WO2019062435A1 - Use of triazolopyrimidine, triazolopyridine compounds and composition thereof for treating prc2-mediated diseases - Google Patents

Use of triazolopyrimidine, triazolopyridine compounds and composition thereof for treating prc2-mediated diseases Download PDF

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Publication number
WO2019062435A1
WO2019062435A1 PCT/CN2018/102833 CN2018102833W WO2019062435A1 WO 2019062435 A1 WO2019062435 A1 WO 2019062435A1 CN 2018102833 W CN2018102833 W CN 2018102833W WO 2019062435 A1 WO2019062435 A1 WO 2019062435A1
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alkyl
group
independently selected
compound
substituted
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PCT/CN2018/102833
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French (fr)
Chinese (zh)
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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
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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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Priority claimed from CN201711408714.6A external-priority patent/CN109575013A/en
Application filed by 中国科学院上海药物研究所, 苏州苏领生物医药有限公司 filed Critical 中国科学院上海药物研究所
Priority to EP18860160.3A priority Critical patent/EP3689875B1/en
Priority to CN201880002779.7A priority patent/CN109843890B/en
Priority to JP2020529171A priority patent/JP6876875B2/en
Priority to US16/651,510 priority patent/US11013745B2/en
Publication of WO2019062435A1 publication Critical patent/WO2019062435A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61K31/535—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
    • A61K31/54—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
    • 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

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and generally relates to a class of triazolopyrimidine, triazolopyridine compounds and pharmaceutical compositions thereof 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 2016/0176682, 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.
  • the present invention relates to a triazolopyrimidine, triazolopyridine compound of the formula I and combinations thereof, and for binding activity evaluation and related biological experiments, which can be used for the preparation of the treatment by EED and/or Or a drug that is mediated by PRC2.
  • 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 EED and/or 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.
  • X 1 is independently selected from N and C-CN;
  • R 2 is independently selected from the group consisting of H, halogen, C 1 -C 4 haloalkyl and C 1 -C 4 alkyl;
  • A is independently selected from the following structures:
  • R 3 , R 4 and R 5 are independently selected from H, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-(C 1 -C 4 alkyl), C 1 -C 4 Haloalkoxy, C 3 -C 6 cycloalkyl;
  • R 7 is independently selected from the group consisting of H, OH, halogen, CN, and C 1 -C 4 alkyl;
  • n are each independently selected from 0, 1 and 2;
  • X 2 is independently selected from the group consisting of O, NR a and S(O) p heteroatoms;
  • p are each independently selected from 0, 1 and 2;
  • R 1 is independently selected from the following structures:
  • p are each independently selected from 0, 1 and 2;
  • p are each independently selected from 0, 1 and 2;
  • p are each independently selected from 0, 1 and 2;
  • R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
  • An alkyl group, -C( O)H, an aryl group, a 5- to 6-membered heteroaryl group containing a carbon atom and 1 to 2 heteroatoms selected from N, O and S; wherein the aryl group and the
  • R f is independently selected from a C 3 -C 8 cyclic alkyl group, a heteroalkyl group containing a carbon atom and 1 to 4 heteroatoms selected from O, N, S(O) p , an aryl group, and a heteroaryl group comprising a carbon atom and 1 to 2 hetero atoms selected from the group consisting of N, NR a , O and S(O) p ; wherein the aryl group and the heteroaryl group are substituted by 0-2 R 1X ;
  • M is independently selected from a 3 to 7 membered saturated or unsaturated cycloalkyl group, a heterocycloalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, and the like a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms;
  • R 1A in the section 4a corresponds to the corresponding definition in R 1A in the section 4a);
  • n are each independently selected from 0, 1 and 2;
  • n are each independently selected from 0-4;
  • p are each independently selected from 0-2;
  • q are each independently selected from 0-3;
  • z are each independently selected from 0 and 1;
  • R 1 is independently selected from the following structures: among them
  • R c is independently selected from OH, halogen, CN, C 1 -C 6 alkyl, carboxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
  • R c is independently selected from OH, halogen, CN, C 1 -C 6 alkyl, carboxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
  • M is independently selected from a 3 to 7 membered saturated or unsaturated cycloalkyl group, a heterocycloalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, and the like a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms;
  • n are each independently selected from 0, 1 and 2;
  • n are each independently selected from 0-4;
  • p are each independently selected from 0-2;
  • q are each independently selected from 0-3;
  • z are each independently selected from 0 and 1;
  • R 1A is independently selected from H, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
  • R 1B and R 1C , R 2B and R 2C , and R 3B and R 3C are independently selected from H, OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
  • R 1D is independently selected from H, -OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 - C 8 cyclic alkyl group;
  • M is independently selected from a 5- to 6-membered saturated or unsaturated cycloalkyl group, a heterocycloalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, and the like a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms;
  • n are each independently selected from 0, 1 and 2;
  • n are each independently selected from 0-4;
  • p are each independently selected from 0-2;
  • q are each independently selected from 0-3;
  • z are each independently selected from 0 and 1;
  • R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
  • R c as defined in the above defined 4a) of the same portion of R c;
  • R j and R k are independently selected from the group consisting of H, CN, C 1 -C 10 alkyl group having 0-3 R s substitutions, C 1 -C 6 haloalkyl group, C 3 -C 10 cyclic alkyl group, and a carbon atom and a heteroalkyl group and a heterocycloalkyl group selected from the group consisting of 1-4 selected from O, N, S(O) p heteroatoms, an alkenyl group or an alkynyl group substituted by R y a 6 to 10 membered aryl group, a carbon atom and 1 to 2 5- to 10-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl group and the heteroaryl group may be substituted by 0 to 2 R 1Y ;
  • R y is independently selected from H, C 3 -C 10 alkyl group having 0-3 R c substitutions, C 1 -C 6 haloalkyl group, C 3 -C 10 cyclic alkyl group, containing carbon atom and 1-4 a heteroalkyl group and a heterocycloalkyl group selected from the group consisting of O, N, S(O) p heteroatoms, NR d R e , OR d , aryl, containing carbon atoms and 1 to 2 selected from N, O and S a 5- to 6-membered heteroaryl group of a hetero atom; wherein the aryl group and the heteroaryl group are substituted by 0-2 R 1X ; R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1- C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alky
  • R c as defined in the above defined 4a) of the same portion of R c;
  • R i is independently selected from the group consisting of H, CN, C1-C4 alkyl
  • n are each independently selected from 0-4;
  • Y is independently selected from the group consisting of O, NR g , S(O) p , -CR i (CH 2 ) m NR g R h and -CR i (CH 2 ) m OR g ;
  • R j and R k are independently selected from H, CN, C 1 -C 10 alkyl substituted with 0-3 R s , C 1 -C 6 haloalkyl, C 3 -C 10 cyclic alkyl, containing carbon Atom and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S(O) p heteroatoms, C 2 -C 10 alkenyl or alkynyl, 6 to 10 membered aryl, containing carbon atoms And 1 to 2 5- to 10-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl and heteroaryl groups may be substituted by 0-2 R 1Y ;
  • p are each independently selected from 0, 1 and 2;
  • R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
  • R 1Y is independently selected from C 1 -C 10 alkyl, halogen, CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
  • p are each independently 0, 1 and 2;
  • R c as defined in the above defined 4a) of the same portion of R c;
  • p are each independently selected from 0, 1 and 2;
  • R i is independently selected from the group consisting of H, CN, and C 1 -C 4 alkyl;
  • n are each independently selected from 0-4;
  • Y is independently selected from the group consisting of O, NR g , S, -CR i NR g R h and -CR i OR g ;
  • R j and R k are independently selected from H, CN, C 1 -C 10 alkyl substituted with 0-3 R s , C 1 -C 6 haloalkyl, C 3 -C 10 cyclic alkyl, containing carbon Atom and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S heteroatoms, C 2 -C 10 alkenyl or alkynyl, 6 to 10 membered aryl, containing carbon atoms and 1 to 2 a 5- to 10-membered heteroaryl group selected from the group consisting of N, O and S heteroatoms; wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1Y ;
  • R s is independently selected from OH, CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl, -(OCH 2 CH 2 ) m OR d , (OCH 2 CH 2 ) m NR d R e , a heteroalkyl group containing a carbon atom and 1 to 2 heteroatoms selected from N, O and S And a heterocycloalkyl group, an aryl group, and a heteroaryl group containing a carbon atom and 1 to 2 hetero atoms selected from N, O and S, wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1Y ;
  • R d, R e and defined in the above 4b) portion R d, R e is the same as defined;
  • R 1Y is independently selected from C 1 -C 10 alkyl, halogen, CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
  • R c as defined in the above defined 4a) of the same portion of R c;
  • p are each independently selected from 0, 1 and 2;
  • R i is independently selected from the group consisting of H, CN, and C 1 -C 4 alkyl;
  • n are each independently selected from 0-4;
  • the compound of formula I has the formula Ia-1 or Ia-2:
  • R 1A , R 1B and R 1C , R 2B and R 2C , R 3B and R 3C , R 1D , n, m, q, Y, M are the same as corresponding definitions in part 4) of formula I ;
  • the compound of formula I has formula Ia-3 or Ia-4:
  • R 1A , R 1B and R 1C , R 2B and R 2C , R 3B and R 3C , R 1D , n, m, q, Y, M are the same as corresponding definitions in part 4) of formula I ;
  • the compound of formula I has formula Ia-5 or Ia-6:
  • the compound of formula I has formula Ia-7 or Ia-8:
  • R g is the same as the corresponding definition in the 4b) part of the 4) part of the formula I;
  • the compound of formula I has formula Ia-9:
  • R g is the same as the corresponding definition in the 4b) part of the 4) part of the formula I;
  • the compound of formula I has one of the following structural formulae:
  • R g is the same as the corresponding definition in the 4b) part of the 4) part of the formula I;
  • the compound of formula I is selected from the group consisting of:
  • the compound further includes stereoisomers, tautomers, atropisomers, isotopically labeled compounds (including hydrazine substituted), medically acceptable salts, polymorphs, solvents
  • the composition can be used to treat a disease or condition mediated by EED and/or PRC2.
  • the method comprises the following steps:
  • compound 12 is subjected to a Suzuki coupling reaction with various types of boronic acid having an R 1 group or its equivalent under the action of a palladium catalyst to obtain a product 13.
  • the amines described in Schemes 1 and 2 can be prepared by the preparation of US2016/0176682A1 (for example, the preparation of A1 in the following reaction formula), or purchased by a reagent company (the following reaction formula, indole A2, purchased from BEHRINGER TECHNOLOGY CO., LTD.
  • the boric acid or its equivalent B can be purchased from a reagent company or prepared according to conventional literature.
  • a reagent or compound having an Rg group such as, but not limited to, an acid anhydride, a sulfonic acid anhydride, an isocyanate, a thioisocyanate, an acid chloride Sulfonyl chloride, carbonate, chloroformate, carbamate, etc., such as, but not limited to, triethylamine, diisopropylethylamine, DMAP, potassium carbonate, sodium hydroxide, potassium hydroxide, Potassium tert-butoxide, NaH, the organic solvent such as, but not limited to, dichloromethane, tetrahydrofuran, acetonitrile, 1,4-dioxane,
  • a reagent or compound having an Rg group such as, but not limited to, an acid anhydride, a sulfonic acid anhydride, an isocyanate, a thioisocyanate, an acid chloride Sulfonyl chloride, carbonate,
  • A, X 1 , R g , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m have the same meanings as defined above.
  • the product 15 obtained by removing the protecting group in the step (3a) of the scheme 3 is condensed with a carboxylic acid having a R j group by a condensing agent to obtain an amide compound 17, for example, but not Limited to carbonyl diimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriene Oxazole, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N' -tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N' , N'
  • (7a) 20 is oxidized with mCPBA or hydrogen peroxide to give compound 23.
  • reaction 15 reduction of a double bond (such as, but not limited to, under hydrogenation reduction conditions) to give 24, followed by reaction with a reagent or compound bearing an Rg group in the presence of a base to give 25, such as but not limited to Anhydride, sulfonic anhydride, isocyanate, thioisocyanate, acid chloride, sulfonyl chloride, carbonate, chloroformate, carbamate, such as, but not limited to, triethylamine, diisopropylethylamine, DMAP, Potassium carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide, NaH, the reaction can be carried out in an organic solvent such as, but not limited to, dichloromethane, tetrahydrofuran, acetonitrile, 1,4-dioxane Hexacyclic ring; or 24 may also be condensed with various carboxylic acids in the presence of a condensing agent to give an amide compound
  • the method comprises the following steps:
  • (3a) 14' is removed from the Boc protecting group by trifluoroacetic acid using dichloromethane as a solvent to give the amine compound 15'.
  • X 1 and Y are the same as defined above.
  • the above-mentioned compounds 14, 14', 18, 18' and 20 can be obtained by a Suzuki reaction according to the step (1d) or the step (2g) in the first or second embodiment.
  • optically active forms of the compounds of the invention are desired, they can be obtained using optically active starting materials, or by resolution of compounds or intermediates using standard procedures known to those skilled in the art, such as separation by chiral chromatography columns. A mixture of stereoisomers is obtained.
  • a pure geometric isomer of a compound of the invention when desired, it can be obtained by using pure geometric isomers as starting materials, or by geometrical isomerization of compounds or intermediates by standard procedures, such as chromatographic separation. The body mixture is obtained.
  • a pharmaceutical composition comprising a triazolopyrimidine, a triazolopyridine compound as described above, a pharmaceutically acceptable salt thereof, an enantiomer, and a non- One or more of the enantiomers or racemates.
  • the pharmaceutical composition further comprises at least one other therapeutic agent.
  • the at least one additional therapeutic agent included in the pharmaceutical composition is selected from the group consisting of other anticancer agents, immunomodulators, anti-allergic agents, antiemetics, pain relieving agents, cytoprotective agents, and combinations thereof.
  • the pharmaceutical composition comprises at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient,
  • the disease or condition comprises diffuse large B-cell lymphoma, follicular lymphoma, other lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate Cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, including neuroblastoma, schwannomas, glioma, glioblastoma and astrocytoma; cervical cancer, colon cancer, melanin Tumor, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma.
  • brain tumors including neuroblastoma, schwannomas, glioma, glioblastoma and astrocytoma
  • cervical cancer
  • a method of treating a disease or condition mediated by EED and/or PRC2 comprising
  • a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof is provided to a subject in need thereof.
  • the disease or condition is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, other lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, Prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, including neuroblastoma, schwannomas, glioma, glioblastoma 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, parathyroid tumor, uterine tumor and soft tissue sarcoma.
  • diffuse large B-cell lymphoma follicular lymphoma, other lymphoma
  • leukemia multiple myel
  • Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-1 (84 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-2 (90 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-3 (123 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-1 (84 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and borate B-2 (90 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-3 (123 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-4 (83 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-5 (102 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-6 (129 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-7 (137 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-3 (62 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-3 (123 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • the bromine 13-2 (63 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and borate B-3 (123 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • the bromine 13-1 (77 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-1 (84 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 13-1 (77 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-3 (123 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-8 (89 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Example 56 Synthesis of Compound SL-ZYE-08, SL-ZYE-08-S, SL-ZYE-08-R
  • SL-ZYE-08 can be further separated by chiral column to obtain a pair of optically pure compounds SL-ZYE-08-S and SL-ZYE-08-R.
  • the chiral column separation method is a conventional method known to those skilled in the art.
  • Bromine 4-4 (69 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-1 (84 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • the bromide 4-5 (68mg, 0.2mmol) was dissolved in 6 mL 1,4-dioxane and 2mL of concentration of Na 2M 2 CO 3 solution was added boric acid ester B-1 (84mg, 0.4mmol) , Ar substitution protection, stirring at room temperature for 10 minutes.
  • the bromide 4-5 (68mg, 0.2mmol) was dissolved in 6 mL 1,4-dioxane and 2mL of concentration of Na 2M 2 CO 3 solution was added boric acid ester B-3 (123mg, 0.4mmol) , Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-10 (101 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-11 (95 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • the bromo 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-12 (103 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • SL-E2 was isolated by chiral chromatography to obtain optically pure compounds SL-E2-S and SL-E2-R.
  • SL-E12 (10 mg) was dissolved in 1 mL of dichloromethane and 0.1 mL of triethylamine (TEA), dissolved by stirring, and methanesulfonic anhydride (Ms 2 O, 8 mg) was added at room temperature for 1 hour, and TLC showed the reaction was completed.
  • TAA triethylamine
  • Ms 2 O methanesulfonic anhydride
  • the bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-14 (44 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • the bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and borate B-15 (47 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • SL-E29 (10 mg) was dissolved in 1 mL of dichloromethane and 0.1 mL of triethylamine (TEA), dissolved by stirring, and acetic anhydride (Ac 2 O, 8 mg) was added at room temperature for 1 hour, and TLC showed the reaction was completed.
  • SL-E29 (10 mg) was dissolved in 1 mL of dichloromethane and 0.1 mL of triethylamine (TEA), dissolved by stirring, and methanesulfonic anhydride (Ms 2 O, 7 mg) was added at room temperature for 1 hour, and TLC showed the reaction was completed.
  • TAA triethylamine
  • Ms 2 O methanesulfonic anhydride
  • SL-E43 was separated by chiral chromatography to obtain optically pure compounds SL-E43-S and SL-E43-R.
  • Example 110 Synthesis of Compound SL-E44, SL-E44-S, SL-E44-R
  • SL-E44 was isolated by chiral chromatography to obtain optically pure compounds SL-E44-S and SL-E44-R.
  • Example 111 Synthesis of Compound SL-E45, SL-E45-S, SL-E45-R
  • SL-E45 was separated by chiral chromatography to obtain optically pure compounds SL-E45-S and SL-E45-R.
  • Example 112 Synthesis of Compound SL-E46, SL-E46-S, SL-E46-R
  • SL-E46 was separated by chiral column to obtain optically pure compounds SL-E46-S and SL-E46-R.
  • SL-E47 was separated by chiral column to obtain optically pure compounds SL-E47-S and SL-E47-R.
  • SL-E48 was separated by chiral column to obtain optically pure compounds SL-E48-S and SL-E48-R.
  • SL-E49 was separated by chiral column to obtain optically pure compounds SL-E49-S and SL-E49-R.
  • SL-E50 was separated by chiral chromatography to obtain optically pure compounds SL-E50-S and SL-E50-R.
  • SL-E51 was separated by chiral chromatography to obtain optically pure compounds SL-E51-S and SL-E51-R.
  • SL-E52 was separated by chiral chromatography to obtain optically pure compounds SL-E52-S and SL-E52-R.
  • the bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and the boronic acid ester SL-B3 (48 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol) was kept at 90 ° C for 40 minutes under Ar protection.
  • the bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate SL-B4 (48 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes.
  • SL-ZYE-119 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-ZYE-121 (4 mg).
  • 1 H NMR 400MHz, DMSO- d 6) ⁇ 9.32 (s, 1H), 8.32 (s, 1H), 7.38 (m, 1H), 6.85 (m, 1H), 6.62 (m, 1H), 4.56- 4.47 (m, 4H), 3.68 (m, 2H), 3.20 (m, 3H), 1.70 (m, 4H), 1.09 (m, 6H).
  • LC-MS: [M+H] + 398.2.
  • the bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and the boronic acid ester SL-B5 (50 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol) was kept at 90 ° C for 40 minutes under the protection of Ar.
  • the bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and the boronic acid ester SL-B6 (49 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol) was kept at 90 ° C for 40 minutes under the protection of Ar.
  • the bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and the boronic acid ester SL-B7 (49 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol) was kept at 90 ° C for 40 minutes under the protection of Ar. After cooling, it was concentrated under reduced pressure and purified by column chromatography to give the title compound SL-ZYE-197 (4.1. Mg).
  • SL-E12 (30 mg) was dissolved in 3 mL of dichloromethane and 0.1 mL of triethylamine (TEA), dissolved by stirring, and methyl chloroformate (15 mg) was added at room temperature to continue the reaction. TLC showed the end of the reaction, directly by column chromatography. Separation and preparation gave the title compound SL-ZYE-183 (5 mg).
  • the activity of the PRC2 enzyme was detected using the TR-FRET method.
  • the enzyme was mixed with different concentrations of the compound and incubated for 30 minutes at room temperature.
  • the biotinylated histone H3 polypeptide substrate and the cofactor S-adenosylmethionine (SAM) were added to initiate the enzymatic reaction.
  • SAM cofactor S-adenosylmethionine
  • the receptor Acceptor and donor Donor were added and incubated for half an hour. Fluorescence signals were detected using a multi-function microplate reader EnVision (Perkin Elmer). Data was analyzed using GraphPad Prism 5.0 software, the value of 50 obtained IC.
  • Example 135 Cell growth inhibition test (11 days)
  • Pfeiffer cells in the exponential growth phase were seeded in 24-well plates at a cell density of 1*10E5 cells/mL. Cells were treated with different concentrations of compounds on the day. Fresh medium and compound were replaced at 4 and 7 days of compound treatment. After 11 days of compound treatment, cell viability was measured using CellTiter-Glo reagent (Promega). Data was analyzed using GraphPad Prism 5.0 software, get 50 values GI.
  • Example 136 Long-term growth inhibition test of pfeiffer cells (14 days)
  • DLBCL Human diffuse large B-cell lymphoma (DLBCL) cell line pfeiffer (from ATCC, CRL-2632) containing 10% fetal bovine serum (Gibco, purchased from Life Technologies, 10099-141) and 1% antibiotic (penicillin and chain) RPMI 1640 medium (Gibco, available from Life Technologies, Inc., 22400-089) purchased from Life Technologies, Inc., 10378016) was cultured in a CO 2 cell incubator (37 ° C, 5% CO 2 ).
  • pfeiffer cells of exponential growth phase were plated in a 24-well plate (purchased from Corning, 3524) in a volume of 1 mL/well and a cell density of 2*10E5 cells/mL. The cells were seeded and placed in a CO 2 incubator for 1 hour. 2 ⁇ L of 9 different concentrations of 3-fold gradient dilutions of compound or DMSO were added to each well in a 24-well plate containing cells at a final concentration ranging from 0.003 to 20 ⁇ M or 0.3 to 2000 nM with a final concentration of 0.2% DMSO.
  • Example 137 Long-term growth inhibition test of cells Karpas-422 and SU-DHL-4 (11 days)
  • DLBCL Human diffuse large B-cell lymphoma (DLBCL) cell lines Karpas-422, SU-DHL-4 (ATCC, CRL-2957) containing 10% fetal bovine serum (Gibco, purchased from Life Technologies, 10099-141) and 1% antibiotic (penicillin and streptomycin, purchased from Life Technologies, 10378016) in RPMI 1640 medium (Gibco, purchased from Life Technologies, Inc., 22400-089) in a CO 2 cell incubator (37 ° C, 5% CO 2 ) ) cultured.
  • RPMI 1640 medium Gibco, purchased from Life Technologies, Inc., 22400-089
  • CO 2 cell incubator 37 ° C, 5% CO 2
  • the cell culture medium volume was 1 mL. After the cells were cultured for 1 hour in a 24-well plate, 2 ⁇ L of the compound or DMSO was added to each well. Each compound has 9 different concentrations, with a final concentration in the cell culture medium ranging from 0.003 to 20 [mu]M or 0.3 to 2000 nM and a final concentration of 0.2% DMSO. At 4 and 7 days of compound treatment, fresh cell culture medium and compound were replaced, and the cell density of the DMSO control well was diluted to 1*10E5/mL, and the cell dilution ratio of the compound well was the same as that of the DMSO control well.
  • Cell viability was determined using CellTiter-Glo reagent (purchased from Promega, G7572): cells treated with compound for 11 days were transferred to a white 384-well plate (OptiPlate-384, available from PerkinElmer, 6007299) at 40 ⁇ L/well. Add an equal volume of CellTiter-Glo reagent. After incubation for 10 minutes at room temperature, 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 IC 50 value of the partial compound of the present invention to the PRC2 enzyme can be up to nM order, which is significantly higher than that of the positive control group EED226 compound; similarly, for Pfeiffer, Karpas-422 and In the SU-DHL-4 cell long-term growth inhibition experiment, the IC 50 values of the various compounds of the present invention also reached the single digit nM order of magnitude, which was significantly higher than the positive control group EED226 compound.
  • test animals were healthy adult male SD rats, 3 in each group, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.
  • Rats were administered EED226, E-Y1, E-Y13, E-Y47, and SL-ZYE-07 by intragastric administration (3mg/kg) at 0.25, 0.5, 1, 2, 4, 8 after administration. 45 ⁇ L of blood was taken from the femoral vein for 24 hours, centrifuged in a heparinized centrifuge tube for 5 min, and plasma samples were separated for analysis. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the plasma of rats after intragastric administration. The content of the test compound.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • AUC last AUC from the time of administration to the last time
  • AUC INF_obs AUC from the time of administration to the time when the theoretical extrapolation is infinitely long
  • the compounds of the present invention have good pharmacological absorption and have obvious pharmacokinetic advantages.
  • Example 139 Liver microsome stability test (mouse, rat, human):
  • Tris pH 7.4 buffer (0.1 M) was prepared: 12.12 g of Tris was dissolved in 1000 mL of H 2 O, adjusted to pH 7.4 with 2N HCl, dispensed at 50 mL/tube, and frozen at -20 °C.
  • VIVID stock solution Dissolve 1 mg of VIVID in 1 mL of acetonitrile, dispense 50 ⁇ L/tube, and store at -20 °C.
  • MgCl 2 solution 100 mM: 1.016 g of MgCl 2 was dissolved in 50 mL of Tris pH 7.4 buffer, dispensed in 1 mL/tube, and frozen at -20 °C.
  • NADPH solution (10 mM): 355 mg of NADPH was dissolved in 42.6 mL of Tris pH 7.4 buffer, dispensed at 1.8 mL/tube, and frozen at -20 °C.
  • Dilution Step 3 Take 245 ⁇ L of working solution into a 96-well compound plate and add 5 ⁇ L of VIVID stock solution.
  • the 96-well compound plate was placed on an shaker for 5 minutes.
  • the logarithm of the residual rate of the drug in the incubation system was plotted against the incubation time, and linear regression was performed to obtain the slope k.
  • the intrinsic clearance rate (Clint, mL/min/g) and the in vivo clearance rate (Cl, mL) were estimated according to the following formula. /min), liver clearance (Clhep, mL/min), metabolic bioavailability (%MF):
  • the compounds of the present invention have good stability in liver microsomes of human, rat and mouse, and have obvious advantages.

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Abstract

Provided in the present invention are a compound represented by general formula I, a pharmaceutically acceptable salt, enantiomer, diastereoisomer or racemate thereof, a preparation method therefor, a pharmaceutical composition containing same, and a use of same in the preparation of drugs for treating diseases or conditions mediated by EED and/or PRC2. The compound of the present invention can be used for treating PRC2-mediated diseases or conditions. (I)

Description

三氮唑并嘧啶、三氮唑并吡啶化合物及其组合物用于治疗PRC2介导的疾病Triazolopyrimidine, triazolopyridine compounds and combinations thereof for the treatment of PRC2-mediated diseases 技术领域Technical field
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、三氮唑并吡啶化合物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。The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and generally relates to a class of triazolopyrimidine, triazolopyridine compounds and pharmaceutical compositions thereof and their use in the treatment of neoplastic diseases. In particular, such compounds may be useful in the manufacture of a medicament for the treatment of a disease or condition mediated by PRC2.
背景技术Background technique
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 2016/0176682，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。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. Thus, EZH2, EED and SUZ12 are considered to be core components of the PRC2 complex. Recent studies have found that the core component of PRC2 is overexpressed in a variety of tumor cells, and its abnormal activity is the direct cause of the onset and deterioration of various malignant tumors. At the same time, recent gene sequencing results in lymphoma patients indicate that EZH2 has an activating mutation in the germinal center B-cell lymphoma (GCB-DLBCL), and the mutant EZH2 changes the substrate specificity of PRC2, thereby increasing H3K27me3 in the cell. Level. Down-regulation of EZH2 or other core components by siRNA methods will significantly inhibit lymphoma cell proliferation, suggesting that the development of GCB-DLBCL is closely related to the overactivation of PRC2. Therefore, 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. Recently, two major pharmaceutical companies, Novartis and Abbott, have invented a small molecule that inhibits PRC2 activity by targeting EED (Reference: Novartis EED226, US 2016/0176682, 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. In summary, 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.
发明内容Summary of the invention
本发明的涉及一种如通式I所示三氮唑并嘧啶、三氮唑并吡啶化合物及其组合物，并且结合活性评价和相关生物学实验，可以用于制备用以治疗由EED及/或PRC2介导的疾病或病症的药物。The present invention relates to a triazolopyrimidine, triazolopyridine compound of the formula I and combinations thereof, and for binding activity evaluation and related biological experiments, which can be used for the preparation of the treatment by EED and/or Or a drug that is mediated by PRC2.
本发明的一个目的是提供一类三氮唑并嘧啶、三氮唑并吡啶化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体。It is an object of the present invention to provide a class of triazolopyrimidine, triazolopyridine compounds, pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof.
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。Another object of the present invention is to provide a process for the preparation of the above compounds.
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。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.
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EED和/或PRC2介导的疾病或病症的药物中的用途。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 EED and/or PRC2.
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。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.
具体地，根据本发明的一个方面，其提供了一种通式I的化合物：In particular, according to one aspect of the invention, there is provided a compound of formula I:
Figure PCTCN2018102833-appb-000001
Figure PCTCN2018102833-appb-000001
其中among them
1)X 1独立地选自N及C-CN； 1) X 1 is independently selected from N and C-CN;
2)R 2独立地选自H、卤素、C 1-C 4卤代烷基及C 1-C 4烷基； 2) R 2 is independently selected from the group consisting of H, halogen, C 1 -C 4 haloalkyl and C 1 -C 4 alkyl;
3)A独立地选自以下结构：
Figure PCTCN2018102833-appb-000002
3) A is independently selected from the following structures:
Figure PCTCN2018102833-appb-000002
Figure PCTCN2018102833-appb-000003
为单键或双键；
Figure PCTCN2018102833-appb-000003
For single or double keys;
R 3、R 4及R 5独立地选自H、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、C 3-C 6环烷基； R 3 , R 4 and R 5 are independently selected from H, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-(C 1 -C 4 alkyl), C 1 -C 4 Haloalkoxy, C 3 -C 6 cycloalkyl;
R 6独立地选自H、OH、＝O及C 1-C 4烷基； R 6 is independently selected from the group consisting of H, OH, =0, and C 1 -C 4 alkyl;
R 7独立地选自H、OH、卤素、CN及C 1-C 4烷基； R 7 is independently selected from the group consisting of H, OH, halogen, CN, and C 1 -C 4 alkyl;
n各自独立地选自0，1及2；n are each independently selected from 0, 1 and 2;
X 2独立地选自O、NR a及S(O) p杂原子； X 2 is independently selected from the group consisting of O, NR a and S(O) p heteroatoms;
每一R a独立地选自H、O、由0-2个R b取代的C 1-C 10烷基、C 1-C 6卤代烷基、-O-(C 1-C 6烷基)、C 1-C 6卤代烷氧基、C 3-C 6环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； Each R a is independently selected from H, O, C 1 -C 10 alkyl substituted by 0-2 R b , C 1 -C 6 haloalkyl, -O-(C 1 -C 6 alkyl), C 1 -C 6 haloalkoxy, C 3 -C 6 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), containing carbon Atom and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S(O) p heteroatoms, -C(=O)H, aryl, containing carbon atoms and 1 to 2 selected from a 5 to 6 membered heteroaryl group of N, O and S heteroatoms;
R b独立地选自卤素、OH、NH 2、NHC(＝O)(C 1-C 4烷基)、NHS(＝O) 2(C 1-C 4烷基)、＝O、CN、C 1-C 4烷基及C 1-C 4烷氧基； R b is independently selected from the group consisting of halogen, OH, NH 2 , NHC(=O)(C 1 -C 4 alkyl), NHS(=O) 2 (C 1 -C 4 alkyl), =0, CN, C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
4)R 1独立地选自以下结构：
Figure PCTCN2018102833-appb-000004
4) R 1 is independently selected from the following structures:
Figure PCTCN2018102833-appb-000004
Figure PCTCN2018102833-appb-000005
为单键或双键；
Figure PCTCN2018102833-appb-000005
For single or double keys;
4a)R 1A独立地选自H、羟基、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、氨基、C 1-C 6直链、支链以及环状的烷氨基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子和1至2个选自N、O及S杂原子的5至6元杂芳基；其中该芳基以及杂芳基可由0-2个R 1X取代； 4a) R 1A is independently selected from H, hydroxy, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 alkane a group, -C(=O)NH(C 1 -C 4 alkyl), an amino group, a C 1 -C 6 straight chain, a branched chain, and a cyclic alkylamino group, containing a carbon atom and 1-4 selected from O Heteroalkyl and heterocycloalkyl of N,S(O) p heteroatoms, -C(=O)H, aryl, containing carbon atoms and 1 to 2 heteroatoms selected from N, O and S a 6-membered heteroaryl; wherein the aryl and heteroaryl are substituted by 0-2 R 1X ;
p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
R c独立地选自OH、卤素、CN、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基、-(OCH 2CH 2) mOR d、NHC(＝O)NR dR e、NHC(＝S)NR dR e、-NHC(＝NH)NR dR e、(OCH 2CH 2) mNR dR e、-C(＝O)R d、-S(＝O)R d、-C(＝O)NR dR e、-S(＝O) 2R d、-NHC(＝O)R d、-NHC(＝S)R d、-NHS(＝O) 2R d、-S(＝O) 2NHR d、包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂烷基和杂环烷基、芳基以及包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂芳基、其中该芳基以及杂芳基可由0-2个R 1X取代； R c is independently selected from OH, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl, -(OCH 2 CH 2 ) m OR d , NHC(=O)NR d R e , NHC(=S)NR d R e , -NHC(=NH)NR d R e , (OCH 2 CH 2 ) m NR d R e , -C(=O)R d , -S(=O)R d , -C(=O)NR d R e , -S(=O) 2 R d ,- NHC (= O) R d, -NHC (= S) R d, -NHS (= O) 2 R d, -S (= O) 2 NHR d, comprising carbon atoms and 1 to 2 heteroatoms selected from N, NR a heteroalkyl and heterocycloalkyl group of a , O and S(O) p heteroatoms, an aryl group, and a heteroatom comprising a carbon atom and 1 to 2 heteroatoms selected from the group consisting of N, NR a , O and S(O) p heteroatoms An aryl group wherein the aryl group and the heteroaryl group are substituted by 0-2 R 1X ;
R d及R e独立地选自H、含0-2个R b取代的C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 6环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、含0-2个O、N、S(O) p杂原子的支链或环状的C 1-C 6杂烷基、-C(＝O)H、芳基及包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂芳基，其中该芳基以及杂芳基可由0-2个R 1X取代； R d and R e are independently selected from H, C 2 -C 6 alkyl substituted with 0-2 R b , C 1 -C 6 haloalkyl, C 3 -C 6 cyclic alkyl, -C(= O) (C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl), containing 0-2 O, N a branched or cyclic C 1 -C 6 heteroalkyl group of a S(O) p hetero atom, -C(=O)H, an aryl group, and a carbon atom and 1 to 2 selected from N, NR a , a heteroaryl group of O and S(O) p heteroatoms, wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1X ;
