液，室温孵育15分钟，然后每孔加入5μL含有1.6M氟化钾KF和100倍稀释的供体的混合液，室温孵育30分钟。将384孔板放入多功能酶标仪EnVision(PerkinElmer)读取荧光信号值。用GraphPad Prism5.0软件分析数据，获得IC 50值。
表1中所述化合物可由上述实施例所述方法制备而成，EED226为阳性化合物(Nat.Chem.Biol.2017,13,381–388)。
化合物 酶活IC 50(μM) 化合物 酶活IC 50(μM)
SL-ZYE-31 0.029 SL-ZYE-35 0.101
SL-ZYE-02 0.018 SL-ZYE-58 0.012
SL-ZYE-37 0.581 SL-ZYE-36 0.003
SL-ZYE-01 0.006 SL-ZYE-32 0.026
SL-ZYE-03 0.025 SL-ZYE-33 0.014
SL-ZYE-39 0.013 SL-ZYE-40 0.010
SL-ZYE-42 0.016 SL-ZYE-45 0.027
SL-ZYE-48 0.010 SL-ZYE-50 0.007
SL-ZYE-44 0.070 SL-ZYE-49 0.065
SL-ZYE-51 0.069 SL-ZYE-47 0.031
SL-ZYE-41 0.163 SL-ZYE-56 0.079
SL-ZYE-57 0.070 SL-ZYE-66 0.003
SL-ZYE-64 0.018 SL-ZYE-65 0.004
SL-ZYE-62 0.004 SL-ZYE-61 0.019
SL-ZYE-63 0.040 SL-ZYE-71 0.152
SL-ZYE-88 0.100 SL-ZYE-136 0.031
SL-ZYE-137 0.021 SL-ZYE-89 0.123
SL-ZYE-64-2 0.112 ZB-EED-10 0.006
ZB-EED-11 0.007 ZB-EED-06 0.02
ZB-EED-09 0.006 ZB-EED-08 <0.01
ZB-EED-22 0.010 ZB-EED-24 0.010
ZB-EED-07 <0.01 ZB-EED-14 <0.02
EED226 0.058 ZB-EED-18 <0.02
实施例：细胞长时生长抑制实验
人弥漫性大B细胞淋巴瘤(DLBCL)细胞株SU-DHL-4(来自ATCC，CRL-2957)用含10％胎牛血清(Gibco，购自Life Technologies公司，10099-141)及1％抗生素(盘尼西林和链霉素，购自Life Technologies公司，10378016)的RPMI 1640培养基(Gibco，购自Life Technologies公司，22400-089)于CO 2细胞培养箱(37℃，5％CO 2)中培养。在细胞长时生长抑制实验中，将指数生长期的SU-DHL-4细胞铺种在24孔板(购自Corning公司，3524)中，体积为1mL/孔，细胞密度为1*10E5个细胞/孔。细胞种板后置于CO 2培养箱中静置培养1小时。在含有细胞的24孔板中加入不同浓度的3倍梯度稀释的化合物，化合物的终浓度范围为0.03nM至20μM。在化合物处理4、7和11天时，更换新鲜的培养基和化合物，将DMSO对照孔的细胞密度稀释到1*10E5个细胞/孔，其他化合物孔的细胞稀释比例与DMSO对照孔相同。使用CellTiter-Glo试剂(购自Promega公司，G7572)测定细胞存活率：将化合物处理4、7、11和14天的细胞按40μL/孔转移到白色384孔板(OptiPlate-384,购自PerkinElmer公司，6007299)中，再加入等体积的CellTiter-Glo试剂。在室温孵育10分钟后用多功能酶标仪EnVision(购自PerkinElmer公司)在400～700nm波长下检测冷发光信号。用GraphPad Prism 5.0软件分析数据，获得IC 50值。
化合物 细胞长时生长抑制实验(14天)IC 50(μM)
SL-ZYE-01 0.035
SL-ZYE-03 0.015
SL-ZYE-58 0.025
SL-ZYE-36 0.002
SL-ZYE-62 0.0005
EED226 0.2
