WO2020156479A1 - Composé azaaryle substitué par un cyclopropène et un benzofurane, et intermédiaire, procédé de préparation et application de celui-ci - Google Patents

Composé azaaryle substitué par un cyclopropène et un benzofurane, et intermédiaire, procédé de préparation et application de celui-ci Download PDF

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WO2020156479A1
WO2020156479A1 PCT/CN2020/073978 CN2020073978W WO2020156479A1 WO 2020156479 A1 WO2020156479 A1 WO 2020156479A1 CN 2020073978 W CN2020073978 W CN 2020073978W WO 2020156479 A1 WO2020156479 A1 WO 2020156479A1
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substituted
group
unsubstituted
compound
cancer
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Chinese (zh)
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马世超
张忠国
张松
袁文佳
王翔
卢鹏
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上海青煜医药科技有限公司
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    • 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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel cyclopropenacbenzofuran substituted azaaryl compound, its pharmaceutically acceptable salt, its hydrate, its prodrug, its stereoisomer or its solvate and their isotope label .
  • the present invention also provides a preparation method of the compound, a composition containing the compound, and a pharmaceutical application for treating diseases related to the mechanism of action of the EED protein and/or PRC2 protein complex.
  • PcG Polycomb Group protein is an important class of chromatin modifying enzymes. It modifies chromatin to regulate gene transcription, which plays an important role in the growth, differentiation and long-term cellular memory of stem cells.
  • PcG proteins are mainly divided into two types of transcription repressive complexes, namely PRC1 (Polycomb Repressive Complex1) and PRC2 (Polycomb Repressive Complex2).
  • PRC2 inhibits the expression of related genes by methylating the lysine 27 (H3K27) of histone 3 in the chromatin.
  • the PRC2 protein complex is mainly composed of core proteins such as EZH2 (Enhancer of Zeste Homolog2) (or its very similar homologous protein EZH1), EED (Embryonic ectoderm Development) and SUZ12 (Suppressor of Zeste12).
  • EZH2 has enzymatic catalytic activity.
  • the SET (Su(var), E(Z), and Trithorax) protein domain can transfer the methyl group of the substrate SAM (S-adenosyl-L-methionine) to H3K27, thereby One to three methylation modification of H3K27.
  • the catalytic activity of EZH2 also depends on other components of PRC2, such as the EED protein that belongs to the WD40 repeat structure protein family.
  • the combination of EED and trimethylated H3K27Me3 on the one hand has a great allosteric promotion effect on the enzyme catalytic function of EZH2, on the other hand, it can also locate the PCR2 complex on the chromatin that needs to be modified.
  • the functional abnormalities of PRC2, such as overexpression or gain-of-function mutations of EZH2 are associated with many clinical tumor diseases, including lung cancer, breast cancer, rectal cancer, prostate cancer, bladder cancer, pancreatic cancer, sarcoma, and lymphoma.
  • PRC2 is also related to a variety of cellular immune functions. For example, EZH2 is involved in regulating lymphocyte activation and can also work with glycolysis to promote T cell responses to tumor cells. Therefore, the development of small molecule inhibitors of PRC2 has important and broad drug development value.
  • EZH2 inhibitors are mainly to develop two strategies, EZH2 inhibitors and EED inhibitors.
  • EZH2 inhibitors currently entering the clinic include EPZ-6438 (Epizyme, clinical phase II), GSK2816126 (GSK, clinical phase I), and CPI-1205 (Constellation, clinical phase I) and so on. Although many EZH2 inhibitors have entered the clinical research phase, these inhibitors all contain a common 2-pyridone pharmacophore.
  • EED inhibitors have an allosteric inhibitory effect on EZH2 enzyme function, and can achieve the same or similar biological functions as EZH2.
  • EED inhibitors can overcome the problem of EZH2 resistance.
  • EED inhibitors can be combined with EZH2 inhibitors to achieve better synergistic effects. Therefore, the development of new EED inhibitors is very important Meaning.