R a独立地选自H、O、由0-2个R b取代的C 1-C 10烷基、C 1-C 6卤代烷基、-O-(C 1-C 6烷基)、C 1-C 6卤代烷氧基、C 3-C 6环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； R a is independently selected from H, O, C 1 -C 10 alkyl substituted by 0-2 R b , C 1 -C 6 haloalkyl, -O-(C 1 -C 6 alkyl), C 1 -C 6 haloalkoxy, C 3 -C 6 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), containing carbon atoms and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S(O) p heteroatoms, -C(=O)H, aryl, containing carbon atoms and 1 to 2 selected from N, 5- to 6-membered heteroaryl groups of O and S heteroatoms;
R b独立地选自卤素、OH、NH 2、-NHC(＝O)(C 1-C 4烷基)、-NHS(＝O) 2(C 1-C 4烷基)、＝O、CN、C 1-C 4烷基及C 1-C 4烷氧基； R b is independently selected from the group consisting of halogen, OH, NH 2 , -NHC(=O)(C 1 -C 4 alkyl), -NHS(=O) 2 (C 1 -C 4 alkyl), =O, CN , C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
R d与R e可通过R d——R e或
Figure PCTCN2018102833-appb-000006
的方式连接，其中Z 1可选自含0-2个R b取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6杂烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)C 1-C 6烷基、-NS(＝O) 2(C 1-C 6烷基)、S(O) p；R b独立地选自卤素、OH、NH 2、-NHC(＝O)(C 1-C 4烷基)、-NHS(＝O) 2(C 1-C 4烷基)、＝O、CN、C 1-C 4烷基及C 1-C 4烷氧基；p各自独立地选自0，1及2； R d and R e may pass R d ——R e or
Figure PCTCN2018102833-appb-000006
Is connected, wherein Z 1 optionally containing from 0-2 R b substituted by C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p hetero atoms 1 -C 6 heteroalkyl Alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)C 1 -C 6 alkyl, -NS(=O) 2 (C 1 -C 6 alkyl ), S(O) p ; R b is independently selected from halogen, OH, NH 2 , -NHC(=O)(C 1 -C 4 alkyl), -NHS(=O) 2 (C 1 -C 4 Alkyl), =O, CN, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; p are each independently selected from 0, 1 and 2;
R 1X独立地选自卤素、OH、CN、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 3-C 8环状烷基和环状杂烷基； R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
R 1B及R 1C独立地选自H、OH、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子和1至2个选自N、O及S杂原子的5至6元杂芳基；其中该芳基以及杂芳基可由0-2个R 1X取代；p各自独立地 为0，1及2； R 1B and R 1C are independently selected from H, OH, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl groups), C 1 -C 6 alkyl group, C 1- C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 Alkyl), -C(=O)NH(C 1 -C 4 alkyl), heteroalkyl and heterocycloalkane containing carbon atoms and from 1 to 4 heteroatoms selected from O, N, S(O) p a group, -C(=O)H, an aryl group, a 5- to 6-membered heteroaryl group containing a carbon atom and 1 to 2 heteroatoms selected from N, O and S; wherein the aryl group and the heteroaryl group may be 0- 2 R 1X substituted; p are each independently 0, 1 and 2;
R 2B及R 2C独立地选自H、OH、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基；其中该芳基以及杂芳基可由0-2个R 1X取代；p各自独立地选自0，1及2； R 2B and R 2C are independently selected from H, OH, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl groups), C 1 -C 6 alkyl group, C 1- C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 Alkyl), -C(=O)NH(C 1 -C 4 alkyl), heteroalkyl and heterocycloalkane containing carbon atoms and from 1 to 4 heteroatoms selected from O, N, S(O) p a group, -C(=O)H, an aryl group, a 5- to 6-membered heteroaryl group containing a carbon atom and 1 to 2 heteroatoms selected from N, O and S; wherein the aryl group and the heteroaryl group may be 0- 2 R 1X substituted; p are each independently selected from 0, 1 and 2;
R 3B及R 3C独立地选自H、-OH、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基；其中该芳基以及杂芳基可由0-2个R 1X取代；p各自独立地选自0，1及2； R 3B and R 3C are independently selected from H, -OH, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl), heteroalkyl and heterocyclic ring containing carbon atoms and 1 to 4 heteroatoms selected from O, N, S(O) p An alkyl group, -C(=O)H, an aryl group, a 5- to 6-membered heteroaryl group containing a carbon atom and 1 to 2 heteroatoms selected from N, O and S; wherein the aryl group and the heteroaryl group are 0 - 2 R 1X substitutions; p are each independently selected from 0, 1 and 2;
或者，R 1B与R 1C、R 2B与R 2C、R 3B与R 3C可和与之连接的碳原子形成羰基(＝O)或者硫羰基(＝S)； Alternatively, R 1B and R 1C , R 2B and R 2C , R 3B and R 3C may form a carbonyl group (=O) or a thiocarbonyl group (=S) with a carbon atom to which they are attached;
R 1D独立地选自H、-OH、卤素、CN、-C(＝O)H、-(O) z-(包含0-2个R c取代C 1-C 6烷基)、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、R f、-OR f、-C(＝O)R c、NR dR e、-C(＝O)NR dR e、-NHC(＝O)R c、-S(＝O) 2R c、-S(＝O) 2NR dR e、-NHS(＝O) 2R d、-(OCH 2CH 2) mOR d、-(OCH 2CH 2) mNR dR e； R 1D is independently selected from H, -OH, halogen, CN, -C(=O)H, -(O) z - (containing 0-2 R c substituted C 1 -C 6 alkyl groups), C 1 - C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , R f , —OR f , —C(=O)R c , NR d R e , —C(=O)NR d R e , NHC(=O)R c , -S(=O) 2 R c , -S(=O) 2 NR d R e , -NHS(=O) 2 R d , -(OCH 2 CH 2 ) m OR d , -(OCH 2 CH 2 ) m NR d R e ;
R f独立地选自C 3-C 8环状烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、芳基及包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂芳基；其中，芳基及杂芳基由0-2个R 1X取代； R f is independently selected from a C 3 -C 8 cyclic alkyl group, a heteroalkyl group containing a carbon atom and 1 to 4 heteroatoms selected from O, N, S(O) p , an aryl group, and a heteroaryl group comprising a carbon atom and 1 to 2 hetero atoms selected from the group consisting of N, NR a , O and S(O) p ; wherein the aryl group and the heteroaryl group are substituted by 0-2 R 1X ;
M独立地选自3至7元饱和的或不饱和的环烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂环烷基、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； M is independently selected from a 3 to 7 membered saturated or unsaturated cycloalkyl group, a heterocycloalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, and the like a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms;
在R 1B及R 1C、R 2B及R 2C、R 3B及R 3C、R 1D以及R f的定义中，R a、R c、R d、R e、p、z、m、R 1X的定义与在4a)部分中的R 1A中的相应的定义相同； Definitions of R a , R c , R d , R e , p, z, m, R 1X in the definitions of R 1B and R 1C , R 2B and R 2C , R 3B and R 3C , R 1D and R f . Corresponding to the corresponding definition in R 1A in the section 4a);
n各自独立地选自0，1及2；n are each independently selected from 0, 1 and 2;
m各自独立地选自0-4；m are each independently selected from 0-4;
p各自独立地选自0-2；p are each independently selected from 0-2;
q各自独立地选自0-3；q are each independently selected from 0-3;
z各自独立地选自0和1；z are each independently selected from 0 and 1;
4a’)优选地，R 1独立地选自以下结构：
Figure PCTCN2018102833-appb-000007
其中 4a') Preferably, R 1 is independently selected from the following structures:
Figure PCTCN2018102833-appb-000007
among them
Figure PCTCN2018102833-appb-000008
为单键或双键；
Figure PCTCN2018102833-appb-000008
For single or double keys;
R 1A独立地选自H、羟基、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、-C(＝O)H； R 1A is independently selected from H, hydroxy, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl) , -C(=O)NH(C 1 -C 4 alkyl), -C(=O)H;
R c独立地选自OH、卤素、CN、C 1-C 6烷基、羧基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R c is independently selected from OH, halogen, CN, C 1 -C 6 alkyl, carboxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
R 1B及R 1C、R 2B及R 2C、以及R 3B及R 3C独立地选自H、OH、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)； R 1B and R 1C , R 2B and R 2C , and R 3B and R 3C are independently selected from H, OH, halogen, CN, -(O) z - (including 0-2 R c substituted C 1 -C 10 Alkyl), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl , -C(=O)(C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl);
或者，R 1B与R 1C、R 2B与R 2C、R 3B与R 3C可和与之连接的碳原子形成羰基(＝O)或者硫羰基(＝S)； Alternatively, R 1B and R 1C , R 2B and R 2C , R 3B and R 3C may form a carbonyl group (=O) or a thiocarbonyl group (=S) with a carbon atom to which they are attached;
R 1D独立地选自H、-OH、卤素、CN、-C(＝O)H、-(O) z-(包含0-2个R c取代C 1-C 6烷基)、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基； R 1D is independently selected from H, -OH, halogen, CN, -C(=O)H, -(O) z - (containing 0-2 R c substituted C 1 -C 6 alkyl groups), C 1 - C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl;
R c独立地选自OH，卤素、CN、C 1-C 6烷基、羧基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R c is independently selected from OH, halogen, CN, C 1 -C 6 alkyl, carboxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
M独立地选自3至7元饱和的或不饱和的环烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂环烷基、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； M is independently selected from a 3 to 7 membered saturated or unsaturated cycloalkyl group, a heterocycloalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, and the like a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms;
n各自独立地选自0，1及2；n are each independently selected from 0, 1 and 2;
m各自独立地选自0-4；m are each independently selected from 0-4;
p各自独立地选自0-2；p are each independently selected from 0-2;
q各自独立地选自0-3；q are each independently selected from 0-3;
z各自独立地选自0和1；z are each independently selected from 0 and 1;
4a”)更优选地，在R 1中， 4a") More preferably, in R 1 ,
R 1A独立地选自H、羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R 1A is independently selected from H, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
R 1B及R 1C、R 2B及R 2C、以及R 3B及R 3C独立地选自H、OH、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R 1B and R 1C , R 2B and R 2C , and R 3B and R 3C are independently selected from H, OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
或者，R 1B与R 1C、R 2B与R 2C、R 3B与R 3C可和与之连接的碳原子形成羰基(＝O)或者硫羰基(＝S)； Alternatively, R 1B and R 1C , R 2B and R 2C , R 3B and R 3C may form a carbonyl group (=O) or a thiocarbonyl group (=S) with a carbon atom to which they are attached;
R 1D独立地选自H、-OH、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R 1D is independently selected from H, -OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 - C 8 cyclic alkyl group;
M独立地选自5至6元饱和的或不饱和的环烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂环烷基、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； M is independently selected from a 5- to 6-membered saturated or unsaturated cycloalkyl group, a heterocycloalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, and the like a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms;
n各自独立地选自0，1及2；n are each independently selected from 0, 1 and 2;
m各自独立地选自0-4；m are each independently selected from 0-4;
p各自独立地选自0-2；p are each independently selected from 0-2;
q各自独立地选自0-3；q are each independently selected from 0-3;
z各自独立地选自0和1；z are each independently selected from 0 and 1;
4b)Y独立地选自O、NR g、S(O) p等杂原子以及CH 2、C＝O、-CR i(CH 2) mNR gR h以及-CR i(CH 2) mOR g； 4b) Y is independently selected from heteroatoms such as O, NR g , S(O) p and CH 2 , C=O, -CR i (CH 2 ) m NR g R h and -CR i (CH 2 ) m OR g ;
R g及R h独立地选自H、O、含0-3个R s取代的C 1-C 10烷基、C 1-C 6卤代烷基、C 3-C 6环状烷基、
Figure PCTCN2018102833-appb-000009
Figure PCTCN2018102833-appb-000010
-C(＝S)NHC(＝O)-R j、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、芳基、包含碳原子和1至2个选自N、O及S杂原子的5至6元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1X取代； R g and R h are independently selected from H, O, C 1 -C 10 alkyl group substituted with 0-3 R s , C 1 -C 6 haloalkyl group, C 3 -C 6 cyclic alkyl group,
Figure PCTCN2018102833-appb-000009
Figure PCTCN2018102833-appb-000010
-C(=S)NHC(=O)-R j , a heteroalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, including a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1X ;
R s独立地选自OH，CN、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基、-(OCH 2CH 2) mOR d、NHC(＝O)NR dR e、NHC(＝S)NR dR e、-NHC(＝NH)NR dR e、(OCH 2CH 2) mNR dR e、-C(＝O)R d、-C(＝S)R d、-S(＝O)R d、-C(＝O)NR dR e、-S(＝O) 2R d、-NHC(＝O)R d、-NHC(＝S)R d、-NHS(＝O) 2R d、-S(＝O) 2NR dR e、-NHS(＝O) 2NR dR e、-C(＝S)NR dR e、NHC(＝O)OR d、NHC(＝S)OR d、-NHS(＝O) 2OR d、NHC(＝O)SR d、NHC(＝S)SR d、-NHC(＝NH)OR d、-C(＝O)OR d、-C(＝O)SR d、-S(＝O) 2OR d、包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂烷基和杂环烷基、芳基以及包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂芳基、其中该芳基以及杂芳基可由0-2个R 1Y取代； R s is independently selected from OH, CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl, -(OCH 2 CH 2 ) m OR d , NHC(=O)NR d R e , NHC(=S)NR d R e , -NHC(=NH)NR d R e , (OCH 2 CH 2 ) m NR d R e , -C(=O)R d , -C(=S)R d , -S(=O)R d , -C(=O)NR d R e , -S (= O) 2 R d, -NHC (= O) R d, -NHC (= S) R d, -NHS (= O) 2 R d, -S (= O) 2 NR d R e, -NHS (=O) 2 NR d R e , -C(=S)NR d R e , NHC(=O)OR d , NHC(=S)OR d , -NHS(=O) 2 OR d , NHC(= O) SR d , NHC(=S)SR d , -NHC(=NH)OR d , -C(=O)OR d , -C(=O)SR d , -S(=O) 2 OR d , a heteroalkyl group and a heterocycloalkyl group containing a carbon atom and 1 to 2 hetero atoms selected from N, NR a , O and S(O) p , an aryl group, and a carbon atom and 1 to 2 selected from N, NR a heteroaryl group of a , O and S(O) p heteroatoms, wherein the aryl group and the heteroaryl group are substituted by 0-2 R 1Y ;
R d及R e独立地选自H、含0-2个R b取代的C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 6环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、含0-2个O、N、S(O) p杂原子的支链或环状的C 1-C 6杂烷基、-C(＝O)H、芳基及包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂芳基，其中该芳基以及杂芳基可由0-2个R 1X取代； R d and R e are independently selected from H, C 2 -C 6 alkyl substituted with 0-2 R b , C 1 -C 6 haloalkyl, C 3 -C 6 cyclic alkyl, -C(= O) (C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl), containing 0-2 O, N a branched or cyclic C 1 -C 6 heteroalkyl group of a S(O) p hetero atom, -C(=O)H, an aryl group, and a carbon atom and 1 to 2 selected from N, NR a , a heteroaryl group of O and S(O) p heteroatoms, wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1X ;
R d与R e可通过以下方式R d——R e或
Figure PCTCN2018102833-appb-000011
连接形成一个环，其中Z 1可选自含0-2个R b取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)C 1-C 6烷基、-NS(＝O) 2(C 1-C 6烷基)、S(O) p， R d and R e can be obtained by the following means R d - R e or
Figure PCTCN2018102833-appb-000011
Linked to form a ring, wherein Z 1 optionally containing from 0-2 R b substituted by C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p 1 -C 6 heteroatoms Alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)C 1 -C 6 alkyl, -NS(=O) 2 (C 1 -C 6 alkyl ), S(O) p ,
R a独立地选自H、O、由0-2个R b取代的C 1-C 10烷基、C 1-C 6卤代烷基、-O-(C 1-C 6烷基)、C 1-C 6卤代烷氧基、C 3-C 6环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； R a is independently selected from H, O, C 1 -C 10 alkyl substituted by 0-2 R b , C 1 -C 6 haloalkyl, -O-(C 1 -C 6 alkyl), C 1 -C 6 haloalkoxy, C 3 -C 6 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), containing carbon atoms and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S(O) p heteroatoms, -C(=O)H, aryl, containing carbon atoms and 1 to 2 selected from N, 5- to 6-membered heteroaryl groups of O and S heteroatoms;
R b独立地选自卤素、OH、NH 2、-NHC(＝O)(C 1-C 4烷基)、-NHS(＝O) 2(C 1-C 4烷基)、＝O、CN、C 1-C 4烷基及C 1-C 4烷氧基；p各自独立地选自0，1及2； R b is independently selected from the group consisting of halogen, OH, NH 2 , -NHC(=O)(C 1 -C 4 alkyl), -NHS(=O) 2 (C 1 -C 4 alkyl), =O, CN , C 1 -C 4 alkyl and C 1 -C 4 alkoxy; p are each independently selected from 0, 1 and 2;
R 1X独立地选自卤素、OH、CN、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 3-C 8环状烷基和环状杂烷基； R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
R 1Y独立地选自C 1-C 10烷基、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2 (C 1-C 4烷基)、NR dR e、-C(＝O)NR dR e、-S(＝O) 2R d、-NHC(＝O)R d、-NHC(＝S)R d、-NHS(＝O) 2R d、-NHC(＝O)NR dR e、-NHC(＝S)NR dR e、-NHS(＝O) 2NR dR e、-C(＝S)NR dR e、-S(＝O) 2NHR d、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、p各自独立地为0，1及2； R 1Y is independently selected from C 1 -C 10 alkyl, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl), C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl) , NR d R e , -C(=O)NR d R e , -S(=O) 2 R d , -NHC(=O)R d , -NHC(=S)R d , -NHS(=O 2 R d , -NHC(=O)NR d R e , -NHC(=S)NR d R e , -NHS(=O) 2 NR d R e , -C(=S)NR d R e , -S(=O) 2 NHR d , heteroalkyl and heterocycloalkyl containing carbon atoms and 1 to 4 heteroatoms selected from O, N, S(O) p , -C(=O)H, p Each is independently 0, 1 and 2;
其中，R c与在上述4a)部分中限定的R c的定义相同； Wherein, R c as defined in the above defined 4a) of the same portion of R c;
其中R d与R e可通过R d——R e或
Figure PCTCN2018102833-appb-000012
的方式连接，其中Z 1可选自含0-2个R b取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6杂烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)C 1-C 6烷基、-NS(＝O) 2(C 1-C 6烷基)、S(O) p， Where R d and R e may pass R d —R e or
Figure PCTCN2018102833-appb-000012
Is connected, wherein Z 1 optionally containing from 0-2 R b substituted by C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p hetero atoms 1 -C 6 heteroalkyl Alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)C 1 -C 6 alkyl, -NS(=O) 2 (C 1 -C 6 alkyl ), S(O) p ,
R b独立地选自卤素、OH、NH 2、-NHC(＝O)(C 1-C 4烷基)、-NHS(＝O) 2(C 1-C 4烷基)、＝O、CN、C 1-C 4烷基及C 1-C 4烷氧基；p各自独立地选自0，1及2； R b is independently selected from the group consisting of halogen, OH, NH 2 , -NHC(=O)(C 1 -C 4 alkyl), -NHS(=O) 2 (C 1 -C 4 alkyl), =O, CN , C 1 -C 4 alkyl and C 1 -C 4 alkoxy; p are each independently selected from 0, 1 and 2;
R j及R k独立地为选自H、CN、含0-3个R s取代的C 1-C 10烷基、C 1-C 6卤代烷基、C 3-C 10环状烷基、包含碳原子以及选自和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、由R y取代的烯基或者炔基
Figure PCTCN2018102833-appb-000013
6至10元芳基、包含碳原子及1至2个选自N、O及S杂原子的5至10元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1Y取代； R j and R k are independently selected from the group consisting of H, CN, C 1 -C 10 alkyl group having 0-3 R s substitutions, C 1 -C 6 haloalkyl group, C 3 -C 10 cyclic alkyl group, and a carbon atom and a heteroalkyl group and a heterocycloalkyl group selected from the group consisting of 1-4 selected from O, N, S(O) p heteroatoms, an alkenyl group or an alkynyl group substituted by R y
Figure PCTCN2018102833-appb-000013
a 6 to 10 membered aryl group, a carbon atom and 1 to 2 5- to 10-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl group and the heteroaryl group may be substituted by 0 to 2 R 1Y ;
其中，R 1Y与在本4b)部分中的上述R s中限定的R 1Y的定义相同； Wherein R 1Y the same as defined in the present 4b) in the above R s R 1Y defined portions;
R y独立地选自H、含0-3个R c取代的C 1-C 10烷基、C 1-C 6卤代烷基、C 3-C 10环状烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、NR dR e、OR d、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1X取代；R 1X独立地选自卤素、OH、CN、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 3-C 8环状烷基和环状杂烷基； R y is independently selected from H, C 3 -C 10 alkyl group having 0-3 R c substitutions, C 1 -C 6 haloalkyl group, C 3 -C 10 cyclic alkyl group, containing carbon atom and 1-4 a heteroalkyl group and a heterocycloalkyl group selected from the group consisting of O, N, S(O) p heteroatoms, NR d R e , OR d , aryl, containing carbon atoms and 1 to 2 selected from N, O and S a 5- to 6-membered heteroaryl group of a hetero atom; wherein the aryl group and the heteroaryl group are substituted by 0-2 R 1X ; R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1- C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
其中，R c与在上述4a)部分中限定的R c的定义相同；R d和R e与在本4b)部分中的上述R s中限定的R d和R e的定义相同； Wherein R c and defined the same as in the above 4a) defined portion R c; R d same as defined above and R s and R e in the present 4b) defining a portion of R d and R e of;
特别地，R g与R h以及R j及R k可通过以下方式R g——R h、
Figure PCTCN2018102833-appb-000014
R j——R k、
Figure PCTCN2018102833-appb-000015
连接，其中Z 1可选自含0-2个R c取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)C 1-C 6烷基、-NS(＝O) 2(C 1-C 6烷基)、S(O) p；p各自独立地选自0，1及2； In particular, R g and R h and R j and R k can be obtained by the following manner R g — R h ,
Figure PCTCN2018102833-appb-000014
R j - R k ,
Figure PCTCN2018102833-appb-000015
Connection, wherein Z 1 selected from the group comprising substituted with 0-2 R c C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p hetero atoms 1 -C 6 alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)C 1 -C 6 alkyl, -NS(=O) 2 (C 1 -C 6 alkyl), S (O) p ; p are each independently selected from 0, 1 and 2;
其中，R c与在上述4a)部分中限定的R c的定义相同； Wherein, R c as defined in the above defined 4a) of the same portion of R c;
R i独立地选自H、CN、C1-C4烷基； R i is independently selected from the group consisting of H, CN, C1-C4 alkyl;
m各自独立地选自0-4；m are each independently selected from 0-4;
4b’)优选地，Y独立地选自O、NR g、S(O) p、-CR i(CH 2) mNR gR h以及-CR i(CH 2) mOR g； 4b') Preferably, Y is independently selected from the group consisting of O, NR g , S(O) p , -CR i (CH 2 ) m NR g R h and -CR i (CH 2 ) m OR g ;
R g及R h独立地选自H、C 1-C 6卤代烷基、
Figure PCTCN2018102833-appb-000016
Figure PCTCN2018102833-appb-000017
-C(＝S)NHC(＝O)-R j、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、芳基、包含碳原子和1至2个选自N、O及S杂原子的5至6元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1X取代； R g and R h are independently selected from H, C 1 -C 6 haloalkyl,
Figure PCTCN2018102833-appb-000016
Figure PCTCN2018102833-appb-000017
-C(=S)NHC(=O)-R j , a heteroalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, including a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1X ;
R j及R k独立地选自H、CN、含0-3个R s取代的C 1-C 10烷基、C 1-C 6卤代烷基、C 3-C 10环状烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、C 2-C 10烯基或者炔基、6至10元芳基、包含碳原子及1至2个选自N、O及S杂原子的5至10元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1Y取代； R j and R k are independently selected from H, CN, C 1 -C 10 alkyl substituted with 0-3 R s , C 1 -C 6 haloalkyl, C 3 -C 10 cyclic alkyl, containing carbon Atom and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S(O) p heteroatoms, C 2 -C 10 alkenyl or alkynyl, 6 to 10 membered aryl, containing carbon atoms And 1 to 2 5- to 10-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl and heteroaryl groups may be substituted by 0-2 R 1Y ;
其中，R s的定义与在上述4b)部分中的R s的定义相同； Wherein the same as defined in the definition of R s and R s in the above 4b) portion;
p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
R 1X独立地选自卤素、OH、CN、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 3-C 8环状烷基和环状杂烷基； R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
R 1Y独立地选自C 1-C 10烷基、卤素、CN、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R 1Y is independently selected from C 1 -C 10 alkyl, halogen, CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
p各自独立地为0，1及2；p are each independently 0, 1 and 2;
特别地，R g与R h以及R j及R k可通过以下方式R g——R h、
Figure PCTCN2018102833-appb-000018
R j——R k、
Figure PCTCN2018102833-appb-000019
连接，其中Z 1可选自含0-2个R c取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)C 1-C 6烷基、-NS(＝O) 2(C 1-C 6烷基)、S(O) p； In particular, R g and R h and R j and R k can be obtained by the following manner R g — R h ,
Figure PCTCN2018102833-appb-000018
R j - R k ,
Figure PCTCN2018102833-appb-000019
Connection, wherein Z 1 selected from the group comprising substituted with 0-2 R c C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p hetero atoms 1 -C 6 alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)C 1 -C 6 alkyl, -NS(=O) 2 (C 1 -C 6 alkyl), S (O) p ;
其中，R c与在上述4a)部分中限定的R c的定义相同； Wherein, R c as defined in the above defined 4a) of the same portion of R c;
p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
R i独立地选自H、CN及C 1-C 4烷基； R i is independently selected from the group consisting of H, CN, and C 1 -C 4 alkyl;
m各自独立地选自0-4；m are each independently selected from 0-4;
4b”)更优选地，Y独立地选自O、NR g、S、-CR iNR gR h以及-CR iOR g； More preferably, Y is independently selected from the group consisting of O, NR g , S, -CR i NR g R h and -CR i OR g ;
R g及R h独立地选自H、C 1-C 6卤代烷基、
Figure PCTCN2018102833-appb-000020
Figure PCTCN2018102833-appb-000021
-C(＝S)NHC(＝O)-R j、包含碳原子和1-4个选自O、N、S杂原子的杂烷基和杂环烷基、芳基、包含碳原子和1至2个选自N、O及S杂原子的5至6元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1X取代； R g and R h are independently selected from H, C 1 -C 6 haloalkyl,
Figure PCTCN2018102833-appb-000020
Figure PCTCN2018102833-appb-000021
-C(=S)NHC(=O)-R j , a heteroalkyl group containing a carbon atom and 1 to 4 heteroatoms selected from O, N, S, an aryl group, a carbon atom and 1 Up to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl and heteroaryl groups may be substituted by 0-2 R 1X ;
R j及R k独立地选自H、CN、含0-3个R s取代的C 1-C 10烷基、C 1-C 6卤代烷基、C 3-C 10环状烷基、包含碳原子和1-4个选自O、N、S杂原子的杂烷基和杂环烷基、C 2-C 10烯基或者炔基、6至10元芳基、包含碳原子及1至2个选自N、O及S杂原子的5至10元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1Y取代； R j and R k are independently selected from H, CN, C 1 -C 10 alkyl substituted with 0-3 R s , C 1 -C 6 haloalkyl, C 3 -C 10 cyclic alkyl, containing carbon Atom and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S heteroatoms, C 2 -C 10 alkenyl or alkynyl, 6 to 10 membered aryl, containing carbon atoms and 1 to 2 a 5- to 10-membered heteroaryl group selected from the group consisting of N, O and S heteroatoms; wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1Y ;
R s独立地选自OH，CN、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基、-(OCH 2CH 2) mOR d、(OCH 2CH 2) mNR dR e、包含碳原子及1至2个选自N、O及S杂原子的杂烷基和杂环烷基、芳基以及包含碳原子及1至2个选 自N、O及S杂原子的杂芳基、其中该芳基以及杂芳基可由0-2个R 1Y取代； R s is independently selected from OH, CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl, -(OCH 2 CH 2 ) m OR d , (OCH 2 CH 2 ) m NR d R e , a heteroalkyl group containing a carbon atom and 1 to 2 heteroatoms selected from N, O and S And a heterocycloalkyl group, an aryl group, and a heteroaryl group containing a carbon atom and 1 to 2 hetero atoms selected from N, O and S, wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1Y ;
其中，R d、R e与在上述4b)部分中限定的R d、R e的定义相同； Wherein, R d, R e and defined in the above 4b) portion R d, R e is the same as defined;
R 1Y独立地选自C 1-C 10烷基、卤素、CN、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R 1Y is independently selected from C 1 -C 10 alkyl, halogen, CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
特别地，R g与R h以及R j及R k可通过以下方式R g——R h、
Figure PCTCN2018102833-appb-000022
R j——R k、
Figure PCTCN2018102833-appb-000023
连接，其中Z 1可选自含0-2个R c取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)C 1-C 6烷基、-NS(＝O) 2(C 1-C 6烷基)、S(O) p； In particular, R g and R h and R j and R k can be obtained by the following manner R g — R h ,
Figure PCTCN2018102833-appb-000022
R j - R k ,
Figure PCTCN2018102833-appb-000023
Connection, wherein Z 1 selected from the group comprising substituted with 0-2 R c C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p hetero atoms 1 -C 6 alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)C 1 -C 6 alkyl, -NS(=O) 2 (C 1 -C 6 alkyl), S (O) p ;
其中，R c与在上述4a)部分中限定的R c的定义相同； Wherein, R c as defined in the above defined 4a) of the same portion of R c;
p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
R i独立地选自H、CN及C 1-C 4烷基； R i is independently selected from the group consisting of H, CN, and C 1 -C 4 alkyl;
m各自独立地选自0-4；m are each independently selected from 0-4;
优选地，所述通式I所述的化合物具有式Ia-1或Ia-2：Preferably, the compound of formula I has the formula Ia-1 or Ia-2:
Figure PCTCN2018102833-appb-000024
Figure PCTCN2018102833-appb-000024
其中，X 1与通式I中的1)部分中的定义相同； Wherein X 1 is the same as defined in part 1) of formula I;
Figure PCTCN2018102833-appb-000025
为单键或双键；
Figure PCTCN2018102833-appb-000025
For single or double keys;
X 2、R 3-R 5、R 6以及n与通式I中的3)部分中的定义相同； X 2 , R 3 -R 5 , R 6 and n are the same as defined in part 3) of formula I;
R 1A、R 1B及R 1C、R 2B及R 2C、R 3B及R 3C、R 1D、n、m、q、Y、M的定义与通式I中的4)部分中的相应的定义相同； The definitions of R 1A , R 1B and R 1C , R 2B and R 2C , R 3B and R 3C , R 1D , n, m, q, Y, M are the same as corresponding definitions in part 4) of formula I ;
优选地，所述通式I所述的化合物具有式Ia-3或Ia-4：Preferably, the compound of formula I has formula Ia-3 or Ia-4:
Figure PCTCN2018102833-appb-000026
Figure PCTCN2018102833-appb-000026
其中，X 1与通式I中的1)部分中的定义相同； Wherein X 1 is the same as defined in part 1) of formula I;
Figure PCTCN2018102833-appb-000027
为单键或双键；
Figure PCTCN2018102833-appb-000027
For single or double keys;
X 2、R 7以及n与通式I中的3)部分中的定义相同； X 2 , R 7 and n are the same as defined in part 3) of formula I;
R 1A、R 1B及R 1C、R 2B及R 2C、R 3B及R 3C、R 1D、n、m、q、Y、M的定义与通式I中的4)部分中的相应的定义相同； The definitions of R 1A , R 1B and R 1C , R 2B and R 2C , R 3B and R 3C , R 1D , n, m, q, Y, M are the same as corresponding definitions in part 4) of formula I ;
优选地，所述通式I所述的化合物具有式Ia-5或Ia-6：Preferably, the compound of formula I has formula Ia-5 or Ia-6:
Figure PCTCN2018102833-appb-000028
Figure PCTCN2018102833-appb-000028
其中，X 1与通式I中的1)部分中的定义相同； Wherein X 1 is the same as defined in part 1) of formula I;
Figure PCTCN2018102833-appb-000029
为单键或双键；
Figure PCTCN2018102833-appb-000029
For single or double keys;
Y的定义与通式I中的4)部分中的相应的定义相同；The definition of Y is the same as the corresponding definition in part 4) of formula I;
优选地，所述通式I所述的化合物具有式Ia-7或Ia-8：Preferably, the compound of formula I has formula Ia-7 or Ia-8:
Figure PCTCN2018102833-appb-000030
Figure PCTCN2018102833-appb-000030
其中，X 1与通式I中的1)部分中的定义相同； Wherein X 1 is the same as defined in part 1) of formula I;
Figure PCTCN2018102833-appb-000031
为单键或双键；
Figure PCTCN2018102833-appb-000031
For single or double keys;
R g的定义与通式I中的4)部分中的4b)部分中的相应的定义相同； The definition of R g is the same as the corresponding definition in the 4b) part of the 4) part of the formula I;
优选地，所述通式I所述的化合物具有式Ia-9：Preferably, the compound of formula I has formula Ia-9:
Figure PCTCN2018102833-appb-000032
Figure PCTCN2018102833-appb-000032
其中，among them,
Figure PCTCN2018102833-appb-000033
为单键或双键；
Figure PCTCN2018102833-appb-000033
For single or double keys;
R g的定义与通式I中的4)部分中的4b)部分中的相应的定义相同； The definition of R g is the same as the corresponding definition in the 4b) part of the 4) part of the formula I;
优选地，所述通式I所述的化合物具有以下结构式之一：Preferably, the compound of formula I has one of the following structural formulae:
Figure PCTCN2018102833-appb-000034
Figure PCTCN2018102833-appb-000034
其中，among them,
M的定义与通式I中的4)部分中的相应的定义相同；The definition of M is the same as the corresponding definition in part 4) of formula I;
R g的定义与通式I中的4)部分中的4b)部分中的相应的定义相同； The definition of R g is the same as the corresponding definition in the 4b) part of the 4) part of the formula I;
优选地，所述通式I所述的化合物选自如下化合物：Preferably, the compound of formula I is selected from the group consisting of:
Figure PCTCN2018102833-appb-000035
Figure PCTCN2018102833-appb-000035
Figure PCTCN2018102833-appb-000036
Figure PCTCN2018102833-appb-000036
Figure PCTCN2018102833-appb-000037
Figure PCTCN2018102833-appb-000037
Figure PCTCN2018102833-appb-000038
Figure PCTCN2018102833-appb-000038
Figure PCTCN2018102833-appb-000039
Figure PCTCN2018102833-appb-000039
Figure PCTCN2018102833-appb-000040
Figure PCTCN2018102833-appb-000040
Figure PCTCN2018102833-appb-000041
Figure PCTCN2018102833-appb-000041
Figure PCTCN2018102833-appb-000042
Figure PCTCN2018102833-appb-000042
优选地，所述化合物还包括其立体异构体，互变异构体，阻转异构体，经同位素标记之化合物(包括氘取代)，医学上可接受的盐，多晶型物，溶剂合物，可以用于治疗由EED及/或PRC2介导的疾病或病症。Preferably, the compound further includes stereoisomers, tautomers, atropisomers, isotopically labeled compounds (including hydrazine substituted), medically acceptable salts, polymorphs, solvents The composition can be used to treat a disease or condition mediated by EED and/or PRC2.
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及中间体。According to another aspect of the invention, methods and intermediates for the preparation of the compounds of the invention are provided.
其中，所述方法包括如下步骤：Wherein, the method comprises the following steps:
方案一Option One
Figure PCTCN2018102833-appb-000043
Figure PCTCN2018102833-appb-000043
(1a)用水合肼处理5-溴-4-氯-2-(甲硫基)嘧啶1，生成5-溴-4-肼基-2-(甲硫基)嘧啶2，(1a) Treatment of 5-bromo-4-chloro-2-(methylthio)pyrimidine 1 with hydrazine hydrate to give 5-bromo-4-indolyl-2-(methylthio)pyrimidine 2,
(1b)再用原甲酸三甲酯将5-溴-4-肼基-2-(甲硫基)嘧啶2转化为三氮唑产物3，(1b) further converting 5-bromo-4-mercapto-2-(methylthio)pyrimidine 2 to triazole product 3 with trimethyl orthoformate,
(1c)将三氮唑产物3与胺NH 2CH 2A发生取代反应生成化合物4， (1c) substituting a triazole product 3 with an amine NH 2 CH 2 A to form a compound 4,
(1d)将化合物4在钯催化剂作用下与各类具有R 1基团的硼酸或其等效物发生铃木(Suzuki)偶联反应，得到产物5。 (1d) Suzuki coupling reaction of compound 4 with various boronic acids having an R 1 group or an equivalent thereof under the action of a palladium catalyst to obtain a product 5.
其中，A、R 1的定义与上文中定义的相同。 Wherein, the definitions of A and R 1 are the same as defined above.
方案二Option II
Figure PCTCN2018102833-appb-000044
Figure PCTCN2018102833-appb-000044
(2a)将氰乙酰胺6与丙炔酸乙酯反应生成中间体7，(2a) reacting cyanoacetamide 6 with ethyl propiolate to form intermediate 7,
(2b)将中间体7用溴素处理发生溴代反应得到溴代物8，(2b) bromination of intermediate 7 with bromine to give brominated product 8,
(2c)将溴代物8与三氯氧磷反应得到中间体9，(2c) reacting bromo 8 with phosphorus oxychloride to give intermediate 9,
(2d)将中间体9由水合肼处理，生成中间体10，(2d) Intermediate 9 is treated with hydrazine hydrate to form intermediate 10,
(2e)将中间体10用原甲酸三甲酯将其转化为三氮唑中间体11，(2e) converting intermediate 10 to triazole intermediate 11 with trimethyl orthoformate,
(2f)将三氮唑中间体11与各种胺发生取代反应生成化合物12，(2f) the triazole intermediate 11 is substituted with various amines to form compound 12,
(2g)最后将化合物12在钯催化剂作用下与各类具有R 1基团的硼酸或其等效物发生铃木(Suzuki)偶联反应，得到产物13。 (2g) Finally, compound 12 is subjected to a Suzuki coupling reaction with various types of boronic acid having an R 1 group or its equivalent under the action of a palladium catalyst to obtain a product 13.
其中，A、R 1的定义与上文中定义的相同。 Wherein, the definitions of A and R 1 are the same as defined above.
在方案一及方案二中所述胺可参见专利US2016/0176682A1制备而得(例如下反应式中A1的制备)，或由试剂公司购买(如下反应式，糠胺A2，购于百灵威科技有限公司)，所述硼酸或其等效物B可由试剂公司购买或根据常规文献制备所得。The amines described in Schemes 1 and 2 can be prepared by the preparation of US2016/0176682A1 (for example, the preparation of A1 in the following reaction formula), or purchased by a reagent company (the following reaction formula, indole A2, purchased from BEHRINGER TECHNOLOGY CO., LTD. The boric acid or its equivalent B can be purchased from a reagent company or prepared according to conventional literature.
Figure PCTCN2018102833-appb-000045
Figure PCTCN2018102833-appb-000045
方案三third solution
Figure PCTCN2018102833-appb-000046
Figure PCTCN2018102833-appb-000046
(3a)14以二氯甲烷为溶剂，在三氟乙酸作用下，去除Boc保护基，得到胺基化合物15，(3a) 14 using dichloromethane as a solvent, removing the Boc protecting group under the action of trifluoroacetic acid to obtain an amine compound 15,
(3b)将胺基化合物15在碱性条件下，与带有R g基团的试剂或化合物反应得到16，所述试剂或化合物例如但不限于酸酐、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，所述碱例如但不限于三乙胺、二异丙基乙基胺、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、四氢呋喃、乙腈、1，4-二氧六环， (3b) reacting the amine compound 15 under basic conditions with a reagent or compound having an Rg group to give 16, such as, but not limited to, an acid anhydride, a sulfonic acid anhydride, an isocyanate, a thioisocyanate, an acid chloride Sulfonyl chloride, carbonate, chloroformate, carbamate, etc., such as, but not limited to, triethylamine, diisopropylethylamine, DMAP, potassium carbonate, sodium hydroxide, potassium hydroxide, Potassium tert-butoxide, NaH, the organic solvent such as, but not limited to, dichloromethane, tetrahydrofuran, acetonitrile, 1,4-dioxane,
其中，A、X 1、R g、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与上文中定义的相同。 Wherein, A, X 1 , R g , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m have the same meanings as defined above.
方案四Option four
(4a)将在方案三的步骤(3a)中去除保护基所得的产物15与含有R j基团的羧酸在缩合剂的作用下发生缩合反应得到酰胺化合物17，所述缩合剂例如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，所述碱例如但不限于三乙胺、二异丙基乙基胺、1,5-二氮杂二环[5.4.0]十一-5-烯，所述有机溶剂例如但不限于二氯甲烷、氯仿、N,N-二甲基甲酰胺、四氢呋喃， (4a) The product 15 obtained by removing the protecting group in the step (3a) of the scheme 3 is condensed with a carboxylic acid having a R j group by a condensing agent to obtain an amide compound 17, for example, but not Limited to carbonyl diimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriene Oxazole, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N' -tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N' , N'-tetramethylurea tetrafluoroborate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-succinimidyl-1 , 1,3,3-tetramethyluronium tetrafluoroborate and 2-(5-norbornene-2,3-diimide)-1,1,3,3-tetramethylurea Tetraammonium tetrafluoroborate, the condensation reaction can be carried out in an organic solvent in the presence of a base such as, but not limited to, triethylamine, diisopropylethylamine, 1,5-diazabicyclo ring [5.4.0] eleven-5-ene, the organic solvent such as but not limited to dichloro , Chloroform, N, N- dimethylformamide, tetrahydrofuran,
其中，A、X 1、R j、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与上文中 定义的相同。 Wherein, the definitions of A, X 1 , R j , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m are the same as defined above.
方案五Option five
Figure PCTCN2018102833-appb-000048
Figure PCTCN2018102833-appb-000048
(5a)将18溶于溶剂中，所述溶剂例如但不限于甲醇、乙醇、乙酸乙酯、四氢呋喃，加入金属催化剂，所述金属催化剂例如但不限于10％钯碳、Pd(OH) 2、雷尼镍、RhCl(PPh 3) 3，通入氢气，室温下反应，得到双键还原的化合物19， (5a) dissolving 18 in a solvent such as, but not limited to, methanol, ethanol, ethyl acetate, tetrahydrofuran, added to a metal catalyst such as, but not limited to, 10% palladium on carbon, Pd(OH) 2 , Raney nickel, RhCl (PPh 3 ) 3 , hydrogen gas is introduced, and reacted at room temperature to obtain compound 19 with double bond reduction.
其中，A、X 1、Y、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与上文中定义的相同， Wherein A, X 1 , Y, R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m have the same meanings as defined above,
方案六Option six
Figure PCTCN2018102833-appb-000049
Figure PCTCN2018102833-appb-000049
(6a)20通过还原反应得到化合物21，随后与mCPBA(间氯过氧苯甲酸)或者双氧水发生氧化反应得到化合物22。(6a)20 gives compound 21 by reduction reaction, followed by oxidation reaction with mCPBA (m-chloroperoxybenzoic acid) or hydrogen peroxide to obtain compound 22.
其中，A、X 1、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与上文中定义的相同 Wherein A, X 1 , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m have the same meanings as defined above
方案七Scheme seven
Figure PCTCN2018102833-appb-000050
Figure PCTCN2018102833-appb-000050
(7a)20与mCPBA或者双氧水发生氧化反应得到化合物23。(7a) 20 is oxidized with mCPBA or hydrogen peroxide to give compound 23.
其中，A、X 1、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与上文中定义的相同。 Wherein, the definitions of A, X 1 , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m are the same as defined above.
方案八Option eight
Figure PCTCN2018102833-appb-000051
Figure PCTCN2018102833-appb-000051
15将双键还原(例如但不限于在氢化还原的条件下)得到24，随后与带有R g基团的试剂或者化合物在碱存在下发生反应得到25，所述试剂或化合物例如但不限于酸酐、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，所述碱例如但不限于三乙胺、二异丙基乙基胺、DMAP、碳酸钾、氢氧化钠、氢氧化钾、叔丁醇钾、NaH，所述反应可以在有机溶剂中进行，所述有机溶剂例如但不限于二氯甲烷、四氢呋喃、乙腈、1，4-二氧六环；或者24也可与各类羧酸在缩合剂的存在下发生缩合反应得到酰胺化合物25，所述缩合剂例如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，所述碱为三乙胺、二异丙基乙基胺、1,5-二氮杂二环[5.4.0]十一-5-烯，所述有机溶剂为二氯甲烷、氯仿、N,N-二甲基甲酰胺、四氢呋喃， 15 reduction of a double bond (such as, but not limited to, under hydrogenation reduction conditions) to give 24, followed by reaction with a reagent or compound bearing an Rg group in the presence of a base to give 25, such as but not limited to Anhydride, sulfonic anhydride, isocyanate, thioisocyanate, acid chloride, sulfonyl chloride, carbonate, chloroformate, carbamate, such as, but not limited to, triethylamine, diisopropylethylamine, DMAP, Potassium carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide, NaH, the reaction can be carried out in an organic solvent such as, but not limited to, dichloromethane, tetrahydrofuran, acetonitrile, 1,4-dioxane Hexacyclic ring; or 24 may also be condensed with various carboxylic acids in the presence of a condensing agent to give an amide compound 25, such as, but not limited to, carbonyl diimidazole, dicyclohexylcarbodiimide, diisopropyl Carbodiimide, 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, 2-(7-azobenzotriazole)-N ,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 6- Chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate Ester, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-succinimidyl-1,1,3,3-tetramethylurea Fluoroborate and 2-(5-norbornene-2,3-diimide)-1,1,3,3-tetramethyluronium tetrafluoroborate quaternary ammonium salt, the condensation reaction can be The reaction is carried out in an organic solvent in the presence of a base, which is triethylamine, diisopropylethylamine, 1,5-diazabicyclo[5.4.0]undec-5-ene, said organic The solvent is dichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran,
其中，A、X 1、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与上文中定义的相同。 Wherein, the definitions of A, X 1 , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m are the same as defined above.