根据以上实施例可以看出，根据本公开的化合物可以具有显著的抑制PRC2的活性，特别是其中SL-ZYE-01、SL-ZYE-36、SL-ZYE-40、SL-ZYE-50、SL-ZYE-62、SL-ZYE-65、SL-ZYE-66、ZB-EED-09、ZB-EED-10和ZB-EED-11等化合物的酶活IC50低于10nM， 具有特别优异的效果，且根据细胞长时生长抑制实验结果可以看出，该类化合物具有显著的抑制SU-DHL-4细胞的活性，特别是SL-ZYE-62与SL-ZYE-36具有非常强效的细胞活性，比阳性化合物的细胞活性提高了近100倍。

Claims (11)

  1. 一种由通式I表示的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体：
    Figure PCTCN2019074755-appb-100001
    1)
    Figure PCTCN2019074755-appb-100002
    为单键或双键；
    2)R 1、R 2及R 3各自独立地为氢、卤素、C 1-C 4烷基、C 1-C 4卤代烷基、-O-(C 1-C 4烷基)、C 1-C 4卤代烷氧基、或C 3-C 6环烷基；
    R 4各自独立地为氢、OH、＝O、或C 1-C 4烷基；
    R 5为氢、卤素或C 1-C 4烷基；
    3)A独立地指定为以下结构：
    Figure PCTCN2019074755-appb-100003
    Figure PCTCN2019074755-appb-100004
    Y为不存在、O、S(O) p、NR Y1、C＝O、C＝S、C(R Y2)R Y3；其中，
    R Y1为氢、CN、氧代、含0-2个R a取代的C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、-C(＝O)R b、-C(＝O)OR b、-C(＝S)R b、-C(＝S)OR b、-C(＝S)SR b、-C(＝O)SR b、-C(＝NH)SR b、-C(＝NH)OR b、-C(＝NH)R b、-S(＝O)R b、-S(＝O) 2R b、-S(＝O) 2NR bR c、-S(＝O) 2OR b、-C(＝O)NR bR c、-C(＝S)NR bR c、-C(＝NH)NR bR c；
    R Y2在每次出现时各自独立地为氢、CN、NO 2、卤素、SCF 3、含0-2个R a取代的C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a；
    R Y3在每次出现时各自独立地为氢、CN、NO 2、卤素、SCF 3、含0-2个R a取代的C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、-(OCH 2CH 2) mOR d、-(OCH 2CH 2) mNR bR c、-OC(＝O)R b、-OC(＝O)NR bR c、-OC(＝O)SR b、-SR d、-SC(＝O)R b、-SC(＝O)OR b、-SC(＝O)NR bR c、-S(＝O) 2R b、-S(＝O) 2NR bR c、-S(＝O) 2OR b、-S(＝O)R b、-N(R e)C(＝O)R b、-N(R e)C(＝O)OR b、-N(R e)C(＝O)NR bR c、-N(R e)C(＝O)SR b、-N(R e)C(＝S)R b、-N(R e)C(＝S)OR b、-N(R e)C(＝S)SR b、-N(R e)C(＝S)NR bR c、-N(R e)C(＝NH)R b、-N(R e)C(＝NH)OR b、-N(R e)C(＝NH)NR bR c、-N(R e)S(＝O) 2R b、-N(R e)S(＝O) 2OR b、-N(R e)S(＝O) 2NR bR c、-C(＝O)R b、-C(＝O)NR bR c、-C(＝O)OR b、-C(＝O)SR b、-C(＝S)R b、-C(＝S)NR bR c；
    或者，R Y2与R Y3彼此连接以形成-R Y2’-Z 2-R Y3’-并分别和与之相连的原子键结，其中Z 2为不存在、-O-、-S(O) p-、或者
    Figure PCTCN2019074755-appb-100005
    其中R w为氢、含0-2个R a取代的C 1-C 6烷基、G a、-C(＝O)R b1-、-C(＝O)OR b1、-NC(＝S)R b1、-C(＝S)OR b1、-C(＝S)SR b1、-C(＝O)SR b1、-C(＝NH)SR b1、-C(＝NH)OR b1、-C(＝NH)R b1、-S(＝O) 2R b1、-S(＝O) 2NR b1R c1、-C(＝O)NR b1R c1、-C(＝S)NR b1R c1、-C(＝NH)NR b1R c1；