  • the cyclopropenyl benzofuran substituted azaaryl compound provided by the present invention is a new type of EED inhibitor, exhibits good inhibitory activity on tumor cells, and has broad prospects for drug development.
  • the present invention provides a compound represented by formula (I), its pharmaceutically acceptable salt, its hydrate, its prodrug, its stereoisomer or its solvate:
  • X is independently C or N
  • R 2 is independently H or halogen (e.g. fluorine);
  • R 3 is independently H or halogen (e.g. fluorine);
  • R 4 is independently H or halogen (e.g. fluorine);
  • n is independently 0 or 1;
  • R 1 is independently hydrogen, halogen (for example, fluorine, bromine or iodine), cyano, R 1a substituted or unsubstituted C 1-8 alkyl (the C 1-8 alkyl such as C 1-4 alkyl, It can be methyl, ethyl, n-propyl or isopropyl), C 1-8 haloalkyl (e.g.
  • C 1-4 haloalkyl R 1a substituted or unsubstituted C 3-8 cycloalkyl (the C 3-8 cycloalkyl such as cyclohexyl), R 1b substituted or unsubstituted C 3-8 cycloalkyl (the C 3-8 cycloalkyl such as cyclohexyl), R 1b substituted or unsubstituted C 3 -8 heteroalkyl (said C 3-8 heteroalkyl having preferably C 1 to 3 hetero atoms independently selected from nitrogen, oxygen, sulfur, or 3-8 heteroalkyl, e.g.
  • R 1c substituted or unsubstituted alkenyl (the alkenyl is for example C 2-10 alkenyl, preferably C 2-6 alkenyl, more preferably vinyl), R 1b substituted or unsubstituted C 5-8 cycloalkenyl (The C 5-8 cycloalkenyl is for example R 1b substituted or unsubstituted heterocyclyl C 5-8 alkenyl group (said C 5-8 heterocycloalkenyl group having preferably C 1 to 3 hetero atoms independently selected from nitrogen, oxygen, or sulfur heteroatoms 5-8 Cycloalkenyl, for example or ), 0-3 R 1d substituted C 6-10 aryl (the C 6-10 aryl such as phenyl) or 0-3 R 1d substituted "having C 1-20 carbon atoms and 1-4 A heteroaryl group independently selected from N, NR 1de1 , O or S(O) 0-2 heteroatoms" (the C 1-20 carbon atom is preferably a
  • R 5c substituted or unsubstituted "having C 1-20 Carbon atoms and 1-4 heterocyclic groups independently selected from NR 1de1 , N, O or S(O) 0-2 heteroatoms" (the C 1-20 carbon atoms are preferably C 1-10 carbon atoms, so The heterocyclic group is preferably a 5-12 membered heterocyclic group, for example or );
  • Each R 1de2 is independently hydrogen or C 1-4 alkyl
  • Each R 1de3 is a C 1-4 alkyl group.