优选地，该方法包括如下步骤：Preferably, the method comprises the following steps:
方案一Option One
Figure PCTCN2018102833-appb-000052
Figure PCTCN2018102833-appb-000052
(1a)用水合肼处理5-溴-4-氯-2-(甲硫基)嘧啶1，生成5-溴-4-肼基-2-(甲硫基) 嘧啶2，(1a) Treatment of 5-bromo-4-chloro-2-(methylthio)pyrimidine 1 with hydrazine hydrate to give 5-bromo-4-indolyl-2-(methylthio)pyrimidine 2,
(1b)再用原甲酸三甲酯将5-溴-4-肼基-2-(甲硫基)嘧啶2转化为三氮唑产物3，(1b) further converting 5-bromo-4-mercapto-2-(methylthio)pyrimidine 2 to triazole product 3 with trimethyl orthoformate,
(1c)将三氮唑产物3与胺NH 2CH 2A发生取代反应生成化合物4， (1c) substituting a triazole product 3 with an amine NH 2 CH 2 A to form a compound 4,
(1d)将化合物4在钯催化剂作用下与各类具有R 1基团的硼酸或其等效物发生铃木(Suzuki)偶联反应，得到产物5， (1d) Suzuki coupling reaction of compound 4 with various boronic acids having R 1 groups or their equivalents under the action of a palladium catalyst to obtain product 5,
其中，A、R 1的定义与上文中定义的相同； Wherein, the definitions of A and R 1 are the same as defined above;
方案二Option II
Figure PCTCN2018102833-appb-000053
Figure PCTCN2018102833-appb-000053
(2a)将氰乙酰胺6与丙炔酸乙酯反应生成中间体7，(2a) reacting cyanoacetamide 6 with ethyl propiolate to form intermediate 7,
(2b)将中间体7用溴素处理发生溴代反应得到溴代物8，(2b) bromination of intermediate 7 with bromine to give brominated product 8,
(2c)将溴代物8与三氯氧磷反应得到中间体9，(2c) reacting bromo 8 with phosphorus oxychloride to give intermediate 9,
(2d)将中间体9由水合肼处理，生成中间体10，(2d) Intermediate 9 is treated with hydrazine hydrate to form intermediate 10,
(2e)将中间体10用原甲酸三甲酯将其转化为三氮唑产物11，(2e) converting intermediate 10 to triazole product 11 using trimethyl orthoformate,
(2f)将三氮唑产物11与各种胺发生取代反应生成化合物12，(2f) the triazole product 11 is substituted with various amines to form compound 12,
(2g)最后将化合物12在钯催化剂作用下与各类具有R 1基团的硼酸或其等效物发生铃木(Suzuki)偶联反应，得到产物13， (2g) Finally, compound 12 is subjected to a Suzuki coupling reaction with various types of boronic acid having an R 1 group or its equivalent under the action of a palladium catalyst to obtain a product 13,
其中，A、R 1的定义与上文中定义的相同； Wherein, the definitions of A and R 1 are the same as defined above;
方案三third solution
Figure PCTCN2018102833-appb-000054
Figure PCTCN2018102833-appb-000054
(3a)14’以二氯甲烷为溶剂，在三氟乙酸作用下，去除Boc保护基，得到胺基化合物15’，(3a) 14' is removed from the Boc protecting group by trifluoroacetic acid using dichloromethane as a solvent to give the amine compound 15'.
(3b)将胺基化合物15’在碱性条件下进一步与带有R g基团的酸酐、磺酸酐、异氰酸酯、硫代异氰酸酯发生反应得到化合物16’，所述碱为三乙胺、二异丙基乙基胺，所 述反应可以在有机溶剂中进行，所述有机溶剂为二氯甲烷、四氢呋喃、乙腈、1，4-二氧六环， (3b) reacting the amine compound 15' with an acid anhydride having an Rg group, a sulfonic acid anhydride, an isocyanate or a thioisocyanate under basic conditions to obtain a compound 16' which is a triethylamine or a diiso Propylethylamine, the reaction can be carried out in an organic solvent, which is dichloromethane, tetrahydrofuran, acetonitrile, 1,4-dioxane,
其中，A、X 1、R g的定义与上文中定义的相同； Wherein, the definitions of A, X 1 , and R g are the same as defined above;
方案四Option four
Figure PCTCN2018102833-appb-000055
Figure PCTCN2018102833-appb-000055
(4a)将在方案三的步骤(3b)中去除保护基所得的产物15’与含有R j基团的羧酸在缩合剂的作用下发生缩合反应得到酰胺化合物17’，所述缩合剂选自羰基二咪唑、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，所述碱为三乙胺、二异丙基乙基胺、1,5-二氮杂二环[5.4.0]十一-5-烯，所述有机溶剂为二氯甲烷、氯仿、N,N-二甲基甲酰胺、四氢呋喃， (4a) The product 15' obtained by removing the protecting group in the step (3b) of the scheme 3 is condensed with a carboxylic acid having a R j group by a condensing agent to obtain an amide compound 17', and the condensing agent is selected. From carbonyl diimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(-3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriene Oxazole, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N' -tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N' , N'-tetramethylurea tetrafluoroborate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-succinimidyl-1 , 1,3,3-tetramethyluronium tetrafluoroborate and 2-(5-norbornene-2,3-diimide)-1,1,3,3-tetramethylurea The quaternary ammonium tetrafluoroborate, the condensation reaction can be carried out in an organic solvent in the presence of a base, which is triethylamine, diisopropylethylamine, 1,5-diazabicyclo[5.4. 0] eleven-5-ene, the organic solvent is dichloromethane, chloroform, N,N-dimethylformamide, Tetrahydrofuran,
其中，A、X 1、R j的定义与上文中定义的相同； Wherein, the definitions of A, X 1 , and R j are the same as defined above;
方案五Option five
Figure PCTCN2018102833-appb-000056
Figure PCTCN2018102833-appb-000056
(5a)18’以甲醇为溶剂，在10％钯碳的催化下，通入氢气，室温下反应6小时，得到双键还原的化合物19’，(5a) 18', using methanol as a solvent, under hydrogen permeation with 10% palladium on carbon, and reacting at room temperature for 6 hours to obtain a double bond-reduced compound 19',
其中，X 1、Y的定义与上文中定义的相同。上述的化合物14、14’、18、18’和20可以按照在方案一或方案二中的步骤(1d)或步骤(2g)经铃木偶联(Suzuki)反应得到。 Wherein, the definitions of X 1 and Y are the same as defined above. The above-mentioned compounds 14, 14', 18, 18' and 20 can be obtained by a Suzuki reaction according to the step (1d) or the step (2g) in the first or second embodiment.
当需要本发明化合物的光学活性形式时，其可以使用光学活性起始材料获得，或者通过使用本领域技术人员已知的标准步骤(例如通过手性色谱柱进行分离)拆分化合物或中间体的立体异构体混合物获得。When optically active forms of the compounds of the invention are desired, they can be obtained using optically active starting materials, or by resolution of compounds or intermediates using standard procedures known to those skilled in the art, such as separation by chiral chromatography columns. A mixture of stereoisomers is obtained.
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。Similarly, when a pure geometric isomer of a compound of the invention is desired, it can be obtained by using pure geometric isomers as starting materials, or by geometrical isomerization of compounds or intermediates by standard procedures, such as chromatographic separation. The body mixture is obtained.
根据本发明的另一方面，提供了一种药物组合物，其包含如上所述的三氮唑并嘧啶、三氮唑并吡啶类化合物、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。According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a triazolopyrimidine, a triazolopyridine compound as described above, a pharmaceutically acceptable salt thereof, an enantiomer, and a non- One or more of the enantiomers or racemates.
优选地，所述药物组合物进一步包含至少一种其他治疗剂。Preferably, the pharmaceutical composition further comprises at least one other therapeutic agent.
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。Preferably, the at least one additional therapeutic agent included in the pharmaceutical composition is selected from the group consisting of other anticancer agents, immunomodulators, anti-allergic agents, antiemetics, pain relieving agents, cytoprotective agents, and combinations thereof.
优选地，所述药物组合物包含至少一种本发明化合物及至少一种药学上可接受的载体、稀释剂或赋形剂，Preferably, the pharmaceutical composition comprises at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient,
根据本发明的另一方面，提供了一种所述化合物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。According to a further aspect of the invention there is provided a use of the compound or pharmaceutical composition for the manufacture of a medicament for the treatment of a disease or condition mediated by EED and/or PRC2.
优选地，所述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。Preferably, the disease or condition comprises diffuse large B-cell lymphoma, follicular lymphoma, other lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate Cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, including neuroblastoma, schwannomas, glioma, glioblastoma and astrocytoma; cervical cancer, colon cancer, melanin Tumor, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma.
根据本发明的另一方面，提供了治疗由EED及/或PRC2介导的疾病或病症的方法，该方法包括According to another aspect of the invention, there is provided a method of treating a disease or condition mediated by EED and/or PRC2, the method comprising
向有需要的受试者提供治疗有效量的通式I所述的化合物或其药物组合物。A therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof is provided to a subject in need thereof.
优选地，所述疾病或病症选自弥漫性大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。Preferably, the disease or condition is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, other lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, Prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, including neuroblastoma, schwannomas, glioma, glioblastoma 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, parathyroid tumor, uterine tumor and soft tissue sarcoma.
具体实施方式Detailed ways
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。All of the features disclosed in this specification, or steps in all methods or processes disclosed, may be combined in any manner other than mutually exclusive features and/or steps. The following examples are illustrative of the scope of the invention and are not intended to limit the scope of the invention.
实施例1：化合物E-Y1的合成Example 1: Synthesis of Compound E-Y1
Figure PCTCN2018102833-appb-000057
Figure PCTCN2018102833-appb-000057
将溴代物4-1(72mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-1(84mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y1，为白色固体(41mg，57％)。 Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-1 (84 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y1 was obtained as white solid (41 mg, 57%).
1H NMR(400MHz,MeOD-d 4)δ9.33(s,1H),7.83(s,1H),6.96(s,1H),6.90–6.84(m,1H),6.69–6.63(m,1H),4.81(s,2H),4.59(t,J＝8.7Hz,2H),4.39(m,2H),3.99(t,J＝5.5Hz,2H),3.38(m,2H),2.62(m,2H).LC-MS:[M+H] +＝368.1。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.33 (s, 1H), 7.83 (s, 1H), 6.96 (s, 1H), 6.90 - 6.84 (m, 1H), 6.69 - 6.63 (m, 1H) ), 4.81 (s, 2H), 4.59 (t, J = 8.7 Hz, 2H), 4.39 (m, 2H), 3.99 (t, J = 5.5 Hz, 2H), 3.38 (m, 2H), 2.62 (m) , 2H). LC-MS: [M+H] + = 368.1.
实施例2：化合物E-Y2的合成Example 2: Synthesis of Compound E-Y2
Figure PCTCN2018102833-appb-000058
Figure PCTCN2018102833-appb-000058
将溴代物4-1(72mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-2(90mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y2，为白色固体(34mg，45％)。 Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-2 (90 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y2 was obtained as white solid (34 mg, 45%).
1H NMR(400MHz,DMSO-d 6)δ9.49(s,1H),8.70(t,J＝4.7Hz,1H),7.67(s,1H),7.26(s,1H),6.94(t,J＝9.5Hz,1H),6.70(dd,J＝8.6,3.9Hz,1H),4.68(d,J＝4.6Hz,2H),4.53(t,J＝8.7Hz,2H),3.36(m,2H),3.29(t,J＝8.6Hz,2H),2.86(t,J＝5.6Hz,2H),2.74(m,2H).LC-MS:[M+H] +＝384.1。 1 H NMR (400MHz, DMSO- d 6) δ9.49 (s, 1H), 8.70 (t, J = 4.7Hz, 1H), 7.67 (s, 1H), 7.26 (s, 1H), 6.94 (t, J = 9.5 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 4.68 (d, J = 4.6 Hz, 2H), 4.53 (t, J = 8.7 Hz, 2H), 3.36 (m, 2H), 3.29 (t, J = 8.6 Hz, 2H), 2.86 (t, J = 5.6 Hz, 2H), 2.74 (m, 2H). LC-MS: [M+H] + = 384.1.
实施例3：化合物E-Y3的合成Example 3: Synthesis of Compound E-Y3
Figure PCTCN2018102833-appb-000059
Figure PCTCN2018102833-appb-000059
将溴代物4-1(72mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-3(123mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y3，为白色固体(67mg，72％)。 Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-3 (123 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y3 was obtained as a white solid (67 mg, 72%).
1H NMR(400MHz,MeOD-d 4)δ9.36(s,1H),7.88(s,1H),6.91–6.82(m,1H),6.73(s,1H),6.66(dd,J＝8.7,3.9Hz,1H),4.81(s,2H),4.59(t,J＝8.7Hz,2H),4.16(s,2H),3.76–3.66(m,2H),3.38(t,J＝8.7Hz,2H),2.62(s,2H),1.52(s,9H).LC-MS:[M+H] +＝467.2。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.36 (s, 1H), 7.88 (s, 1H), 6.91 - 6.82 (m, 1H), 6.73 (s, 1H), 6.66 (dd, J = 8.7 , 3.9 Hz, 1H), 4.81 (s, 2H), 4.59 (t, J = 8.7 Hz, 2H), 4.16 (s, 2H), 3.76 - 3.66 (m, 2H), 3.38 (t, J = 8.7 Hz) , 2H), 2.62 (s, 2H), 1.52 (s, 9H). LC-MS: [M+H] + = 467.2.
实施例4：化合物E-Y4的合成Example 4: Synthesis of Compound E-Y4
Figure PCTCN2018102833-appb-000060
Figure PCTCN2018102833-appb-000060
将溴代物4-2(58mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-1(84mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y4，为白色固体(37mg，64％)。 Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-1 (84 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y4 was obtained as white solid (37 mg, 64%).
1H NMR(400MHz,MeOD-d 4)δ9.24(s,1H),7.70(s,1H),7.46(d,J＝0.9Hz,1H),7.06(s,1H),6.44–6.31(m,2H),4.77(s,2H),4.37(m,2H),3.96(t,J＝5.5Hz,2H),2.60(m,2H).LC-MS:[M+H] +＝298.1。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.24 (s, 1H), 7.70 (s, 1H), 7.46 (d, J = 0.9 Hz, 1H), 7.06 (s, 1H), 6.44 - 6.31 ( m, 2H), 4.77 (s, 2H), 4.37 (m, 2H), 3.96 (t, J = 5.5 Hz, 2H), 2.60 (m, 2H). LC-MS: [M+H] + =298.1 .
实施例5：化合物E-Y5的合成Example 5: Synthesis of Compound E-Y5
Figure PCTCN2018102833-appb-000061
Figure PCTCN2018102833-appb-000061
将溴代物4-2(58mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-2(90mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y5，为白色固体(37mg，60％)。 Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and borate B-2 (90 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y5 was obtained as white solid (37 mg, 60%).
1H NMR(400MHz,MeOD-d 4)δ9.25(s,1H),7.68(s,1H),7.48(d,J＝0.9Hz,1H),6.85–6.81(m,1H),6.42–6.36(m,2H),4.79(s,2H),3.43–3.37(m,2H),2.93(t,J＝5.7Hz,2H),2.81(dd,J＝5.7,2.0Hz,2H).LC-MS:[M+H] +＝314.1。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.25 (s, 1H), 7.68 (s, 1H), 7.48 (d, J = 0.9 Hz, 1H), 6.85 - 6.81 (m, 1H), 6.42 - 6.36 (m, 2H), 4.79 (s, 2H), 3.43 - 3.37 (m, 2H), 2.93 (t, J = 5.7 Hz, 2H), 2.81 (dd, J = 5.7, 2.0 Hz, 2H). LC -MS: [M+H] + = 314.1.
实施例6：化合物E-Y6的合成Example 6: Synthesis of Compound E-Y6
Figure PCTCN2018102833-appb-000062
Figure PCTCN2018102833-appb-000062
将溴代物4-2(58mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的 Na 2CO 3水溶液中，加入硼酸酯B-3(123mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y6，为白色固体(55mg，70％)。 Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-3 (123 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y6 was obtained as a white solid (55 mg, 70%).
1H NMR(400MHz,MeOD-d 4)δ9.24(s,1H),7.68(s,1H),7.47(dd,J＝1.8,0.8Hz,1H),6.94(s,1H),6.40(ddd,J＝5.1,3.2,2.2Hz,2H),4.78(s,2H),4.15(m,2H),3.69(m,2H),2.62(m,2H),1.51(s,9H).LC-MS:[M+H] +＝397.1。 1 H NMR (400MHz, MeOD- d 4) δ9.24 (s, 1H), 7.68 (s, 1H), 7.47 (dd, J = 1.8,0.8Hz, 1H), 6.94 (s, 1H), 6.40 ( Ddd, J=5.1, 3.2, 2.2 Hz, 2H), 4.78 (s, 2H), 4.15 (m, 2H), 3.69 (m, 2H), 2.62 (m, 2H), 1.51 (s, 9H). -MS: [M+H] + = 397.1.
实施例7：化合物E-Y7的合成Example 7: Synthesis of Compound E-Y7
Figure PCTCN2018102833-appb-000063
Figure PCTCN2018102833-appb-000063
将溴代物4-2(58mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-4(83mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y7，为白色固体(38mg，64％)。 Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-4 (83 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y7 was obtained as white solid (38 mg, 64%).
1H NMR(400MHz,MeOD-d 4)δ9.24(s,1H),7.66(s,1H),7.49(s,1H),6.83(s,1H),6.44–6.36(m,2H),4.79(s,2H),2.52(s,2H),2.31(s,2H),1.87(dd,J＝11.7,6.1Hz,2H),1.79–1.70(m,2H).LC-MS:[M+H] +＝296.1。 1 H NMR (400MHz, MeOD- d 4) δ9.24 (s, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 6.83 (s, 1H), 6.44-6.36 (m, 2H), 4.79 (s, 2H), 2.52 (s, 2H), 2.31 (s, 2H), 1.87 (dd, J = 11.7, 6.1 Hz, 2H), 1.79 - 1.70 (m, 2H). LC-MS: [M +H] + =296.1.
实施例8：化合物E-Y8的合成Example 8: Synthesis of Compound E-Y8
Figure PCTCN2018102833-appb-000064
Figure PCTCN2018102833-appb-000064
将溴代物4-2(58mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-5(102mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y8，为白色固体(39mg，57％)。 Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-5 (102 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y8 was obtained as white solid (39 mg, 57%).
1H NMR(400MHz,MeOD-d 4)δ9.24(s,1H),7.65(s,1H),7.48(d,J＝1.0Hz,1H),7.20(d,J＝6.9Hz,1H),7.12(t,J＝6.9Hz,1H),7.03(t,J＝7.0Hz,1H),6.80(d,J＝7.3Hz,1H),6.46–6.38(m,2H),6.34(t,J＝4.6Hz,1H),4.81(s,2H),2.91(t,J＝8.0Hz,2H),2.46 (td,J＝8.0,4.7Hz,2H).LC-MS:[M+H] +＝344.1。 1 H NMR (400MHz, MeOD- d 4) δ9.24 (s, 1H), 7.65 (s, 1H), 7.48 (d, J = 1.0Hz, 1H), 7.20 (d, J = 6.9Hz, 1H) , 7.12 (t, J = 6.9 Hz, 1H), 7.03 (t, J = 7.0 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H), 6.46 - 6.38 (m, 2H), 6.34 (t, J=4.6 Hz, 1H), 4.81 (s, 2H), 2.91 (t, J = 8.0 Hz, 2H), 2.46 (td, J = 8.0, 4.7 Hz, 2H). LC-MS: [M+H] + =344.1.
实施例9：化合物E-Y9的合成Example 9: Synthesis of Compound E-Y9
Figure PCTCN2018102833-appb-000065
Figure PCTCN2018102833-appb-000065
将溴代物4-2(58mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-6(129mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y9，为白色固体(42mg，51％)。 Bromine 4-2 (58 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-6 (129 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y9 was obtained as white solid (42 mg, 51%).
1H NMR(400MHz,MeOD-d 4)δ9.23(s,1H),7.62(s,1H),7.47(dd,J＝1.8,0.9Hz,1H),6.76(s,1H),6.39(ddd,J＝5.1,3.2,1.3Hz,2H),4.77(s,2H),3.75(m,1H),2.68–2.51(m,3H),2.25–2.14(m,1H),2.04(m,1H),1.80–1.68(m,1H),1.46(s,9H).LC-MS:[M+H] +＝411.2。 1 H NMR (400MHz, MeOD- d 4) δ9.23 (s, 1H), 7.62 (s, 1H), 7.47 (dd, J = 1.8,0.9Hz, 1H), 6.76 (s, 1H), 6.39 ( Ddd, J=5.1, 3.2, 1.3 Hz, 2H), 4.77 (s, 2H), 3.75 (m, 1H), 2.68–2.51 (m, 3H), 2.25–2.14 (m, 1H), 2.04 (m, 1H), 1.80 - 1.68 (m, 1H), 1.46 (s, 9H). LC-MS: [M+H] + = 411.2.
实施例10：化合物E-Y10的合成Example 10: Synthesis of Compound E-Y10
Figure PCTCN2018102833-appb-000066
Figure PCTCN2018102833-appb-000066
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，浓缩后直接经HPLC分离，流动相：40％乙腈/60％水(含0.1％TFA)，保留时间4.7分钟，产率70％。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), stirred at room temperature for 30 min, concentrated and separated directly by HPLC, mobile phase: 40% acetonitrile / 60% Water (containing 0.1% TFA), retention time 4.7 minutes, yield 70%.
LC-MS:[M+H] +＝367.1。 LC-MS: [M+H] + = 367.1.
实施例11：化合物E-Y11的合成Example 11: Synthesis of Compound E-Y11
Figure PCTCN2018102833-appb-000067
Figure PCTCN2018102833-appb-000067
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，浓缩后直接经HPLC分离，流动相：40％乙腈/60％水(含0.1％TFA)，保留时间5.4分钟。产率82％。Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), stirred at room temperature for 30 min, concentrated and separated directly by HPLC, mobile phase: 40% acetonitrile / 60% Water (containing 0.1% TFA) with a retention time of 5.4 minutes. The yield was 82%.
1H NMR(400MHz,MeOD-d 4)δ9.27(s,1H),7.77(s,1H),7.45(dd,J＝1.8,0.8Hz,1H),7.02(s,1H),6.38(dt,J＝3.2,2.2Hz,2H),4.79(s,2H),3.92(m,2H),3.50(t,J＝6.1Hz,2H),2.95–2.85(m,2H).LC-MS:[M+H] +＝297.1。 1 H NMR (400MHz, MeOD- d 4) δ9.27 (s, 1H), 7.77 (s, 1H), 7.45 (dd, J = 1.8,0.8Hz, 1H), 7.02 (s, 1H), 6.38 ( Dt, J = 3.2, 2.2 Hz, 2H), 4.79 (s, 2H), 3.92 (m, 2H), 3.50 (t, J = 6.1 Hz, 2H), 2.95 - 2.85 (m, 2H). LC-MS :[M+H] + =297.1.
实施例12：化合物E-Y12的合成Example 12: Synthesis of Compound E-Y12
Figure PCTCN2018102833-appb-000068
Figure PCTCN2018102833-appb-000068
将化合物E-Y9(41mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，浓缩后直接经HPLC分离，流动相：40％乙腈/60％水(含0.1％TFA)，保留时间5.4分钟。产率69％。Compound E-Y9 (41 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), stirred at room temperature for 30 min, concentrated and separated directly by HPLC, mobile phase: 40% acetonitrile / 60% Water (containing 0.1% TFA) with a retention time of 5.4 minutes. The yield was 69%.
1H NMR(400MHz,MeOD-d 4)δ9.29(s,1H),7.79(s,1H),7.46(s,1H),6.61(s,1H),6.45–6.34(m,2H),4.79(s,2H),3.51(m,1H),2.70(m,2H),2.41–2.32(m,1H),2.20(m,1H),1.91(m,2H).LC-MS:[M+H] +＝311.1。 1 H NMR (400MHz, MeOD- d 4) δ9.29 (s, 1H), 7.79 (s, 1H), 7.46 (s, 1H), 6.61 (s, 1H), 6.45-6.34 (m, 2H), 4.79 (s, 2H), 3.51 (m, 1H), 2.70 (m, 2H), 2.41 - 2.32 (m, 1H), 2.20 (m, 1H), 1.91 (m, 2H). LC-MS: [M +H] + =311.1.
实施例13：化合物E-Y13的合成Example 13: Synthesis of Compound E-Y13
Figure PCTCN2018102833-appb-000069
Figure PCTCN2018102833-appb-000069
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入甲磺酸酐(Ms 2O，26mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y13，为白色固体(24mg，两步收率51％)。 Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, and methanesulfonic anhydride (Ms 2 O, 26 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y13 was obtained as a white solid (24 mg, yield of 51% in two steps).
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.67(t,J＝4.9Hz,1H),7.71(s,1H),7.32(s,1H),7.01–6.88(m,1H),6.70(dd,J＝8.6,4.0Hz,1H),4.69(d,J＝4.8Hz,2H),4.54(t,J＝8.8Hz,2H),3.94(m,2H),3.40(m,2H),3.29(m,2H),2.95(s,3H),2.70(m,2H).LC-MS:[M+H] +＝445.1。 1 H NMR (400MHz, DMSO- d 6) δ9.46 (s, 1H), 8.67 (t, J = 4.9Hz, 1H), 7.71 (s, 1H), 7.32 (s, 1H), 7.01-6.88 ( m,1H), 6.70 (dd, J=8.6, 4.0 Hz, 1H), 4.69 (d, J = 4.8 Hz, 2H), 4.54 (t, J = 8.8 Hz, 2H), 3.94 (m, 2H), 3.40 (m, 2H), 3.29 (m, 2H), 2.95 (s, 3H), 2.70 (m, 2H). LC-MS: [M+H] + = 445.1.
实施例14：化合物E-Y14的合成Example 14: Synthesis of Compound E-Y14
Figure PCTCN2018102833-appb-000070
Figure PCTCN2018102833-appb-000070
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入对甲苯磺酸酸酐(Ts 2O，48mg，0.15mmol)，继 续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y14，为白色固体(16mg，两步收率32％)。 Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, p-toluenesulfonic acid anhydride (Ts 2 O, 48 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y14 was obtained as a white solid (16 mg,yield 32% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.45(s,1H),7.89–7.64(m,3H),7.44(d,J＝7.9Hz,2H),6.85(t,J＝9.4Hz,1H),6.76(s,1H),6.64(dd,J＝8.5,3.6Hz,1H),4.77(s,2H),4.57(t,J＝8.6Hz,2H),3.79(s,2H),3.44–3.33(m,4H),2.67(s,2H),2.45(s,3H).LC-MS:[M+H] +＝521.2。 1 H NMR (400MHz, MeOD- d 4) δ9.45 (s, 1H), 7.89-7.64 (m, 3H), 7.44 (d, J = 7.9Hz, 2H), 6.85 (t, J = 9.4Hz, 1H), 6.76 (s, 1H), 6.64 (dd, J = 8.5, 3.6 Hz, 1H), 4.77 (s, 2H), 4.57 (t, J = 8.6 Hz, 2H), 3.79 (s, 2H), 3.44 - 3.33 (m, 4H), 2.67 (s, 2H), 2.45 (s, 3H). LC-MS: [M+H] + = 521.2.
实施例15：化合物E-Y15的合成Example 15: Synthesis of Compound E-Y15
Figure PCTCN2018102833-appb-000071
Figure PCTCN2018102833-appb-000071
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入乙酸酐(Ac 2O，15mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y15，为白色固体(14mg，两步收率35％)。 Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved. Acetic anhydride (Ac 2 O, 15 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y15 was obtained as a white solid (14 mg, yield of 35% in two steps).
1H NMR(400MHz,DMSO-d 6)δ9.46(d,J＝1.1Hz,1H),8.65(s,1H),7.70(d,J＝8.3Hz,1H),7.27(d,J＝21.1Hz,1H),6.97–6.89(m,1H),6.71(dd,J＝8.7,3.8Hz,1H),4.69(d,J＝4.2Hz,2H),4.54(t,J＝8.7Hz,2H),4.19(d,J＝25.2Hz,2H),3.67(dt,J＝11.2,5.7Hz,2H),3.28(t,J＝8.7Hz,2H),2.64(s,1H),2.52(s,1H),2.06(d,J＝15.7Hz,3H).LC-MS:[M+H] +＝409.1。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.46 (d, J = 1.1 Hz, 1H), 8.65 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 21.1 Hz, 1H), 6.97 - 6.89 (m, 1H), 6.71 (dd, J = 8.7, 3.8 Hz, 1H), 4.69 (d, J = 4.2 Hz, 2H), 4.54 (t, J = 8.7 Hz, 2H), 4.19 (d, J = 25.2 Hz, 2H), 3.67 (dt, J = 11.2, 5.7 Hz, 2H), 3.28 (t, J = 8.7 Hz, 2H), 2.64 (s, 1H), 2.52 ( s, 1H), 2.06 (d, J = 15.7 Hz, 3H). LC-MS: [M+H] + = 409.1.
实施例16：化合物E-Y16的合成Example 16: Synthesis of Compound E-Y16
Figure PCTCN2018102833-appb-000072
Figure PCTCN2018102833-appb-000072
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入苯甲酸酐((PhCO) 2O，34mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y16，为白色固体(14mg，两步收率30％)。 Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, and benzoic anhydride ((PhCO) 2 O, 34 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour, and TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y16 was obtained as a white solid (14 mg, 30% yield in two steps).
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.66(s,1H),7.70(s,1H),7.47(d,J＝3.9Hz,5H),7.01–6.90(m,1H),6.71(dd,J＝8.7,3.9Hz,1H),4.69(d,J＝4.9Hz,2H),4.54(t,J＝8.8Hz,2H),4.35(s,1H),4.15(s,1H),3.87(s,1H),3.56(s,1H),3.28(t,J＝8.6Hz,2H),2.64(s,2H).LC-MS:[M+H] +＝471.1。 1 H NMR (400MHz, DMSO- d 6) δ9.46 (s, 1H), 8.66 (s, 1H), 7.70 (s, 1H), 7.47 (d, J = 3.9Hz, 5H), 7.01-6.90 ( m, 1H), 6.71 (dd, J = 8.7, 3.9 Hz, 1H), 4.69 (d, J = 4.9 Hz, 2H), 4.54 (t, J = 8.8 Hz, 2H), 4.35 (s, 1H), 4.15 (s, 1H), 3.87 (s, 1H), 3.56 (s, 1H), 3.28 (t, J = 8.6 Hz, 2H), 2.64 (s, 2H). LC-MS: [M+H] + =471.1.
实施例17：化合物E-Y17的合成Example 17: Synthesis of Compound E-Y17
Figure PCTCN2018102833-appb-000073
Figure PCTCN2018102833-appb-000073
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入异氰酸乙酯(11mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y17，为白色固体(17mg，两步收率40％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved. Ethyl isocyanate (11 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y17 was obtained as a white solid (17 mg, yield of 40% in two steps).
1H NMR(400MHz,DMSO-d 6)δ9.45(s,1H),8.64(s,1H),7.69(s,1H),7.27(s,1H),6.95(t,J＝9.2Hz,1H),6.78–6.64(m,1H),6.51(s,1H),4.69(s,2H),4.54(t,J＝8.8Hz,2H),4.03(s,2H),3.54(s,2H),3.27(m,2H),3.15–2.98(m,2H),1.03(t,J＝7.1Hz,3H).LC-MS:[M+H] +＝438.2。 1 H NMR (400MHz, DMSO- d 6) δ9.45 (s, 1H), 8.64 (s, 1H), 7.69 (s, 1H), 7.27 (s, 1H), 6.95 (t, J = 9.2Hz, 1H), 6.78–6.64 (m, 1H), 6.51 (s, 1H), 4.69 (s, 2H), 4.54 (t, J = 8.8 Hz, 2H), 4.03 (s, 2H), 3.54 (s, 2H) ), 3.27 (m, 2H), 3.15 - 2.98 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + = 438.2.
实施例18：化合物E-Y18的合成Example 18: Synthesis of Compound E-Y18
Figure PCTCN2018102833-appb-000074
Figure PCTCN2018102833-appb-000074
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入叔丁基异氰酸酯(11mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y18，为白色固体(15mg，两步收率33％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved. T-butyl isocyanate (11 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y18 was obtained as a white solid (15 mg, yield of 33% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.38(s,1H),7.93(s,1H),6.93–6.83(m,1H),6.69(s,1H),6.66(dd,J＝8.7,3.9Hz,1H),4.82(s,2H),4.59(t,J＝8.7Hz,2H),4.10(d,J＝2.9Hz,2H),3.66(t,J＝5.6Hz,2H),3.39(t,J＝7.7Hz,2H),2.62(s,2H),1.38(s,9H).LC-MS:[M+H] +＝466.2。 1 H NMR (400MHz, MeOD- d 4) δ9.38 (s, 1H), 7.93 (s, 1H), 6.93-6.83 (m, 1H), 6.69 (s, 1H), 6.66 (dd, J = 8.7 , 3.9 Hz, 1H), 4.82 (s, 2H), 4.59 (t, J = 8.7 Hz, 2H), 4.10 (d, J = 2.9 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 3.39 (t, J = 7.7 Hz, 2H), 2.62 (s, 2H), 1.38 (s, 9H). LC-MS: [M+H] + = 466.2.
实施例19：化合物E-Y19的合成Example 19: Synthesis of Compound E-Y19
Figure PCTCN2018102833-appb-000075
Figure PCTCN2018102833-appb-000075
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟 乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入异硫氰酸乙酯(13mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y19，为白色固体(14mg，两步收率31％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved. Ethyl isothiocyanate (13 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y19 was obtained as a white solid (14 mg, yield of 31% in two steps).
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.66(d,J＝5.0Hz,1H),7.71(d,J＝9.9Hz,2H),7.27(s,1H),7.02–6.90(m,1H),6.71(dd,J＝8.5,3.8Hz,1H),4.70(d,J＝4.7Hz,2H),4.54(t,J＝8.7Hz,2H),4.41(s,2H),4.07(t,J＝5.4Hz,2H),3.55(dd,J＝12.3,6.8Hz,2H),3.27(d,J＝8.7Hz,2H),2.61(s,2H),1.12(t,J＝7.1Hz,3H).LC-MS:[M+H] +＝454.1。 1 H NMR (400MHz, DMSO- d 6) δ9.46 (s, 1H), 8.66 (d, J = 5.0Hz, 1H), 7.71 (d, J = 9.9Hz, 2H), 7.27 (s, 1H) , 7.02–6.90 (m, 1H), 6.71 (dd, J=8.5, 3.8 Hz, 1H), 4.70 (d, J=4.7 Hz, 2H), 4.54 (t, J=8.7 Hz, 2H), 4.41 ( s, 2H), 4.07 (t, J = 5.4 Hz, 2H), 3.55 (dd, J = 12.3, 6.8 Hz, 2H), 3.27 (d, J = 8.7 Hz, 2H), 2.61 (s, 2H), 1.12 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + = 454.1.
实施例20：化合物E-Y20的合成Example 20: Synthesis of Compound E-Y20
Figure PCTCN2018102833-appb-000076
Figure PCTCN2018102833-appb-000076
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入乙酸酐(Ac 2O，15mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y20，为白色固体(14mg，两步收率42％)。 Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved. Acetic anhydride (Ac 2 O, 15 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y20 was obtained as a white solid (14 mg, yield of 42% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.33(s,1H),7.91(s,1H),7.49(s,1H),6.73(brs,1H),6.48–6.36(m,2H),4.83(s,2H),4.30(m,2H),3.84(m,2H),2.67(m,2H),2.20(s,3H).LC-MS:[M+H] +＝339.1。 1 H NMR (400MHz, MeOD- d 4) δ9.33 (s, 1H), 7.91 (s, 1H), 7.49 (s, 1H), 6.73 (brs, 1H), 6.48-6.36 (m, 2H), 4.83 (s, 2H), 4.30 (m, 2H), 3.84 (m, 2H), 2.67 (m, 2H), 2.20 (s, 3H). LC-MS: [M+H] + = 339.1.
实施例21：化合物E-Y21的合成Example 21: Synthesis of Compound E-Y21
Figure PCTCN2018102833-appb-000077
Figure PCTCN2018102833-appb-000077
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入苯甲酸酐((PhCO) 2O，15mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y21，为白色固体(13mg，两步收率32％)。 Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, and benzoic anhydride ((PhCO) 2 O, 15 mg, 0.15 mmol) was added at room temperature. The reaction was continued for 1 hour, and TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y21 was obtained as a white solid (yield: 32% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.30(s,1H),7.82(s,1H),7.51(m,5H),7.48(s,1H),6.92(s,1H),6.47–6.36(m,2H),4.82(s,2H),4.46(m,1H),4.24(m,1H),4.06(m,1H),3.71(m,1H),2.74(m,2H).LC-MS:[M+H] +＝401.1 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.30 (s, 1H), 7.82 (s, 1H), 7.51 (m, 5H), 7.48 (s, 1H), 6.92 (s, 1H), 6.47– 6.36 (m, 2H), 4.82 (s, 2H), 4.46 (m, 1H), 4.24 (m, 1H), 4.06 (m, 1H), 3.71 (m, 1H), 2.74 (m, 2H). -MS:[M+H] + =401.1
实施例22：化合物E-Y22的合成Example 22: Synthesis of Compound E-Y22
Figure PCTCN2018102833-appb-000078
Figure PCTCN2018102833-appb-000078
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入甲磺酸酐(Ms 2O，26mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y22，为白色固体(18mg，两步收率47％)。 Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, and methanesulfonic anhydride (Ms 2 O, 26 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y22 was obtained as a white solid (18 mg, yield of 47% in two steps).
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.86(s,1H),7.71(s,1H),7.63(s,1H),7.30(s,1H),6.43(m,2H),4.73(s,2H),3.94(m,2H),3.40(m,2H),2.95(s,3H),2.69(m,2H).LC-MS:[M+H] +＝375.1。 1 H NMR (400MHz, DMSO- d 6) δ9.43 (s, 1H), 8.86 (s, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.30 (s, 1H), 6.43 ( m, 2H), 4.73 (s, 2H), 3.94 (m, 2H), 3.40 (m, 2H), 2.95 (s, 3H), 2.69 (m, 2H). LC-MS: [M+H] + =375.1.
实施例23：化合物E-Y23的合成Example 23: Synthesis of Compound E-Y23
Figure PCTCN2018102833-appb-000079
Figure PCTCN2018102833-appb-000079
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入对甲苯磺酸酸酐(Ts 2O，48mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y23，为白色固体(16mg，两步收率35％)。 Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, p-toluenesulfonic acid anhydride (Ts 2 O, 48 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y23 was obtained as a white solid (16 mg, yield of 35% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.24(s,1H),7.76(d,J＝7.9Hz,2H),7.67(s,1H),7.47(s,1H),7.46(d,J＝8.4Hz,2H),6.93(s,1H),6.40(m,2H),4.78(s,2H),3.82(m,2H),3.36(m,2H),2.71(m,2H),2.46(s,3H).LC-MS:[M+H] +＝451.1。 1 H NMR (400MHz, MeOD- d 4) δ9.24 (s, 1H), 7.76 (d, J = 7.9Hz, 2H), 7.67 (s, 1H), 7.47 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.93 (s, 1H), 6.40 (m, 2H), 4.78 (s, 2H), 3.82 (m, 2H), 3.36 (m, 2H), 2.71 (m, 2H), 2.46 (s, 3H). LC-MS: [M+H] + = 451.1.
实施例24：化合物E-Y24的合成Example 24: Synthesis of Compound E-Y24
Figure PCTCN2018102833-appb-000080
Figure PCTCN2018102833-appb-000080
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入异氰酸乙酯(11mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y24，为白色固体(20mg，两步收率55％)。Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved. Ethyl isocyanate (11 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y24 was obtained as a white solid (20 mg, yield of 55% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.25(s,1H),7.70(s,1H),7.47(d,J＝1.0Hz,1H),6.98(m,1H),6.44–6.36(m,2H),4.79(s,2H),4.11(d,J＝2.8Hz,2H),3.69(t,J＝5.6Hz,2H),3.25(q,J＝7.2Hz,2H),2.66(d,J＝16.7Hz,2H),1.16(t,J＝7.2Hz,3H).LC-MS:[M+H] +＝368.1。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.25 (s, 1H), 7.70 (s, 1H), 7.47 (d, J = 1.0 Hz, 1H), 6.98 (m, 1H), 6.44 - 6.36 ( m, 2H), 4.79 (s, 2H), 4.11 (d, J = 2.8 Hz, 2H), 3.69 (t, J = 5.6 Hz, 2H), 3.25 (q, J = 7.2 Hz, 2H), 2.66 ( d, J = 16.7 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H). LC-MS: [M+H] + = 368.1.
实施例25：化合物E-Y25的合成Example 25: Synthesis of Compound E-Y25
Figure PCTCN2018102833-appb-000081
Figure PCTCN2018102833-appb-000081
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入叔丁基异氰酸酯(11mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y25，为白色固体(14mg，两步收率37％)。Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved. T-butyl isocyanate (11 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y25 was obtained as a white solid (14 mg,yield 37% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.28(s,1H),7.76(s,1H),7.48(m,1H),6.90(s,1H),6.45–6.34(m,2H),4.80(s,2H),4.10(d,J＝2.5Hz,2H),3.65(t,J＝5.6Hz,2H),2.63(m,2H),1.38(s,9H).LC-MS:[M+H] +＝396.1。 1 H NMR (400MHz, MeOD- d 4) δ9.28 (s, 1H), 7.76 (s, 1H), 7.48 (m, 1H), 6.90 (s, 1H), 6.45-6.34 (m, 2H), 4.80 (s, 2H), 4.10 (d, J = 2.5 Hz, 2H), 3.65 (t, J = 5.6 Hz, 2H), 2.63 (m, 2H), 1.38 (s, 9H). LC-MS: [ M+H] + = 396.1.
实施例26：化合物E-Y26的合成Example 26: Synthesis of Compound E-Y26
Figure PCTCN2018102833-appb-000082
Figure PCTCN2018102833-appb-000082
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入对甲苯异氰酸酯(20mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y26，为白色固体(20mg，两步收率46％)。Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 Amine (TEA), stirred and dissolved, p-toluene isocyanate (20 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y26 was obtained as a white solid (20 mg, yield 46%).
1H NMR(400MHz,DMSO-d 6)δ9.44(s,1H),8.81(m,1H),8.46(s,1H),7.72(s,1H),7.63(s,1H),7.37(d,J＝8.4Hz,2H),7.32(s,1H),7.05(d,J＝8.2Hz,2H),6.43(s,2H),4.74(d,J＝4.8Hz,2H),4.22(s,2H),3.69(t,J＝5.4Hz,2H),2.62(s,2H),2.24(s,3H).LC-MS:[M+H] +＝430.1。 1 H NMR (400MHz, DMSO- d 6) δ9.44 (s, 1H), 8.81 (m, 1H), 8.46 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.37 ( d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 7.05 (d, J = 8.2 Hz, 2H), 6.43 (s, 2H), 4.74 (d, J = 4.8 Hz, 2H), 4.22 ( s, 2H), 3.69 (t, J = 5.4 Hz, 2H), 2.62 (s, 2H), 2.24 (s, 3H). LC-MS: [M+H] + =430.1.
