WO2019062435A1 - Utilisation de triazolopyrimidine, de composés de triazolopyridine et d'une composition de ceux-ci pour le traitement de maladies médiées par prc2 - Google Patents

Utilisation de triazolopyrimidine, de composés de triazolopyridine et d'une composition de ceux-ci pour le traitement de maladies médiées par prc2 Download PDF

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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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English (en)
Chinese (zh)
Inventor
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/zh
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/fr
Priority to JP2020529171A priority patent/JP6876875B2/ja
Priority to CN201880002779.7A priority patent/CN109843890B/zh
Priority to US16/651,510 priority patent/US11013745B2/en
Publication of WO2019062435A1 publication Critical patent/WO2019062435A1/fr

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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

La présente invention concerne un composé représenté par la formule générale I, un sel pharmaceutiquement acceptable, un énantiomère, un diastéréoisomère ou un racémate de celui-ci, un procédé de préparation associé, une composition pharmaceutique contenant ceux-ci et une utilisation de ceux-ci dans la préparation de médicaments pour le traitement de maladies ou affections médiées par EED et/ou PRC2. Le composé selon la présente invention peut être utilisé pour le traitement de maladies ou affections médiées par PRC2. (I)
PCT/CN2018/102833 2017-09-28 2018-08-29 Utilisation de triazolopyrimidine, de composés de triazolopyridine et d'une composition de ceux-ci pour le traitement de maladies médiées par prc2 WO2019062435A1 (fr)

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JP2020529171A JP6876875B2 (ja) 2017-09-28 2018-08-29 Ｐｒｃ２介在の疾患を治療するためのトリアゾロピリミジン、トリアゾロピリジン化合物及びその組成物
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JP2023502889A (ja) * 2019-11-01 2023-01-26 上海科技大学 Ｅｅｄ阻害剤、その製造方法およびその使用
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WO2021083380A1 (fr) * 2019-11-01 2021-05-06 上海科技大学 Inhibiteur d'eed, son procédé de préparation et son utilisation
CN113004233B (zh) * 2019-12-18 2022-12-20 南京优氟医药科技有限公司 一种用于制备prc2抑制剂的化合物、其制备方法和用途
CN113004233A (zh) * 2019-12-18 2021-06-22 南京优氟医药科技有限公司 一种用于制备prc2抑制剂的化合物、其制备方法和用途
JP7546780B2 (ja) 2021-02-10 2024-09-06 シャンハイ ブルーレイ バイオファーマ カンパニー，リミティド アザヘテロアリール化合物、その調製方法及び使用

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