  • each letter and group in the compound of the above general formula are as follows, and the definitions of undefined letters and groups are as described above:
  • R 1 is hydrogen, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, or any of the following structures:
  • each letter and group in the compound of the above general formula are as follows, and the definitions of undefined letters and groups are as described above:
  • each letter and group in the compound of the above general formula are as follows, and the definitions of undefined letters and groups are as described above:
  • R 1de4 is a C 1-4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • R 1 is R 1b substituted or unsubstituted C 5-8 heterocycloalkenyl (the C 5-8 heterocycloalkenyl is preferably C having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 5-8 heterocycloalkenyl, more preferably C 5-8 heterocycloalkenyl having one nitrogen, oxygen or sulfur heteroatom; for example or ), 0-3 R 1d substituted C 6-10 aryl (the C 6-10 aryl such as phenyl) or 0-3 R 1d substituted "having C 1-20 carbon atoms and 1- 4 heteroaryl groups independently selected from N, NR 1de1 , O or S(O) 0-2 heteroatoms" (the C 1-20 carbon atom is preferably a C 1-10 carbon atom, the heteroaryl group It is preferably a 5-12 membered heteroaryl group, more preferably a heteroaryl group having C 3-5 carbon atoms and 1-2 heteroatoms independently selected from N and O, such as furyl, pyrid
  • the number of R 1d is 0, 1, or 2;
  • each R 1a is independently halogen or hydroxyl (e.g. fluorine, chlorine, bromine or iodine);
  • R 1de3 is methyl
  • each letter and group in the compound of the above general formula are as follows, and the definitions of undefined letters and groups are as described above:
  • each letter and group in the compound of the above general formula are as follows, and the definitions of undefined letters and groups are as described above:
  • R 1 is R 1b substituted or unsubstituted C 5-8 heterocycloalkenyl (the C 5-8 heterocycloalkenyl is preferably C having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 5-8 heterocycloalkenyl, more preferably C 5-8 heterocycloalkenyl having one nitrogen, oxygen or sulfur heteroatom; for example or );
  • the number of R 1d is 0, 1, or 2;
  • R 1a substituted or unsubstituted C 1-4 alkoxy such as methoxy
  • R 1a substituted or unsubstituted C 1-4 alkyl for example methyl, ethyl, n-propyl or isopropyl
  • -C( O)NR 1de1 R 1de
  • R 1 is substituted with 0-3
  • R 1d is "having C 1-20 carbon atoms and 1-4 heteroatoms independently selected from N, NR 1de1, O, or S (O) 0-2 heteroaryl group is an aryl group
  • the C 1-20 carbon atoms are preferably C 1-10 carbon atoms
  • the heteroaryl group is preferably a 5-12 membered heteroaryl group, more preferably having C 3-5 carbon atoms and 1-2 independently selected from N Heteroaryl groups with heteroatoms of O, such as furyl, pyridyl, pyrazolyl, isothiazolyl or pyrimidinyl, for example );
  • the number of R 1d is 0, 1, or 2;
  • each R 1a is independently halogen (such as fluorine, chlorine, bromine or iodine) and hydroxyl;
  • R 1de1 and R 1de2 are hydrogen.
  • R 1 is a single ring.
  • each letter and group in the compound of the above general formula are as follows, and the definitions of undefined letters and groups are as described above:
  • R 1 is fluorine, bromine, iodine
  • each letter and group in the compound of the above general formula are as follows, and the definitions of undefined letters and groups are as described above:
  • each letter and group in the compound of the above general formula are as follows, and the definitions of undefined letters and groups are as described above:
  • the compound represented by formula (I) is a compound represented by formula (Ia) below,
  • R 1 is a C 6-10 aryl group substituted with 0-3 R 1d (the C 6-10 aryl group is for example phenyl),
  • the number of R 1d is 0, 1, or 2;
  • each R 1a is independently halogen (e.g. fluorine, chlorine, bromine or iodine).
  • halogen e.g. fluorine, chlorine, bromine or iodine.