实施例27：化合物E-Y27的合成Example 27: Synthesis of Compound E-Y27
Figure PCTCN2018102833-appb-000083
Figure PCTCN2018102833-appb-000083
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入对氯苯异氰酸酯(23mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y27，为白色固体(23mg，两步收率51％)。Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, p-chlorophenyl isocyanate (23 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y27 was obtained as a white solid (yield: 51%, yield: 51%).
1H NMR(400MHz,DMSO-d 6)δ9.44(s,1H),8.81(s,1H),8.70(s,1H),7.72(s,1H),7.63(s,1H),7.54(d,J＝8.9Hz,2H),7.32(s,1H),7.29(d,J＝8.9Hz,2H),6.43(s,2H),4.74(s,2H),4.23(s,2H),3.71(t,J＝5.6Hz,2H),2.63(s,2H).LC-MS:[M+H] +＝450.1。 1 H NMR (400MHz, DMSO- d 6) δ9.44 (s, 1H), 8.81 (s, 1H), 8.70 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.54 ( d, J = 8.9 Hz, 2H), 7.32 (s, 1H), 7.29 (d, J = 8.9 Hz, 2H), 6.43 (s, 2H), 4.74 (s, 2H), 4.23 (s, 2H), 3.71 (t, J = 5.6 Hz, 2H), 2.63 (s, 2H). LC-MS: [M+H] + = 450.1.
实施例28：化合物E-Y28的合成Example 28: Synthesis of Compound E-Y28
Figure PCTCN2018102833-appb-000084
Figure PCTCN2018102833-appb-000084
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入异氰酸苄酯(20mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y28，为白色固体(20mg，两步收率47％)。Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved. Benzyl isocyanate (20 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y28 was obtained as a white solid (20 mg, yield of 47% in two steps).
1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.79(s,1H),7.69(s,1H),7.63(s,1H),7.37–7.25(m,5H),7.21(t,J＝6.6Hz,1H),7.16(dd,J＝14.8,9.1Hz,1H),6.43(d,J＝1.7Hz,2H),4.74(s,2H),4.29(d,J＝5.8Hz,2H),4.11(s,2H),3.60(t,J＝5.6Hz,2H),2.55(s,2H).LC-MS:[M+H] +＝430.1。 1 H NMR (400MHz, DMSO- d 6) δ9.43 (s, 1H), 8.79 (s, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.37-7.25 (m, 5H), 7.21 (t, J = 6.6 Hz, 1H), 7.16 (dd, J = 14.8, 9.1 Hz, 1H), 6.43 (d, J = 1.7 Hz, 2H), 4.74 (s, 2H), 4.29 (d, J) = 5.8 Hz, 2H), 4.11 (s, 2H), 3.60 (t, J = 5.6 Hz, 2H), 2.55 (s, 2H). LC-MS: [M+H] + =430.1.
实施例29：化合物E-Y29的合成Example 29: Synthesis of Compound E-Y29
Figure PCTCN2018102833-appb-000085
Figure PCTCN2018102833-appb-000085
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入戊二酸酐(17mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y29，为白色固体(20mg，两步收率47％)。Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, and glutaric anhydride (17 mg, 0.15 mmol) was added at room temperature to continue the reaction for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5), which was directly separated by column chromatography. The title compound E-Y29 was obtained as a white solid (20 mg,yield 47% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.32(s,1H),7.89(d,J＝4.5Hz,1H),7.49(s,1H),6.76(d,J＝26.4Hz,1H),6.46–6.34(m,2H),4.83(s,2H),4.31(m,2H),3.92–3.79(m,2H),2.67(m,2H),2.60–2.49(m,2H),2.46–2.36(m,2H),1.95(m,2H).LC-MS:[M+H] +＝411.1。 1 H NMR (400MHz, MeOD- d 4) δ9.32 (s, 1H), 7.89 (d, J = 4.5Hz, 1H), 7.49 (s, 1H), 6.76 (d, J = 26.4Hz, 1H) , 6.46–6.34 (m, 2H), 4.83 (s, 2H), 4.31 (m, 2H), 3.92–3.79 (m, 2H), 2.67 (m, 2H), 2.60–2.49 (m, 2H), 2.46 - 2.36 (m, 2H), 1.95 (m, 2H). LC-MS: [M+H] + = 411.1.
实施例30：化合物E-Y30的合成Example 30: Synthesis of Compound E-Y30
Figure PCTCN2018102833-appb-000086
Figure PCTCN2018102833-appb-000086
将化合物E-Y9(41mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入乙酸酐(Ac 2O，15mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y30，为白色固体(12mg，两步收率33％)。 Compound E-Y9 (41 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved. Acetic anhydride (Ac 2 O, 15 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y30 was obtained as a white solid (12 mg, yield of 33% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.33(s,1H),7.94(s,1H),7.49(dd,J＝1.8,0.8Hz,1H),6.49(s,1H),6.47–6.37(m,2H),4.84(s,2H),4.06(m,1H),2.62(m,3H),2.32–2.15(m,1H),2.07(m,1H),1.99(s,3H),1.80(m,1H).LC-MS:[M+H] +＝353.1。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.33 (s, 1H), 7.94 (s, 1H), 7.49 (dd, J = 1.8, 0.8 Hz, 1H), 6.49 (s, 1H), 6.47– 6.37 (m, 2H), 4.84 (s, 2H), 4.06 (m, 1H), 2.62 (m, 3H), 2.32 - 2.15 (m, 1H), 2.07 (m, 1H), 1.99 (s, 3H) , 1.80 (m, 1H). LC-MS: [M+H] + = 353.1.
实施例31：化合物E-Y31的合成Example 31: Synthesis of Compound E-Y31
Figure PCTCN2018102833-appb-000087
Figure PCTCN2018102833-appb-000087
将化合物E-Y9(41mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入苯甲酸酐((PhCO) 2O，15mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y31，为白色固体(12mg，两步收率27％)。 Compound E-Y9 (41 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, and benzoic anhydride ((PhCO) 2 O, 15 mg, 0.15 mmol) was added at room temperature. The reaction was continued for 1 hour, and TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y31 was obtained as a white solid (12 mg, yield of 27% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.29(s,1H),7.90–7.83(m,2H),7.81(s,1H),7.56(m,1H),7.51–7.44(m,3H),6.73(m,1H),6.47–6.37(m,2H),4.81(s,2H),4.30(m,1H),2.73(m,3H),2.21(m,1H),2.05(m,1H),1.97(m,1H).LC-MS:[M+H] +＝415.1。 1 H NMR (400MHz, MeOD-d 4 ) δ 9.29 (s, 1H), 7.90 - 7.83 (m, 2H), 7.81 (s, 1H), 7.56 (m, 1H), 7.51 - 7.44 (m, 3H) ), 6.73 (m, 1H), 6.47 - 6.37 (m, 2H), 4.81 (s, 2H), 4.30 (m, 1H), 2.73 (m, 3H), 2.21 (m, 1H), 2.05 (m, 1H), 1.97 (m, 1 H). LC-MS: [M+H] + = 415.1.
实施例32：化合物E-Y32的合成Example 32: Synthesis of Compound E-Y32
Figure PCTCN2018102833-appb-000088
Figure PCTCN2018102833-appb-000088
将化合物E-Y9(41mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入甲磺酸酐(Ms 2O，26mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y32，为白色固体(11mg，两步收率29％)。 Compound E-Y9 (41 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, and methanesulfonic anhydride (Ms 2 O, 26 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y32 was obtained as a white solid (11 mg,yield 29% in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.32(s,1H),7.89(s,1H),7.49(dd,J＝1.8,0.8Hz,1H),6.51(m,1H),6.45–6.38(m,2H),4.83(s,2H),3.66(m,1H),3.03(s,3H),2.67(m,3H), 2.38–2.25(m,1H),2.23–2.14(m,1H),1.94–1.79(m,1H).LC-MS:[M+H] +＝389.1。 1 H NMR (400MHz, MeOD- d 4) δ9.32 (s, 1H), 7.89 (s, 1H), 7.49 (dd, J = 1.8,0.8Hz, 1H), 6.51 (m, 1H), 6.45- 6.38 (m, 2H), 4.83 (s, 2H), 3.66 (m, 1H), 3.03 (s, 3H), 2.67 (m, 3H), 2.38 - 2.25 (m, 1H), 2.23 - 2.14 (m, 1H), 1.94 - 1.79 (m, 1H). LC-MS: [M+H] + = 389.1.
实施例33：化合物E-Y33的合成Example 33: Synthesis of Compound E-Y33
Figure PCTCN2018102833-appb-000089
Figure PCTCN2018102833-appb-000089
将化合物E-Y9(41mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入戊二酸酐(17mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y33，为白色固体(16mg，两步收率38％)。Compound E-Y9 (41 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, and glutaric anhydride (17 mg, 0.15 mmol) was added at room temperature to continue the reaction for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5), which was directly separated by column chromatography. The title compound E-Y33 was obtained as a white solid (16 mg,yield 38% in two steps).
1H NMR(400MHz,DMSO-d 6)δ12.21(brs,1H),9.41(s,1H),8.75(s,1H),7.85(d,J＝6.9Hz,1H),7.64(d,J＝4.0Hz,2H),7.19(s,1H),6.42(s,2H),4.72(s,2H),3.85(m,1H),2.60(m,2H),2.48–2.33(m,2H),2.21(m,2H),2.11(m,2H),1.91(m,1H),1.73(m,2H),1.61(m,1H).LC-MS:[M+H] +＝425.1。 1 H NMR (400MHz, DMSO- d 6) δ12.21 (brs, 1H), 9.41 (s, 1H), 8.75 (s, 1H), 7.85 (d, J = 6.9Hz, 1H), 7.64 (d, J = 4.0 Hz, 2H), 7.19 (s, 1H), 6.42 (s, 2H), 4.72 (s, 2H), 3.85 (m, 1H), 2.60 (m, 2H), 2.48 - 2.33 (m, 2H) ), 2.21 (m, 2H), 2.11 (m, 2H), 1.91 (m, 1H), 1.73 (m, 2H), 1.61 (m, 1H). LC-MS: [M+H] + = 425.1.
实施例34：化合物E-Y34的合成Example 34: Synthesis of Compound E-Y34
Figure PCTCN2018102833-appb-000090
Figure PCTCN2018102833-appb-000090
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(76mg，0.2mmol)，2,2-二氟丙酸(18mg，0.16mmol),反应6h，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y34，为白色固体(10mg，两步收率25％)。Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA) and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 1 mL DMF and 0.1 mL diisopropyl Ethylamine (DIEPA), stirred and dissolved, HATU (76 mg, 0.2 mmol), 2,2-difluoropropionic acid (18 mg, 0.16 mmol) was added at room temperature for 6 h, and TLC showed the end of reaction (DCM:MeOH = 10: 1, Rf = 0.5), the reaction solution was poured into water, and a large amount of ethyl acetate was extracted, dried and concentrated, and purified by column chromatography (DCM: MeOH = 30:1) to give the title compound E-Y34 as white solid (10 mg) , two-step yield of 25%).
1H NMR(400MHz,MeOD-d 4)δ9.29(s,1H),7.82(m,1H),7.49(dd,J＝1.8,0.8Hz,1H),6.91(m,1H),6.50–6.35(m,2H),4.81(s,2H),4.51(m,1H),4.34(m,1H),4.03(t,J＝5.6Hz,1H),3.93(t,J＝5.6Hz,1H),2.76(m,2H),1.87(td,J＝19.9,6.4Hz,3H).LC-MS:[M+H] +＝389.1。 1 H NMR (400MHz, MeOD- d 4) δ9.29 (s, 1H), 7.82 (m, 1H), 7.49 (dd, J = 1.8,0.8Hz, 1H), 6.91 (m, 1H), 6.50- 6.35 (m, 2H), 4.81 (s, 2H), 4.51 (m, 1H), 4.34 (m, 1H), 4.03 (t, J = 5.6 Hz, 1H), 3.93 (t, J = 5.6 Hz, 1H) ), 2.76 (m, 2H), 1.87 (td, J = 19.9, 6.4 Hz, 3H). LC-MS: [M+H] + = 389.1.
实施例35：化合物E-Y35的合成Example 35: Synthesis of Compound E-Y35
Figure PCTCN2018102833-appb-000091
Figure PCTCN2018102833-appb-000091
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(76mg，0.2mmol)，N,N-二甲基甘氨酸(17mg，0.16mmol)，反应6h，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y35，为白色固体(11mg，两步收率28％)。Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA) and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 1 mL DMF and 0.1 mL diisopropyl Ethylamine (DIEPA), dissolved in a solution of HATU (76 mg, 0.2 mmol), N,N-dimethylglycine (17 mg, 0.16 mmol) at room temperature for 6 h, TLC showed the end of reaction (DCM:MeOH = 10: 1, Rf = 0.5), the reaction solution was poured into water, extracted with a large amount of ethyl acetate, dried and concentrated, and purified by column chromatography (DCM: MeOH = 30:1) to give the title compound E-Y35 as white solid (11 mg) , two-step yield of 28%).
1H NMR(400MHz,MeOD-d 4)δ9.29(s,1H),7.77(d,J＝8.5Hz,1H),7.48(m,1H),6.92(d,J＝30.7Hz,1H),6.47–6.32(m,2H),4.81(s,2H),4.38(s,1H),4.35(m,1H),4.32(s,1H),4.20(m,1H),3.93(t,J＝5.8Hz,1H),3.70(t,J＝5.7Hz,1H),3.00(d,J＝3.4Hz,6H).LC-MS:[M+H] +＝382.1。 1 H NMR (400MHz, MeOD- d 4) δ9.29 (s, 1H), 7.77 (d, J = 8.5Hz, 1H), 7.48 (m, 1H), 6.92 (d, J = 30.7Hz, 1H) , 6.47–6.32 (m, 2H), 4.81 (s, 2H), 4.38 (s, 1H), 4.35 (m, 1H), 4.32 (s, 1H), 4.20 (m, 1H), 3.93 (t, J = 5.8 Hz, 1H), 3.70 (t, J = 5.7 Hz, 1H), 3.00 (d, J = 3.4 Hz, 6H). LC-MS: [M+H] + = 382.1.
实施例36：化合物E-Y36的合成Example 36: Synthesis of Compound E-Y36
Figure PCTCN2018102833-appb-000092
Figure PCTCN2018102833-appb-000092
将化合物E-Y6(39mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(76mg，0.2mmol)，吗啉-4-基乙酸(23mg，0.16mmol)，反应6h，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y36，为白色固体(9mg，两步收率21％)。Compound E-Y6 (39 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA) and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 1 mL DMF and 0.1 mL diisopropyl Ethylamine (DIEPA), stirred and dissolved, HATU (76 mg, 0.2 mmol), morpholin-4-ylacetic acid (23 mg, 0.16 mmol) was added at room temperature for 6 h, and TLC showed the end of reaction (DCM: MeOH = 10:1) , Rf=0.5), and the reaction mixture was poured into water, and a large amount of ethyl acetate was evaporated. The yield in two steps is 21%).
LC-MS:[M+H] +＝424.2。 LC-MS: [M+H] + = 424.2.
实施例37：化合物E-Y37的合成Example 37: Synthesis of Compound E-Y37
Figure PCTCN2018102833-appb-000093
Figure PCTCN2018102833-appb-000093
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入异氰酸苄酯(20mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y37，为白色固体(12mg，两步收率23％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved. Benzyl isocyanate (20 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y37 was obtained as a white solid (12 mg, yield of 23% in two steps).
1H NMR(400MHz,DMSO-d 6)δ9.45(s,1H),8.64(t,J＝4.9Hz,1H),7.69(s,1H),7.30(dd,J＝12.0,5.0Hz,6H),7.25–7.12(m,2H),7.00–6.91(m,1H),6.70(dd,J＝8.6,3.8Hz,1H),4.69(d,J＝4.9Hz,2H),4.54(t,J＝8.7Hz,2H),4.28(d,J＝5.6Hz,2H),4.10(s,2H),3.28(t,J＝8.8Hz,3H),2.55(s,2H).LC-MS:[M+H] +＝500.1。 1 H NMR (400MHz, DMSO- d 6) δ9.45 (s, 1H), 8.64 (t, J = 4.9Hz, 1H), 7.69 (s, 1H), 7.30 (dd, J = 12.0,5.0Hz, 6H), 7.25–7.12 (m, 2H), 7.00–6.91 (m, 1H), 6.70 (dd, J=8.6, 3.8 Hz, 1H), 4.69 (d, J=4.9 Hz, 2H), 4.54 (t , J = 8.7 Hz, 2H), 4.28 (d, J = 5.6 Hz, 2H), 4.10 (s, 2H), 3.28 (t, J = 8.8 Hz, 3H), 2.55 (s, 2H). LC-MS :[M+H] + =500.1.
实施例38：化合物E-Y38的合成Example 38: Synthesis of Compound E-Y38
Figure PCTCN2018102833-appb-000094
Figure PCTCN2018102833-appb-000094
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入对氯苯异氰酸酯(23mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y38，为白色固体(18mg，两步收率34％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, p-chlorophenyl isocyanate (23 mg, 0.15 mmol) was added at room temperature, and the reaction was continued for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y38 was obtained as a white solid (18 mg,yield: 34%).
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.67(d,J＝21.7Hz,2H),7.72(s,1H),7.54(d,J＝8.1Hz,2H),7.29(d,J＝8.4Hz,3H),6.95(s,1H),6.72(s,1H),4.70(s,2H),4.53(d,J＝8.2Hz,2H),4.23(s,2H),3.70(s,2H),3.29(s,2H),2.63(s,2H).LC-MS:[M+H] +＝520.1。 1 H NMR (400MHz, DMSO- d 6) δ9.46 (s, 1H), 8.67 (d, J = 21.7Hz, 2H), 7.72 (s, 1H), 7.54 (d, J = 8.1Hz, 2H) , 7.29 (d, J = 8.4 Hz, 3H), 6.95 (s, 1H), 6.72 (s, 1H), 4.70 (s, 2H), 4.53 (d, J = 8.2 Hz, 2H), 4.23 (s, 2H), 3.70 (s, 2H), 3.29 (s, 2H), 2.63 (s, 2H). LC-MS: [M+H] + = 520.1.
实施例39：化合物E-Y39的合成Example 39: Synthesis of Compound E-Y39
Figure PCTCN2018102833-appb-000095
Figure PCTCN2018102833-appb-000095
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入苯甲酰基异硫氰酸酯(24mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y39，为白色固体(10mg，两步收率19％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 Amine (TEA), dissolved by stirring, benzoyl isothiocyanate (24 mg, 0.15 mmol) was added at room temperature, the reaction was continued for 1 hour, and TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). The title compound E-Y39 was obtained as a white solid (10 mg, yield of 19% in two steps).
1H NMR(400MHz,DMSO-d 6)δ10.89(d,J＝17.5Hz,1H),9.47(d,J＝5.7Hz,1H),8.69(s,1H),7.98(t,J＝8.1Hz,2H),7.75(d,J＝25.1Hz,1H),7.63(s,1H),7.53(d,J＝8.1Hz,2H),7.21(s,1H),7.01–6.91(m,1H),6.79–6.63(m,1H),4.76(s,1H),4.70(d,J＝5.0Hz,2H),4.54(t,J＝8.6Hz,2H),4.36(s,2H),3.82(s,1H),3.29(t,J＝8.7Hz,3H),2.79(s,2H).LC-MS:[M+H] +＝530.1。 1 H NMR (400MHz, DMSO- d 6) δ10.89 (d, J = 17.5Hz, 1H), 9.47 (d, J = 5.7Hz, 1H), 8.69 (s, 1H), 7.98 (t, J = 8.1 Hz, 2H), 7.75 (d, J = 25.1 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.21 (s, 1H), 7.01 - 6.91 (m, 1H), 6.79–6.63 (m, 1H), 4.76 (s, 1H), 4.70 (d, J = 5.0 Hz, 2H), 4.54 (t, J = 8.6 Hz, 2H), 4.36 (s, 2H), 3.82 (s, 1H), 3.29 (t, J = 8.7 Hz, 3H), 2.79 (s, 2H). LC-MS: [M+H] + = 530.1.
实施例40：化合物E-Y40的合成Example 40: Synthesis of Compound E-Y40
Figure PCTCN2018102833-appb-000096
Figure PCTCN2018102833-appb-000096
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(CAS号：148893-10-1)(76mg，0.2mmol)，吗啉-4-基乙酸(23mg，0.16mmol)，反应6h，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y40，为白色固体(5mg，两步收率10％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), stirred at room temperature for 30 min, and the solvent was concentrated to dryness and then 1 mL DMF and 0.1 mL diisopropyl Ethylamine (DIEPA), dissolved by stirring, and added HATU (CAS No.: 148893-10-1) (76 mg, 0.2 mmol), morpholin-4-yl acetic acid (23 mg, 0.16 mmol) at room temperature for 6 h, TLC showed After completion of the reaction (DCM: MeOH = 10:1, Rf = 0.5), the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, and concentrated to dryness and purified by column chromatography (DCM: MeOH = 30:1) E-Y40 is a white solid (5 mg, 10% yield in two steps).
1H NMR(400MHz,DMSO-d 6)δ9.48(d,J＝2.5Hz,1H),8.72(s,1H),7.73(d,J＝9.0Hz,1H),7.31(d,J＝17.2Hz,1H),6.95(t,J＝9.4Hz,1H),6.71(dd,J＝8.6,3.7Hz,1H),4.70(m,2H),4.54(t,J＝8.4Hz,2H),4.44(d,J＝25.8Hz,2H),4.23(d,J＝30.0Hz,2H),3.96(m,2H),3.78(m,2H),3.61(m,2H),3.44(m,2H),3.29(m,2H),3.17(m,2H),2.67(m,2H).LC-MS:[M+H] +＝494.2。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.48 (d, J = 2.5 Hz, 1H), 8.72 (s, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 17.2 Hz, 1H), 6.95 (t, J = 9.4 Hz, 1H), 6.71 (dd, J = 8.6, 3.7 Hz, 1H), 4.70 (m, 2H), 4.54 (t, J = 8.4 Hz, 2H) , 4.44 (d, J = 25.8 Hz, 2H), 4.23 (d, J = 30.0 Hz, 2H), 3.96 (m, 2H), 3.78 (m, 2H), 3.61 (m, 2H), 3.44 (m, 2H), 3.29 (m, 2H), 3.17 (m, 2H), 2.67 (m, 2H). LC-MS: [M+H] + =494.2.
实施例41：化合物E-Y41的合成Example 41: Synthesis of Compound E-Y41
Figure PCTCN2018102833-appb-000097
Figure PCTCN2018102833-appb-000097
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(76mg，0.2mmol)，噁唑-5-羧酸(18mg，0.16mmol)，反应6h，TLC显示反应结675F(DCM:MeOH＝10:1，Rf＝0.5)，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y41，为白色固体(10mg，两步收率22％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), stirred at room temperature for 30 min, and the solvent was concentrated to dryness and then 1 mL DMF and 0.1 mL diisopropyl Ethylamine (DIEPA), dissolved in a solution of HATU (76 mg, 0.2 mmol), oxazole-5-carboxylic acid (18 mg, 0.16 mmol) at rt for 6 h, TLC showed reaction 675F (DCM:MeOH = 10: 1, Rf = 0.5), the reaction liquid was poured into water, and a large amount of ethyl acetate was extracted, dried and concentrated, and purified by column chromatography (DCM: MeOH = 30:1) to give the title compound E-Y41 as white solid (10 mg) , two-step yield 22%).
1H NMR(400MHz,MeOD-d 4)δ9.32(s,1H),8.41(s,1H),7.81(s,1H),7.77(s,1H),6.95(s,1H),6.91–6.81(m,1H),6.66(dd,J＝8.6,3.9Hz,1H),4.80(s,2H),4.59(t,J＝8.7Hz,3H),4.43(m,1H),4.05(m,2H),3.38(t,J＝8.7Hz,2H),2.93–2.65(m,2H).LC-MS:[M+H] +＝462.2。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.32 (s, 1H), 8.41 (s, 1H), 7.81 (s, 1H), 7.77 (s, 1H), 6.95 (s, 1H), 6.91 - 6.81 (m, 1H), 6.66 (dd, J = 8.6, 3.9 Hz, 1H), 4.80 (s, 2H), 4.59 (t, J = 8.7 Hz, 3H), 4.43 (m, 1H), 4.05 (m) , 2H), 3.38 (t, J = 8.7 Hz, 2H), 2.93 - 2.65 (m, 2H). LC-MS: [M+H] + = 462.2.
实施例42：化合物E-Y42的合成Example 42: Synthesis of Compound E-Y42
Figure PCTCN2018102833-appb-000098
Figure PCTCN2018102833-appb-000098
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(76mg，0.2mmol)，1,3-二甲基-1H-吡唑-5-甲酸(22mg，0.16mmol)，反应6h，TLC显示反应结束(DCM:MeOH ＝10:1，Rf＝0.5)，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y42，为白色固体(10mg，两步收率19％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), stirred at room temperature for 30 min, and the solvent was concentrated to dryness and then 1 mL DMF and 0.1 mL diisopropyl Ethylamine (DIEPA), stirred and dissolved, added HATU (76 mg, 0.2 mmol), 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (22 mg, 0.16 mmol) at room temperature for 6 h, TLC showed reaction (DCM: MeOH = 10:1, Rf = 0.5), and the mixture was poured into water, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography (DCM: MeOH = 30:1) -Y42, as a white solid (10 mg, 19% yield in two steps).
1H NMR(400MHz,MeOD-d 4)δ9.40(s,1H),7.98(s,1H),6.95–6.80(m,1H),6.76–6.52(m,2H),6.37(s,1H),4.82(s,2H),4.59(t,J＝8.7Hz,2H),4.40(d,J＝24.2Hz,2H),4.01(d,J＝10.7Hz,1H),3.87(s,4H),3.39(t,J＝8.5Hz,2H),2.72(s,2H),2.28(s,3H).LC-MS:[M+H] +＝489.2。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.40 (s, 1H), 7.98 (s, 1H), 6.95 - 6.80 (m, 1H), 6.76 - 6.52 (m, 2H), 6.37 (s, 1H) ), 4.82 (s, 2H), 4.59 (t, J = 8.7 Hz, 2H), 4.40 (d, J = 24.2 Hz, 2H), 4.01 (d, J = 10.7 Hz, 1H), 3.87 (s, 4H) ), 3.39 (t, J = 8.5 Hz, 2H), 2.72 (s, 2H), 2.28 (s, 3H). LC-MS: [M+H] + = 489.2.
实施例43：化合物E-Y43的合成Example 43: Synthesis of Compound E-Y43
Figure PCTCN2018102833-appb-000099
Figure PCTCN2018102833-appb-000099
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(76mg，0.2mmol)，四氢吡喃-4-甲酸(21mg，0.16mmol)，反应6h，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y43，为白色固体(10mg，两步收率21％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), stirred at room temperature for 30 min, and the solvent was concentrated to dryness and then 1 mL DMF and 0.1 mL diisopropyl Ethylamine (DIEPA), dissolved in a solution of HATU (76 mg, 0.2 mmol), tetrahydropyran-4-carboxylic acid (21 mg, 0.16 mmol), for 6 h, TLC showed the end of reaction (DCM:MeOH = 10: 1, Rf = 0.5), the reaction liquid was poured into water, and a large amount of ethyl acetate was extracted, dried and concentrated, and purified by column chromatography (DCM: MeOH = 30:1) to give the object compound E-Y43 as white solid (10 mg) , two-step yield 21%).
1H NMR(400MHz,MeOD-d 4)δ9.36(s,1H),7.86(d,J＝5.7Hz,1H),6.91–6.58(m,3H),4.79m,2H),4.58(m,2H),4.38(s,1H),4.27(s,1H),3.99(m,2H),3.87(m,2H),3.55(m,2H),3.37(m,2H),3.04(m,1H),2.65(m,2H),1.83(m,2H),1.68(m,2H).LC-MS:[M+H] +＝479.2。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.36 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 6.91 - 6.58 (m, 3H), 4.79 m, 2H), 4.58 (m) , 2H), 4.38 (s, 1H), 4.27 (s, 1H), 3.99 (m, 2H), 3.87 (m, 2H), 3.55 (m, 2H), 3.37 (m, 2H), 3.04 (m, 1H), 2.65 (m, 2H), 1.83 (m, 2H), 1.68 (m, 2H). LC-MS: [M+H] + = 479.2.
实施例44：化合物E-Y44的合成Example 44: Synthesis of Compound E-Y44
Figure PCTCN2018102833-appb-000100
Figure PCTCN2018102833-appb-000100
将溴代物4-1(72mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-7(137mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y44，为白色固体(18mg，36％)。 Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-7 (137 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y44 was obtained as white solid (18 mg, 36%).
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.67(s,1H),7.69(s,1H),7.38(dd,J＝7.5,4.3Hz,6H),7.24(s,1H),7.03–6.88(m,1H),6.70(dd,J＝8.7,3.9Hz,1H),5.12(d,J＝12.1Hz,2H),4.68(s,2H),4.61–4.46(m,2H),4.17(m,2H),3.65(m,2H),3.28(t,J＝8.7Hz,2H),2.58(m,2H).LC-MS:[M+H] +＝501.1。 1 H NMR (400MHz, DMSO- d 6) δ9.46 (s, 1H), 8.67 (s, 1H), 7.69 (s, 1H), 7.38 (dd, J = 7.5,4.3Hz, 6H), 7.24 ( s, 1H), 7.03–6.88 (m, 1H), 6.70 (dd, J=8.7, 3.9 Hz, 1H), 5.12 (d, J = 12.1 Hz, 2H), 4.68 (s, 2H), 4.61–4.46 (m, 2H), 4.17 (m, 2H), 3.65 (m, 2H), 3.28 (t, J = 8.7 Hz, 2H), 2.58 (m, 2H). LC-MS: [M+H] + = 501.1.
实施例45：化合物E-Y45的合成Example 45: Synthesis of Compound E-Y45
Figure PCTCN2018102833-appb-000101
Figure PCTCN2018102833-appb-000101
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入丙烯酸酐(20mg，0.15mmol)，继续反应1小时，TLC显示反应结束(DCM:MeOH＝10:1，Rf＝0.5)，直接由柱层析分离制备(DCM:MeOH＝30:1)，得到目标化合物E-Y45，为白色固体(14mg，两步收率35％)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 The amine (TEA) was stirred and dissolved, and acrylic acid anhydride (20 mg, 0.15 mmol) was added at room temperature to continue the reaction for 1 hour. TLC showed the end of the reaction (DCM: MeOH = 10:1, Rf = 0.5). (DCM: MeOH = 30:1) toield of the desired compound E-Y45 as a white solid (14 mg, 35% yield in two steps).
1H NMR(400MHz,MeOH-d 4)δ9.38(s,1H),7.92(s,1H),6.94–6.80(m,2H),6.79–6.68(m,1H),6.65(dd,J＝8.6,3.9Hz,1H),6.27(d,J＝16.7Hz,1H),5.81(d,J＝10.6Hz,1H),4.81(s,2H),4.59(t,J＝8.7Hz,2H),4.37(m,2H),3.92(m,2H),3.38(m,2H),2.68(m,2H).LC-MS:[M+H] +＝421.1。 1 H NMR (400MHz, MeOH- d 4) δ9.38 (s, 1H), 7.92 (s, 1H), 6.94-6.80 (m, 2H), 6.79-6.68 (m, 1H), 6.65 (dd, J = 8.6, 3.9 Hz, 1H), 6.27 (d, J = 16.7 Hz, 1H), 5.81 (d, J = 10.6 Hz, 1H), 4.81 (s, 2H), 4.59 (t, J = 8.7 Hz, 2H) ), 4.37 (m, 2H), 3.92 (m, 2H), 3.38 (m, 2H), 2.68 (m, 2H). LC-MS: [M+H] + = 421.1.
实施例46：化合物E-Y46的合成Example 46: Synthesis of Compound E-Y46
Figure PCTCN2018102833-appb-000102
Figure PCTCN2018102833-appb-000102
将溴代物4-3(62mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-3(123mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y46，为白色固体(32mg，40％)。 Bromine 4-3 (62 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-3 (123 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y46 was obtained as white solid (32mg, 40%).
1H NMR(400MHz,MeOD-d 4)δ9.43(s,1H),7.71(s,1H),7.47(m,1H),7.16(m,1H),6.99(m,2H),4.91(s,2H),4.08(m,2H),3.57(m,2H),2.78(m,2H),1.44(s,9H).LC-MS:[M+H] +＝412.1。 1 H NMR (400MHz, MeOD- d 4) δ9.43 (s, 1H), 7.71 (s, 1H), 7.47 (m, 1H), 7.16 (m, 1H), 6.99 (m, 2H), 4.91 ( s, 2H), 4.08 (m, 2H), 3.57 (m, 2H), 2.78 (m, 2H), 1.44 (s, 9H). LC-MS: [M+H] + = 412.1.
实施例47：化合物E-Y47的合成Example 47: Synthesis of Compound E-Y47
Figure PCTCN2018102833-appb-000103
Figure PCTCN2018102833-appb-000103
化合物E-Y1(10mg)溶解于2mL甲醇中，加入10％Pd/C(5mg)室温下反应6小时，过滤，柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y47，为白色固体(8mg，80％)。Compound E-Y1 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (5 mg) at room temperature for 6 hours, filtered, and purified by column chromatography (DCM:MeOH = 20:1) Y47 is a white solid (8 mg, 80%).
1H NMR(400MHz,MeOD-d 4)δ9.33(s,1H),7.74(s,1H),6.93–6.80(m,1H),6.66(dd,J＝8.7,3.8Hz,1H),4.78(s,2H),4.59(t,J＝8.7Hz,2H),4.09(d,J＝11.2Hz,2H),3.71–3.57(m,2H),3.38(t,J＝8.7Hz,2H),3.21(m,1H),1.96(m,4H).LC-MS:[M+H] +＝370.1。 1 H NMR (400MHz, MeOD- d 4) δ9.33 (s, 1H), 7.74 (s, 1H), 6.93-6.80 (m, 1H), 6.66 (dd, J = 8.7,3.8Hz, 1H), 4.78(s,2H), 4.59(t,J=8.7Hz,2H),4.09(d,J=11.2Hz,2H),3.71–3.57(m,2H),3.38(t,J=8.7Hz,2H ), 3.21 (m, 1H), 1.96 (m, 4H). LC-MS: [M+H] + = 370.1.
实施例48：化合物E-Y48的合成Example 48: Synthesis of Compound E-Y48
Figure PCTCN2018102833-appb-000104
Figure PCTCN2018102833-appb-000104
化合物E-Y17(10mg)溶解于2mL甲醇中，加入10％Pd/C(5mg)室温下反应6小时，过滤，柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y48，为白色固体(5mg，50％)。Compound E-Y17 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (5 mg) at room temperature for 6 hours, filtered, and purified by column chromatography (DCM:MeOH = 20:1) Y48, as a white solid (5 mg, 50%).
1H NMR(400MHz,MeOD-d 4)δ9.27(s,1H),7.58(s,1H),6.99–6.77(m,1H),6.66(dd,J＝8.5,3.7Hz,1H),4.76(s,2H),4.59(t,J＝8.7Hz,2H),4.20(m,2H),3.37(m,2H),3.23(dd,J＝14.2,7.1Hz,2H),2.96(t,J＝11.7Hz,2H),2.04(m,4H),1.15(t,J＝7.2Hz,3H).LC-MS:[M+H] +＝440.2。 1 H NMR (400MHz, MeOD- d 4) δ9.27 (s, 1H), 7.58 (s, 1H), 6.99-6.77 (m, 1H), 6.66 (dd, J = 8.5,3.7Hz, 1H), 4.76(s, 2H), 4.59 (t, J = 8.7 Hz, 2H), 4.20 (m, 2H), 3.37 (m, 2H), 3.23 (dd, J = 14.2, 7.1 Hz, 2H), 2.96 (t , J = 11.7 Hz, 2H), 2.04 (m, 4H), 1.15 (t, J = 7.2 Hz, 3H). LC-MS: [M+H] + = 440.2.
实施例49：化合物E-Y49的合成Example 49: Synthesis of Compound E-Y49
Figure PCTCN2018102833-appb-000105
Figure PCTCN2018102833-appb-000105
化合物E-Y18(10mg)溶解于2mL甲醇中，加入10％Pd/C(5mg)室温下反应6小时，过滤，柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y49，为白色固体(6mg，60％)。Compound E-Y18 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (5 mg) at room temperature for 6 hours, filtered, and purified by column chromatography (DCM:MeOH = 20:1) Y49 is a white solid (6 mg, 60%).
1H NMR(400MHz,DMSO-d 6)δ9.40(s,1H),8.44(s,1H),7.49(s,1H),7.02–6.87(m,1H),6.70(dd,J＝8.6,3.9Hz,1H),4.64(d,J＝4.8Hz,2H),4.54(t,J＝8.8Hz,2H),4.10(d,J＝12.9Hz,2H),3.29(t,J＝8.7Hz,2H),2.96(s,1H),2.77–2.64(m,2H),1.90–1.68(m,4H),1.27(s,9H).LC-MS:[M+H] +＝468.2。 1 H NMR (400MHz, DMSO- d 6) δ9.40 (s, 1H), 8.44 (s, 1H), 7.49 (s, 1H), 7.02-6.87 (m, 1H), 6.70 (dd, J = 8.6 , 3.9 Hz, 1H), 4.64 (d, J = 4.8 Hz, 2H), 4.54 (t, J = 8.8 Hz, 2H), 4.10 (d, J = 12.9 Hz, 2H), 3.29 (t, J = 8.7) Hz, 2H), 2.96 (s, 1H), 2.77 - 2.64 (m, 2H), 1.90 - 1.68 (m, 4H), 1.27 (s, 9H). LC-MS: [M+H] + = 468.2.
实施例50：化合物E-Y50的合成Example 50: Synthesis of Compound E-Y50
Figure PCTCN2018102833-appb-000106
Figure PCTCN2018102833-appb-000106
化合物E-Y15(10mg)溶解于2mL甲醇中，加入10％Pd/C(5mg)室温下反应6小时，过滤，柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y50，为白色固体(7mg，72％)。The compound E-Y15 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (5 mg) at room temperature for 6 hours, filtered, and purified by column chromatography (DCM:MeOH = 20:1) Y50 was a white solid (7 mg, 72%).
1H NMR(400MHz,MeOD)δ9.28(s,1H),7.63(s,1H),6.92–6.78(m,1H),6.66(dd,J＝8.7,3.9Hz,1H),4.77(s,2H),4.71(m,1H),4.59(t,J＝8.7Hz,2H),4.09(m,1H),3.37(t,J＝8.6Hz,2H),3.30–3.14(m,1H),2.80(m,1H),2.25–2.18(m,1H),2.17(s,3H),2.06(m,2H),1.91(m,1H),1.81(m,1H).LC-MS:[M+H] +＝411.2。 1 H NMR (400MHz, MeOD) δ9.28 (s, 1H), 7.63 (s, 1H), 6.92-6.78 (m, 1H), 6.66 (dd, J = 8.7,3.9Hz, 1H), 4.77 (s , 2H), 4.71 (m, 1H), 4.59 (t, J = 8.7 Hz, 2H), 4.09 (m, 1H), 3.37 (t, J = 8.6 Hz, 2H), 3.30 - 3.14 (m, 1H) , 2.80 (m, 1H), 2.25 - 2.18 (m, 1H), 2.17 (s, 3H), 2.06 (m, 2H), 1.91 (m, 1H), 1.81 (m, 1H). LC-MS: [ M+H] + = 411.2.
实施例51：化合物E-Y51的合成Example 51: Synthesis of Compound E-Y51
Figure PCTCN2018102833-appb-000107
Figure PCTCN2018102833-appb-000107
将溴代物13-2(63mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-3(123mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y51，为白色固体(17mg，20％)。 The bromine 13-2 (63 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and borate B-3 (123 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y51 was obtained as a white solid (17 mg, 20%).
1H NMR(400MHz,MeOD-d 4)δ9.48(s,1H),7.50(s,1H),7.34(s,1H),6.95(s,1H),6.47(m,2H),5.08(s,2H),4.18(m,2H),3.72(m,2H),2.62(m,2H),1.48(s,9H).LC-MS:[M+H] +＝421.2。 1 H NMR (400MHz, MeOD- d 4) δ9.48 (s, 1H), 7.50 (s, 1H), 7.34 (s, 1H), 6.95 (s, 1H), 6.47 (m, 2H), 5.08 ( s, 2H), 4.18 (m, 2H), 3.72 (m, 2H), 2.62 (m, 2H), 1.48 (s, 9H). LC-MS: [M+H] + = 421.2.
实施例52：化合物E-Y52的合成Example 52: Synthesis of Compound E-Y52
Figure PCTCN2018102833-appb-000108
Figure PCTCN2018102833-appb-000108
将溴代物13-1(77mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-1(84mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝ 20:1)，得到目标化合物E-Y52，为白色固体(20mg，21％)。LC-MS:[M+H] +＝392.2。 The bromine 13-1 (77 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-1 (84 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y52 was obtained as white solid (20 mg, 21%). LC-MS: [M+H] + = 392.2.
实施例53：化合物E-Y53的合成Example 53: Synthesis of Compound E-Y53
Figure PCTCN2018102833-appb-000109
Figure PCTCN2018102833-appb-000109
将溴代物13-1(77mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-3(123mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y53，为白色固体(13mg，14％)。LC-MS:[M+H] +＝491.2。 Bromine 13-1 (77 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-3 (123 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The title compound E-Y53 was obtained as white solid (13 mg, 14%). LC-MS: [M+H] + =495.