    R b1与R c1在每次出现时各自独立地为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、或者被1-2个取代基取代的C 1-C 6烷基，所述取代基选自CN、SCF 3、-(OCH 2CH 2) mOR z1、-(OCH 2CH 2) mNR z1R z2、N(R z3)C(＝O)R z1、-N(R z3)C(＝O)OR z1、-N(R z3)C(＝O)NR z1R z2、-N(R z3)C(＝NH)NR z1R z2、-N(R z3)S(＝O) 2R z1、-N(R z3)S(＝O) 2NR z1R z2、-OC(＝O)NR z1R z2、-C(＝O)NR z1R z2、-S(＝O) 2R z1、-S(O) 2NR z1R z2、-S(＝O)R z1、C 1-C 6卤代烷基、和G b；
    其中，R Y2’和R Y3’在每次出现时各自独立地为不存在、C 1-C 3亚烷基、C 1-C 3卤代亚烷基、或者被1-2个取代基取代的C 1-C 3亚烷基；所述取代基选自CN、-(OCH 2CH 2) mOR z1、-(OCH 2CH 2) mNR z1R z2、N(R z3)C(＝O)R z1、-N(R z3)C(＝O)OR z1、-N(R z3)C(＝O)NR z1R z2、-N(R z3)C(＝NH)NR z1R z2、-N(R z3)S(＝O) 2R z1、-N(R z3)S(＝O) 2NR z1R z2、-OC(＝O)NR z1R z2、-C(＝O)NR z1R z2、-S(＝O) 2R z1、-S(O) 2NR z1R z2、C 1-C 3烷基、C 1-C 6卤代烷基、和G b；
    R a在每次出现时各自独立地为卤素、CN、SCF 3、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、-(OCH 2CH 2) mOR d、-(OCH 2CH 2) mNR bR c、-OC(＝O)R b、-OC(＝O)NR bR c、-OC(＝O)SR b、-SR d、-SC(＝O)R b、-SC(＝O)OR b、-SC(＝O)NR bR c、-S(＝O) 2R b、-S(＝O) 2NR bR c、-S(＝O) 2OR b、-S(＝O)R b、-N(R e)C(＝O)R b、-N(R e)C(＝O)OR b、-N(R e)C(＝O)NR bR c、-N(R e)C(＝O)SR b、-N(R e)C(＝S)R b、-N(R e)C(＝S)OR b、-N(R e)C(＝S)SR b、-N(R e)C(＝S)NR bR c、-N(R e)C(＝NH)R b、-N(R e)C(＝NH)OR b、-N(R e)C(＝NH)NR bR c、-N(R e)S(＝O) 2R b、-N(R e)S(＝O) 2OR b、-N(R e)S(＝O) 2NR bR c、-C(＝O)R b、-C(＝O)NR bR c、-C(＝O)OR b、-C(＝O)SR b、-C(＝S)R b、-C(＝S)NR bR c；
    R b、R c、R d及R e在每次出现时各自独立地为氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、或者被1-2个取代基取代的C 1-C 6烷基，所述取代基选自CN、SCF 3、-(OCH 2CH 2) mOR z1、-(OCH 2CH 2) mNR z1R z2、N(R z3)C(＝O)R z1、-N(R z3)C(＝O)OR z1、-N(R z3)C(＝O)NR z1R z2、-N(R z3)C(＝NH)NR z1R z2、-N(R z3)S(＝O) 2R z1、-N(R z3)S(＝O) 2NR z1R z2、-OC(＝O)NR z1R z2、-C(＝O)NR z1R z2、-S(＝O) 2R z1、-S(O) 2NR z1R z2、-S(＝O)R z1、C 1-C 6卤代烷基、和G b；
    R z1、R z2和R z3在每次出现时各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、或C 1-C 6卤代烷基；
    或者，R b与R c彼此连接以形成-R b’-Z 1-R c’-并分别和与之相连的原子键结，其中，所述-Z 1-为不存在、-O-、-S(O) p-、或者