  • each letter and group in the compound represented by formula (Ia) are as follows, and the definitions of undefined letters and groups are as described above:
  • R 1 is substituted with 0-3
  • R 1d is "having C 1-20 carbon atoms and 1-4 heteroatoms independently selected from N, NR 1de1, O, or S (O) 0-2 heteroaryl group is an aryl group
  • the C 1-20 carbon atoms are preferably C 1-10 carbon atoms
  • the heteroaryl group is preferably a 5-12 membered heteroaryl group, more preferably having C 3-5 carbon atoms and 1-2 independently selected from N Heteroaryl groups with heteroatoms of O, such as furyl, pyridyl, pyrazolyl, isothiazolyl or pyrimidinyl, for example );
  • the number of R 1d is 0, 1, or 2;
  • each R 1d is independently halogen (such as fluorine, chlorine, bromine or iodine), R 1a substituted or unsubstituted C 1-4 alkoxy (such as methoxy), R 1a substituted or unsubstituted C 1-4 alkyl (such as methyl, ethyl, n-propyl or isopropyl), NR 1de1 R 1de2 (such as -NH 2 ) or having C 1-20 carbon atoms and 1-4 independently selected from NR 1de1 , N, O or S(O) 0-2 heteroatomic heterocyclic group (the C 1-20 carbon atom is preferably C 1-10 carbon atom, and the heterocyclic group is preferably 5-12 membered heterocyclic group , More preferably C 3-5 carbon atoms and 1-2 heterocyclic groups selected from N and O heteroatoms; for example );
  • R 1d is independently halogen (such as fluorine, chlorine, bromine or iodine)
  • each R 1a is independently halogen (such as fluorine, chlorine, bromine or iodine) and hydroxyl;
  • R 1de1 and R 1de2 are hydrogen.
  • each letter and group in the compound represented by formula (Ia) are as follows, and the definitions of undefined letters and groups are as described above:
  • the compound represented by formula (Ia) is selected from any of the following compounds:
  • the compound represented by formula (I) is a compound represented by formula (Ib) below,
  • each letter and group in the compound represented by formula (Ib) are as follows, and the definitions of undefined letters and groups are as described above:
  • R 1 is 0-3 R 1d substituted C 6-10 aryl (the C 6-10 aryl is for example phenyl) or 0-3 R 1d substituted "having C 1-20 carbon atoms and 1 -4 heteroatoms independently selected from N, NR 1de1, O, or S (O) heteroaryl group of 0-2 hetero atoms "(the C 1- 20 carbon atoms, preferably a C 1-10 carbon atoms, the heteroaryl The group is preferably a 5-12 membered heteroaryl group, more preferably a heteroaryl group having C 3-5 carbon atoms and 1-2 heteroatoms independently selected from N and O);
  • halogen for example, fluorine, chlorine, bromine or iodine
  • C 1-4 alkyl for example, methyl, ethyl, n-propyl or isopropyl
  • each letter and group in the compound represented by formula (Ib) are as follows, and the definitions of undefined letters and groups are as described above:
  • R 1 is substituted with 0-3
  • R 1d is "having C 1-20 carbon atoms and 1-4 heteroatoms independently selected from N, NR 1de1, O, or S (O) 0-2 heteroaryl group aryl"
  • the C 1-20 carbon atoms are preferably C 1-10 carbon atoms, and the heteroaryl group is preferably a 5-12 membered heteroaryl group, more preferably having C 3-5 carbon atoms and 1-2 independently selected from Heteroaryl groups of N and O heteroatoms, such as );
  • the number of R 1d is 0, 1, or 2;
  • halogen for example, fluorine, chlorine, bromine or iodine
  • C 1-4 alkyl for example, methyl, ethyl, n-propyl or isopropyl
  • each letter and group in the compound represented by formula (Ib) are as follows, and the definitions of undefined letters and groups are as described above:
  • the compound represented by formula (Ib) is selected from any of the following compounds:
  • the present invention further provides a compound represented by formula (I), compounds isotopically-labeled pharmaceutically acceptable salt thereof, a hydrate thereof, a prodrug, a stereoisomer or a solvate thereof, wherein the isotope is selected from 2 H , 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the atoms that can be isotopically labeled in the compound represented by formula (I) include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, etc., which can be isotopes 2 H, 3 H, 11 C, respectively. , 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I etc. instead.
  • W represents halogen, preferably Br;
  • X, n, R 1 , R 2 , R 3 and R 4 are as defined above.
  • W represents halogen (such as fluorine, chlorine, bromine or iodine), preferably Br;
  • X, n, R 1 , R 2 , R 3 and R 4 are as defined above, and W 1 is boric acid, boric acid ester or boron Acid salt (e.g. -B(OH) 2 or ).