实施例54：化合物E-Y54的合成Example 54: Synthesis of Compound E-Y54
Figure PCTCN2018102833-appb-000110
Figure PCTCN2018102833-appb-000110
将化合物E-Y3(46mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后再加入1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(76mg，0.2mmol)，N,N-二甲基甘氨酸(17mg，0.16mmol)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物E-Y54(6mg)。Compound E-Y3 (46 mg, 0.1 mmol) was dissolved in 3 mL dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), stirred at room temperature for 30 min, and the solvent was concentrated to dryness and then 1 mL DMF and 0.1 mL diisopropyl Ethylamine (DIEPA), stirred and dissolved, and added HATU (76 mg, 0.2 mmol), N,N-dimethylglycine (17 mg, 0.16 mmol) at room temperature for 1 h. TLC showed the reaction was completed and the reaction mixture was poured into water. A large amount of ethyl acetate was extracted, dried and concentrated, and purified by column chromatography to give the object compound E-Y54 (6 mg).
1H NMR(400MHz,DMSO-d 6)δ9.54(d,J＝3.3Hz,1H),8.79(s,1H),7.70(d,J＝6.1Hz,1H),7.30(s,1H),6.95(t,J＝9.4Hz,1H),6.70(dd,J＝8.5,3.7Hz,1H),4.69(d,J＝4.6Hz,2H),4.53(t,J＝8.7Hz,2H),4.24(d,J＝41.1Hz,2H),3.71(s,2H),3.48(s,2H),3.29(t,J＝8.7Hz,2H),2.60(d,J＝38.4Hz,2H),2.37(s,6H).LC-MS:[M+H] +＝452.2。 1 H NMR (400MHz, DMSO- d 6) δ9.54 (d, J = 3.3Hz, 1H), 8.79 (s, 1H), 7.70 (d, J = 6.1Hz, 1H), 7.30 (s, 1H) , 6.95 (t, J = 9.4 Hz, 1H), 6.70 (dd, J = 8.5, 3.7 Hz, 1H), 4.69 (d, J = 4.6 Hz, 2H), 4.53 (t, J = 8.7 Hz, 2H) , 4.24 (d, J = 41.1 Hz, 2H), 3.71 (s, 2H), 3.48 (s, 2H), 3.29 (t, J = 8.7 Hz, 2H), 2.60 (d, J = 38.4 Hz, 2H) , 2.37 (s, 6H). LC-MS: [M+H] + = 452.2.
实施例55:化合物SL-ZYE-07的合成Example 55: Synthesis of Compound SL-ZYE-07
Figure PCTCN2018102833-appb-000111
Figure PCTCN2018102833-appb-000111
将溴代物4-1(72mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-8(89mg，0.4mmol)，Ar置换保护，室温下搅拌10 分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物SL-ZYE-07(47mg，62％)。 1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),8.51(s,1H),7.56(s,1H),6.91(t,J＝9.3Hz,1H),6.69(m,2H),4.65(d,J＝3.8Hz,2H),4.51(t,J＝8.5Hz,2H),3.71(m,2H),3.62(m,2H),3.26(m,2H),2.79(m,2H),2.45(m,2H).LC-MS:[M+H] +＝382.2。 Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-8 (89 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The target compound SL-ZYE-07 (47 mg, 62%) was obtained. 1 H NMR (400MHz, DMSO- d 6) δ9.39 (s, 1H), 8.51 (s, 1H), 7.56 (s, 1H), 6.91 (t, J = 9.3Hz, 1H), 6.69 (m, 2H), 4.65 (d, J = 3.8 Hz, 2H), 4.51 (t, J = 8.5 Hz, 2H), 3.71 (m, 2H), 3.62 (m, 2H), 3.26 (m, 2H), 2.79 ( m, 2H), 2.45 (m, 2H). LC-MS: [M+H] + = 382.2.
实施例56:化合物SL-ZYE-08,SL-ZYE-08-S,SL-ZYE-08-R的合成Example 56: Synthesis of Compound SL-ZYE-08, SL-ZYE-08-S, SL-ZYE-08-R
Figure PCTCN2018102833-appb-000112
Figure PCTCN2018102833-appb-000112
化合物SL-ZYE-07(10mg)溶解于2mL甲醇中，加入10％Pd/C(5mg)室温下反应6小时，过滤，柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物SL-ZYE-08(8mg，82％)。The compound SL-ZYE-07 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (5 mg) at room temperature for 6 hours, filtered, and separated by column chromatography (DCM: MeOH = 20:1) to give the title compound. SL-ZYE-08 (8 mg, 82%).
1H NMR(400MHz,CDCl 3+MeOD-d 4)δ9.05(s,1H),7.41(s,1H),6.82–6.64(m,1H),6.56(dd,J＝8.6,3.9Hz,1H),4.60(s,2H),4.52(t,J＝8.7Hz,2H),3.91–3.77(m,2H),3.69(ddd,J＝19.0,10.7,6.3Hz,2H),3.27(t,J＝8.7Hz,2H),3.16(d,J＝7.8Hz,1H),2.05–1.91(m,4H),1.84(dd,J＝9.0,5.1Hz,2H).LC-MS:[M+H] +＝384.2。 1 H NMR (400 MHz, CDCl 3 +MeOD-d 4 ) δ 9.05 (s, 1H), 7.41 (s, 1H), 6.82 - 6.64 (m, 1H), 6.56 (dd, J = 8.6, 3.9 Hz, 1H), 4.60 (s, 2H), 4.52 (t, J = 8.7 Hz, 2H), 3.91 - 3.77 (m, 2H), 3.69 (ddd, J = 19.0, 10.7, 6.3 Hz, 2H), 3.27 (t , J = 8.7 Hz, 2H), 3.16 (d, J = 7.8 Hz, 1H), 2.05 - 1.91 (m, 4H), 1.84 (dd, J = 9.0, 5.1 Hz, 2H). LC-MS: [M +H] + =384.2.
SL-ZYE-08可进一步通过手性色谱柱分离获得一对光学纯的化合物SL-ZYE-08-S和SL-ZYE-08-R，分离条件为：(手性柱：Chiralcel OD-3，4.6mm x 250mm,particle size:3μm,流动相：正己烷:异丙醇＝50:50，流速＝1ml/min，得到两个流分，流分1(Rt＝17.085分钟)；流分2(Rt＝18.627分钟)。所述手性色谱柱分离方法为本领域技术人员已知的常规方法。SL-ZYE-08 can be further separated by chiral column to obtain a pair of optically pure compounds SL-ZYE-08-S and SL-ZYE-08-R. The separation conditions are: (chiral column: Chiralcel OD-3, 4.6 mm x 250 mm, particle size: 3 μm, mobile phase: n-hexane: isopropanol = 50:50, flow rate = 1 ml/min, two fractions were obtained, fraction 1 (Rt = 17.085 min); fraction 2 ( Rt = 18.66 minutes). The chiral column separation method is a conventional method known to those skilled in the art.
实施例57:化合物SL-ZYE-09的合成Example 57: Synthesis of Compound SL-ZYE-09
Figure PCTCN2018102833-appb-000113
Figure PCTCN2018102833-appb-000113
将E-Y2(5mg)溶解于1mL二氯甲烷中，加入mCPBA(间氯过氧苯甲酸)(2mg)， Ar置换保护，室温下搅拌120分钟。减压浓缩，由柱层析分离制备，得到目标化合物SL-ZYE-09(2mg)。E-Y2 (5 mg) was dissolved in 1 mL of dichloromethane, and mCPBA (m-chloroperoxybenzoic acid) (2 mg) was added thereto, and the mixture was replaced with Ar, and stirred at room temperature for 120 minutes. The organic layer was concentrated under reduced pressure and purified by column chromatography to give the title compound SL-ZYE-09 (2 mg).
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.70(t,J＝5.1Hz,1H),7.76(s,1H),7.12(t,J＝4.6Hz,1H),7.01–6.85(m,1H),6.70(dd,J＝8.7,3.9Hz,1H),4.69(d,J＝4.9Hz,2H),4.54(t,J＝8.7Hz,2H),3.99(s,2H),3.37(t,J＝6.2Hz,2H),3.28(t,J＝8.7Hz,2H),3.17(d,J＝5.3Hz,2H).LC-MS:[M+H] +＝416.1。 1 H NMR (400MHz, DMSO- d 6) δ9.46 (s, 1H), 8.70 (t, J = 5.1Hz, 1H), 7.76 (s, 1H), 7.12 (t, J = 4.6Hz, 1H) , 7.01–6.85 (m, 1H), 6.70 (dd, J=8.7, 3.9 Hz, 1H), 4.69 (d, J=4.9 Hz, 2H), 4.54 (t, J=8.7 Hz, 2H), 3.99 ( s, 2H), 3.37 (t, J = 6.2 Hz, 2H), 3.28 (t, J = 8.7 Hz, 2H), 3.17 (d, J = 5.3 Hz, 2H). LC-MS: [M+H] + =416.1.
实施例58:化合物SL-ZYE-11的合成Example 58: Synthesis of Compound SL-ZYE-11
Figure PCTCN2018102833-appb-000114
Figure PCTCN2018102833-appb-000114
将溴代物4-4(69mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-1(84mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物SL-ZYE-11(17mg)。 Bromine 4-4 (69 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-1 (84 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The target compound SL-ZYE-11 (17 mg) was obtained.
1H NMR(400MHz,CDCl 3+MeOD-d 4)δ9.08(s,1H),7.56(s,1H),7.14(s,1H),7.02(d,J＝7.4Hz,1H),6.79(d,J＝8.0Hz,1H),6.66(d,J＝7.9Hz,1H),4.53(t,J＝8.7Hz,2H),4.35(s,2H),3.92(t,J＝5.3Hz,2H),3.30(s,2H),3.19(t,J＝8.4Hz,2H),2.53(s,2H).LC-MS:[M+H] +＝350.2。 1 H NMR (400 MHz, CDCl 3 +MeOD-d 4 ) δ 9.08 (s, 1H), 7.56 (s, 1H), 7.14 (s, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 4.35 (s, 2H), 3.92 (t, J = 5.3 Hz) , 2H), 3.30 (s, 2H), 3.19 (t, J = 8.4 Hz, 2H), 2.53 (s, 2H). LC-MS: [M+H] + = 350.2.
实施例59:化合物SL-ZYE-14的合成Example 59: Synthesis of Compound SL-ZYE-14
Figure PCTCN2018102833-appb-000115
Figure PCTCN2018102833-appb-000115
化合物SL-ZYE-11(10mg)溶解于2mL甲醇中，加入10％Pd/C(5mg)室温下反应6小时，过滤，柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物SL-ZYE-14(5mg)。The compound SL-ZYE-11 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (5 mg) at room temperature for 6 hours, filtered, and separated by column chromatography (DCM: MeOH = 20:1) to give the title compound. SL-ZYE-14 (5 mg).
1H NMR(400MHz,DMSO-d 6)δ9.41(s,1H),8.55(t,J＝5.4Hz,1H),7.45(s,1H),7.06(t,J＝7.8Hz,1H),6.85(d,J＝7.5Hz,1H),6.69(d,J＝7.9Hz,1H),4.63(d,J＝5.3Hz,2H),4.54(t,J＝8.7Hz,2H),3.96(dd,J＝10.8,3.6Hz,2H),3.51–3.44(m,2H),3.22(t,J＝8.7Hz,2H),3.09(ddd,J＝15.4,7.9,3.7Hz,1H),2.01–1.87(m,2H),1.82(d,J＝12.5Hz,2H).LC-MS:[M+H] +＝352.2。 1 H NMR (400MHz, DMSO- d 6) δ9.41 (s, 1H), 8.55 (t, J = 5.4Hz, 1H), 7.45 (s, 1H), 7.06 (t, J = 7.8Hz, 1H) , 6.85 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 4.63 (d, J = 5.3 Hz, 2H), 4.54 (t, J = 8.7 Hz, 2H), 3.96 (dd, J = 10.8, 3.6 Hz, 2H), 3.51 - 3.44 (m, 2H), 3.22 (t, J = 8.7 Hz, 2H), 3.09 (ddd, J = 15.4, 7.9, 3.7 Hz, 1H), 2.01 - 1.87 (m, 2H), 1.82 (d, J = 12.5 Hz, 2H). LC-MS: [M+H] + = 352.2.
实施例60:化合物SL-ZYE-17的合成Example 60: Synthesis of Compound SL-ZYE-17
Figure PCTCN2018102833-appb-000116
Figure PCTCN2018102833-appb-000116
将溴代物4-5(68mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-1(84mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物SL-ZYE-17(17mg)。 The bromide 4-5 (68mg, 0.2mmol) was dissolved in 6 mL 1,4-dioxane and 2mL of concentration of Na 2M 2 CO 3 solution was added boric acid ester B-1 (84mg, 0.4mmol) , Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The target compound SL-ZYE-17 (17 mg) was obtained.
1H NMR(400MHz,MeOD-d 4)δ9.26(s,1H),7.78(d,J＝2.3Hz,1H),7.74(s,1H),7.47(d,J＝7.9Hz,1H),7.30(d,J＝7.6Hz,2H),7.08(s,1H),7.03(s,1H),5.07(s,2H),4.39(d,J＝2.6Hz,2H),3.98(t,J＝5.5Hz,2H),2.63(s,2H).LC-MS:[M+H] +＝348.1。 1 H NMR (400MHz, MeOD- d 4) δ9.26 (s, 1H), 7.78 (d, J = 2.3Hz, 1H), 7.74 (s, 1H), 7.47 (d, J = 7.9Hz, 1H) , 7.30 (d, J = 7.6 Hz, 2H), 7.08 (s, 1H), 7.03 (s, 1H), 5.07 (s, 2H), 4.39 (d, J = 2.6 Hz, 2H), 3.98 (t, J = 5.5 Hz, 2H), 2.63 (s, 2H). LC-MS: [M+H] + = 348.1.
实施例61:化合物SL-ZYE-18的合成Example 61: Synthesis of Compound SL-ZYE-18
Figure PCTCN2018102833-appb-000117
Figure PCTCN2018102833-appb-000117
将溴代物4-5(68mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-3(123mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物SL-ZYE-18(15mg)。 The bromide 4-5 (68mg, 0.2mmol) was dissolved in 6 mL 1,4-dioxane and 2mL of concentration of Na 2M 2 CO 3 solution was added boric acid ester B-3 (123mg, 0.4mmol) , Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The target compound SL-ZYE-18 (15 mg) was obtained.
1H NMR(400MHz,CDCl 3)δ8.77(s,1H),7.71(s,1H),7.67(d,J＝2.3Hz,1H),7.51(s,1H),7.31–7.29(m,4H),6.90(s,1H),5.08(d,J＝5.3Hz,2H),4.18(s,2H),3.70(s,2H),2.64(s,2H),1.51(s,9H).LC-MS:[M+H] +＝447.1。 1 H NMR (400MHz, CDCl 3 ) δ8.77 (s, 1H), 7.71 (s, 1H), 7.67 (d, J = 2.3Hz, 1H), 7.51 (s, 1H), 7.31-7.29 (m, 4H), 6.90 (s, 1H), 5.08 (d, J = 5.3 Hz, 2H), 4.18 (s, 2H), 3.70 (s, 2H), 2.64 (s, 2H), 1.51 (s, 9H). LC-MS: [M+H] + = 447.1.
实施例62:化合物E-Y20-H的合成Example 62: Synthesis of Compound E-Y20-H
Figure PCTCN2018102833-appb-000118
Figure PCTCN2018102833-appb-000118
化合物E-Y20(10mg)溶解于2mL甲醇中，加入10％Pd/C(3mg)室温下反应6小时，过滤，柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y20-H(4mg，40％)。Compound E-Y20 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (3 mg) at room temperature for 6 hours, filtered, and purified by column chromatography (DCM:MeOH = 20:1) Y20-H (4 mg, 40%).
1H NMR(400MHz,MeOD-d 4)δ9.23(s,1H),7.57(d,J＝0.7Hz,1H),7.47(dd,J＝1.8,0.9Hz,1H),6.42–6.36(m,2H),4.77(s,2H),4.73(m,1H),4.09(m,1H),3.35–3.17(m,2H),2.80(dd,J＝12.9,10.2Hz,1H),2.24–2.18(m,1H),2.17(s,3H),2.07(m,1H),1.87(m,2H).LC-MS:[M+H] +＝341.1。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.23 (s, 1H), 7.57 (d, J = 0.7 Hz, 1H), 7.47 (dd, J = 1.8, 0.9 Hz, 1H), 6.42 - 6.36 ( m, 2H), 4.77 (s, 2H), 4.73 (m, 1H), 4.09 (m, 1H), 3.35 - 3.17 (m, 2H), 2.80 (dd, J = 12.9, 10.2 Hz, 1H), 2.24 - 2.18 (m, 1H), 2.17 (s, 3H), 2.07 (m, 1H), 1.87 (m, 2H). LC-MS: [M+H] + = 341.1.
实施例63:化合物E-Y13-H的合成Example 63: Synthesis of Compound E-Y13-H
Figure PCTCN2018102833-appb-000119
Figure PCTCN2018102833-appb-000119
化合物E-Y13(10mg)溶解于2mL甲醇中，加入10％Pd/C(5mg)室温下反应6小时，过滤，柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y13-H(7mg，71％)。Compound E-Y13 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (5 mg) at room temperature for 6 hours, filtered, and purified by column chromatography (DCM:MeOH = 20:1) Y13-H (7 mg, 71%).
1H NMR(400MHz,DMSO-d 6)δ9.41(s,1H),8.48(t,J＝5.2Hz,1H),7.50(s,1H),6.98–6.90(m,1H),6.70(dd,J＝8.6,3.9Hz,1H),4.64(d,J＝5.0Hz,2H),4.54(t,J＝8.7Hz,2H),3.69(d,J＝11.6Hz,2H),3.29(t,J＝8.7Hz,2H),3.01(m,1H),2.91(s,3H),2.85(dd,J＝8.7,6.0Hz,2H),2.07–1.85(m,4H).LC-MS:[M+H] +＝447.2。 1 H NMR (400MHz, DMSO- d 6) δ9.41 (s, 1H), 8.48 (t, J = 5.2Hz, 1H), 7.50 (s, 1H), 6.98-6.90 (m, 1H), 6.70 ( Dd, J = 8.6, 3.9 Hz, 1H), 4.64 (d, J = 5.0 Hz, 2H), 4.54 (t, J = 8.7 Hz, 2H), 3.69 (d, J = 11.6 Hz, 2H), 3.29 ( t, J = 8.7 Hz, 2H), 3.01 (m, 1H), 2.91 (s, 3H), 2.85 (dd, J = 8.7, 6.0 Hz, 2H), 2.07 - 1.85 (m, 4H). LC-MS :[M+H] + =447.2.
实施例64:化合物E-Y2-H与SL-ZYE-34的合成Example 64: Synthesis of Compound E-Y2-H and SL-ZYE-34
Figure PCTCN2018102833-appb-000120
Figure PCTCN2018102833-appb-000120
化合物E-Y2(10mg)溶解于2mL甲醇中，加入10％Pd/C(5mg)室温下反应6小时，过滤，旋干溶剂得到E-Y2-H，LC-MS:[M+H] +＝386.1。 Compound E-Y2 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (5 mg) at room temperature for 6 hours, filtered, and the solvent was evaporated to give E-Y2-H, LC-MS: [M+H] + =386.1.
将5mg E-Y2-H溶于1mL二氯甲烷溶液，往溶液中加入mCPBA(5mg)，室温反应3小时，柱层析分离制备，得到目标化合物SL-ZYE-34(1.5mg)。5 mg of E-Y2-H was dissolved in 1 mL of a dichloromethane solution, and mCPBA (5 mg) was added to the solution, and the mixture was reacted at room temperature for 3 hours, and separated by column chromatography to give the title compound SL-ZYE-34 (1.5 mg).
1H NMR(400MHz,MeOD-d 4)δ9.27(s,1H),7.63(s,1H),6.92–6.78(m,1H),6.65(dd, J＝8.6,3.7Hz,1H),4.76(s,2H),4.59(t,J＝8.7Hz,2H),3.45–3.33(m,5H),3.17(d,J＝11.8Hz,2H),2.55–2.33(m,4H).LC-MS:[M+H] +＝418.2。 1 H NMR (400MHz, MeOD- d 4) δ9.27 (s, 1H), 7.63 (s, 1H), 6.92-6.78 (m, 1H), 6.65 (dd, J = 8.6,3.7Hz, 1H), 4.76(s, 2H), 4.59 (t, J = 8.7 Hz, 2H), 3.45 - 3.33 (m, 5H), 3.17 (d, J = 11.8 Hz, 2H), 2.55 - 2.33 (m, 4H). LC -MS: [M+H] + = 418.2.
实施例65:化合物SL-ZYE-23的合成Example 65: Synthesis of Compound SL-ZYE-23
Figure PCTCN2018102833-appb-000121
Figure PCTCN2018102833-appb-000121
将溴代物4-1(72mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-10(101mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物SL-ZYE-23(14mg)。 Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-10 (101 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The target compound SL-ZYE-23 (14 mg) was obtained.
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.67(s,1H),7.72(s,1H),7.27(s,1H),7.00–6.87(m,1H),6.70(dd,J＝8.7,3.8Hz,2H),4.70(d,J＝4.8Hz,2H),4.54(t,J＝8.6Hz,2H),4.30(d,J＝5.7Hz,2H),3.27(t,J＝8.7Hz,2H),2.68(s,2H),1.45(s,9H),1.29(d,J＝6.4Hz,3H),1.09(d,J＝6.4Hz,3H).LC-MS:[M+H] +＝495.3。 1 H NMR (400MHz, DMSO- d 6) δ9.46 (s, 1H), 8.67 (s, 1H), 7.72 (s, 1H), 7.27 (s, 1H), 7.00-6.87 (m, 1H), 6.70 (dd, J = 8.7, 3.8 Hz, 2H), 4.70 (d, J = 4.8 Hz, 2H), 4.54 (t, J = 8.6 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.27 (t, J = 8.7 Hz, 2H), 2.68 (s, 2H), 1.45 (s, 9H), 1.29 (d, J = 6.4 Hz, 3H), 1.09 (d, J = 6.4 Hz, 3H). LC-MS: [M+H] + =495.
实施例66:化合物SL-ZYE-24的合成Example 66: Synthesis of Compound SL-ZYE-24
Figure PCTCN2018102833-appb-000122
Figure PCTCN2018102833-appb-000122
将溴代物4-1(72mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-11(95mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物SL-ZYE-24(21mg)。 Bromine 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-11 (95 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The target compound SL-ZYE-24 (21 mg) was obtained.
1H NMR(400MHz,CDCl 3)δ8.93(s,1H),7.66(s,1H),7.24(s,1H),6.88–6.70(m,1H),6.61(dd,J＝8.7,4.0Hz,1H),6.35(s,1H),4.79(d,J＝5.5Hz,2H),4.61(t,J＝8.7Hz,2H),4.51(s,1H),3.94–3.82(m,1H),3.50(m,1H),3.38(t,J＝8.8Hz,2H),2.45(t,J＝16.4Hz,2H),1.38(d,J＝6.2Hz,3H),1.35(d,J＝6.8Hz,3H).LC-MS:[M+H] +＝396.2。 1 H NMR (400MHz, CDCl 3 ) δ8.93 (s, 1H), 7.66 (s, 1H), 7.24 (s, 1H), 6.88-6.70 (m, 1H), 6.61 (dd, J = 8.7,4.0 Hz, 1H), 6.35 (s, 1H), 4.79 (d, J = 5.5 Hz, 2H), 4.61 (t, J = 8.7 Hz, 2H), 4.51 (s, 1H), 3.94 - 3.82 (m, 1H) ), 3.50 (m, 1H), 3.38 (t, J = 8.8 Hz, 2H), 2.45 (t, J = 16.4 Hz, 2H), 1.38 (d, J = 6.2 Hz, 3H), 1.35 (d, J) = 6.8 Hz, 3H). LC-MS: [M+H] + = 396.2.
实施例67:化合物SL-ZYE-28的合成Example 67: Synthesis of Compound SL-ZYE-28
Figure PCTCN2018102833-appb-000123
Figure PCTCN2018102833-appb-000123
将溴代物4-1(72mg，0.2mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-12(103mg，0.4mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(7.3mg，0.02mmol)，20％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(21.2mg，0.04mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物SL-ZYE-28(27mg，32％)。 The bromo 4-1 (72 mg, 0.2 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-12 (103 mg, 0.4 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (7.3 mg, 0.02 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (21.2 mg, 0.04 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 20:1) The target compound SL-ZYE-28 (27 mg, 32%) was obtained.
1H NMR(400MHz,MeOD-d 4)δ9.44(s,1H),8.07(s,1H),7.23–7.14(m,1H),6.94–6.79(m,4H),6.68(dd,J＝8.6,3.9Hz,1H),6.17(t,J＝3.9Hz,1H),4.92(d,J＝3.9Hz,2H),4.88(s,2H),4.61(t,J＝8.7Hz,2H),3.43(t,J＝8.7Hz,2H).LC-MS:[M+H] +＝416.2。 1 H NMR (400 MHz, MeOD-d 4 ) δ 9.44 (s, 1H), 8.07 (s, 1H), 7.23 - 7.14 (m, 1H), 6.94 - 6.79 (m, 4H), 6.68 (dd, J = 8.6, 3.9 Hz, 1H), 6.17 (t, J = 3.9 Hz, 1H), 4.92 (d, J = 3.9 Hz, 2H), 4.88 (s, 2H), 4.61 (t, J = 8.7 Hz, 2H) ), 3.43 (t, J = 8.7 Hz, 2H). LC-MS: [M+H] + = 416.2.
实施例68:化合物E-Y54-H的合成Example 68: Synthesis of Compound E-Y54-H
Figure PCTCN2018102833-appb-000124
Figure PCTCN2018102833-appb-000124
化合物E-Y54(10mg)溶解于2mL甲醇中，加入10％Pd/C(5mg)室温下反应6小时，过滤，柱层析分离制备(DCM:MeOH＝20:1)，得到目标化合物E-Y54-H(5mg)。Compound E-Y54 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (5 mg) at room temperature for 6 hours, filtered, and purified by column chromatography (DCM:MeOH = 20:1) Y54-H (5 mg).
1H NMR(400MHz,MeOD-d 4)δ9.27(s,1H),7.57(s,1H),6.91–6.81(m,1H),6.65(dd,J＝8.6,3.9Hz,1H),4.76(s,2H),4.70(d,J＝13.5Hz,1H),4.58(t,J＝8.7Hz,2H),4.10(d,J＝13.9Hz,1H),3.60(dd,J＝16.9,6.6Hz,2H),3.36(dd,J＝10.0,7.6Hz,2H),3.25(d,J＝16.0Hz,2H),2.84(m,1H),2.52(s,6H),2.07(m,2H),1.91(m,2H).LC-MS:[M+H] +＝454.2。 1 H NMR (400MHz, MeOD- d 4) δ9.27 (s, 1H), 7.57 (s, 1H), 6.91-6.81 (m, 1H), 6.65 (dd, J = 8.6,3.9Hz, 1H), 4.76(s, 2H), 4.70 (d, J = 13.5 Hz, 1H), 4.58 (t, J = 8.7 Hz, 2H), 4.10 (d, J = 13.9 Hz, 1H), 3.60 (dd, J = 16.9) , 6.6 Hz, 2H), 3.36 (dd, J = 10.0, 7.6 Hz, 2H), 3.25 (d, J = 16.0 Hz, 2H), 2.84 (m, 1H), 2.52 (s, 6H), 2.07 (m) , 2H), 1.91 (m, 2H). LC-MS: [M+H] + = 454.2.
实施例69:化合物SL-E1的合成Example 69: Synthesis of Compound SL-E1
Figure PCTCN2018102833-appb-000125
Figure PCTCN2018102833-appb-000125
将溴代物4-1(36mg，0.1mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-13(64mg，0.2mmol)，Ar置换保护，室温下搅拌10 分钟。加入10％氯化烯丙基钯(II)二聚物(3.5mg，0.01mmol)，20％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(11mg，0.02mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备得到目标化合物SL-E1(11mg)。LC-MS:[M+H] +＝481.2。 Bromine 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and boronic acid ester B-13 (64 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl The sodium sulfonate sulfonate hydrate (11 mg, 0.02 mmol) was reacted at 90 ° C for 40 minutes under the protection of Ar. After cooling, the mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound SL-E1 (11 mg). LC-MS: [M+H] + = 481.2.
实施例70:化合物SL-E2的合成Example 70: Synthesis of Compound SL-E2
Figure PCTCN2018102833-appb-000126
Figure PCTCN2018102833-appb-000126
化合物SL-E1(10mg)溶解于2mL甲醇中，加入10％Pd/C(5mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E2(7mg)。LC-MS:[M+H] +＝483.2。 The compound SL-E1 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (5 mg) at room temperature for 6 hours, filtered, and purified by column chromatography to give the title compound SL-E2 (7 mg). LC-MS: [M+H] + = 483.2.
参考实施例56，SL-E2可通过手性色谱柱分离获得光学纯化合物SL-E2-S和SL-E2-R。Referring to Example 56, SL-E2 was isolated by chiral chromatography to obtain optically pure compounds SL-E2-S and SL-E2-R.
实施例71:化合物SL-E3的合成Example 71: Synthesis of Compound SL-E3
Figure PCTCN2018102833-appb-000127
Figure PCTCN2018102833-appb-000127
化合物SL-E3(9mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E3(5mg)。LC-MS:[M+H] +＝497.2。 The compound SL-E3 (9 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E3 (5 mg). LC-MS: [M+H] + = 497.2.
实施例72:化合物SL-E4的合成Example 72: Synthesis of Compound SL-E4
Figure PCTCN2018102833-appb-000128
Figure PCTCN2018102833-appb-000128
化合物SL-E3(9mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E4(5mg)。LC-MS:[M+H] +＝398.1。 The compound SL-E3 (9 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E4 (5 mg). LC-MS: [M+H] + = 398.1.
实施例73:化合物SL-E5的合成Example 73: Synthesis of Compound SL-E5
Figure PCTCN2018102833-appb-000129
Figure PCTCN2018102833-appb-000129
将化合物E-Y10(20mg)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg)以及2-(1-吡咯烷基)乙酸(CAS:37386-15-5)(13mg)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E5(3mg)。LC-MS:[M+H] +＝478.2。 Compound E-Y10 (20 mg) was dissolved in 1 mL of DMF and 0.1 mL of diisopropylethylamine (DIEPA), dissolved by stirring, and HATU (38 mg) and 2-(1-pyrrolidinyl)acetic acid (CAS: 37386-15-5) (13mg), reaction 1h, TLC showed the end of the reaction, the reaction mixture was poured into water, extracted with a large amount of ethyl acetate, dried and concentrated to give the title compound SL-E5 (3 mg). LC-MS: [M+H] + = 478.2.
实施例74:化合物SL-E6的合成Example 74: Synthesis of Compound SL-E6
Figure PCTCN2018102833-appb-000130
Figure PCTCN2018102833-appb-000130
将化合物E-Y10(20mg)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg，0.1mmol)以及N,N-二乙基甘氨酸(13mg，0.1mmol)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E6(6mg)。LC-MS:[M+H] +＝480.2。 Compound E-Y10 (20 mg) was dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA), stirred and dissolved, and HATU (38 mg, 0.1 mmol) and N,N-diethylglycine (13 mg) were added at room temperature. The reaction mixture was poured into water, extracted with a large amount of ethyl acetate, dried and concentrated, and purified by column chromatography to give the title compound SL-E6 (6 mg). LC-MS: [M+H] + = 480.2.
实施例75:化合物SL-E7的合成Example 75: Synthesis of Compound SL-E7
Figure PCTCN2018102833-appb-000131
Figure PCTCN2018102833-appb-000131
将化合物E-Y10(20mg)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg)以及甲氧基乙酸(CAS:625-45-6)(9mg)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E7(2mg)。LC-MS:[M+H] +＝439.2。 Compound E-Y10 (20 mg) was dissolved in 1 mL of DMF and 0.1 mL of diisopropylethylamine (DIEPA), dissolved by stirring, and HATU (38 mg) and methoxyacetic acid (CAS: 625-45-6) were added at room temperature. (9 mg), 1 h of reaction, TLC showed the reaction was completed, the reaction mixture was poured into water, and ethyl acetate was extracted, dried and concentrated, and purified by column chromatography to give the title compound SL-E7 (2 mg). LC-MS: [M+H] + = 439.2.
实施例76:化合物SL-E8的合成Example 76: Synthesis of Compound SL-E8
Figure PCTCN2018102833-appb-000132
Figure PCTCN2018102833-appb-000132
将化合物E-Y10(20mg)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)， 搅拌溶解，室温下加入HATU(38mg，0.1mmol)以及酸(oxetane-3-carboxylic acid)(10mg，0.1mmol)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E8(2.5mg)。LC-MS:[M+H] +＝451.2。 Compound E-Y10 (20 mg) was dissolved in 1 mL of DMF and 0.1 mL of diisopropylethylamine (DIEPA), stirred and dissolved, and HATU (38 mg, 0.1 mmol) and acid (oxetane-3-carboxylic acid) were added at room temperature ( 10 mg, 0.1 mmol), 1 h of reaction, TLC showed the reaction was completed, the reaction mixture was poured into water, and ethyl acetate was extracted, dried and concentrated, and then purified by column chromatography to give the title compound SL-E8 (2.5 mg). LC-MS: [M+H] + = 451.2.
实施例77:化合物SL-E9的合成Example 77: Synthesis of Compound SL-E9
Figure PCTCN2018102833-appb-000133
Figure PCTCN2018102833-appb-000133
将化合物E-Y10(20mg)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg)以及2-(2-甲氧基乙氧基)乙酸(CAS号:16024-56-9)(14mg)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E9(5mg)。LC-MS:[M+H] +＝483.2。 Compound E-Y10 (20 mg) was dissolved in 1 mL of DMF and 0.1 mL of diisopropylethylamine (DIEPA), dissolved by stirring, and HATU (38 mg) and 2-(2-methoxyethoxy)acetic acid were added at room temperature. (CAS No.: 16024-56-9) (14mg), 1h reaction, TLC showed the end of the reaction, the reaction solution was poured into water, extracted with a large amount of ethyl acetate, concentrated by drying, and separated by column chromatography to obtain the target compound SL-E9 (5mg). LC-MS: [M+H] + = 483.2.
实施例78:化合物SL-E10的合成Example 78: Synthesis of Compound SL-E10
Figure PCTCN2018102833-appb-000134
Figure PCTCN2018102833-appb-000134
将化合物E-Y10(20mg)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg，0.1mmol)以及1-甲基哌啶-4-甲酸(15mg，0.1mmol)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E10(6mg)。LC-MS:[M+H] +＝492.2。 Compound E-Y10 (20 mg) was dissolved in 1 mL of DMF and 0.1 mL of diisopropylethylamine (DIEPA), dissolved by stirring, and HATU (38 mg, 0.1 mmol) and 1-methylpiperidine-4-carboxylic acid were added at room temperature. (15 mg, 0.1 mmol), 1 h of reaction, TLC showed the reaction was completed, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, dried and concentrated to give the title compound SL-E10 (6 mg). LC-MS: [M+H] + =495.
实施例79:化合物SL-E11的合成Example 79: Synthesis of Compound SL-E11
Figure PCTCN2018102833-appb-000135
Figure PCTCN2018102833-appb-000135
将化合物E-Y10(20mg)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg，0.1mmol)以及酸(CAS号:1158712-36-7)(22mg，0.1mmol)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E11(7mg)。LC-MS:[M+H] +＝562.2。 Compound E-Y10 (20 mg) was dissolved in 1 mL of DMF and 0.1 mL of diisopropylethylamine (DIEPA), dissolved by stirring, and HATU (38 mg, 0.1 mmol) and acid (CAS No.: 1158712-36-7) were added at room temperature. (22 mg, 0.1 mmol), 1 h of reaction, TLC showed the reaction was completed, the reaction mixture was poured into water, and ethyl acetate was extracted, dried, concentrated, and purified by column chromatography to give the title compound SL-E11 (7 mg). LC-MS: [M+H] + = 562.2.
实施例80:化合物SL-E12的合成Example 80: Synthesis of Compound SL-E12
Figure PCTCN2018102833-appb-000136
Figure PCTCN2018102833-appb-000136
将化合物SL-E1(96mg，0.2mmol)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，浓缩后直接经HPLC分离得到产物SL-E12(50mg)，LC-MS:[M+H] +＝381.2。 The compound SL-E1 (96 mg, 0.2 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), stirred at room temperature for 30 min, concentrated, and directly separated by HPLC to give the product SL-E12 (50 mg), LC -MS: [M+H] + = 381.2.
实施例81:化合物SL-E13的合成Example 81: Synthesis of Compound SL-E13
Figure PCTCN2018102833-appb-000137
Figure PCTCN2018102833-appb-000137
将SL-E12(25mg)溶解于1mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入乙酸酐(Ac 2O，15mg)，反应1小时，TLC显示反应结束后，由柱层析分离制备得到目标化合物SL-E13(6mg)。LC-MS:[M+H] +＝423.2。 SL-E12 (25 mg) was dissolved in 1 mL of dichloromethane and 0.1 mL of triethylamine (TEA), dissolved by stirring, and acetic anhydride (Ac 2 O, 15 mg) was added at room temperature for 1 hour, and TLC showed the reaction was completed. The title compound SL-E13 (6 mg) was obtained by column chromatography. LC-MS: [M+H] + = 423.2.
实施例82:化合物SL-E14的合成Example 82: Synthesis of Compound SL-E14
Figure PCTCN2018102833-appb-000138
Figure PCTCN2018102833-appb-000138
将SL-E12(10mg)溶解于1mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入甲磺酸酐(Ms 2O，8mg)，反应1小时，TLC显示反应结束后，由柱层析分离制备得到目标化合物SL-E14(3mg)。 1H NMR(400MHz,DMSO-d 6)δ9.44(s,1H),8.63(m,1H),7.67(s,1H),6.99–6.90(m,1H),6.82(t,J＝5.9Hz,1H),6.70(dd,J＝8.7,3.8Hz,1H),4.68(d,J＝4.9Hz,2H),4.54(t,J＝8.7Hz,2H),4.03(d,J＝6.0Hz,2H),3.57–3.48(m,2H),3.31–3.24(m,2H),2.91(s,3H),2.83(m,2H),1.91(m,2H).LC-MS:[M+H] +＝459.2。 SL-E12 (10 mg) was dissolved in 1 mL of dichloromethane and 0.1 mL of triethylamine (TEA), dissolved by stirring, and methanesulfonic anhydride (Ms 2 O, 8 mg) was added at room temperature for 1 hour, and TLC showed the reaction was completed. The title compound SL-E14 (3 mg) was obtained by column chromatography. 1 H NMR (400MHz, DMSO- d 6) δ9.44 (s, 1H), 8.63 (m, 1H), 7.67 (s, 1H), 6.99-6.90 (m, 1H), 6.82 (t, J = 5.9 Hz, 1H), 6.70 (dd, J = 8.7, 3.8 Hz, 1H), 4.68 (d, J = 4.9 Hz, 2H), 4.54 (t, J = 8.7 Hz, 2H), 4.03 (d, J = 6.0) Hz, 2H), 3.57–3.48 (m, 2H), 3.31–3.24 (m, 2H), 2.91 (s, 3H), 2.83 (m, 2H), 1.91 (m, 2H). LC-MS: [M +H] + =459.2.
实施例83:化合物SL-E15的合成Example 83: Synthesis of Compound SL-E15
Figure PCTCN2018102833-appb-000139
Figure PCTCN2018102833-appb-000139
将化合物SL-E12(19mg，0.05mmol)溶解于1mL DMF和0.1mL二异丙基乙基 胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg，0.1mmol)以及N,N-二甲基甘氨酸(11mg，0.1mmol)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E15(2mg)。LC-MS:[M+H] +＝466.3。 Compound SL-E12 (19 mg, 0.05 mmol) was dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA), stirred and dissolved, and HATU (38 mg, 0.1 mmol) and N,N-dimethyl group were added at room temperature. Glycine (11 mg, 0.1 mmol) was reacted for 1 h, and TLC showed the reaction was completed. The reaction mixture was poured into water, extracted with ethyl acetate, dried and concentrated, and purified by column chromatography to give the title compound SL-E15 (2 mg). LC-MS: [M+H] + = 466.3.
实施例84:化合物SL-E16的合成Example 84: Synthesis of Compound SL-E16
Figure PCTCN2018102833-appb-000140
Figure PCTCN2018102833-appb-000140
将化合物SL-E12(19mg，0.05mmol)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg，0.1mmol)以及2-(1-吡咯烷基)乙酸(CAS:37386-15-5)(14mg)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E16(2mg)。LC-MS:[M+H] +＝492.2。 Compound SL-E12 (19 mg, 0.05 mmol) was dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA), stirred and dissolved, and HATU (38 mg, 0.1 mmol) and 2-(1-pyrrolidine) were added at room temperature. Acetic acid (CAS: 37386-15-5) (14mg), reaction for 1h, TLC showed the end of the reaction, the reaction solution was poured into water, extracted with a large amount of ethyl acetate, dried and concentrated, and separated by column chromatography to obtain the target compound SL -E16 (2 mg). LC-MS: [M+H] + =495.
实施例85:化合物SL-E17的合成Example 85: Synthesis of Compound SL-E17
Figure PCTCN2018102833-appb-000141
Figure PCTCN2018102833-appb-000141
将化合物SL-E12(19mg，0.05mmol)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg，0.1mmol)以及N,N-二乙基甘氨酸(13mg)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E17(2mg)。LC-MS:[M+H] +＝494.4。 Compound SL-E12 (19 mg, 0.05 mmol) was dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA), stirred and dissolved, and HATU (38 mg, 0.1 mmol) and N,N-diethyl were added at room temperature. Glycine (13 mg) was reacted for 1 h, and TLC showed the reaction was completed. The reaction mixture was poured into water, extracted with ethyl acetate, dried and concentrated, and purified by column chromatography to give the title compound SL-E17 (2 mg). LC-MS: [M+H] + =495.