    Figure PCTCN2019074755-appb-100006
    其中，R b’和R c’在每次出现时各自独立地为不存在、C 1-C 6亚烷基、C 1-C 3卤代亚烷基、或者被1-2个取代基取代的C 1-C 6亚烷基；所述取代基选自CN、-(OCH 2CH 2) mOR z1、-(OCH 2CH 2) mNR z1R z2、N(R z3)C(＝O)R z1、-N(R z3)C(＝O)OR z1、-N(R z3)C(＝O)NR z1R z2、-N(R z3)C(＝NH)NR z1R z2、-N(R z3)S(＝O) 2R z1、-N(R z3)S(＝O) 2NR z1R z2、-OC(＝O)NR z1R z2、-C(＝O)NR z1R z2、-S(＝O) 2R z1、-S(O) 2NR z1R z2、C 1-C 3烷基、C 1-C 6卤代烷基、和G b；
    G a和G b在每次出现时各自独立地为C6-C10芳基、5-10元杂芳基、3-9元非芳族杂环基、C3-C8环烷基、或C5-C8环烯基，并且其各自独立地为未取代的或被1、2、3、4、或5个R v取代；
    R v在每次出现时各自独立地为C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、C 1-C 6卤代烷基、NO 2、CN、SCF 3、氧代、-OR h、-OC(＝O)R i、-OC(＝O)NR jR k、-SR h、-S(＝O) 2R h、-S(＝O) 2NR jR k、-C(＝O)R h、-C(＝O)OR h、-C(＝O)NR jR k、-NR jR k、-N(R h)C(＝O)R i、-N(R h)S(＝O) 2R i、-N(R h)C(＝O)OR i、-N(R h)C(＝O)NR jR k、-(C 1-C 6亚烷基)-OR h、-(C 1-C 6亚烷基)-OC(＝O)R i、-(C 1-C 6亚烷基)-OC(＝O)NR jR k、-(C 1-C 6亚烷基)-S(＝O) 2R h、-(C 1-C 6亚烷基)-S(＝O) 2NR jR k、-(C 1-C 6亚烷基)-C(＝O)R h、-(C 1-C 6亚烷基)-C(＝O)OR h、-(C 1-C 6亚烷基)-C(＝O)NR jR k、-(C 1-C 6亚烷基)-NR jR k、-(C 1-C 6亚烷基)-N(R h)C(＝O)R i、-(C 1-C 6亚烷基)-N(R h)S(＝O) 2R i、-(C 1-C 6亚烷基)-N(R h)C(＝O)OR i、-(C 1-C 6亚烷基)-N(R h)C(＝O)NR jR k、或-(C 1-C 6亚烷基)-CN；
    R h、R j、R k在每次出现时各自独立地为氢、C 1-C 6烷基、或C 1-C 6卤代烷基；和R i在每次出现时独立地为C 1-C 6烷基、或C 1-C 6卤代烷基，
    n各自独立地为0、1、或2；
    p各自独立地为0、1、或2；
    m各自独立地为0、1、2、3、或4；
    q各自独立地为0、1、2、或3；
    3a)当A为
    Figure PCTCN2019074755-appb-100007
    时，
    R 1A及R 1B、R 2A及R 2B、R 3A及R 3B、R 4A及R 4B在每次出现时各自独立地为氢、羟基、卤素、CN、NO 2、C 1-C 6烷基、C 1-C 6卤代烷基、G a；
    或者，R 1A与R 1B、R 2A与R 2B和与之连接的碳原子形成羰基(＝O)或硫羰基(＝S)；
    或者，同碳上的取代基R 1A与R 1B、R 2A与R 2B、R 3A与R 3B以及R 4A与R 4B彼此连接以形成-R 1A’-Z 2-R 1B’-、-R 2A’-Z 2-R 2B’-、-R 3A’-Z 2-R 3B’-、-R 4A’-Z 2-R 4B’-并分别和与之相连的原子键结形成一个螺环，其中Z 2为不存在、-O-、-S(O) p-、或者
    Figure PCTCN2019074755-appb-100008
    或者，不同碳上的取代基R 1A及R 2A、R 1A及R 3A、R 3A及R 4A彼此连接以形成-R 1A’-Z 3-R 2A’-、-R 1A’-Z 3-R 3A’-、-R 3A’-Z 3-R 4A’-并分别和与之相连的原子键结，其中Z 3为不存在、-O-、-S(O) p-、或者
    Figure PCTCN2019074755-appb-100009