  • R 1A is selected from
  • the present invention also provides a preparation method of compound A, which comprises the following steps:
  • the present invention also provides a method for preparing compound C1 and its salt, and the reaction process is as follows:
  • the bromine atom of C1-5 is catalyzed by cyano group substitution to obtain compound For C1-6, the cyano group is reduced to an amine group and protected with in-situ Boc anhydride to obtain C1-7, and C1-7 is removed to obtain C1.
  • the solvent involved in the present invention is selected from: dichloromethane, chloroform, 1,2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP, THF or a combination thereof.
  • the bases involved in the present invention include organic bases and inorganic bases.
  • the organic base involved in the present invention is selected from TEA, DIPEA or a combination thereof.
  • the inorganic base involved in the present invention is selected from sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, LiHMDS, LDA, butyl lithium or a combination thereof.
  • the present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salt, its hydrate, its prodrug, its stereoisomer or its solvate or the aforementioned isotope-labeled compound, or Application of the above-mentioned pharmaceutical composition in preparing medicine.
  • the compound represented by formula (I), its pharmaceutically acceptable salt, its hydrate, its prodrug, its stereoisomer or its solvate or the aforementioned isotope-labeled compound is used in combination with other drugs; More preferably, the other drugs are selected from anticancer drugs, tumor immune drugs, anti-allergic drugs, antiemetics, analgesics, and cytoprotective drugs.
  • the present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salt, its hydrate, its prodrug, its stereoisomer or its solvate or the aforementioned isotope-labeled compound used in combination with other drugs,
  • the other drugs are selected from: anticancer drugs, tumor immune drugs, anti-allergic drugs, antiemetics, analgesics, cytoprotective drugs, etc., and the combined use has better effects.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • C 1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, 6 carbon atoms).
  • the total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • Cyano refers to -CN.
  • Amino refers to -NH 2 .
  • Ester group means R can be alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl or heteroarylalkyl, and the like.
  • Amide means Each R can independently be hydrogen, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, or heteroarylalkyl, and the like.
  • Substituted amino group refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, aralkyl groups, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroaralkylamino.
  • Carboxy refers to -COOH.
  • alkyl refers to a fully saturated linear or branched hydrocarbon chain group, Consists of only carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4) carbon atoms, and is connected to the rest of the molecule through a single bond Partial connections, such as but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.
  • haloalkyl means that one or more hydrogen atoms in an alkyl group (as defined in the present invention) are halogenated (as defined in the present invention). ), the number of halogens can be one or more; when the number of halogens is more than one, the halogens are the same or different.
  • fluoroalkyl means that the alkyl group is substituted with one or more fluorines.
  • haloalkyl groups include, but are not limited to, trifluoromethyl and difluoromethyl.
  • alkenyl means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10 One, more preferably 2 to 6, more preferably 2 to 4) a straight or branched hydrocarbon chain group connected to the rest of the molecule through a single bond, such as but not limited to vinyl, propylene Group, allyl group, but-1-enyl group, but-2-enyl group, pent-1-enyl group, pent-1-enyl group, etc.
  • cyclic hydrocarbon group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed of only carbon atoms and hydrogen atoms, which may include fused rings System, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and it is saturated or unsaturated and can be passed through any suitable
  • the carbon atom is connected to the rest of the molecule by a single bond. Unless specifically indicated otherwise in this specification, the carbon atoms in the cyclic hydrocarbon group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indene Group, indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzo Cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, Fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.
  • cycloalkyl means a saturated cyclic hydrocarbon group.
  • cycloalkenyl means a cyclic hydrocarbon group having at least one double bond (such as a carbon-carbon double bond).
  • the cycloalkenyl group can be connected to the rest of the molecule through the atom of the double bond.
  • heterocyclic group means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic group.
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or more ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; in the heterocyclic group
  • the nitrogen, carbon, or sulfur atoms of may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom and through a single bond.