实施例86:化合物SL-E18的合成Example 86: Synthesis of Compound SL-E18
Figure PCTCN2018102833-appb-000142
Figure PCTCN2018102833-appb-000142
将化合物SL-E12(19mg，0.05mmol)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg)以及甲氧基乙酸(CAS:625-45-6)(11mg)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E18(3mg)。LC-MS:[M+H] +＝453.2。 Compound SL-E12 (19 mg, 0.05 mmol) was dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA), stirred and dissolved, and HATU (38 mg) and methoxyacetic acid (CAS: 625-45) were added at room temperature. -6) (11 mg), 1 h of reaction, TLC showed the reaction was completed, the reaction mixture was poured into water, and ethyl acetate was extracted, dried and concentrated, and purified by column chromatography to give the title compound SL-E18 (3 mg). LC-MS: [M+H] + = 453.2.
实施例87:化合物SL-E19的合成Example 87: Synthesis of Compound SL-E19
Figure PCTCN2018102833-appb-000143
Figure PCTCN2018102833-appb-000143
将化合物SL-E12(19mg，0.05mmol)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg，0.1mmol)以及酸(oxetane-3-carboxylic acid)(10mg，0.1mmol)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E19(1.5mg)。LC-MS:[M+H] +＝465.2。 Compound SL-E12 (19 mg, 0.05 mmol) was dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA), stirred and dissolved, and HATU (38 mg, 0.1 mmol) and acid (oxetane-3-carboxylic) were added at room temperature. Acid (10 mg, 0.1 mmol) was reacted for 1 h. TLC showed that the reaction was completed. The reaction mixture was poured into water, and ethyl acetate was extracted, dried and concentrated to give the title compound SL-E19 (1.5 mg). LC-MS: [M+H] + = 465.2.
实施例88:化合物SL-E20的合成Example 88: Synthesis of Compound SL-E20
Figure PCTCN2018102833-appb-000144
Figure PCTCN2018102833-appb-000144
将化合物SL-E12(19mg，0.05mmol)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg)以及2-(2-甲氧基乙氧基)乙酸(CAS号:16024-56-9)(15mg)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E20(2mg)。LC-MS:[M+H] +＝497.2。 Compound SL-E12 (19 mg, 0.05 mmol) was dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA), stirred and dissolved, and HATU (38 mg) and 2-(2-methoxyethoxy) were added at room temperature. Acetic acid (CAS No.: 16024-56-9) (15mg), reaction for 1h, TLC showed the end of the reaction, the reaction solution was poured into water, extracted with a large amount of ethyl acetate, dried and concentrated, and separated by column chromatography to obtain the target compound SL-E20 (2 mg). LC-MS: [M+H] + = 497.2.
实施例89:化合物SL-E21的合成Example 89: Synthesis of Compound SL-E21
Figure PCTCN2018102833-appb-000145
Figure PCTCN2018102833-appb-000145
将化合物SL-E12(19mg，0.05mmol)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg，0.1mmol)以及1-甲基哌啶-4-甲酸(15mg，0.1mmol)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E21(3mg)。LC-MS:[M+H] +＝506.2。 Compound SL-E12 (19 mg, 0.05 mmol) was dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA), stirred and dissolved, and HATU (38 mg, 0.1 mmol) and 1-methylpiperidine were added at room temperature. 4-carboxylic acid (15 mg, 0.1 mmol) was reacted for 1 h. TLC showed the reaction was completed, and the reaction mixture was poured into water, and ethyl acetate was extracted, dried and concentrated to give the title compound SL-E21 (3 mg). LC-MS: [M+H] + = 506.2.
实施例90:化合物SL-E22的合成Example 90: Synthesis of Compound SL-E22
Figure PCTCN2018102833-appb-000146
Figure PCTCN2018102833-appb-000146
将化合物SL-E12(19mg，0.05mmol)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(38mg，0.1mmol)以及酸(CAS号:1158712-36-7)(22mg，0.1mmol)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E22(0.8mg)。LC-MS:[M+H] +＝576.2。 Compound SL-E12 (19 mg, 0.05 mmol) was dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA), stirred and dissolved, and HATU (38 mg, 0.1 mmol) and acid (CAS No.: 1158712-) were added at room temperature. 36-7) (22mg, 0.1mmol), 1h reaction, TLC showed the end of the reaction, the reaction solution was poured into water, extracted with a large amount of ethyl acetate, concentrated by drying, and separated by column chromatography to obtain the target compound SL-E22 (0.8mg) ). LC-MS: [M+H] + = 576.2.
实施例91:化合物SL-E23的合成Example 91: Synthesis of Compound SL-E23
Figure PCTCN2018102833-appb-000147
Figure PCTCN2018102833-appb-000147
将溴代物4-1(36mg，0.1mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-14(44mg，0.2mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(3.5mg，0.01mmol)，20％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(11mg，0.02mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备得到目标化合物SL-E23，为白色固体(6mg)。 1H NMR(400MHz,DMSO-d 6)δ9.47(d,J＝6.2Hz,1H),8.67(d,J＝4.9Hz,1H),7.71(d,J＝8.4Hz,1H),7.30(m,1H),6.94(t,J＝9.4Hz,1H),6.70(dd,J＝8.5,3.8Hz,1H),4.69(d,J＝4.8Hz,2H),4.57(m,2H),3.47(m,2H),3.28(t,J＝8.8Hz,2H),2.97(m,2H),2.69(m,2H),2.56(m,3H).LC-MS:[M+H] +＝381.2。 The bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate B-14 (44 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol), maintained at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography to give the title compound SL-E23 as white solid. (6mg). 1 H NMR (400MHz, DMSO- d 6) δ9.47 (d, J = 6.2Hz, 1H), 8.67 (d, J = 4.9Hz, 1H), 7.71 (d, J = 8.4Hz, 1H), 7.30 (m, 1H), 6.94 (t, J = 9.4 Hz, 1H), 6.70 (dd, J = 8.5, 3.8 Hz, 1H), 4.69 (d, J = 4.8 Hz, 2H), 4.57 (m, 2H) , 3.47 (m, 2H), 3.28 (t, J = 8.8 Hz, 2H), 2.97 (m, 2H), 2.69 (m, 2H), 2.56 (m, 3H). LC-MS: [M+H] + =381.2.
实施例92:化合物SL-E24的合成Example 92: Synthesis of Compound SL-E24
Figure PCTCN2018102833-appb-000148
Figure PCTCN2018102833-appb-000148
将溴代物4-1(36mg，0.1mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯B-15(47mg，0.2mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(3.5mg，0.01mmol)，20％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(11mg，0.02mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备得到目标化合物SL-E24(3.5mg)。 1H NMR(400MHz,CD 3OD+CDCl 3)δ9.31(s,1H),7.94(s,1H),7.18(s,1H),6.83(m,1H),6.65(m,1H),4.79(s,2H),4.60(t,J＝8.8Hz,2H),3.64(t,J＝7.3Hz,2H),3.37(m,2H),3.06(s,3H),2.99(m,2H).LC-MS:[M+H] +＝395.1。 The bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and borate B-15 (47 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol), kept at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and purified by column chromatography to give the title compound SL-E24 (3.5 mg) . 1 H NMR (400 MHz, CD 3 OD + CDCl 3 ) δ 9.31 (s, 1H), 7.94 (s, 1H), 7.18 (s, 1H), 6.83 (m, 1H), 6.65 (m, 1H), 4.79 (s, 2H), 4.60 (t, J = 8.8 Hz, 2H), 3.64 (t, J = 7.3 Hz, 2H), 3.37 (m, 2H), 3.06 (s, 3H), 2.99 (m, 2H) ). LC-MS: [M+H] + = 395.1.
实施例93:化合物SL-E25的合成Example 93: Synthesis of Compound SL-E25
Figure PCTCN2018102833-appb-000149
Figure PCTCN2018102833-appb-000149
化合物SL-E23(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E25(5mg)。 1H NMR(400MHz,CD 3OD)δ9.29(s,1H),7.61(s,1H),6.90–6.80(m,1H),6.63(m,1H),4.76(s,2H),4.66–4.51(m,2H),3.58–3.44(m,2H),3.40–3.34(m,2H),3.23–3.11(m,1H),3.09–2.95(m,2H),2.83(s,3H),2.27–2.17(m,4H).LC-MS:[M+H] +＝383.2。 The compound SL-E23 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E25 (5 mg). 1 H NMR (400 MHz, CD 3 OD) δ 9.29 (s, 1H), 7.61 (s, 1H), 6.90 - 6.80 (m, 1H), 6.63 (m, 1H), 4.76 (s, 2H), 4.66 –4.51 (m, 2H), 3.58–3.44 (m, 2H), 3.40–3.34 (m, 2H), 3.23–3.11 (m, 1H), 3.09–2.95 (m, 2H), 2.83 (s, 3H) , 2.27–2.17 (m, 4H). LC-MS: [M+H] + = 383.2.
实施例94:化合物SL-E26的合成Example 94: Synthesis of Compound SL-E26
Figure PCTCN2018102833-appb-000150
Figure PCTCN2018102833-appb-000150
化合物SL-E24(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E26(2mg)。 1H NMR(400MHz,CDCl 3)δ8.94(s,1H),7.45(s,1H),6.84(t,J＝9.4Hz,1H),6.66(dd,J＝8.6,3.9Hz,1H),6.37(m,1H),4.77(d,J＝5.3Hz,2H),4.63(t,J＝8.7Hz,2H),3.49(m,2H),3.39(m,3H),2.99(s,3H),2.75(m,2H),2.33(m,2H).LC-MS:[M+H] +＝397.2。 The compound SL-E24 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and purified by column chromatography to give the title compound SL-E26 (2 mg). 1 H NMR (400MHz, CDCl 3 ) δ8.94 (s, 1H), 7.45 (s, 1H), 6.84 (t, J = 9.4Hz, 1H), 6.66 (dd, J = 8.6,3.9Hz, 1H) , 6.37 (m, 1H), 4.77 (d, J = 5.3 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.49 (m, 2H), 3.39 (m, 3H), 2.99 (s, 3H), 2.75 (m, 2H), 2.33 (m, 2H). LC-MS: [M+H] + = 397.2.
实施例95:化合物SL-E29的合成Example 95: Synthesis of Compound SL-E29
Figure PCTCN2018102833-appb-000151
Figure PCTCN2018102833-appb-000151
将化合物SL-ZYE-23(50mg，0.1mmol)溶解于3mL二氯甲烷(DCM)和1mL三 氟乙酸(TFA)中，室温搅拌30min，浓缩后直接经HPLC分离得到产物SL-E29(38mg)，LC-MS:[M+H] +＝395.2。 The compound SL-ZYE-23 (50 mg, 0.1 mmol) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), stirred at room temperature for 30 min, concentrated, and directly isolated by HPLC to give product SL-E29 (38 mg) , LC-MS: [M+H] + = 395.2.
实施例96:化合物SL-E30的合成Example 96: Synthesis of Compound SL-E30
Figure PCTCN2018102833-appb-000152
Figure PCTCN2018102833-appb-000152
将SL-E29(10mg)溶解于1mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入乙酸酐(Ac 2O，8mg)，反应1小时，TLC显示反应结束后，由柱层析分离制备得到目标化合物SL-E30(4mg)。LC-MS:[M+H] +＝437.2。 SL-E29 (10 mg) was dissolved in 1 mL of dichloromethane and 0.1 mL of triethylamine (TEA), dissolved by stirring, and acetic anhydride (Ac 2 O, 8 mg) was added at room temperature for 1 hour, and TLC showed the reaction was completed. The target compound SL-E30 (4 mg) was obtained by column chromatography. LC-MS: [M+H] + = 437.2.
实施例97:化合物SL-E31的合成Example 97: Synthesis of Compound SL-E31
Figure PCTCN2018102833-appb-000153
Figure PCTCN2018102833-appb-000153
将SL-E29(10mg)溶解于1mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入甲磺酸酐(Ms 2O，7mg)，反应1小时，TLC显示反应结束后，由柱层析分离制备得到目标化合物SL-E31(3mg)。LC-MS:[M+H] +＝473.2。 SL-E29 (10 mg) was dissolved in 1 mL of dichloromethane and 0.1 mL of triethylamine (TEA), dissolved by stirring, and methanesulfonic anhydride (Ms 2 O, 7 mg) was added at room temperature for 1 hour, and TLC showed the reaction was completed. The title compound SL-E31 (3 mg) was obtained by column chromatography. LC-MS: [M+H] + = 473.2.
实施例98:化合物SL-E32的合成Example 98: Synthesis of Compound SL-E32
Figure PCTCN2018102833-appb-000154
Figure PCTCN2018102833-appb-000154
将化合物SL-E29(12mg)溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)，搅拌溶解，室温下加入HATU(30mg)以及N,N-二甲基甘氨酸(9mg)，反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E32(4mg)。LC-MS:[M+H] +＝480.2。 Compound SL-E29 (12 mg) was dissolved in 1 mL of DMF and 0.1 mL of diisopropylethylamine (DIEPA), dissolved by stirring, and HATU (30 mg) and N,N-dimethylglycine (9 mg) were added at room temperature. After 1 h, TLC showed the reaction was completed, and the reaction mixture was poured into water, and ethyl acetate was extracted, dried and concentrated to give the title compound SL-E32 (4 mg). LC-MS: [M+H] + = 480.2.
实施例99:化合物SL-E33的合成Example 99: Synthesis of Compound SL-E33
Figure PCTCN2018102833-appb-000155
Figure PCTCN2018102833-appb-000155
化合物SL-E30(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E33(4mg)。LC-MS:[M+H] +＝439.2。 The compound SL-E30 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and purified by column chromatography to give the title compound SL-E33 (4 mg). LC-MS: [M+H] + = 439.2.
实施例100:化合物SL-E34的合成Example 100: Synthesis of Compound SL-E34
Figure PCTCN2018102833-appb-000156
Figure PCTCN2018102833-appb-000156
化合物SL-E31(9mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E34(4mg)。LC-MS:[M+H] +＝475.2。 The compound SL-E31 (9 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and purified by column chromatography to give the title compound SL-E34 (4 mg). LC-MS: [M+H] + = 475.2.
实施例101:化合物SL-E35的合成Example 101: Synthesis of Compound SL-E35
Figure PCTCN2018102833-appb-000157
Figure PCTCN2018102833-appb-000157
化合物SL-E32(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E35(4mg)。LC-MS:[M+H] +＝482.2。 The compound SL-E32 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and purified by column chromatography to give the title compound SL-E35 (4 mg). LC-MS: [M+H] + = 482.2.
实施例102:化合物SL-E36的合成Example 102: Synthesis of Compound SL-E36
Figure PCTCN2018102833-appb-000158
Figure PCTCN2018102833-appb-000158
化合物SL-E5(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E36(5mg)。LC-MS:[M+H] +＝480.2。 The compound SL-E5 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E36 (5 mg). LC-MS: [M+H] + = 480.2.
实施例103:化合物SL-E37的合成Example 103: Synthesis of Compound SL-E37
Figure PCTCN2018102833-appb-000159
Figure PCTCN2018102833-appb-000159
化合物SL-E6(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E37(5mg)。LC-MS:[M+H] +＝482.2。 The compound SL-E6 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E37 (5 mg). LC-MS: [M+H] + = 482.2.
实施例104:化合物SL-E38的合成Example 104: Synthesis of Compound SL-E38
Figure PCTCN2018102833-appb-000160
Figure PCTCN2018102833-appb-000160
化合物SL-E7(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E38(5mg)。LC-MS:[M+H] +＝441.2。 The compound SL-E7 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E38 (5 mg). LC-MS: [M+H] + = 441.2.
实施例105:化合物SL-E39的合成Example 105: Synthesis of Compound SL-E39
Figure PCTCN2018102833-appb-000161
Figure PCTCN2018102833-appb-000161
将化合物E-Y3(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应3小时，硅藻土过滤，将滤液旋干后，溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后，再次溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)中，室温下加入HATU(15mg)以及酸(oxetane-3-carboxylic acid)(9mg)，反应1h，将反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E39(0.7mg)。LC-MS:[M+H] +＝453.4。 The compound E-Y3 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 3 hours, filtered through Celite, and the filtrate was dried and dissolved in 3 mL of dichloromethane (DCM). In 1 mL of trifluoroacetic acid (TFA), stir at room temperature for 30 min, concentrate the solvent, dissolve again in 1 mL of DMF and 0.1 mL of diisopropylethylamine (DIEPA), add HATU (15 mg) and acid (oxetane) at room temperature. -3-carboxylic acid) (9 mg), 1 h, the reaction mixture was poured into water, and ethyl acetate was evaporated. LC-MS: [M+H] + = 453.4.
实施例106:化合物SL-E40的合成Example 106: Synthesis of Compound SL-E40
Figure PCTCN2018102833-appb-000162
Figure PCTCN2018102833-appb-000162
化合物SL-E9(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E40(5mg)。LC-MS:[M+H] +＝485.2。 The compound SL-E9 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E40 (5 mg). LC-MS: [M+H] + = 485.2.
实施例107:化合物SL-E41的合成Example 107: Synthesis of Compound SL-E41
Figure PCTCN2018102833-appb-000163
Figure PCTCN2018102833-appb-000163
SL-E10(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E41(5mg)。LC-MS:[M+H] +＝494.3。 SL-E10 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E41 (5 mg). LC-MS: [M+H] + =495.
实施例108:化合物SL-E42的合成Example 108: Synthesis of Compound SL-E42
Figure PCTCN2018102833-appb-000164
Figure PCTCN2018102833-appb-000164
SL-E11(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E42(5mg)。LC-MS:[M+H] +＝564.2。 SL-E11 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E42 (5 mg). LC-MS: [M+H] + = 564.2.
实施例109:化合物SL-E43,SL-E43-S,SL-E43-R的合成Example 109: Synthesis of Compound SL-E43, SL-E43-S, SL-E43-R
Figure PCTCN2018102833-appb-000165
Figure PCTCN2018102833-appb-000165
SL-E13(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E43(5mg)。LC-MS:[M+H] +＝425.2。 SL-E13 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E43 (5 mg). LC-MS: [M+H] + = 425.2.
参考实施例56，SL-E43通过手性色谱柱分离获得光学纯化合物SL-E43-S和SL-E43-R。Referring to Example 56, SL-E43 was separated by chiral chromatography to obtain optically pure compounds SL-E43-S and SL-E43-R.
实施例110:化合物SL-E44,SL-E44-S,SL-E44-R的合成Example 110: Synthesis of Compound SL-E44, SL-E44-S, SL-E44-R
Figure PCTCN2018102833-appb-000166
Figure PCTCN2018102833-appb-000166
SL-E14(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E44(5mg)。LC-MS:[M+H] +＝461.2。 SL-E14 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E44 (5 mg). LC-MS: [M+H] + = 461.2.
参考实施例56，SL-E44通过手性色谱柱分离获得光学纯化合物SL-E44-S和SL-E44-R。Referring to Example 56, SL-E44 was isolated by chiral chromatography to obtain optically pure compounds SL-E44-S and SL-E44-R.
实施例111:化合物SL-E45,SL-E45-S,SL-E45-R的合成Example 111: Synthesis of Compound SL-E45, SL-E45-S, SL-E45-R
Figure PCTCN2018102833-appb-000167
Figure PCTCN2018102833-appb-000167
SL-E15(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E45(5mg)。LC-MS:[M+H] +＝468.2。 SL-E15 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E45 (5 mg). LC-MS: [M+H] + = 468.2.
参考实施例56，SL-E45通过手性色谱柱分离获得光学纯化合物SL-E45-S和SL-E45-R。Referring to Example 56, SL-E45 was separated by chiral chromatography to obtain optically pure compounds SL-E45-S and SL-E45-R.
实施例112:化合物SL-E46,SL-E46-S,SL-E46-R的合成Example 112: Synthesis of Compound SL-E46, SL-E46-S, SL-E46-R
Figure PCTCN2018102833-appb-000168
Figure PCTCN2018102833-appb-000168
SL-E16(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E46(4mg)。LC-MS:[M+H] +＝494.2。 SL-E16 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E46 (4 mg). LC-MS: [M+H] + =495.
参考实施例56，SL-E46通过手性色谱柱分离获得光学纯化合物SL-E46-S和 SL-E46-R。Referring to Example 56, SL-E46 was separated by chiral column to obtain optically pure compounds SL-E46-S and SL-E46-R.
实施例113:化合物SL-E47的合成Example 113: Synthesis of Compound SL-E47
Figure PCTCN2018102833-appb-000169
Figure PCTCN2018102833-appb-000169
SL-E17(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E47(4mg)。LC-MS:[M+H] +＝496.2。 SL-E17 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E47 (4 mg). LC-MS: [M+H] + =495.
参考实施例56，SL-E47通过手性色谱柱分离获得光学纯化合物SL-E47-S和SL-E47-R。Referring to Example 56, SL-E47 was separated by chiral column to obtain optically pure compounds SL-E47-S and SL-E47-R.
实施例114:化合物SL-E48的合成Example 114: Synthesis of Compound SL-E48
Figure PCTCN2018102833-appb-000170
Figure PCTCN2018102833-appb-000170
SL-E18(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E48(4mg)。LC-MS:[M+H] +＝455.2。 SL-E18 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E48 (4 mg). LC-MS: [M+H] + = 455.2.
参考实施例56，SL-E48通过手性色谱柱分离获得光学纯化合物SL-E48-S和SL-E48-R。Referring to Example 56, SL-E48 was separated by chiral column to obtain optically pure compounds SL-E48-S and SL-E48-R.
实施例115:化合物SL-E49的合成Example 115: Synthesis of Compound SL-E49
Figure PCTCN2018102833-appb-000171
Figure PCTCN2018102833-appb-000171
将化合物SL-E2(10mg)溶解于3mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌30min，将溶剂浓缩干后，溶解于1mL DMF和0.1mL二异丙基乙基胺(DIEPA)中，室温下加入HATU(30mg)以及酸(oxetane-3-carboxylic acid)(9mg)， 反应1h，TLC显示反应结束，反应液倒入水中，大量乙酸乙酯萃取，干燥浓缩，经柱层析分离制备，得到目标化合物SL-E49(1.2mg)。LC-MS:[M+H] +＝467.2。 Compound SL-E2 (10 mg) was dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA), and stirred at room temperature for 30 min. The solvent was concentrated to dryness and dissolved in 1 mL of DMF and 0.1 mL of diisopropylethyl In the amine (DIEPA), HATU (30 mg) and oxetane-3-carboxylic acid (9 mg) were added at room temperature for 1 h. TLC showed the end of the reaction. The reaction mixture was poured into water, extracted with ethyl acetate and concentrated. The title compound SL-E49 (1.2 mg) was obtained by column chromatography. LC-MS: [M+H] + = 467.2.
参考实施例56，SL-E49通过手性色谱柱分离获得光学纯化合物SL-E49-S和SL-E49-R。Referring to Example 56, SL-E49 was separated by chiral column to obtain optically pure compounds SL-E49-S and SL-E49-R.
实施例116:化合物SL-E50的合成Example 116: Synthesis of Compound SL-E50
Figure PCTCN2018102833-appb-000172
Figure PCTCN2018102833-appb-000172
SL-E20(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E50(4mg)。LC-MS:[M+H] +＝499.2。 SL-E20 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E50 (4 mg). LC-MS: [M+H] + =495.
参考实施例56，SL-E50通过手性色谱柱分离获得光学纯化合物SL-E50-S和SL-E50-R。Referring to Example 56, SL-E50 was separated by chiral chromatography to obtain optically pure compounds SL-E50-S and SL-E50-R.
实施例117:化合物SL-E51的合成Example 117: Synthesis of Compound SL-E51
Figure PCTCN2018102833-appb-000173
Figure PCTCN2018102833-appb-000173
SL-E21(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E51(4mg)。LC-MS:[M+H] +＝508.3。 SL-E21 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E51 (4 mg). LC-MS: [M+H] + = 508.3.
参考实施例56，SL-E51通过手性色谱柱分离获得光学纯化合物SL-E51-S和SL-E51-R。Referring to Example 56, SL-E51 was separated by chiral chromatography to obtain optically pure compounds SL-E51-S and SL-E51-R.
实施例118:化合物SL-E52的合成Example 118: Synthesis of Compound SL-E52
Figure PCTCN2018102833-appb-000174
Figure PCTCN2018102833-appb-000174
SL-E22(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E52(4mg)。LC-MS:[M+H] +＝578.2。 SL-E22 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E52 (4 mg). LC-MS: [M+H] + = 578.2.
参考实施例56，SL-E52通过手性色谱柱分离获得光学纯化合物SL-E52-S和SL-E52-R。Referring to Example 56, SL-E52 was separated by chiral chromatography to obtain optically pure compounds SL-E52-S and SL-E52-R.
实施例119:化合物SL-E53的合成Example 119: Synthesis of Compound SL-E53
Figure PCTCN2018102833-appb-000175
Figure PCTCN2018102833-appb-000175
SL-ZYE-28(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-E53(4mg)。LC-MS:[M+H] +＝418.3。 SL-ZYE-28 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-E53 (4 mg). LC-MS: [M+H] + = 418.3.
实施例120:化合物SL-ZYE-119的合成Example 120: Synthesis of Compound SL-ZYE-119
Figure PCTCN2018102833-appb-000176
Figure PCTCN2018102833-appb-000176
将溴代物4-1(36mg，0.1mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯SL-B3(48mg，0.2mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(3.5mg，0.01mmol)，20％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(11mg，0.02mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备得到目标化合物SL-ZYE-119(4.1mg)。1H NMR(400MHz,DMSO-d 6)δ9.44(s,1H),8.61(m,1H),7.66(s,1H),7.30(m,1H),6.94(m,1H),6.70(m,1H),4.69(m,2H),4.54(m,2H),4.30(m,2H),3.29(m,2H),2.40(m,2H),1.23(s,6H).LC-MS:[M+H] +＝396.2。 The bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and the boronic acid ester SL-B3 (48 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol) was kept at 90 ° C for 40 minutes under Ar protection. After cooling, it was concentrated under reduced pressure and purified by column chromatography to give the title compound SL-ZYE-119 (4.1. Mg). 1H NMR (400MHz, DMSO-d 6 ) δ 9.44 (s, 1H), 8.61 (m, 1H), 7.66 (s, 1H), 7.30 (m, 1H), 6.94 (m, 1H), 6.70 (m) , 1H), 4.69 (m, 2H), 4.54 (m, 2H), 4.30 (m, 2H), 3.29 (m, 2H), 2.40 (m, 2H), 1.23 (s, 6H). LC-MS: [M+H] + = 396.2.
实施例121:化合物SL-ZYE-120的合成Example 121: Synthesis of Compound SL-ZYE-120
Figure PCTCN2018102833-appb-000177
Figure PCTCN2018102833-appb-000177
将溴代物4-1(36mg，0.1mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯SL-B4(48mg，0.2mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(3.5mg，0.01mmol)，20％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(11mg，0.02mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备得到目标化合物SL-ZYE-120(4.1mg)。 1H NMR(400MHz,DMSO-d 6)δ9.44(s,1H),8.62(m,1H),7.67(m,1H),7.27(m,1H),6.93(m,1H),6.70(m,1H),4.69(m,2H),4.52(m,2H),3.84(m,2H),3.26(m,2H),2.42(m,2H),1.28(s,6H).LC-MS:[M+H] +＝396.2。 The bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and borate SL-B4 (48 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol), maintained at 90 ° C for 40 minutes under Ar protection, cooled, concentrated under reduced pressure, and separated by column chromatography to give the title compound SL-ZYE-120 (4.1) Mg). 1 H NMR (400MHz, DMSO- d 6) δ9.44 (s, 1H), 8.62 (m, 1H), 7.67 (m, 1H), 7.27 (m, 1H), 6.93 (m, 1H), 6.70 ( m,1H), 4.69 (m, 2H), 4.52 (m, 2H), 3.84 (m, 2H), 3.26 (m, 2H), 2.42 (m, 2H), 1.28 (s, 6H). LC-MS :[M+H] + =396.2.
实施例122:化合物SL-ZYE-121的合成Example 122: Synthesis of Compound SL-ZYE-121
Figure PCTCN2018102833-appb-000178
Figure PCTCN2018102833-appb-000178
SL-ZYE-119(10mg)溶解于2mL甲醇中，加入10％Pd/C(4mg)室温下反应6小时，过滤，柱层析分离制备，得到目标化合物SL-ZYE-121(4mg)。 1H NMR(400MHz,DMSO-d 6)δ9.32(s,1H),8.32(s,1H),7.38(m,1H),6.85(m,1H),6.62(m,1H),4.56-4.47(m,4H),3.68(m,2H),3.20(m,3H),1.70(m,4H),1.09(m,6H).LC-MS:[M+H] +＝398.2。 SL-ZYE-119 (10 mg) was dissolved in 2 mL of methanol, and reacted with 10% Pd/C (4 mg) at room temperature for 6 hours, filtered, and separated by column chromatography to give the title compound SL-ZYE-121 (4 mg). 1 H NMR (400MHz, DMSO- d 6) δ9.32 (s, 1H), 8.32 (s, 1H), 7.38 (m, 1H), 6.85 (m, 1H), 6.62 (m, 1H), 4.56- 4.47 (m, 4H), 3.68 (m, 2H), 3.20 (m, 3H), 1.70 (m, 4H), 1.09 (m, 6H). LC-MS: [M+H] + = 398.2.
实施例123:化合物SL-ZYE-195的合成Example 123: Synthesis of Compound SL-ZYE-195
Figure PCTCN2018102833-appb-000179
Figure PCTCN2018102833-appb-000179
将溴代物4-1(36mg，0.1mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯SL-B5(50mg，0.2mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(3.5mg，0.01mmol)，20％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(11mg，0.02mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备得到目标化合物SL-ZYE-195(4.1mg)。 1H NMR(400MHz,DMSO-d 6)δ9.45(s,1H),8.63(m,1H),7.68(m,1H),7.28(m,1H),6.93(m,1H),6.71(m,1H),4.68(d,J＝4.0Hz,2H),4.54(J＝8.0Hz,2H),3.27(J＝8.0Hz,2H),2.38(m,2H),1.29(s,6H),1.24(s,6H).LC-MS:[M+H] +＝424.2。 The bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and the boronic acid ester SL-B5 (50 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol) was kept at 90 ° C for 40 minutes under the protection of Ar. After cooling, it was concentrated under reduced pressure, and the title compound SL-ZYE-195 was obtained by column chromatography. Mg). 1 H NMR (400MHz, DMSO- d 6) δ9.45 (s, 1H), 8.63 (m, 1H), 7.68 (m, 1H), 7.28 (m, 1H), 6.93 (m, 1H), 6.71 ( m, 1H), 4.68 (d, J = 4.0 Hz, 2H), 4.54 (J = 8.0 Hz, 2H), 3.27 (J = 8.0 Hz, 2H), 2.38 (m, 2H), 1.29 (s, 6H) , 1.24 (s, 6H). LC-MS: [M+H] + = 424.2.
实施例124:化合物SL-ZYE-196的合成Example 124: Synthesis of Compound SL-ZYE-196
Figure PCTCN2018102833-appb-000180
Figure PCTCN2018102833-appb-000180
将溴代物4-1(36mg，0.1mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯SL-B6(49mg，0.2mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(3.5mg，0.01mmol)，20％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(11mg，0.02mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备得到目标化合物SL-ZYE-196(4.1mg)。 1H NMR(400MHz,DMSO-d 6)δ9.44(s,1H),8.61(m,1H),7.66(m,1H),7.32(m,1H),6.94(m,1H),6.70(m,1H),4.68(d,J＝4.0Hz,2H),4.54(t,J＝8.0Hz,2H),4.34(m,2H),3.70(m,1H),3.29(J＝8.0Hz,2H),2.56-2.21(m,2H),1.25(d,J＝4.0Hz,3H).LC-MS:[M+H] +＝382.2。 The bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2M aqueous Na 2 CO 3 solution, and the boronic acid ester SL-B6 (49 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol) was kept at 90 ° C for 40 minutes under the protection of Ar. After cooling, it was concentrated under reduced pressure and separated by column chromatography to give the title compound SL-ZYE-196 (4.1. Mg). 1 H NMR (400MHz, DMSO- d 6) δ9.44 (s, 1H), 8.61 (m, 1H), 7.66 (m, 1H), 7.32 (m, 1H), 6.94 (m, 1H), 6.70 ( m, 1H), 4.68 (d, J = 4.0 Hz, 2H), 4.54 (t, J = 8.0 Hz, 2H), 4.34 (m, 2H), 3.70 (m, 1H), 3.29 (J = 8.0 Hz, 2H), 2.56-2.21 (m, 2H), 1.25 (d, J = 4.0 Hz, 3H). LC-MS: [M+H] + = 382.2.
实施例125:化合物SL-ZYE-197的合成Example 125: Synthesis of Compound SL-ZYE-197
Figure PCTCN2018102833-appb-000181
Figure PCTCN2018102833-appb-000181
将溴代物4-1(36mg，0.1mmol)溶解于6mL 1,4-二氧六环和2mL浓度为2M的Na 2CO 3水溶液中，加入硼酸酯SL-B7(49mg，0.2mmol)，Ar置换保护，室温下搅拌10分钟。加入10％氯化烯丙基钯(II)二聚物(3.5mg，0.01mmol)，20％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(11mg，0.02mmol)，在Ar保护下保持在90℃反应40分钟，冷却后减压浓缩，由柱层析分离制备得到目标化合物SL-ZYE-197(4.1mg)。 The bromo 4-1 (36 mg, 0.1 mmol) was dissolved in 6 mL of 1,4-dioxane and 2 mL of a 2 M aqueous Na 2 CO 3 solution, and the boronic acid ester SL-B7 (49 mg, 0.2 mmol) was added. Ar substitution protection, stirring at room temperature for 10 minutes. Add 10% allyl palladium (II) dimer (3.5 mg, 0.01 mmol), 20% 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl Sodium 3-sulfonate hydrate (11 mg, 0.02 mmol) was kept at 90 ° C for 40 minutes under the protection of Ar. After cooling, it was concentrated under reduced pressure and purified by column chromatography to give the title compound SL-ZYE-197 (4.1. Mg).
1H NMR(400MHz,DMSO-d 6)δ9.44(s,1H),8.63(m,1H),7.67(m,1H),7.28(m,1H),6.94(m,1H),6.71(m,1H),4.69(d,J＝4.0Hz,2H),4.53(t,J＝8.0Hz,2H),4.37(m,1H),4.06(m,1H),3.68(m,1H),3.28(J＝8.0Hz,2H),2.60-2.32(m,2H),1.26(d,J＝4.0Hz,3H).LC-MS:[M+H] +＝382.2。 1 H NMR (400MHz, DMSO- d 6) δ9.44 (s, 1H), 8.63 (m, 1H), 7.67 (m, 1H), 7.28 (m, 1H), 6.94 (m, 1H), 6.71 ( m, 1H), 4.69 (d, J = 4.0 Hz, 2H), 4.53 (t, J = 8.0 Hz, 2H), 4.37 (m, 1H), 4.06 (m, 1H), 3.68 (m, 1H), 3.28 (J=8.0 Hz, 2H), 2.60-2.32 (m, 2H), 1.26 (d, J = 4.0 Hz, 3H). LC-MS: [M+H] + = 382.2.
实施例126：化合物SL-ZYE-144的合成Example 126: Synthesis of Compound SL-ZYE-144
Figure PCTCN2018102833-appb-000182
Figure PCTCN2018102833-appb-000182
将化合物E-Y3(46mg)溶解于5mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入乙基磺酰氯(20mg)，继续反应，TLC显示反应结束，直接由柱层析分离制备，得到目标化合物SL-ZYE-144(7mg)。Compound E-Y3 (46 mg) was dissolved in 5 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA) and stirred at room temperature. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 mL of triethylamine (TEA) The mixture was stirred and dissolved. Ethylsulfonyl chloride (20 mg) was added at room temperature, and the reaction was continued. TLC showed the reaction was completed, which was directly separated by column chromatography to give the title compound SL-ZYE-144 (7 mg).
1H NMR(400MHz,CDCl 3)δ9.00(s,1H),7.64(s,1H),7.24(m,1H),6.78(m,1H),6.61(m,2H),4.80(s,2H),4.61(t,J＝8.7Hz,2H),4.06(m,2H),3.61(t,J＝5.6Hz,2H),3.38(t,J＝8.7Hz,2H),3.04(q,J＝7.4Hz,2H),2.72(m,2H),1.40(t,J＝7.4Hz,3H).LC-MS:[M+H] +＝459.1。 1 H NMR (400MHz, CDCl 3 ) δ9.00 (s, 1H), 7.64 (s, 1H), 7.24 (m, 1H), 6.78 (m, 1H), 6.61 (m, 2H), 4.80 (s, 2H), 4.61 (t, J = 8.7 Hz, 2H), 4.06 (m, 2H), 3.61 (t, J = 5.6 Hz, 2H), 3.38 (t, J = 8.7 Hz, 2H), 3.04 (q, J = 7.4 Hz, 2H), 2.72 (m, 2H), 1.40 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + = 459.1.
实施例127：化合物SL-ZYE-146的合成Example 127: Synthesis of Compound SL-ZYE-146
Figure PCTCN2018102833-appb-000183
Figure PCTCN2018102833-appb-000183
将化合物E-Y3(46mg)溶解于5mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入环丙基磺酰氯(20mg)，继续反应，TLC显示反应结束，直接由柱层析分离制备，得到目标化合物SL-ZYE-146(6mg)。Compound E-Y3 (46 mg) was dissolved in 5 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA) and stirred at room temperature. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 mL of triethylamine (TEA) The mixture was stirred and dissolved, and cyclopropylsulfonyl chloride (20 mg) was added thereto at room temperature to continue the reaction. TLC showed the reaction was completed and was directly separated by column chromatography to give the title compound SL-ZYE-146 (6 mg).
1H NMR(400MHz,CDCl 3)δ9.03(s,1H),7.64(s,1H),7.23(m,1H),6.77(m,2H),6.58(dd,J＝8.7,3.9Hz,1H),4.78(d,J＝5.3Hz,2H),4.60(t,J＝8.7Hz,2H),4.08(m,2H),3.60(t,J＝5.7Hz,2H),3.37(t,J＝8.7Hz,2H),2.74(m,2H),2.42–2.27(m,1H),1.32–1.14(m,2H),1.11–0.88(m,2H).LC-MS:[M-H] +＝469.2。 1 H NMR (400 MHz, CDCl 3 ) δ 9.03 (s, 1H), 7.64 (s, 1H), 7.23 (m, 1H), 6.77 (m, 2H), 6.58 (dd, J = 8.7, 3.9 Hz, 1H), 4.78 (d, J = 5.3 Hz, 2H), 4.60 (t, J = 8.7 Hz, 2H), 4.08 (m, 2H), 3.60 (t, J = 5.7 Hz, 2H), 3.37 (t, J=8.7 Hz, 2H), 2.74 (m, 2H), 2.42–2.27 (m, 1H), 1.32–1.14 (m, 2H), 1.11–0.88 (m, 2H). LC-MS: [MH] + =469.2.
实施例128：化合物SL-ZYE-147的合成Example 128: Synthesis of Compound SL-ZYE-147
Figure PCTCN2018102833-appb-000184
Figure PCTCN2018102833-appb-000184
将化合物E-Y3(46mg)溶解于5mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入氯甲酸甲酯(15mg)，继续反应，TLC显示反应结束，直接由柱层析分离制备，得到目标化合物SL-ZYE-147(5mg)。Compound E-Y3 (46 mg) was dissolved in 5 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA) and stirred at room temperature. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 mL of triethylamine (TEA) The mixture was stirred and dissolved, and methyl chloroformate (15 mg) was added at room temperature to continue the reaction. TLC showed the reaction was completed and was directly separated by column chromatography to give the title compound SL-ZYE-147 (5 mg).
1H NMR(400MHz,DMSO-d 6)δ9.45(s,1H),8.64(m,1H),7.69(s,1H),7.26(s,1H),6.93(m,1H),6.71(m,1H),4.69(m,2H),4.54(m,2H),4.12(m,2H),3.64(s,3H),3.61(m,2H),3.28(m,2H),2.57(m,2H).LC-MS:[M+H] +＝425.2。 1 H NMR (400MHz, DMSO- d 6) δ9.45 (s, 1H), 8.64 (m, 1H), 7.69 (s, 1H), 7.26 (s, 1H), 6.93 (m, 1H), 6.71 ( m,1H), 4.69 (m, 2H), 4.54 (m, 2H), 4.12 (m, 2H), 3.64 (s, 3H), 3.61 (m, 2H), 3.28 (m, 2H), 2.57 (m) , 2H). LC-MS: [M+H] + = 425.2.
实施例129：化合物SL-ZYE-148的合成Example 129: Synthesis of compound SL-ZYE-148
Figure PCTCN2018102833-appb-000185
Figure PCTCN2018102833-appb-000185
将化合物E-Y3(46mg)溶解于5mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入氯甲酸乙酯(15mg)，继续反应，TLC显示反应结束，直接由柱层析分离制备，得到目标化合物SL-ZYE-148(4mg)。Compound E-Y3 (46 mg) was dissolved in 5 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA) and stirred at room temperature. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 mL of triethylamine (TEA) The mixture was stirred and dissolved, and ethyl chloroformate (15 mg) was added at room temperature to continue the reaction. TLC showed the reaction was completed, and was directly separated by column chromatography to give the title compound SL-ZYE-148 (4 mg).