    其中，所述R 1A’及R 1B’、R 2A’及R 2B’、R 3A’及R 3B’、R 4A’及R 4B’在每次出现时各自独立地为不存在、C 1-C 6亚烷基、C 1-C 6卤代亚烷基、或者被1-2个取代基取代的C 1-C 3亚烷基；所述取代基选自CN、卤素或者C 1-C 3烷基；
    3b)当A为
    Figure PCTCN2019074755-appb-100010
    时，
    R 1A及R 1B、R 4A及R 4B在每次出现时各自独立地为氢、羟基、卤素、CN、NO 2、C 1-C 6烷基、C 1-C 6卤代烷基、G a；
    或者，R 1A与R 1B和与之连接的碳原子形成羰基(＝O)或者硫羰基(＝S)；
    或者，同碳上的取代基R 1A与R 1B及R 4A与R 4B彼此连接以形成-R 1A’-Z 2-R 1B’-、-R 4A’-Z 2-R 4B’-并分别和与之相连的原子键结形成一个螺环，其中Z 2为不存在、-O-、-S(O) p-、或者
    Figure PCTCN2019074755-appb-100011
    其中，所述R 1A’及R 1B’、R 4A’及R 4B’在每次出现时各自独立地为不存在、C 1-C 6亚烷基、C 1-C 6卤代亚烷基、或者被1-2个取代基取代的C 1-C 3亚烷基；所述取代基选自CN、卤素或者C 1-C 3烷基；
    M 1为6-10元芳环、5-10元杂芳环、3-9元非芳族碳环、3-9元非芳族杂环，并且M 1为未取代的或被1或2个R 6取代；
    R 6在每次出现时各自独立地为C 1-C 6烷基、卤素、C 1-C 6卤代烷基、NO 2、CN、SCF 3、氧代、-OR h、-OC(＝O)NR jR k、-S(＝O) 2R h、-(C 1-C 6亚烷基)S(＝O) 2R h、-S(＝O) 2NR jR k、-C(＝O)R h、-C(＝O)OR h、-C(＝O)NR jR k、-NR jR k、-N(R h)C(＝O)R i、-N(R h)S(＝O) 2R i、-N(R h)C(＝O)OR i、-N(R h)C(＝O)NR jR k；
    3c)当A为
    Figure PCTCN2019074755-appb-100012
    时，
    X为C、CH或者N
    R 2A及R 2B、R 3A及R 3B、R 4A及R 4B在每次出现时各自独立地为氢、羟基、卤素、CN、NO 2、C 1-C 6烷基、C 1-C 6卤代烷基、G a；
    或者，R 2A与R 2B和与之连接的碳原子形成羰基(＝O)或者硫羰基(＝S)；
    M 2为6-10元芳环、5-10元杂芳环、3-9元非芳族碳环、3-9元非芳族杂环，并且M 2为未取代的或被1或2个R 6取代；
    R 6在每次出现时各自独立地为C 1-C 6烷基、卤素、C 1-C 6卤代烷基、NO 2、CN、SCF 3、氧代、-OR h、-OC(＝O)NR jR k、-S(＝O) 2R h、-(C 1-C 6亚烷基)S(＝O) 2R h、-S(＝O) 2NR jR k、-C(＝O)R h、-C(＝O)OR h、-C(＝O)NR jR k、-NR jR k、-N(R h)C(＝O)R i、-N(R h)S(＝O) 2R i、-N(R h)C(＝O)OR i、-N(R h)C(＝O)NR jR k。
  2. 根据权利要求1所述的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体，其中，
    所述通式I所述的化合物具有式Ia-1、Ia-2或Ia-3：
    Figure PCTCN2019074755-appb-100013
    其中，
    Figure PCTCN2019074755-appb-100014
    为单键或双键；
    所述X、M 1、M 2、R 1、R 2、R 3、R 4、R 5、R 6、R 1A、R 1B、R 2A、R 2B、R 3A、R 3B、R 4A、R 4B和n、m、q的定义与权利要求1中所述的相同，且所述Y为不存在、O、S(O) p、NR Y1、C(R Y2)R Y3；