  • one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged ring or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur
  • the group is more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged ring or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]non Alkyl-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, in
  • heteroalkyl means a C 3-8 heteroalkyl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms).
  • the aryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the aryl group passes through The atoms on the aromatic ring are connected to the rest of the molecule through a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
  • arylalkyl refers to the above-defined alkyl group substituted by the above-defined aryl group.
  • heteroaryl means having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 nitrogen atoms in the ring. 5 to 16 membered conjugated ring system group of heteroatoms of, oxygen and sulfur.
  • heteroaryl groups can be monocyclic, bicyclic, tricyclic or more cyclic ring systems, and can also be fused with cycloalkyl or heterocyclic groups as defined above, provided that the hetero The aryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably contains 1 to 4 selected heteroatoms.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, Quinolinyl, Isoquinolinyl, Diazonaphthyl, Naphthyridinyl, Quinoxolinyl, Pteridinyl, Carbazolyl, Carboline, Phenanthridinyl, Phenanthrolinyl, Acridine Group, phen
  • heteroarylalkyl refers to the above-defined alkyl group substituted by the above-defined heteroaryl group.
  • “optionally” means that the event or condition described later may or may not occur, and the description includes both occurrence and non-occurrence of the event or condition.
  • “optionally substituted aryl” means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
  • substituents described in the claims and specification of the present invention are selected from alkyl, alkenyl, alkynyl, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, cyano, nitro , Optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic alkyl.
  • substituted or “substituent” means that one or more hydrogen atoms are replaced by a designated group.
  • substituents can be one or more; when the substitution position is not specified, the substitution can be at any position, but only the formation of a stable or chemically feasible chemical can be Allowed.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • n 2
  • each R has independent options, that is, the two Rs can be the same or different.
  • substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • part refers to specific fragments or functional groups in a molecule.
  • the chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.
  • the compound of the present invention contains an olefinic double bond, unless otherwise specified, the compound of the present invention is intended to include E- and Z-geometric isomers.
  • Tautomer refers to an isomer formed by transferring a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention will also be included in the scope of the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may contain one or more chiral carbon atoms, and therefore may produce enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include, but are not limited to, formate, acetate, and 2,2-dichloroacetate , Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexanoate Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate,
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include but are not limited to the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethyl
  • pharmaceutical composition refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (such as a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredients and then exert the biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing undesirable biological activity. Reacts or interacts in an undesirable manner with any components included in the composition.
  • pharmaceutically acceptable excipients include, but are not limited to, any adjuvants, carriers, excipients, glidants, enhancers that are approved by relevant government authorities as acceptable for human or livestock use.
  • the "tumor” of the present invention includes but is not limited to brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, sarcoma, melanoma, articular chondroma, cholangiocarcinoma, leukemia, gastrointestinal Stromal tumor, diffuse large B-cell lymphoma, follicular lymphoma and other lymphomas, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate Cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, multiple myeloma, mesothelioma , Malignant rhabdoid tumor,
  • preventive include reducing the likelihood of a disease or condition from occurring or worsening.
  • treatment and other similar synonyms include the following meanings:
  • an effective amount refers to at least one agent or compound that is sufficient to relieve one or more symptoms of the disease or condition being treated after administration The amount.
  • the result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired changes in the biological system.
  • the "effective amount” for treatment is the amount of the composition containing the compound disclosed herein that is required to provide significant disease relief clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
  • the terms “administration”, “administration”, “administration” and the like refer to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.
  • drug combination refers to drug treatments obtained by mixing or combining more than one active ingredient. It includes fixed and non-fixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • non-fixed combination refers to the simultaneous administration, co-administration or sequential administration of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapy, such as the administration of three or more active ingredients.
  • the functional group of the intermediate compound may need to be protected by an appropriate protecting group.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl) , Tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable sulfhydryl protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protective groups is detailed in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymer resin.