1H NMR(400MHz,CDCl 3)δ9.12(s,1H),7.64(s,1H),7.26–7.09(m,1H),7.00(m,1H),6.74(t,J＝9.2Hz,1H),6.57(dd,J＝8.6,3.9Hz,1H),4.78(d,J＝4.9Hz,2H),4.58(t,J＝8.8Hz,2H),4.23–4.10(m,4H),3.72(d,J＝5.3Hz,2H),3.35(t,J＝9.0Hz,2H),2.63(m,2H),1.29(t,J＝7.0Hz,3H).LC-MS:[M+H] +＝439.2。 1 H NMR (400MHz, CDCl 3 ) δ9.12 (s, 1H), 7.64 (s, 1H), 7.26-7.09 (m, 1H), 7.00 (m, 1H), 6.74 (t, J = 9.2Hz, 1H), 6.57 (dd, J = 8.6, 3.9 Hz, 1H), 4.78 (d, J = 4.9 Hz, 2H), 4.58 (t, J = 8.8 Hz, 2H), 4.23 - 4.10 (m, 4H), 3.72 (d, J = 5.3 Hz, 2H), 3.35 (t, J = 9.0 Hz, 2H), 2.63 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H). LC-MS: [M+ H] + = 439.2.
实施例130:化合物SL-ZYE-161的合成Example 130: Synthesis of Compound SL-ZYE-161
Figure PCTCN2018102833-appb-000186
Figure PCTCN2018102833-appb-000186
将化合物E-Y3(46mg)溶解于5mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入丙酰氯(10mg)，继续反应，TLC显示反应结束，直接由柱层析分离制备，得到目标化合物SL-ZYE-161(4mg)。 1H NMR(400MHz,CDCl 3)δ9.76(m,1H),8.19(m,1H),7.62(m,1H),7.34-7.13(m,1H),6.82–6.67(m,1H),6.58(m,1H),4.79(m,2H),4.57(m,2H),4.26(m,2H),3.82(m,2H),3.39(m,2H),2.65(m,2H),2.50–2.29(m,2H),1.17(m,3H).LC-MS:[M+H] +＝423.2。 Compound E-Y3 (46 mg) was dissolved in 5 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA) and stirred at room temperature. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 mL of triethylamine (TEA) The mixture was stirred and dissolved, and propionyl chloride (10 mg) was added thereto at room temperature to continue the reaction. TLC showed the end of the reaction, which was directly separated by column chromatography to give the title compound SL-ZYE-161 (4 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 9.76 (m, 1H), 8.19 (m, 1H), 7.62 (m, 1H), 7.34 - 7.13 (m, 1H), 6.82 - 6.67 (m, 1H), 6.58 (m, 1H), 4.79 (m, 2H), 4.57 (m, 2H), 4.26 (m, 2H), 3.82 (m, 2H), 3.39 (m, 2H), 2.65 (m, 2H), 2.50 - 2.29 (m, 2H), 1.17 (m, 3H). LC-MS: [M+H] + = 423.2.
实施例131:化合物SL-ZYE-162的合成Example 131: Synthesis of Compound SL-ZYE-162
Figure PCTCN2018102833-appb-000187
Figure PCTCN2018102833-appb-000187
将化合物E-Y3(46mg)溶解于5mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入丙酰氯(10mg)，继续反应，TLC显示反应结束，直接由柱层析分离制备，得到目标化合物SL-ZYE-162(4mg)。 1H NMR(400MHz,CDCl 3)δ9.35(m,1H),7.81(m,1H),7.64(m,1H),7.33-7.10(m,1H),6.74(m,1H),6.57(m,1H),4.77(m,2H),4.57(m,2H),4.29(m,2H),3.85(m,2H),3.34(m,2H),2.77-2.60(m,2H),1.84(m,1H),0.85(m,4H).LC-MS:[M+H] +＝435.2。 Compound E-Y3 (46 mg) was dissolved in 5 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA) and stirred at room temperature. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 mL of triethylamine (TEA) The mixture was stirred and dissolved, and propionyl chloride (10 mg) was added thereto at room temperature to continue the reaction. TLC showed the reaction was completed and was directly separated by column chromatography to give the title compound SL-ZYE-162 (4 mg). 1 H NMR (400MHz, CDCl 3 ) δ9.35 (m, 1H), 7.81 (m, 1H), 7.64 (m, 1H), 7.33-7.10 (m, 1H), 6.74 (m, 1H), 6.57 ( m,1H), 4.77 (m, 2H), 4.57 (m, 2H), 4.29 (m, 2H), 3.85 (m, 2H), 3.34 (m, 2H), 2.77-2.60 (m, 2H), 1.84 (m, 1H), 0.85 (m, 4H). LC-MS: [M+H] + = 435.2.
实施例132:化合物SL-ZYE-145的合成Example 132: Synthesis of Compound SL-ZYE-145
Figure PCTCN2018102833-appb-000188
Figure PCTCN2018102833-appb-000188
将化合物E-Y3(46mg)溶解于5mL二氯甲烷(DCM)和1mL三氟乙酸(TFA)中，室温搅拌，将溶剂浓缩干后再加入3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入异丙基磺酰氯(20mg)，继续反应，TLC显示反应结束，直接由柱层析分离制备，得到目标化合物SL-ZYE-145(7mg)。Compound E-Y3 (46 mg) was dissolved in 5 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA) and stirred at room temperature. The solvent was concentrated to dryness and then 3 mL of dichloromethane and 0.1 mL of triethylamine (TEA) The mixture was stirred and dissolved, and isopropylsulfonyl chloride (20 mg) was added at room temperature to continue the reaction. TLC showed that the reaction was completed and was directly separated by column chromatography to give the title compound SL-ZYE-145 (7 mg).
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.69(m,1H),7.70(s,1H),7.33(m,1H),6.96(d,J＝8.7Hz,1H),6.71(d,J＝3.9Hz,1H),4.69(m,2H),4.55(d,J＝8.7Hz,2H),4.04(m,2H),3.53(d,J＝5.7Hz,2H),3.47–3.37(m,1H),3.32–3.24(m,2H),2.66(m,2H),1.25(s,3H),1.23(s,3H).LC-MS:[M+H] +＝473.2。 1 H NMR (400MHz, DMSO- d 6) δ9.46 (s, 1H), 8.69 (m, 1H), 7.70 (s, 1H), 7.33 (m, 1H), 6.96 (d, J = 8.7Hz, 1H), 6.71 (d, J = 3.9 Hz, 1H), 4.69 (m, 2H), 4.55 (d, J = 8.7 Hz, 2H), 4.04 (m, 2H), 3.53 (d, J = 5.7 Hz, 2H), 3.47–3.37 (m, 1H), 3.32–3.24 (m, 2H), 2.66 (m, 2H), 1.25 (s, 3H), 1.23 (s, 3H). LC-MS: [M+H ] + =473.2.
实施例133:化合物SL-ZYE-183的合成Example 133: Synthesis of Compound SL-ZYE-183
Figure PCTCN2018102833-appb-000189
Figure PCTCN2018102833-appb-000189
将SL-E12(30mg)溶于3mL二氯甲烷和0.1mL三乙胺(TEA)，搅拌溶解，室温下加入氯甲酸甲酯(15mg)，继续反应，TLC显示反应结束，直接由柱层析分离制备， 得到目标化合物SL-ZYE-183(5mg)。 1H NMR(400MHz,DMSO-d 6)δ9.43(s,1H),8.60(m,1H),7.62(s,1H),6.98–6.90(m,1H),6.82(m,1H),6.69(m,1H),4.67(d,J＝5.0Hz,2H),4.53(t,J＝8.7Hz,2H),4.07(m,2H),3.59(m,5H),3.28(t,J＝8.7Hz,2H),2.72(m,2H),1.86(m,2H).LC-MS:[M+H] +＝439.2。 SL-E12 (30 mg) was dissolved in 3 mL of dichloromethane and 0.1 mL of triethylamine (TEA), dissolved by stirring, and methyl chloroformate (15 mg) was added at room temperature to continue the reaction. TLC showed the end of the reaction, directly by column chromatography. Separation and preparation gave the title compound SL-ZYE-183 (5 mg). 1 H NMR (400MHz, DMSO- d 6) δ9.43 (s, 1H), 8.60 (m, 1H), 7.62 (s, 1H), 6.98-6.90 (m, 1H), 6.82 (m, 1H), 6.69 (m, 1H), 4.67 (d, J = 5.0 Hz, 2H), 4.53 (t, J = 8.7 Hz, 2H), 4.07 (m, 2H), 3.59 (m, 5H), 3.28 (t, J) = 8.7 Hz, 2H), 2.72 (m, 2H), 1.86 (m, 2H). LC-MS: [M+H] + = 439.2.
实施例134：多梳抑制复合物2(PRC2)酶活性测定实验Example 134: Multi-comb inhibition complex 2 (PRC2) enzyme activity assay
使用TR-FRET方法检测PRC2酶的活性。首先，酶与不同浓度的化合物混合，室温孵育30分钟。加入生物素标记的组蛋白H3多肽底物和辅因子S-腺苷甲硫氨酸(SAM)起始酶促反应。室温反应4小时后，加入受体Acceptor和供体Donor，孵育半小时。用多功能酶标仪EnVision(Perkin Elmer公司)检测荧光信号。用GraphPad Prism 5.0软件分析数据，获得IC 50值。 The activity of the PRC2 enzyme was detected using the TR-FRET method. First, the enzyme was mixed with different concentrations of the compound and incubated for 30 minutes at room temperature. The biotinylated histone H3 polypeptide substrate and the cofactor S-adenosylmethionine (SAM) were added to initiate the enzymatic reaction. After 4 hours of reaction at room temperature, the receptor Acceptor and donor Donor were added and incubated for half an hour. Fluorescence signals were detected using a multi-function microplate reader EnVision (Perkin Elmer). Data was analyzed using GraphPad Prism 5.0 software, the value of 50 obtained IC.
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)，N/A代表未分析。The compounds described in Table 1 were prepared by the method described in the above examples, EED226 was a positive compound (Nat. Chem. Biol. 2017, 13, 381-388), and N/A represents unanalyzed.
Figure PCTCN2018102833-appb-000190
Figure PCTCN2018102833-appb-000190
Figure PCTCN2018102833-appb-000191
Figure PCTCN2018102833-appb-000191
Figure PCTCN2018102833-appb-000192
Figure PCTCN2018102833-appb-000192
Figure PCTCN2018102833-appb-000193
Figure PCTCN2018102833-appb-000193
Figure PCTCN2018102833-appb-000194
Figure PCTCN2018102833-appb-000194
Figure PCTCN2018102833-appb-000195
Figure PCTCN2018102833-appb-000195
Figure PCTCN2018102833-appb-000196
Figure PCTCN2018102833-appb-000196
Figure PCTCN2018102833-appb-000197
Figure PCTCN2018102833-appb-000197
Figure PCTCN2018102833-appb-000198
Figure PCTCN2018102833-appb-000198
实施例135：细胞长时生长抑制实验(11天)Example 135: Cell growth inhibition test (11 days)
将指数生长期的Pfeiffer细胞种在24孔板中，细胞密度为1*10E5cells/mL。当天加入不同浓度的化合物处理细胞。在化合物处理4天和7天时，更换新鲜的培养基和化合物。化合物处理11天后，用CellTiter-Glo试剂(Promega公司)测定细胞存活率。用GraphPad Prism 5.0软件分析数据，获得GI 50值。 Pfeiffer cells in the exponential growth phase were seeded in 24-well plates at a cell density of 1*10E5 cells/mL. Cells were treated with different concentrations of compounds on the day. Fresh medium and compound were replaced at 4 and 7 days of compound treatment. After 11 days of compound treatment, cell viability was measured using CellTiter-Glo reagent (Promega). Data was analyzed using GraphPad Prism 5.0 software, get 50 values GI.
表2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)。The compounds described in Table 2 were prepared by the methods described in the above examples, and EED226 was a positive compound (Nat. Chem. Biol. 2017, 13, 381-388).
Figure PCTCN2018102833-appb-000199
Figure PCTCN2018102833-appb-000199
Figure PCTCN2018102833-appb-000200
Figure PCTCN2018102833-appb-000200
Figure PCTCN2018102833-appb-000201
Figure PCTCN2018102833-appb-000201
Figure PCTCN2018102833-appb-000202
Figure PCTCN2018102833-appb-000202
实施例136：pfeiffer细胞长时生长抑制实验(14天)Example 136: Long-term growth inhibition test of pfeiffer cells (14 days)
人弥漫性大B细胞淋巴瘤(DLBCL)细胞株pfeiffer(来自ATCC，CRL-2632)用含10％胎牛血清(Gibco，购自Life Technologies公司，10099-141)及1％抗生素(青霉素和链霉素，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pfeiffer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2*10E5个细胞/mL。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孔板中每孔加入2μL 9种不同浓度的3倍梯度稀释的化合物或DMSO，化合物的终浓度范围为0.003～20μM或0.3～2000nM， DMSO的终浓度为0.2％。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2*10E5个细胞/mL，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(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。 Human diffuse large B-cell lymphoma (DLBCL) cell line pfeiffer (from ATCC, CRL-2632) containing 10% fetal bovine serum (Gibco, purchased from Life Technologies, 10099-141) and 1% antibiotic (penicillin and chain) RPMI 1640 medium (Gibco, available from Life Technologies, Inc., 22400-089) purchased from Life Technologies, Inc., 10378016) was cultured in a CO 2 cell incubator (37 ° C, 5% CO 2 ). In the cell long-term growth inhibition experiment, pfeiffer cells of exponential growth phase were plated in a 24-well plate (purchased from Corning, 3524) in a volume of 1 mL/well and a cell density of 2*10E5 cells/mL. The cells were seeded and placed in a CO 2 incubator for 1 hour. 2 μL of 9 different concentrations of 3-fold gradient dilutions of compound or DMSO were added to each well in a 24-well plate containing cells at a final concentration ranging from 0.003 to 20 μM or 0.3 to 2000 nM with a final concentration of 0.2% DMSO. At 4, 7 and 11 days of compound treatment, fresh medium and compound were exchanged, and the cell density of the DMSO control wells was diluted to 2*10E5 cells/mL, and the cell dilution ratio of the other compound wells was the same as that of the DMSO control wells. Cell viability was determined using CellTiter-Glo reagent (purchased from Promega, G7572): cells treated with compound for 14 days were transferred to a white 384-well plate (OptiPlate-384, available from PerkinElmer, 6007299) at 40 μL/well. Add an equal volume of CellTiter-Glo reagent. After incubation for 10 minutes at room temperature, the cold luminescence signal was detected using a multi-plate reader EnVision (PerkinElmer) at a wavelength of 400-700 nm. Data was analyzed using GraphPad Prism 5.0 software, the value of 50 obtained IC.
表3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)。The compounds described in Table 3 were prepared by the methods described in the above examples, and EED226 was a positive compound (Nat. Chem. Biol. 2017, 13, 381-388).
Figure PCTCN2018102833-appb-000203
Figure PCTCN2018102833-appb-000203
Figure PCTCN2018102833-appb-000204
Figure PCTCN2018102833-appb-000204
Figure PCTCN2018102833-appb-000205
Figure PCTCN2018102833-appb-000205
实施例137：细胞Karpas-422、SU-DHL-4长时生长抑制实验(11天)Example 137: Long-term growth inhibition test of cells Karpas-422 and SU-DHL-4 (11 days)
人弥漫性大B细胞淋巴瘤(DLBCL)细胞株Karpas-422、SU-DHL-4(ATCC，CRL-2957)用含10％胎牛血清(Gibco，购自Life Technologies公司，10099-141)及1％抗生素(青霉素和链霉素，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Karpas-422、SU-DHL-4细胞铺种在24孔板(购自Corning公司，3524)中，细胞密度为1*10E5个/mL，细胞培养基体积为1mL。细胞在24孔板中培养1小时后，每孔加入2μL化合物或DMSO。每个化合物有9个不同的浓度，在细胞培养基中的终浓度范围为0.003～20μM或0.3～2000nM，DMSO的终浓度为0.2％。在化合物处理4、7天时，更换新鲜的细胞培养基和化合物，将DMSO对照孔的细胞密度稀释到1*10E5个/mL，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11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。 Human diffuse large B-cell lymphoma (DLBCL) cell lines Karpas-422, SU-DHL-4 (ATCC, CRL-2957) containing 10% fetal bovine serum (Gibco, purchased from Life Technologies, 10099-141) and 1% antibiotic (penicillin and streptomycin, purchased from Life Technologies, 10378016) in RPMI 1640 medium (Gibco, purchased from Life Technologies, Inc., 22400-089) in a CO 2 cell incubator (37 ° C, 5% CO 2 ) ) cultured. In the cell growth inhibition assay, Karpas-422 and SU-DHL-4 cells in the exponential growth phase were plated in 24-well plates (purchased from Corning, 3524) at a cell density of 1*10E5/mL. The cell culture medium volume was 1 mL. After the cells were cultured for 1 hour in a 24-well plate, 2 μL of the compound or DMSO was added to each well. Each compound has 9 different concentrations, with a final concentration in the cell culture medium ranging from 0.003 to 20 [mu]M or 0.3 to 2000 nM and a final concentration of 0.2% DMSO. At 4 and 7 days of compound treatment, fresh cell culture medium and compound were replaced, and the cell density of the DMSO control well was diluted to 1*10E5/mL, and the cell dilution ratio of the compound well was the same as that of the DMSO control well. Cell viability was determined using CellTiter-Glo reagent (purchased from Promega, G7572): cells treated with compound for 11 days were transferred to a white 384-well plate (OptiPlate-384, available from PerkinElmer, 6007299) at 40 μL/well. Add an equal volume of CellTiter-Glo reagent. After incubation for 10 minutes at room temperature, 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.
表4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)。The compounds described in Table 4 were prepared by the methods described in the above examples, and EED226 was a positive compound (Nat. Chem. Biol. 2017, 13, 381-388).
Figure PCTCN2018102833-appb-000206
Figure PCTCN2018102833-appb-000206
Figure PCTCN2018102833-appb-000207
Figure PCTCN2018102833-appb-000207
Figure PCTCN2018102833-appb-000208
Figure PCTCN2018102833-appb-000208
由以上表1至表4中的数据可以看出，本发明的部分化合物对PRC2酶的IC 50值可达nM数量级，显著高于阳性对照组EED226化合物；同样的，对于Pfeiffer，Karpas-422以及SU-DHL-4细胞长时生长抑制实验，本发明的多个化合物的IC 50值也达到了个位数nM数量级，显著高于阳性对照组EED226化合物。 It can be seen from the data in Tables 1 to 4 above that the IC 50 value of the partial compound of the present invention to the PRC2 enzyme can be up to nM order, which is significantly higher than that of the positive control group EED226 compound; similarly, for Pfeiffer, Karpas-422 and In the SU-DHL-4 cell long-term growth inhibition experiment, the IC 50 values of the various compounds of the present invention also reached the single digit nM order of magnitude, which was significantly higher than the positive control group EED226 compound.
实施例138：大鼠口服药代动力学研究Example 138: Oral pharmacokinetic study in rats
1、以健康雄性SD大鼠为受试动物，灌胃给予EED226,E-Y1，E-Y13,E-Y47，SL-ZYE-07(3mg/kg)，应用LC/MS/MS法测定给药后不同时间点大鼠血浆中的药物浓度。研究本发明的化合物在大鼠体内的药代动力学行为，评价其药动学特性。1. Healthy male Sprague-Dawley rats were used as test animals, and EED226, E-Y1, E-Y13, E-Y47, SL-ZYE-07 (3mg/kg) were administered by gavage, and determined by LC/MS/MS method. The concentration of the drug in the rat plasma at different time points after the drug. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic properties were evaluated.
2、试验动物为健康成年雄性SD大鼠，每组3只，购自上海西普尔-必凯实验动物有限公司。2. The test animals were healthy adult male SD rats, 3 in each group, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.
3、药物配制：化合物EED226,E-Y1，E-Y13,E-Y47溶于DMSO/0.5％HPMC(5/95,v/v)配制。而化合物SL-ZYE-07则溶于0.5％HPMC(含0.5％Tween 80)，涡旋振荡，超声，使固体物质分散均匀，得淡白色混悬液。3. Drug preparation: Compounds EED226, E-Y1, E-Y13, E-Y47 were dissolved in DMSO/0.5% HPMC (5/95, v/v). The compound SL-ZYE-07 was dissolved in 0.5% HPMC (containing 0.5% Tween 80), vortexed, and sonicated to uniformly disperse the solid matter to obtain a pale white suspension.
4、操作：大鼠灌胃(3mg/kg)给药EED226,E-Y1，E-Y13,E-Y47,SL-ZYE-07于给药后0.25，0.5，1，2，4，8，24小时经股静脉取血45μL，置肝素化的离心管中离心5min，分离血浆样品分析，我们采用液相色谱串联质谱(LC-MS/MS)法测定不同化合物灌胃给药后大鼠血浆的待测化合物含量。4. Operation: Rats were administered EED226, E-Y1, E-Y13, E-Y47, and SL-ZYE-07 by intragastric administration (3mg/kg) at 0.25, 0.5, 1, 2, 4, 8 after administration. 45 μL of blood was taken from the femoral vein for 24 hours, centrifuged in a heparinized centrifuge tube for 5 min, and plasma samples were separated for analysis. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the plasma of rats after intragastric administration. The content of the test compound.
本发明化合物的药代动力学参数如下：The pharmacokinetic parameters of the compounds of the invention are as follows:
Figure PCTCN2018102833-appb-000209
Figure PCTCN2018102833-appb-000209
Figure PCTCN2018102833-appb-000210
Figure PCTCN2018102833-appb-000210
AUC last：从给药时间开始到最后一个时间点的这段时间的AUC AUC last : AUC from the time of administration to the last time
AUC INF_obs:从给药时间开始到理论外推无穷远的时间点的这段时间的AUC AUC INF_obs : AUC from the time of administration to the time when the theoretical extrapolation is infinitely long
结论：本发明的化合物药代吸收良好，具有明显的药代动力学优势。Conclusion: The compounds of the present invention have good pharmacological absorption and have obvious pharmacokinetic advantages.
实施例139：肝微粒体稳定性实验(小鼠、大鼠、人)：Example 139: Liver microsome stability test (mouse, rat, human):
试剂和材料:Reagents and materials:
名称name 供应商supplier 货号/批号Item number / batch number
人肝微粒体Human liver microsome BDBD H34H34
小鼠肝微粒体Mouse liver microsome RildRild M11M11
大鼠肝微粒体Rat liver microsome BDBD R40/R42R40/R42
NADPHNADPH RocheRoche N8100-1000N8100-1000
VIVID BOMCCVIVID BOMCC LifeLife P2980P2980
384孔黑板384-hole blackboard GreinerGreiner 781209781209
96孔孵育板96-well incubation plate CorningCorning 39573957
96孔化合物板96-well compound plate ApricotdesignsApricotdesigns DWP-16-96-SQ-CDWP-16-96-SQ-C
MgCl 2 MgCl 2 SigmaSigma M9272-100GM9272-100G
TRIZMA BASETRIZMA BASE SigmaSigma T1503-1KGT1503-1KG
BSABSA Roche分装Roche dispensing A8020-100A8020-100
DMSODMSO MerckMerck K42958652 225K42958652 225
甲醇Methanol MerckMerck I622207203I622207203
化合物信息Compound information
化合物E-Y1，E-Y13,E-Y15，E-Y40，E-Y43，E-Y47，E-Y50，E-Y54，E-Y54-H，SL-E23的贮备液(10mM in DMSO)Stock solution of compound E-Y1, E-Y13, E-Y15, E-Y40, E-Y43, E-Y47, E-Y50, E-Y54, E-Y54-H, SL-E23 (10 mM in DMSO)
实验步骤Experimental procedure
1.开启JANUS及温控装置，初始化后冲洗管道至管道内无气泡。1. Turn on the JANUS and temperature control device. After initialization, flush the pipe to the pipe without bubbles.
2.准备实验用缓冲液2. Prepare the experimental buffer
准备Tris pH 7.4缓冲液(0.1M)：将12.12g Tris溶解在1000mL H 2O中，用2N HCl调pH至7.4，分装50mL/管，-20℃冻存。 Tris pH 7.4 buffer (0.1 M) was prepared: 12.12 g of Tris was dissolved in 1000 mL of H 2 O, adjusted to pH 7.4 with 2N HCl, dispensed at 50 mL/tube, and frozen at -20 °C.
准备H 2O/0.1％BSA缓冲液：将200μL 25％BSA加入到50mL H 2O中。 Preparation of H 2 O/0.1% BSA buffer: 200 μL of 25% BSA was added to 50 mL of H 2 O.
准备VIVID贮备液：将1mg VIVID溶解在1mL乙腈中，分装50μL/管，-20℃冻存。Prepare the VIVID stock solution: Dissolve 1 mg of VIVID in 1 mL of acetonitrile, dispense 50 μL/tube, and store at -20 °C.
准备MgCl 2溶液(100mM)：将1.016g MgCl 2溶解在50mL Tris pH 7.4缓冲液中，分装1mL/管，-20℃冻存。 Preparation of MgCl 2 solution (100 mM): 1.016 g of MgCl 2 was dissolved in 50 mL of Tris pH 7.4 buffer, dispensed in 1 mL/tube, and frozen at -20 °C.
准备NADPH溶液(10mM)：将355mg NADPH溶解在42.6mL Tris pH 7.4缓冲液中，分装1.8mL/管，-20℃冻存。Preparation of NADPH solution (10 mM): 355 mg of NADPH was dissolved in 42.6 mL of Tris pH 7.4 buffer, dispensed at 1.8 mL/tube, and frozen at -20 °C.
准备空白对照：取7.937mL Tris、163μL RLM、450μL MgCL 2溶液、450μL NADPH溶液和9mL甲醇混匀，分装1mL/管，-20℃冻存。 Prepare a blank control: Mix 7.937 mL Tris, 163 μL RLM, 450 μL MgCL 2 solution, 450 μL NADPH solution and 9 mL methanol, dispense 1 mL/tube, and store at -20 °C.
3.准备化合物工作溶液3. Prepare the compound working solution
稀释步骤1：取10μL化合物贮备液加入90μL DMSO＝1mM贮备液。Dilution step 1: 10 μL of the compound stock solution was added to 90 μL of DMSO = 1 mM stock solution.
稀释步骤2：取2μL 1mM贮备液加入1mL H2O/0.1％BSA缓冲液＝0.2μM工作溶液。Dilution step 2: 2 μL of 1 mM stock solution was added to 1 mL of H 2 O / 0.1% BSA buffer = 0.2 μM working solution.
稀释步骤3：取245μL工作溶液到96孔化合物板中，加入5μL VIVID贮备液。Dilution Step 3: Take 245 μL of working solution into a 96-well compound plate and add 5 μL of VIVID stock solution.
将96孔化合物板放在震荡器上震荡5分钟。The 96-well compound plate was placed on an shaker for 5 minutes.
4.打开JANUS电脑里的STM运行EXCEL文件，按EXCEL文件指示操作并运行JANUS程序。4. Open the STM run EXCEL file on the JANUS computer, press the EXCEL file to instruct and run the JANUS program.
5.JANUS程序运行结束后，向384孔黑板的20列加入乙腈/水50:50(V/V)，向384孔黑板的21列加入空白对照。5. After the JANUS program is finished, add acetonitrile/water 50:50 (V/V) to the 20 columns of the 384-well blackboard, and add a blank control to the 21 columns of the 384-well blackboard.
6.在酶标仪上读板(420nm-465nm)，确定VIVID荧光强度。6. Read the plate (420 nm - 465 nm) on a microplate reader to determine the VIVID fluorescence intensity.
7.封板并震荡均匀离心后，将样品板提交至LC/MS仪进行样品分析。7. After sealing the plate and shaking it evenly, centrifuge the sample plate and submit it to the LC/MS instrument for sample analysis.
数据分析：data analysis:
以孵育体系中药物的剩余率的对数值对孵育时间作图，进行线性回归得到斜率k，按以下公式推测体内固有清除率(Clint，mL/min/g)值、体内清除率(Cl，mL/min)、肝清除率(Clhep，mL/min)、代谢生物利用度(％MF)：The logarithm of the residual rate of the drug in the incubation system was plotted against the incubation time, and linear regression was performed to obtain the slope k. The intrinsic clearance rate (Clint, mL/min/g) and the in vivo clearance rate (Cl, mL) were estimated according to the following formula. /min), liver clearance (Clhep, mL/min), metabolic bioavailability (%MF):
Figure PCTCN2018102833-appb-000211
Figure PCTCN2018102833-appb-000211
Figure PCTCN2018102833-appb-000212
Figure PCTCN2018102833-appb-000212
Figure PCTCN2018102833-appb-000213
Figure PCTCN2018102833-appb-000213
Figure PCTCN2018102833-appb-000214
Figure PCTCN2018102833-appb-000214
化合物肝微粒体稳定性结果：Compound liver microsome stability results:
Figure PCTCN2018102833-appb-000215
Figure PCTCN2018102833-appb-000215
Figure PCTCN2018102833-appb-000216
Figure PCTCN2018102833-appb-000216
结论：本发明的化合物在人、大鼠、小鼠的肝微粒体稳定性良好，具有明显的优势。Conclusion: The compounds of the present invention have good stability in liver microsomes of human, rat and mouse, and have obvious advantages.