    R Y1为氢、CN、氧代、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、G a、-C(＝O)R b、-C(＝O)OR b、-C(＝S)R b、-C(＝S)OR b、-C(＝S)SR b、-C(＝O)SR b、-C(＝NH)SR b、-C(＝NH)OR b、-C(＝NH)R b、-S(＝O)R b、-S(＝O) 2R b、-S(＝O) 2NR bR c、-S(＝O) 2OR b、-C(＝O)NR bR c、-C(＝S)NR bR c、-C(＝NH)NR bR c；
    R Y2在每次出现时各自独立地为氢、CN、NO 2、卤素、C 1-C 6烷基；
    R Y3在每次出现时各自独立地为氢、CN、NO 2、卤素、C 1-C 6烷基、G a、-C(＝O)OR b；-(OCH 2CH 2) mOR d、-(OCH 2CH 2) mNR bR c、-N(R e)C(＝O)R b、-N(R e)C(＝O)OR b、-N(R e)C(＝O)NR bR c、-N(R e)C(＝O)SR b、-N(R e)C(＝S)R b、-N(R e)C(＝S)OR b、-N(R e)C(＝S)SR b、-N(R e)C(＝S)NR bR c、-N(R e)C(＝NH)R b、-N(R e)C(＝NH)OR b、-N(R e)C(＝NH)NR bR c、-N(R e)S(＝O) 2R b、-N(R e)S(＝O) 2OR b、-N(R e)S(＝O) 2NR bR c；
    G a、p、R b、R c、R d、和R e的定义与权利要求1中所述的相同。
  3. 根据权利要求1所述的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体，其中，
    所述通式I所述的化合物具有式Ia-4
    Figure PCTCN2019074755-appb-100015
    其中，R 1为氢或F；
    m、q的定义与权利要求1相同，
    R 1A、R 1B、R 2A、R 2B、R 3A、R 3B、R 4A或R 4B各自独立地为氢或者C 1-C 3烷基；
    或者，R 1A与R 1B、R 2A与R 2B和与之连接的碳原子形成羰基(＝O)、硫羰基(＝S)；
    或者，同碳上的取代基R 1A与R 1B、R 2A与R 2B、R 3A与R 3B以及R 4A与R 4B彼此连接以形成-R 1A’-Z 2-R 1B’-、-R 2A’-Z 2-R 2B’-、-R 3A’-Z 2-R 3B’-、-R 4A’-Z 2-R 4B’-并分别和与之相连的原子键结形成一个螺环，其中Z 2为不存在、-O-；
    或者，不同碳上的取代基R 1A及R 2A、R 1A及R 3A、R 3A及R 4A彼此连接以形成-R 1A’-Z 3-R 2A’-、-R 1A’-Z 3-R 3A’-、-R 3A’-Z 3-R 4A’-并分别和与之相连的原子键结，其中Z 3为不存在、或者-O-，
    其中，所述R 1A’及R 1B’、R 2A’及R 2B’、R 3A’及R 3B’、R 4A’及R 4B’在每次出现时各自独立地为不存在、C 1-C 3亚烷基；
    所述Y为O、S(O) p、NR Y1；
    R Y1为氢、CN、氧代、C 1-C 6烷基、G a、-C(＝O)R b、-C(＝O)OR b、-C(＝S)R b、-S(＝O) 2R b、-S(＝O) 2NR bR c、-C(＝O)NR bR c、-C(＝NH)NR bR c；
    G a、p、R b和R c的定义与权利要求1中所述的相同。
  4. 根据权利要求1所述的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体，其中，
    所述通式I所述的化合物具有式Ia-5
    Figure PCTCN2019074755-appb-100016
    其中，R 1为氢或F；
    R 6各自独立地为卤素；
    R 1A、R 1B各自独立地为氢或者C 1-C 3烷基；或者R 1A、R 1B彼此连接并和与之相连的碳形成3至6元饱和环烷烃螺环；
    M 1、n、q的定义与权利要求1相同，
    所述Y为O、S(O) p、NR Y1；
    R Y1为氢、CN、氧代、C 1-C 6烷基、G a、-C(＝O)R b、-C(＝O)OR b、-C(＝S)R b、-S(＝O) 2R b、-S(＝O) 2NR bR c、-C(＝O)NR bR c、-C(＝NH)NR bR c；
    G a、p、R b和R c的定义与权利要求1中所述的相同。
  5. 根据权利要求1所述的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体，其中，