Claims (13)

  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：A compound represented by the formula I, a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof:
    Figure PCTCN2018102833-appb-100001
    Figure PCTCN2018102833-appb-100001
    1)X 1独立地选自N及C-CN； 1) X 1 is independently selected from N and C-CN;
    2)R 2独立地选自H、卤素、C 1-C 4卤代烷基及C 1-C 4烷基； 2) R 2 is independently selected from the group consisting of H, halogen, C 1 -C 4 haloalkyl and C 1 -C 4 alkyl;
    3)A独立地选自以下结构：
    Figure PCTCN2018102833-appb-100002
    3) A is independently selected from the following structures:
    Figure PCTCN2018102833-appb-100002
    Figure PCTCN2018102833-appb-100003
    为单键或双键；
    Figure PCTCN2018102833-appb-100003
    For single or double keys;
    R 3、R 4及R 5独立地选自H、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、C 3-C 6环烷基； R 3 , R 4 and R 5 are independently selected from H, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-(C 1 -C 4 alkyl), C 1 -C 4 Haloalkoxy, C 3 -C 6 cycloalkyl;
    R 6独立地选自H、OH、＝O及C 1-C 4烷基； R 6 is independently selected from the group consisting of H, OH, =0, and C 1 -C 4 alkyl;
    R 7独立地选自H、OH、卤素、CN及C 1-C 4烷基； R 7 is independently selected from the group consisting of H, OH, halogen, CN, and C 1 -C 4 alkyl;
    n各自独立地选自0，1及2；n are each independently selected from 0, 1 and 2;
    X 2独立地选自O、NR a及S(O) p杂原子； X 2 is independently selected from the group consisting of O, NR a and S(O) p heteroatoms;
    每一R a独立地选自H、O、由0-2个R b取代的C 1-C 10烷基、C 1-C 6卤代烷基、-O-(C 1-C 6烷基)、C 1-C 6卤代烷氧基、C 3-C 6环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； Each R a is independently selected from H, O, C 1 -C 10 alkyl substituted by 0-2 R b , C 1 -C 6 haloalkyl, -O-(C 1 -C 6 alkyl), C 1 -C 6 haloalkoxy, C 3 -C 6 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), containing carbon Atom and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S(O) p heteroatoms, -C(=O)H, aryl, containing carbon atoms and 1 to 2 selected from a 5 to 6 membered heteroaryl group of N, O and S heteroatoms;
    R b独立地选自卤素、OH、NH 2、-NHC(＝O)(C 1-C 4烷基)、-NHS(＝O) 2(C 1-C 4烷基)、＝O、CN、C 1-C 4烷基及C 1-C 4烷氧基； R b is independently selected from the group consisting of halogen, OH, NH 2 , -NHC(=O)(C 1 -C 4 alkyl), -NHS(=O) 2 (C 1 -C 4 alkyl), =O, CN , C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
    p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
    4)R 1独立地选自以下结构：
    Figure PCTCN2018102833-appb-100004
    4) R 1 is independently selected from the following structures:
    Figure PCTCN2018102833-appb-100004
    Figure PCTCN2018102833-appb-100005
    为单键或双键；
    Figure PCTCN2018102833-appb-100005
    For single or double keys;
    4a)R 1A独立地选自H、羟基、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、氨基、C 1-C 6直链、支链以及环状的烷 氨基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子和1至2个选自N、O及S杂原子的5至6元杂芳基；其中该芳基以及杂芳基可由0-2个R 1X取代； 4a) R 1A is independently selected from H, hydroxy, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 alkane a group, -C(=O)NH(C 1 -C 4 alkyl), an amino group, a C 1 -C 6 straight chain, a branched chain, and a cyclic alkylamino group, containing a carbon atom and 1-4 selected from O Heteroalkyl and heterocycloalkyl of N,S(O) p heteroatoms, -C(=O)H, aryl, containing carbon atoms and 1 to 2 heteroatoms selected from N, O and S a 6-membered heteroaryl; wherein the aryl and heteroaryl are substituted by 0-2 R 1X ;
    p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
    R c独立地选自OH、卤素、CN、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基、-(OCH 2CH 2) mOR d、NHC(＝O)NR dR e、NHC(＝S)NR dR e、-NHC(＝NH)NR dR e、(OCH 2CH 2) mNR dR e、-C(＝O)R d、-S(＝O)R d、-C(＝O)NR dR e、-S(＝O) 2R d、-NHC(＝O)R d、-NHC(＝S)R d、-NHS(＝O) 2R d、-S(＝O) 2NHR d、包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂烷基和杂环烷基、芳基以及包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂芳基、其中该芳基以及杂芳基可由0-2个R 1X取代； R c is independently selected from OH, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl, -(OCH 2 CH 2 ) m OR d , NHC(=O)NR d R e , NHC(=S)NR d R e , -NHC(=NH)NR d R e , (OCH 2 CH 2 ) m NR d R e , -C(=O)R d , -S(=O)R d , -C(=O)NR d R e , -S(=O) 2 R d ,- NHC (= O) R d, -NHC (= S) R d, -NHS (= O) 2 R d, -S (= O) 2 NHR d, comprising carbon atoms and 1 to 2 heteroatoms selected from N, NR a heteroalkyl and heterocycloalkyl group of a , O and S(O) p heteroatoms, an aryl group, and a heteroatom comprising a carbon atom and 1 to 2 heteroatoms selected from the group consisting of N, NR a , O and S(O) p heteroatoms An aryl group wherein the aryl group and the heteroaryl group are substituted by 0-2 R 1X ;
    R d及R e独立地选自H、含0-2个R b取代的C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 6环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、含0-2个O、N、S(O) p杂原子的支链或环状的C 1-C 6杂烷基、-C(＝O)H、芳基及包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂芳基，其中该芳基以及杂芳基可由0-2个R 1X取代； R d and R e are independently selected from H, C 2 -C 6 alkyl substituted with 0-2 R b , C 1 -C 6 haloalkyl, C 3 -C 6 cyclic alkyl, -C(= O) (C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl), containing 0-2 O, N a branched or cyclic C 1 -C 6 heteroalkyl group of a S(O) p hetero atom, -C(=O)H, an aryl group, and a carbon atom and 1 to 2 selected from N, NR a , a heteroaryl group of O and S(O) p heteroatoms, wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1X ;
    R a独立地选自H、O、由0-2个R b取代的C 1-C 10烷基、C 1-C 6卤代烷基、-O-(C 1-C 6烷基)、C 1-C 6卤代烷氧基、C 3-C 6环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； R a is independently selected from H, O, C 1 -C 10 alkyl substituted by 0-2 R b , C 1 -C 6 haloalkyl, -O-(C 1 -C 6 alkyl), C 1 -C 6 haloalkoxy, C 3 -C 6 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), containing carbon atoms and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S(O) p heteroatoms, -C(=O)H, aryl, containing carbon atoms and 1 to 2 selected from N, 5- to 6-membered heteroaryl groups of O and S heteroatoms;
    R b独立地选自卤素、OH、NH 2、-NHC(＝O)(C 1-C 4烷基)、-NHS(＝O) 2(C 1-C 4烷基)、＝O、CN、C 1-C 4烷基及C 1-C 4烷氧基； R b is independently selected from the group consisting of halogen, OH, NH 2 , -NHC(=O)(C 1 -C 4 alkyl), -NHS(=O) 2 (C 1 -C 4 alkyl), =O, CN , C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
    p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
    R d与R e可通过R d——R e或
    Figure PCTCN2018102833-appb-100006
    的方式连接，其中Z 1可选自含0-2个R b取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6杂烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)(C 1-C 6烷基)、-NS(＝O) 2(C 1-C 6烷基)、S(O) p；R b独立地选自卤素、OH、NH 2、-NHC(＝O)(C 1-C 4烷基)、-NHS(＝O) 2(C 1-C 4烷基)、＝O、CN、C 1-C 4烷基及C 1-C 4烷氧基；p各自独立地选自0，1及2；     R d and R e may pass R d ——R e or
    Figure PCTCN2018102833-appb-100006
    Is connected, wherein Z 1 optionally containing from 0-2 R b substituted by C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p hetero atoms 1 -C 6 heteroalkyl Alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)(C 1 -C 6 alkyl), -NS(=O) 2 (C 1 -C 6 Alkyl), S(O) p ; R b is independently selected from the group consisting of halogen, OH, NH 2 , -NHC(=O)(C 1 -C 4 alkyl), -NHS(=O) 2 (C 1 - C 4 alkyl), =O, CN, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; p are each independently selected from 0, 1 and 2;
    R 1X独立地选自卤素、OH、CN、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 3-C 8环状烷基和环状杂烷基； R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
    R 1B及R 1C独立地选自H、OH、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子和1至2个选自N、O及S杂原子的5至6元杂芳基；其中该芳基以及杂芳基可由0-2个R 1X取代；p各自独立地为0，1及2； R 1B and R 1C are independently selected from H, OH, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl groups), C 1 -C 6 alkyl group, C 1- C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 Alkyl), -C(=O)NH(C 1 -C 4 alkyl), heteroalkyl and heterocycloalkane containing carbon atoms and from 1 to 4 heteroatoms selected from O, N, S(O) p a group, -C(=O)H, an aryl group, a 5- to 6-membered heteroaryl group containing a carbon atom and 1 to 2 heteroatoms selected from N, O and S; wherein the aryl group and the heteroaryl group may be 0- 2 R 1X substituted; p are each independently 0, 1 and 2;
    R 2B及R 2C独立地选自H、OH、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p 杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基；其中该芳基以及杂芳基可由0-2个R 1X取代；p各自独立地选自0，1及2； R 2B and R 2C are independently selected from H, OH, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl groups), C 1 -C 6 alkyl group, C 1- C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 Alkyl), -C(=O)NH(C 1 -C 4 alkyl), heteroalkyl and heterocycloalkane containing carbon atoms and from 1 to 4 heteroatoms selected from O, N, S(O) p a group, -C(=O)H, an aryl group, a 5- to 6-membered heteroaryl group containing a carbon atom and 1 to 2 heteroatoms selected from N, O and S; wherein the aryl group and the heteroaryl group may be 0- 2 R 1X substituted; p are each independently selected from 0, 1 and 2;
    R 3B及R 3C独立地选自H、-OH、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基；其中该芳基以及杂芳基可由0-2个R 1X取代；p各自独立地选自0，1及2； R 3B and R 3C are independently selected from H, -OH, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl), heteroalkyl and heterocyclic ring containing carbon atoms and 1 to 4 heteroatoms selected from O, N, S(O) p An alkyl group, -C(=O)H, an aryl group, a 5- to 6-membered heteroaryl group containing a carbon atom and 1 to 2 heteroatoms selected from N, O and S; wherein the aryl group and the heteroaryl group are 0 - 2 R 1X substitutions; p are each independently selected from 0, 1 and 2;
    或者，R 1B与R 1C、R 2B与R 2C、R 3B与R 3C可和与之连接的碳原子形成羰基(＝O)或者硫羰基(＝S)； Alternatively, R 1B and R 1C , R 2B and R 2C , R 3B and R 3C may form a carbonyl group (=O) or a thiocarbonyl group (=S) with a carbon atom to which they are attached;
    R 1D独立地选自H、-OH、卤素、CN、-C(＝O)H、-(O) z-(包含0-2个R c取代C 1-C 6烷基)、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、R f、-OR f、-C(＝O)R c、NR dR e、-C(＝O)NR dR e、-NHC(＝O)R c、-S(＝O) 2R c、-S(＝O) 2NR dR e、-NHS(＝O) 2R d、-(OCH 2CH 2) mOR d、-(OCH 2CH 2) mNR dR e； R 1D is independently selected from H, -OH, halogen, CN, -C(=O)H, -(O) z - (containing 0-2 R c substituted C 1 -C 6 alkyl groups), C 1 - C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , R f , —OR f , —C(=O)R c , NR d R e , —C(=O)NR d R e , NHC(=O)R c , -S(=O) 2 R c , -S(=O) 2 NR d R e , -NHS(=O) 2 R d , -(OCH 2 CH 2 ) m OR d , -(OCH 2 CH 2 ) m NR d R e ;
    R f独立地选自C 3-C 8环状烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、芳基及包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂芳基；其中，芳基及杂芳基由0-2个R 1X取代； R f is independently selected from a C 3 -C 8 cyclic alkyl group, a heteroalkyl group containing a carbon atom and 1 to 4 heteroatoms selected from O, N, S(O) p , an aryl group, and a heteroaryl group comprising a carbon atom and 1 to 2 hetero atoms selected from the group consisting of N, NR a , O and S(O) p ; wherein the aryl group and the heteroaryl group are substituted by 0-2 R 1X ;
    M独立地选自3至7元饱和的或不饱和的环烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂环烷基、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； M is independently selected from a 3 to 7 membered saturated or unsaturated cycloalkyl group, a heterocycloalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, and the like a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms;
    在R 1B及R 1C、R 2B及R 2C、R 3B及R 3C、R 1D以及R f的定义中，R a、R c、R d、R e、p、z、m、R 1X的定义与在4a)部分中的R 1A中的相应的定义相同； Definitions of R a , R c , R d , R e , p, z, m, R 1X in the definitions of R 1B and R 1C , R 2B and R 2C , R 3B and R 3C , R 1D and R f . Corresponding to the corresponding definition in R 1A in the section 4a);
    n各自独立地选自0，1及2；n are each independently selected from 0, 1 and 2;
    m各自独立地选自0-4；m are each independently selected from 0-4;
    p各自独立地选自0-2；p are each independently selected from 0-2;
    q各自独立地选自0-3；q are each independently selected from 0-3;
    z各自独立地选自0和1；z are each independently selected from 0 and 1;
    4a’)优选地，R 1独立地选自以下结构：
    Figure PCTCN2018102833-appb-100007
    其中     4a') Preferably, R 1 is independently selected from the following structures:
    Figure PCTCN2018102833-appb-100007
    among them
    Figure PCTCN2018102833-appb-100008
    为单键或双键；
    Figure PCTCN2018102833-appb-100008
    For single or double keys;
    R 1A独立地选自H、羟基、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、-C(＝O)H； R 1A is independently selected from H, hydroxy, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl) , -C(=O)NH(C 1 -C 4 alkyl), -C(=O)H;
    R c独立地选自OH、卤素、CN、C 1-C 6烷基、羧基、C 1-C 6卤代烷基、C 1-C 6烷氧基、 C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R c is independently selected from OH, halogen, CN, C 1 -C 6 alkyl, carboxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
    R 1B及R 1C、R 2B及R 2C、以及R 3B及R 3C独立地选自H、OH、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)； R 1B and R 1C , R 2B and R 2C , and R 3B and R 3C are independently selected from H, OH, halogen, CN, -(O) z - (including 0-2 R c substituted C 1 -C 10 Alkyl), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl , -C(=O)(C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl);
    或者，R 1B与R 1C、R 2B与R 2C、R 3B与R 3C可和与之连接的碳原子形成羰基(＝O)或者硫羰基(＝S)； Alternatively, R 1B and R 1C , R 2B and R 2C , R 3B and R 3C may form a carbonyl group (=O) or a thiocarbonyl group (=S) with a carbon atom to which they are attached;
    R 1D独立地选自H、-OH、卤素、CN、-C(＝O)H、-(O) z-(包含0-2个R c取代C 1-C 6烷基)、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基； R 1D is independently selected from H, -OH, halogen, CN, -C(=O)H, -(O) z - (containing 0-2 R c substituted C 1 -C 6 alkyl groups), C 1 - C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl;
    R c独立地选自OH，卤素、CN、C 1-C 6烷基、羧基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R c is independently selected from OH, halogen, CN, C 1 -C 6 alkyl, carboxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
    M独立地选自3至7元饱和的或不饱和的环烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂环烷基、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； M is independently selected from a 3 to 7 membered saturated or unsaturated cycloalkyl group, a heterocycloalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, and the like a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms;
    n各自独立地选自0，1及2；n are each independently selected from 0, 1 and 2;
    m各自独立地选自0-4；m are each independently selected from 0-4;
    p各自独立地选自0-2；p are each independently selected from 0-2;
    q各自独立地选自0-3；q are each independently selected from 0-3;
    z各自独立地选自0和1；z are each independently selected from 0 and 1;
    4a”)更优选地，在R 1中， 4a") More preferably, in R 1 ,
    R 1A独立地选自H、羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R 1A is independently selected from H, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
    R 1B及R 1C、R 2B及R 2C、以及R 3B及R 3C独立地选自H、OH、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R 1B and R 1C , R 2B and R 2C , and R 3B and R 3C are independently selected from H, OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 Haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
    或者，R 1B与R 1C、R 2B与R 2C、R 3B与R 3C可和与之连接的碳原子形成羰基(＝O)或者硫羰基(＝S)； Alternatively, R 1B and R 1C , R 2B and R 2C , R 3B and R 3C may form a carbonyl group (=O) or a thiocarbonyl group (=S) with a carbon atom to which they are attached;
    R 1D独立地选自H、-OH、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R 1D is independently selected from H, -OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 - C 8 cyclic alkyl group;
    M独立地选自5至6元饱和的或不饱和的环烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂环烷基、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基； M is independently selected from a 5- to 6-membered saturated or unsaturated cycloalkyl group, a heterocycloalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, and the like a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms;
    n各自独立地选自0，1及2；n are each independently selected from 0, 1 and 2;
    m各自独立地选自0-4；m are each independently selected from 0-4;
    p各自独立地选自0-2；p are each independently selected from 0-2;
    q各自独立地选自0-3；q are each independently selected from 0-3;
    z各自独立地选自0和1；z are each independently selected from 0 and 1;
    4b)Y独立地选自O、NR g、S(O) p等杂原子以及CH 2、C＝O、-CR i(CH 2) mNR gR h以及-CR i(CH 2) mOR g； 4b) Y is independently selected from heteroatoms such as O, NR g , S(O) p and CH 2 , C=O, -CR i (CH 2 ) m NR g R h and -CR i (CH 2 ) m OR g ;
    R g及R h独立地选自H、O、含0-3个R s取代的C 1-C 10烷基、C 1-C 6卤代烷基、C 3-C 6环状烷基、
    Figure PCTCN2018102833-appb-100009
    Figure PCTCN2018102833-appb-100010
    -C(＝S)NHC(＝O)-R j、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、芳基、包含碳原子和1至2个选自N、O及S杂原子的5至6元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1X取代；     R g and R h are independently selected from H, O, C 1 -C 10 alkyl group substituted with 0-3 R s , C 1 -C 6 haloalkyl group, C 3 -C 6 cyclic alkyl group,
    Figure PCTCN2018102833-appb-100009
    Figure PCTCN2018102833-appb-100010
    -C(=S)NHC(=O)-R j , a heteroalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, including a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1X ;
    R s独立地选自OH，CN、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基、-(OCH 2CH 2) mOR d、NHC(＝O)NR dR e、NHC(＝S)NR dR e、-NHC(＝NH)NR dR e、(OCH 2CH 2) mNR dR e、-C(＝O)R d、-C(＝S)R d、-S(＝O)R d、-C(＝O)NR dR e、-S(＝O) 2R d、-NHC(＝O)R d、-NHC(＝S)R d、-NHS(＝O) 2R d、-S(＝O) 2NR dR e、-NHS(＝O) 2NR dR e、-C(＝S)NR dR e、NHC(＝O)OR d、NHC(＝S)OR d、-NHS(＝O) 2OR d、NHC(＝O)SR d、NHC(＝S)SR d、-NHC(＝NH)OR d、-C(＝O)OR d、-C(＝O)SR d、-S(＝O) 2OR d、包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂烷基和杂环烷基、芳基以及包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂芳基、其中该芳基以及杂芳基可由0-2个R 1Y取代； R s is independently selected from OH, CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl, -(OCH 2 CH 2 ) m OR d , NHC(=O)NR d R e , NHC(=S)NR d R e , -NHC(=NH)NR d R e , (OCH 2 CH 2 ) m NR d R e , -C(=O)R d , -C(=S)R d , -S(=O)R d , -C(=O)NR d R e , -S (= O) 2 R d, -NHC (= O) R d, -NHC (= S) R d, -NHS (= O) 2 R d, -S (= O) 2 NR d R e, -NHS (=O) 2 NR d R e , -C(=S)NR d R e , NHC(=O)OR d , NHC(=S)OR d , -NHS(=O) 2 OR d , NHC(= O) SR d , NHC(=S)SR d , -NHC(=NH)OR d , -C(=O)OR d , -C(=O)SR d , -S(=O) 2 OR d , a heteroalkyl group and a heterocycloalkyl group containing a carbon atom and 1 to 2 hetero atoms selected from N, NR a , O and S(O) p , an aryl group, and a carbon atom and 1 to 2 selected from N, NR a heteroaryl group of a , O and S(O) p heteroatoms, wherein the aryl group and the heteroaryl group are substituted by 0-2 R 1Y ;
    R d及R e独立地选自H、含0-2个R b取代的C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 6环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、-C(＝O)NH(C 1-C 4烷基)、含0-2个O、N、S(O) p杂原子的支链或环状的C 1-C 6杂烷基、-C(＝O)H、芳基及包含碳原子及1至2个选自N、NR a、O及S(O) p杂原子的杂芳基，其中该芳基以及杂芳基可由0-2个R 1X取代； R d and R e are independently selected from H, C 2 -C 6 alkyl substituted with 0-2 R b , C 1 -C 6 haloalkyl, C 3 -C 6 cyclic alkyl, -C(= O) (C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl), containing 0-2 O, N a branched or cyclic C 1 -C 6 heteroalkyl group of a S(O) p hetero atom, -C(=O)H, an aryl group, and a carbon atom and 1 to 2 selected from N, NR a , a heteroaryl group of O and S(O) p heteroatoms, wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1X ;
    R d与R e可通过以下方式R d——R e或
    Figure PCTCN2018102833-appb-100011
    连接形成一个环，其中Z 1可选自含0-2个R b取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)(C 1-C 6烷基)、-NS(＝O) 2(C 1-C 6烷基)、S(O) p，     R d and R e can be obtained by the following means R d - R e or
    Figure PCTCN2018102833-appb-100011
    Linked to form a ring, wherein Z 1 optionally containing from 0-2 R b substituted by C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p 1 -C 6 heteroatoms Alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)(C 1 -C 6 alkyl), -NS(=O) 2 (C 1 -C 6 Alkyl), S(O) p ,
    R a独立地选自H、O、由0-2个R b取代的C 1-C 10烷基、C 1-C 6卤代烷基、-O-(C 1-C 6烷基)、C 1-C 6卤代烷氧基、C 3-C 6环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基；R b独立地选自卤素、OH、NH 2、-NHC(＝O)(C 1-C 4烷基)、-NHS(＝O) 2(C 1-C 4烷基)、＝O、CN、C 1-C 4烷基及C 1-C 4烷氧基；p各自独立地选自0，1及2； R a is independently selected from H, O, C 1 -C 10 alkyl substituted by 0-2 R b , C 1 -C 6 haloalkyl, -O-(C 1 -C 6 alkyl), C 1 -C 6 haloalkoxy, C 3 -C 6 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), containing carbon atoms and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S(O) p heteroatoms, -C(=O)H, aryl, containing carbon atoms and 1 to 2 selected from N, 5 to 6-membered heteroaryl of O and S heteroatoms; R b is independently selected from halogen, OH, NH 2 , -NHC(=O)(C 1 -C 4 alkyl), -NHS(=O) 2 (C 1 -C 4 alkyl), =O, CN, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; p are each independently selected from 0, 1 and 2;
    R 1X独立地选自卤素、OH、CN、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 3-C 8环状烷基和环状杂烷基； R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
    R 1Y独立地选自C 1-C 10烷基、卤素、CN、-(O) z-(包含0-2个R c取代C 1-C 10烷基)、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、SCF 3、C 3-C 8环状烷基、-C(＝O)(C 1-C 4烷基)、-CO 2(C 1-C 4烷基)、NR dR e、-C(＝O)NR dR e、-S(＝O) 2R d、-NHC(＝O)R d、-NHC(＝S)R d、-NHS(＝O) 2R d、-NHC(＝O)NR dR e、-NHC(＝S)NR dR e、-NHS(＝O) 2NR dR e、-C(＝S)NR dR e、-S(＝O) 2NHR d、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、-C(＝O)H、p各自独立地为0，1及2； R 1Y is independently selected from C 1 -C 10 alkyl, halogen, CN, -(O) z - (containing 0-2 R c substituted C 1 -C 10 alkyl), C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, SCF 3 , C 3 -C 8 cyclic alkyl, -C(=O)(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl) , NR d R e , -C(=O)NR d R e , -S(=O) 2 R d , -NHC(=O)R d , -NHC(=S)R d , -NHS(=O 2 R d , -NHC(=O)NR d R e , -NHC(=S)NR d R e , -NHS(=O) 2 NR d R e , -C(=S)NR d R e , -S(=O) 2 NHR d , heteroalkyl and heterocycloalkyl containing carbon atoms and 1 to 4 heteroatoms selected from O, N, S(O) p , -C(=O)H, p Each is independently 0, 1 and 2;
    其中，R c与在上述4a)部分中限定的R c的定义相同； Wherein, R c as defined in the above defined 4a) of the same portion of R c;
    其中R d与R e可通过R d——R e或
    Figure PCTCN2018102833-appb-100012
    的方式连接，其中Z 1可选自含0-2个R b取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6杂烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)(C 1-C 6烷基)、-NS(＝O) 2(C 1-C 6烷基)、S(O) p，     Where R d and R e may pass R d —R e or
    Figure PCTCN2018102833-appb-100012
    Is connected, wherein Z 1 optionally containing from 0-2 R b substituted by C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p hetero atoms 1 -C 6 heteroalkyl Alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)(C 1 -C 6 alkyl), -NS(=O) 2 (C 1 -C 6 Alkyl), S(O) p ,
    R b独立地选自卤素、OH、NH 2、-NHC(＝O)(C 1-C 4烷基)、-NHS(＝O) 2(C 1-C 4烷基)、＝O、CN、C 1-C 4烷基及C 1-C 4烷氧基；p各自独立地选自0，1及2； R b is independently selected from the group consisting of halogen, OH, NH 2 , -NHC(=O)(C 1 -C 4 alkyl), -NHS(=O) 2 (C 1 -C 4 alkyl), =O, CN , C 1 -C 4 alkyl and C 1 -C 4 alkoxy; p are each independently selected from 0, 1 and 2;
    R j及R k独立地为选自H、CN、含0-3个R s取代的C 1-C 10烷基、C 1-C 6卤代烷基、C 3-C 10环状烷基、包含碳原子以及选自和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、由R y取代的烯基或者炔基
    Figure PCTCN2018102833-appb-100013
    6至10元芳基、包含碳原子及1至2个选自N、O及S杂原子的5至10元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1Y取代；     R j and R k are independently selected from the group consisting of H, CN, C 1 -C 10 alkyl group having 0-3 R s substitutions, C 1 -C 6 haloalkyl group, C 3 -C 10 cyclic alkyl group, and a carbon atom and a heteroalkyl group and a heterocycloalkyl group selected from the group consisting of 1-4 selected from O, N, S(O) p heteroatoms, an alkenyl group or an alkynyl group substituted by R y
    Figure PCTCN2018102833-appb-100013
    a 6 to 10 membered aryl group, a carbon atom and 1 to 2 5- to 10-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl group and the heteroaryl group may be substituted by 0 to 2 R 1Y ;
    其中，R 1Y与在本4b)部分中的上述R s中限定的R 1Y的定义相同； Wherein R 1Y the same as defined in the present 4b) in the above R s R 1Y defined portions;
    R y独立地选自H、含0-3个R c取代的C 1-C 10烷基、C 1-C 6卤代烷基、C 3-C 10环状烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、NR dR e、OR d、芳基、包含碳原子及1至2个选自N、O及S杂原子的5至6元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1X取代；R 1X独立地选自卤素、OH、CN、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 3-C 8环状烷基和环状杂烷基； R y is independently selected from H, C 3 -C 10 alkyl group having 0-3 R c substitutions, C 1 -C 6 haloalkyl group, C 3 -C 10 cyclic alkyl group, containing carbon atom and 1-4 a heteroalkyl group and a heterocycloalkyl group selected from the group consisting of O, N, S(O) p heteroatoms, NR d R e , OR d , aryl, containing carbon atoms and 1 to 2 selected from N, O and S a 5- to 6-membered heteroaryl group of a hetero atom; wherein the aryl group and the heteroaryl group are substituted by 0-2 R 1X ; R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1- C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
    其中，R c与在上述4a)部分中限定的R c的定义相同；R d和R e与在本4b)部分中的上述R s中限定的R d和R e的定义相同； Wherein R c and defined the same as in the above 4a) defined portion R c; R d same as defined above and R s and R e in the present 4b) defining a portion of R d and R e of;
    特别地，R g与R h以及R j及R k可通过以下方式R g——R h、
    Figure PCTCN2018102833-appb-100014
    R j——R k、
    Figure PCTCN2018102833-appb-100015
    连接，其中Z 1可选自含0-2个R c取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)(C 1-C 6烷基)、-NS(＝O) 2(C 1-C 6烷基)、S(O) p；p各自独立地选自0，1及2；     In particular, R g and R h and R j and R k can be obtained by the following manner R g — R h ,
    Figure PCTCN2018102833-appb-100014
    R j - R k ,
    Figure PCTCN2018102833-appb-100015
    Connection, wherein Z 1 selected from the group comprising substituted with 0-2 R c C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p hetero atoms 1 -C 6 alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)(C 1 -C 6 alkyl), -NS(=O) 2 (C 1 -C 6 alkyl) , S(O) p ; p are each independently selected from 0, 1 and 2;
    其中，R c与在上述4a)部分中限定的R c的定义相同； Wherein, R c as defined in the above defined 4a) of the same portion of R c;
    R i独立地选自H、CN、C1-C4烷基； R i is independently selected from the group consisting of H, CN, C1-C4 alkyl;
    m各自独立地选自0-4；m are each independently selected from 0-4;
    4b’)优选地，Y独立地选自O、NR g、S(O) p、-CR i(CH 2) mNR gR h以及-CR i(CH 2) mOR g； 4b') Preferably, Y is independently selected from the group consisting of O, NR g , S(O) p , -CR i (CH 2 ) m NR g R h and -CR i (CH 2 ) m OR g ;
    R g及R h独立地选自H、C 1-C 6卤代烷基、
    Figure PCTCN2018102833-appb-100016
    Figure PCTCN2018102833-appb-100017
    -C(＝S)NHC(＝O)-R j、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、芳基、包含碳原子和1至2个选自N、O及S杂原子的5至6元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1X取代；     R g and R h are independently selected from H, C 1 -C 6 haloalkyl,
    Figure PCTCN2018102833-appb-100016
    Figure PCTCN2018102833-appb-100017
    -C(=S)NHC(=O)-R j , a heteroalkyl group containing a carbon atom and 1 to 4 hetero atoms selected from O, N, S(O) p , an aryl group, including a carbon atom and 1 to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1X ;
    R j及R k独立地选自H、CN、含0-3个R s取代的C 1-C 10烷基、C 1-C 6卤代烷基、C 3-C 10环状烷基、包含碳原子和1-4个选自O、N、S(O) p杂原子的杂烷基和杂环烷基、C 2-C 10 烯基或者炔基、6至10元芳基、包含碳原子及1至2个选自N、O及S杂原子的5至10元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1Y取代； R j and R k are independently selected from H, CN, C 1 -C 10 alkyl substituted with 0-3 R s , C 1 -C 6 haloalkyl, C 3 -C 10 cyclic alkyl, containing carbon Atom and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S(O) p heteroatoms, C 2 -C 10 alkenyl or alkynyl, 6 to 10 membered aryl, containing carbon atoms And 1 to 2 5- to 10-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl and heteroaryl groups may be substituted by 0-2 R 1Y ;
    其中，R s的定义与在上述4b)部分中的R s的定义相同； Wherein the same as defined in the definition of R s and R s in the above 4b) portion;
    p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
    R 1X独立地选自卤素、OH、CN、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 3-C 8环状烷基和环状杂烷基； R 1X is independently selected from halogen, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 8 cyclic alkyl and cyclic heteroalkyl;
    R 1Y独立地选自C 1-C 10烷基、卤素、CN、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R 1Y is independently selected from C 1 -C 10 alkyl, halogen, CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
    p各自独立地为0，1及2；p are each independently 0, 1 and 2;
    特别地，R g与R h以及R j及R k可通过以下方式R g——R h、
    Figure PCTCN2018102833-appb-100018
    R j——R k、
    Figure PCTCN2018102833-appb-100019
    连接，其中Z 1可选自含0-2个R c取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)(C 1-C 6烷基)、-NS(＝O) 2(C 1-C 6烷基)、S(O) p；     In particular, R g and R h and R j and R k can be obtained by the following manner R g — R h ,
    Figure PCTCN2018102833-appb-100018
    R j - R k ,
    Figure PCTCN2018102833-appb-100019
    Connection, wherein Z 1 selected from the group comprising substituted with 0-2 R c C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p hetero atoms 1 -C 6 alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)(C 1 -C 6 alkyl), -NS(=O) 2 (C 1 -C 6 alkyl) , S(O) p ;
    其中，R c与在上述4a)部分中限定的R c的定义相同； Wherein, R c as defined in the above defined 4a) of the same portion of R c;
    p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
    R i独立地选自H、CN及C 1-C 4烷基； R i is independently selected from the group consisting of H, CN, and C 1 -C 4 alkyl;
    m各自独立地选自0-4；m are each independently selected from 0-4;
    4b”)更优选地，Y独立地选自O、NR g、S、-CR iNR gR h以及-CR iOR g； More preferably, Y is independently selected from the group consisting of O, NR g , S, -CR i NR g R h and -CR i OR g ;
    R g及R h独立地选自H、C 1-C 6卤代烷基、
    Figure PCTCN2018102833-appb-100020
    Figure PCTCN2018102833-appb-100021
    -C(＝S)NHC(＝O)-R j、包含碳原子和1-4个选自O、N、S杂原子的杂烷基和杂环烷基、芳基、包含碳原子和1至2个选自N、O及S杂原子的5至6元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1X取代；     R g and R h are independently selected from H, C 1 -C 6 haloalkyl,
    Figure PCTCN2018102833-appb-100020
    Figure PCTCN2018102833-appb-100021
    -C(=S)NHC(=O)-R j , a heteroalkyl group containing a carbon atom and 1 to 4 heteroatoms selected from O, N, S, an aryl group, a carbon atom and 1 Up to 2 5- to 6-membered heteroaryl groups selected from N, O and S heteroatoms; wherein the aryl and heteroaryl groups may be substituted by 0-2 R 1X ;
    R j及R k独立地选自H、CN、含0-3个R s取代的C 1-C 10烷基、C 1-C 6卤代烷基、C 3-C 10环状烷基、包含碳原子和1-4个选自O、N、S杂原子的杂烷基和杂环烷基、C 2-C 10烯基或者炔基、6至10元芳基、包含碳原子及1至2个选自N、O及S杂原子的5至10元杂芳基；其中，该芳基以及杂芳基可由0-2个R 1Y取代； R j and R k are independently selected from H, CN, C 1 -C 10 alkyl substituted with 0-3 R s , C 1 -C 6 haloalkyl, C 3 -C 10 cyclic alkyl, containing carbon Atom and 1-4 heteroalkyl and heterocycloalkyl selected from O, N, S heteroatoms, C 2 -C 10 alkenyl or alkynyl, 6 to 10 membered aryl, containing carbon atoms and 1 to 2 a 5- to 10-membered heteroaryl group selected from the group consisting of N, O and S heteroatoms; wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1Y ;
    R s独立地选自OH，CN、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基、-(OCH 2CH 2) mOR d、(OCH 2CH 2) mNR dR e、包含碳原子及1至2个选自N、O及S杂原子的杂烷基和杂环烷基、芳基以及包含碳原子及1至2个选自N、O及S杂原子的杂芳基、其中该芳基以及杂芳基可由0-2个R 1Y取代； R s is independently selected from OH, CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl, -(OCH 2 CH 2 ) m OR d , (OCH 2 CH 2 ) m NR d R e , a heteroalkyl group containing a carbon atom and 1 to 2 heteroatoms selected from N, O and S And a heterocycloalkyl group, an aryl group, and a heteroaryl group containing a carbon atom and 1 to 2 hetero atoms selected from N, O and S, wherein the aryl group and the heteroaryl group may be substituted by 0-2 R 1Y ;
    其中，R d、R e与在上述4b)部分中限定的R d、R e的定义相同； Wherein, R d, R e and defined in the above 4b) portion R d, R e is the same as defined;
    R 1Y独立地选自C 1-C 10烷基、卤素、CN、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 8环状烷基； R 1Y is independently selected from C 1 -C 10 alkyl, halogen, CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 cyclic alkyl;
    特别地，R g与R h以及R j及R k可通过以下方式R g——R h、
    Figure PCTCN2018102833-appb-100022
    R j——R k、
    Figure PCTCN2018102833-appb-100023
    连接，其中Z 1可选自含0-2个R c取代的C 1-C 6烷基、含0-2个O、N、S(O) p杂原子的C 1-C 6烷基、O、-N(C 1-C 6烷基)、-NH、-N(C＝O)C 1-C 6烷基、NS(＝O) 2(C 1-C 6烷基)、S(O) p；     In particular, R g and R h and R j and R k can be obtained by the following manner R g — R h ,
    Figure PCTCN2018102833-appb-100022
    R j - R k ,
    Figure PCTCN2018102833-appb-100023
    Connection, wherein Z 1 selected from the group comprising substituted with 0-2 R c C 1 -C 6 alkyl group, containing 0-2 O, N, S (O) C p hetero atoms 1 -C 6 alkyl, O, -N(C 1 -C 6 alkyl), -NH, -N(C=O)C 1 -C 6 alkyl, NS(=O) 2 (C 1 -C 6 alkyl), S( O) p ;
    其中，R c与在上述4a)部分中限定的R c的定义相同； Wherein, R c as defined in the above defined 4a) of the same portion of R c;
    p各自独立地选自0，1及2；p are each independently selected from 0, 1 and 2;
    R i独立地选自H、CN及C 1-C 4烷基； R i is independently selected from the group consisting of H, CN, and C 1 -C 4 alkyl;
    m各自独立地选自0-4。m are each independently selected from 0-4.
  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，The compound according to claim 1, a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein
    所述通式I所述的化合物具有式Ia-1或Ia-2：The compound of formula I has the formula Ia-1 or Ia-2:
    Figure PCTCN2018102833-appb-100024
    Figure PCTCN2018102833-appb-100024
    其中，X 1与权利要求1中所述通式I中的1)部分中的定义相同； Wherein X 1 is the same as defined in the part 1) of the formula I described in claim 1;
    Figure PCTCN2018102833-appb-100025
    为单键或双键；
    Figure PCTCN2018102833-appb-100025
    For single or double keys;
    X 2、R 3-R 5、R 6以及n与权利要求1中所述通式I中的3)部分中的定义相同； X 2 , R 3 to R 5 , R 6 and n are the same as defined in part 3) of the formula I described in claim 1;
    R 1A、R 1B及R 1C、R 2B及R 2C、R 3B及R 3C、R 1D、n、m、q、Y、M的定义与权利要求1中所述通式I中的4)部分中的相应的定义相同。 Definitions of R 1A , R 1B and R 1C , R 2B and R 2C , R 3B and R 3C , R 1D , n, m, q, Y, M and part 4) of the general formula I described in claim 1 The corresponding definitions in the same are the same.
  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A compound according to claim 1, a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof, wherein
    所述通式I所述的化合物具有式Ia-3或Ia-4：The compound of formula I has the formula Ia-3 or Ia-4:
    Figure PCTCN2018102833-appb-100026
    Figure PCTCN2018102833-appb-100026
    其中，among them,
    X 1与权利要求1中所述通式I中的1)部分中的定义相同； X 1 is the same as defined in the part 1) of the formula I described in claim 1;
    Figure PCTCN2018102833-appb-100027
    为单键或双键；
    Figure PCTCN2018102833-appb-100027
    For single or double keys;
    X 2、R 7以及n与权利要求1中所述通式I中的3)部分中的定义相同； X 2 , R 7 and n are the same as defined in part 3) of the formula I described in claim 1;
    R 1A、R 1B及R 1C、R 2B及R 2C、R 3B及R 3C、R 1D、n、m、q、Y、M的定义与权利要求1中所述通式I中的4)部分中的相应的定义相同。 Definitions of R 1A , R 1B and R 1C , R 2B and R 2C , R 3B and R 3C , R 1D , n, m, q, Y, M and part 4) of the general formula I described in claim 1 The corresponding definitions in the same are the same.
  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A compound according to claim 1, a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof, wherein
    所述通式I所述的化合物具有式Ia-5或Ia-6：The compound of formula I has formula Ia-5 or Ia-6:
    Figure PCTCN2018102833-appb-100028
    Figure PCTCN2018102833-appb-100028
    其中，among them,
    X 1与权利要求1中所述通式I中的1)部分中的定义相同； X 1 is the same as defined in the part 1) of the formula I described in claim 1;
    Figure PCTCN2018102833-appb-100029
    为单键或双键；
    Figure PCTCN2018102833-appb-100029
    For single or double keys;
    Y的定义与权利要求1中所述通式I中的4)部分中的相应的定义相同。The definition of Y is the same as the corresponding definition in the portion 4) of the formula I described in claim 1.
  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A compound according to claim 1, a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof, wherein
    所述通式I所述的化合物具有式Ia-7或Ia-8：The compound of formula I has formula Ia-7 or Ia-8:
    Figure PCTCN2018102833-appb-100030
    Figure PCTCN2018102833-appb-100030
    其中，among them,
    X 1与权利要求1中所述通式I中的1)部分中的定义相同； X 1 is the same as defined in the part 1) of the formula I described in claim 1;
    Figure PCTCN2018102833-appb-100031
    为单键或双键；
    Figure PCTCN2018102833-appb-100031
    For single or double keys;
    R g的定义与权利要求1中所述通式I中的4)部分中的4b)部分中的相应的定义相同。 The definition of R g is the same as the corresponding definition in the 4b) part of the 4) part of the formula I described in claim 1.
  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A compound according to claim 1, a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof, wherein
    所述通式I所述的化合物具有式Ia-9:The compound of formula I has formula Ia-9:
    Figure PCTCN2018102833-appb-100032
    Figure PCTCN2018102833-appb-100032
    其中，among them,
    Figure PCTCN2018102833-appb-100033
    为单键或双键；
    Figure PCTCN2018102833-appb-100033
    For single or double keys;
    R g的定义与权利要求1中所述通式I中的4)部分中的4b)部分中的相应的定义相同。 The definition of R g is the same as the corresponding definition in the 4b) part of the 4) part of the formula I described in claim 1.
  7. 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A compound according to claim 1, a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof, wherein
    所述通式I所述的化合物具有以下结构式之一：The compound of formula I has one of the following structural formulae:
    Figure PCTCN2018102833-appb-100034
    Figure PCTCN2018102833-appb-100034
    其中，among them,
    M的定义与权利要求1中所述通式I中的4)部分中的相应的定义相同；The definition of M is the same as the corresponding definition in the part 4) of the formula I described in claim 1;
    R g的定义与权利要求1中所述通式I中的4)部分中的4b)部分中的相应的定义相同。 The definition of R g is the same as the corresponding definition in the 4b) part of the 4) part of the formula I described in claim 1.
  8. 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A compound according to claim 1, a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof, wherein
    所述通式I所述的化合物选自如下化合物：The compound of formula I is selected from the group consisting of:
    Figure PCTCN2018102833-appb-100035
    Figure PCTCN2018102833-appb-100035
    Figure PCTCN2018102833-appb-100036
    Figure PCTCN2018102833-appb-100036
    Figure PCTCN2018102833-appb-100037
    Figure PCTCN2018102833-appb-100037
    Figure PCTCN2018102833-appb-100038
    Figure PCTCN2018102833-appb-100038
    Figure PCTCN2018102833-appb-100039
    Figure PCTCN2018102833-appb-100039
    Figure PCTCN2018102833-appb-100040
    Figure PCTCN2018102833-appb-100040
    Figure PCTCN2018102833-appb-100041
    Figure PCTCN2018102833-appb-100041
    Figure PCTCN2018102833-appb-100042
    Figure PCTCN2018102833-appb-100042
  9. 一种用于制备根据权利要求1所述的由通式I表示的化合物的方法，所述方法包括如下步骤：A method for the preparation of a compound represented by the general formula I according to claim 1, the method comprising the steps of:
    方案一Option One
    Figure PCTCN2018102833-appb-100043
    Figure PCTCN2018102833-appb-100043
    (1a)用水合肼处理5-溴-4-氯-2-(甲硫基)嘧啶1，生成5-溴-4-肼基-2-(甲硫基)嘧啶2，(1a) Treatment of 5-bromo-4-chloro-2-(methylthio)pyrimidine 1 with hydrazine hydrate to give 5-bromo-4-indolyl-2-(methylthio)pyrimidine 2,
    (1b)再用原甲酸三甲酯将5-溴-4-肼基-2-(甲硫基)嘧啶2转化为三氮唑产物3，(1c)将三氮唑产物3与胺NH 2CH 2A发生取代反应生成化合物4， (1b) Conversion of 5-bromo-4-mercapto-2-(methylthio)pyrimidine 2 to triazole product 3 with trimethyl orthoformate, (1c) triazole product 3 with amine NH 2 CH 2 A undergoes a substitution reaction to form compound 4,
    (1d)将化合物4在钯催化剂作用下与各类具有R 1基团的硼酸或其等效物发生铃木偶联反应，得到产物5， (1d) Supramol coupling reaction of compound 4 with various boronic acids having R 1 groups or their equivalents under the action of a palladium catalyst to obtain product 5,
    其中，A、R 1的定义与在权利要求1中定义的相同； Wherein, the definitions of A and R 1 are the same as defined in claim 1;
    方案二Option II
    Figure PCTCN2018102833-appb-100044
    Figure PCTCN2018102833-appb-100044
    (2a)将氰乙酰胺6与丙炔酸乙酯反应生成中间体7，(2a) reacting cyanoacetamide 6 with ethyl propiolate to form intermediate 7,
    (2b)将中间体7用溴素处理发生溴代反应得到溴代物8，(2b) bromination of intermediate 7 with bromine to give brominated product 8,
    (2c)将溴代物8与三氯氧磷反应得到中间体9，(2c) reacting bromo 8 with phosphorus oxychloride to give intermediate 9,
    (2d)将中间体9由水合肼处理，生成中间体10，(2d) Intermediate 9 is treated with hydrazine hydrate to form intermediate 10,
    (2e)将中间体10用原甲酸三甲酯将其转化为三氮唑产物11，(2e) converting intermediate 10 to triazole product 11 using trimethyl orthoformate,
    (2f)将三氮唑产物11与各种胺发生取代反应生成化合物12，(2f) the triazole product 11 is substituted with various amines to form compound 12,
    (2g)最后将化合物12在钯催化剂作用下与各类具有R 1基团的硼酸或其等效物发生铃木偶联(Suzuki)反应，得到产物13， (2g) Finally, compound 12 is subjected to a Suzuki reaction with various types of boronic acid having an R 1 group or its equivalent under the action of a palladium catalyst to obtain a product 13,
    其中，A、R 1的定义与在权利要求1中定义的相同； Wherein, the definitions of A and R 1 are the same as defined in claim 1;
    方案三third solution
    Figure PCTCN2018102833-appb-100045
    Figure PCTCN2018102833-appb-100045
    (3a)14以二氯甲烷为溶剂，在三氟乙酸作用下，去除Boc保护基，得到胺基化合物15，(3a) 14 using dichloromethane as a solvent, removing the Boc protecting group under the action of trifluoroacetic acid to obtain an amine compound 15,
    (3b)将胺基化合物15在碱性条件下进一步与带有R g基团的试剂或化合物反应得到16，所述试剂或化合物例如但不限于酸酐、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， (3b) further reacting the amine compound 15 under basic conditions with a reagent or compound having an Rg group to give 16, such as, but not limited to, an acid anhydride, a sulfonic acid anhydride, an isocyanate, a thioisocyanate, an acid chloride , sulfonyl chloride, carbonate, chloroformate, carbamate,
    其中，A、X 1、R g、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与在权利要求1中定义的相同； Wherein A, X 1 , R g , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m have the same meanings as defined in claim 1;
    方案四Option four
    Figure PCTCN2018102833-appb-100046
    Figure PCTCN2018102833-appb-100046
    (4a)将在方案三的步骤(3a)中去除保护基所得的产物15与含有R j基团的羧酸在缩合剂的作用下发生缩合反应得到酰胺化合物17， (4a) The product 15 obtained by removing the protecting group in the step (3a) of the scheme 3 is condensed with a carboxylic acid having a R j group by a condensing agent to obtain an amide compound 17,
    其中，A、X 1、R j、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与在权利要求1中定义的相同； Wherein A, X 1 , R j , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m have the same definitions as defined in claim 1;
    方案五Option five
    Figure PCTCN2018102833-appb-100047
    Figure PCTCN2018102833-appb-100047
    (5a)将18溶于溶剂中，所述溶剂例如但不限于甲醇、乙醇、乙酸乙酯、四氢呋喃，加入金属催化剂，所述金属催化剂例如但不限于10％钯碳、Pd(OH) 2、雷尼镍、RhCl(PPh 3) 3，通入氢气，室温下反应，得到双键还原的化合物19， (5a) dissolving 18 in a solvent such as, but not limited to, methanol, ethanol, ethyl acetate, tetrahydrofuran, added to a metal catalyst such as, but not limited to, 10% palladium on carbon, Pd(OH) 2 , Raney nickel, RhCl (PPh 3 ) 3 , hydrogen gas is introduced, and reacted at room temperature to obtain compound 19 with double bond reduction.
    其中，A、X 1、Y、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与在权利要求1中定义的相同； Wherein A, X 1 , Y, R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m have the same definitions as defined in claim 1;
    方案六Option six
    Figure PCTCN2018102833-appb-100048
    Figure PCTCN2018102833-appb-100048
    (6a)20通过还原反应得到化合物21，随后与mCPBA(间氯过氧苯甲酸)或者双氧水发生氧化反应得到化合物22，(6a)20 is obtained by reduction reaction to obtain compound 21, followed by oxidation reaction with mCPBA (m-chloroperoxybenzoic acid) or hydrogen peroxide to obtain compound 22,
    其中，A、X 1、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与在权利要求1中定义的相同； Wherein A, X 1 , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m have the same definitions as defined in claim 1;
    方案七Scheme seven
    Figure PCTCN2018102833-appb-100049
    Figure PCTCN2018102833-appb-100049
    (7a)20与mCPBA或者双氧水发生氧化反应得到化合物23，(7a) 20 is oxidized with mCPBA or hydrogen peroxide to give compound 23,
    其中，A、X 1、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与在权利要求1中定义的相同； Wherein A, X 1 , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m have the same definitions as defined in claim 1;
    方案八Option eight
    Figure PCTCN2018102833-appb-100050
    Figure PCTCN2018102833-appb-100050
    15将双键还原得到24，随后与带有R g基团的试剂或化合物在碱存在下反应得到化合物25，所述试剂或化合物例如但不限于酸酐、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；或者24与各类羧酸在缩合剂的存在下发生缩合反应得到酰胺化合物25， 15 reduction of the double bond to give 24, followed by reaction with a reagent or compound bearing an Rg group in the presence of a base to give compound 25, such as, but not limited to, an anhydride, a sulfonic anhydride, an isocyanate, a thioisocyanate, an acid chloride a sulfonyl chloride, a carbonate, a chloroformate or a carbamate; or a condensation reaction of 24 with a carboxylic acid in the presence of a condensing agent to give an amide compound 25,
    其中，A、X 1、R 1A、R 1B、R 1C、R 2B、R 2C、R 3B、R 3C、q、m的定义与在权利要求1中定义的相同。 Here, the definitions of A, X 1 , R 1A , R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , q , m are the same as defined in claim 1.
  10. 一种药物组合物，其包含根据权利要求1-8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。A pharmaceutical composition comprising a compound according to any one of claims 1-8, a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof One or more, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  11. 根据权利要求10所述的药物组合物，其中The pharmaceutical composition according to claim 10, wherein
    所述药物组合物进一步包含至少一种其他治疗剂，The pharmaceutical composition further comprises at least one other therapeutic agent,
    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。Preferably, the at least one additional therapeutic agent included in the pharmaceutical composition is selected from the group consisting of other anticancer agents, immunomodulators, anti-allergic agents, antiemetics, pain relieving agents, cytoprotective agents, and combinations thereof.
  12. 根据权利要求1-8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10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。The compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof or the pharmaceutical composition according to claim 10 Use in the manufacture of a medicament for the treatment of a disease or condition mediated by EED and/or PRC2.
  13. 根据权利要求12所述的用途，其中The use according to claim 12, wherein
    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。The disease or condition mediated by EED and/or PRC2 includes diffuse large B-cell lymphoma, follicular lymphoma, other lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor , hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, including neuroblastoma, schwannomas, glioma, glioblastoma 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, parathyroid tumor, uterine tumor and soft tissue sarcoma .
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JP2023502889A (en) * 2019-11-01 2023-01-26 上海科技大学 EED INHIBITOR, METHOD OF MANUFACTURE THEREOF AND USE THEREOF
CN114929707A (en) * 2019-11-01 2022-08-19 上海科技大学 EED inhibitor and preparation method and application thereof
WO2021083380A1 (en) * 2019-11-01 2021-05-06 上海科技大学 Eed inhibitor, and preparation method therefor and use thereof
EP4056570A4 (en) * 2019-11-01 2023-12-20 ShanghaiTech University Eed inhibitor, and preparation method therefor and use thereof
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CN114929707B (en) * 2019-11-01 2024-04-09 上海科技大学 EED inhibitor and preparation method and application thereof
JP7481689B2 (en) 2019-11-01 2024-05-13 上海科技大学 EED inhibitors, methods for their preparation and uses
CN113004233B (en) * 2019-12-18 2022-12-20 南京优氟医药科技有限公司 Compound for preparing PRC2 inhibitor, preparation method and application thereof
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