    所述通式I所述的化合物具有式Ia-6、Ia-7、Ia-8、或者Ia-9
    Figure PCTCN2019074755-appb-100017
    其中，R 1为氢或F；R 6各自独立地为卤素；
    M 1为苯环或者吡啶环；
    q各自独立地为1或者2；n各自独立地为0、1、或2；
    R 1A、R 1B各自独立地为氢或者C 1-C 3烷基；或者R 1A、R 1B彼此连接并和与之相连的碳形成3至6元饱和环烷烃螺环；
    R 2A、R 2B各自独立地为氢或者C 1-C 3烷基；或者R 2A、R 2B彼此连接并和与之相连的碳形成3至6元饱和环烷烃螺环；
    Y为O、S(O) 2、或者NR Y1；R Y1为氢、CN、C 1-C 3烷基、环丙基、-C(＝S)R b、-C(＝O)R b、-C(＝O)OR b、-S(＝O) 2R b、-C(＝O)NR bR c、-C(＝NH)NR bR c、-S(＝O) 2NR bR c；R b和R c的定义与权利要求1相同。
  6. 根据权利要求1所述的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体，其中，
    所述通式I所述的化合物具有式Ia-10、Ia-11、Ia-12或者Ia-13，
    Figure PCTCN2019074755-appb-100018
    R 6各自独立地为卤素；
    M 1为苯环或者吡啶环；
    q各自独立地为1或者2；n各自独立地为0、1、或2；
    R 1A、R 1B各自独立地为氢或者甲基；或者R 1A、R 1B彼此连接并和与之相连的碳形成环丙螺环；
    R 2A、R 2B各自独立地为氢或者甲基；或者R 2A、R 2B彼此连接并和与之相连的碳形成环丙螺环；
    Y为O、S(O) 2、或者NR Y1；R Y1为氢、CN、C 1-C 3烷基、环丙基、-C(＝O)R b、-C(＝O)OR b、-S(＝O) 2R b、-C(＝O)NHR b；R b为氢、甲基、乙基、异丙基或者环丙基。
  7. 一种化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体，其中
    所述的化合物选自如下化合物：
    Figure PCTCN2019074755-appb-100019
    Figure PCTCN2019074755-appb-100020
    Figure PCTCN2019074755-appb-100021
    Figure PCTCN2019074755-appb-100022
  8. 一种药物组合物，其包含根据权利要求1-7中任一项所述的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体中的一种或多种，以及至少一种药学上可接受的载体、稀释剂或赋形剂。
  9. 根据权利要求8所述的药物组合物，其中
    所述药物组合物进一步包含至少一种其他治疗剂，
    优选地，所述药物组合物中包含的所述至少一种其他治疗剂选自其他抗癌剂、免疫调节剂、抗过敏剂、止吐剂、疼痛缓解剂、细胞保护剂及其组合。
  10. 根据权利要求1-7中任一项所述的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体或根据权利要求8所述的药物组合物在制备用于治疗由EED和/或PRC2介导的疾病或病症的药物中的用途。
  11. 根据权利要求10所述的用途，其中
    所述由EED和/或PRC2介导的疾病或病症包括弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、其他淋巴瘤、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、肝细胞癌、前列腺癌、乳腺癌、胆管及胆囊癌、膀胱癌；脑瘤、包括神经母细胞瘤、神经鞘瘤、神经胶质瘤、神经胶质母细胞瘤及星细胞瘤；子宫颈癌、结肠癌、黑色素瘤、子宫内膜癌、食道癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾细胞癌、直肠癌、甲状腺癌、副甲状腺肿瘤、子宫肿瘤及软组织肉瘤。
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