  • the starting materials used in the following examples can be purchased from chemical vendors such as Aldrich, TCI, Alfa Aesar, Glasgow, Anaiji, etc., or can be synthesized by known methods.
  • the ice bath refers to -5°C to 0°C
  • the room temperature refers to 10°C to 30°C
  • the reflux temperature generally refers to the solvent reflux temperature under normal pressure.
  • An overnight reaction means that the time is 8-15 hours. In the following examples, if the specific operating temperature is not limited, it is all carried out at room temperature.
  • the separation and purification of the intermediate and the final product is by normal phase or reverse phase chromatography column separation or other suitable methods.
  • the normal phase flash chromatography column uses ethyl acetate and n-hexane or methanol and dichloromethane as the mobile phase.
  • Reversed-phase preparative high pressure liquid chromatography (HPLC) uses a C18 column and uses UV214nm and 254nm to detect, and its mobile phase is A (water and 0.1% formic acid), B (acetonitrile) or mobile phase A (water and 0.1% hydrogen carbonate) Ammonium), B (acetonitrile).
  • Step 2 Synthesis of 5-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (B1):
  • Step 7 Intermediate tert-butyl ((5-fluoro-1aS,6bS-dihydro-1H-cyclopropeno[b]benzofuran-6-yl)methyl)carbamate (C1-h) And ((5-Fluoro-1aR,6bR-dihydro-1H-cyclopropeno[b]benzofuran-6-yl)methyl)carbamate (C1-i):
  • the tert-butyl ((5-fluoro-1a,6b-dihydro-1H-cyclopropeno[b]benzofuran-6-yl)methyl)carbamate (C1-g) (1.2g, 4.3mmol) was further purified by the following chiral SFC: Column: AD-H 20x250mm, 10um (Daicel), flow rate: 80g/min, mobile phase: 13% (0.2% ammonia methanol/methanol) in CO2, detection: 214nM to give tert-butyl ((5-fluoro-1aS,6bS-dihydro-1H-cyclopropeno[b]benzofuran-6-yl)methyl)carbamate (C1-h)(0.57 g, 47.5% yield), Rt: 0.71min; and ((5-fluoro-1aR,6bR-dihydro-1H-cyclopropeno[b]benzofuran-6-yl)methyl)carbamate (
  • Example 17 4-(5-(((5-Fluoro-1a,6b-dihydro-1H-cyclopropyl[b]benzofuran-6-yl)methyl)amino)-[1,2, 4]Triazolo[4,3]tert-butyl-c]pyrimidin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Example 20 8-(2,4-Difluorophenyl)-N-((5-fluoro-1a,6b-dihydro-1H-cyclopropeno[b]benzofuran-6-yl)methyl )-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine
  • Example 27 8-(1,3-Dimethyl-1H-pyrazol-4-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropeno[ b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine
  • Example 32 4-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropeno[b]benzofuran-6-yl)methyl)amino) -[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzamide
  • Example 33 8-(6-chloropyridin-3-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropeno[b]benzofuran- 6-yl)methyl)-[1,2,4]triazolo[4,-c]pyrimidin-5-amine
  • Example 35 8-(2-chloropyridin-3-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropeno[b]benzofuran- 6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine
  • Example 38 (3-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropeno[b]benzofuran-6-yl)methyl)amino )-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)pyridin-2-yl)methanol
  • Example 40 N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropeno[b]benzofuran-6-yl)methyl)-8-(1- Methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine
  • Example 41 8-(3,5-Dimethylisothiazol-4-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropeno[b ]Benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine
  • Example 48 4-(5-(((5-Fluoro-1a,6b-dihydro-1H-cyclopropeno[b]benzofuran-6-yl)methyl)amino)pyrido[4,3 -d]pyrimidin-8-yl)benzamide
  • Example 51 8-(3,5-Dimethylisothiazol-4-yl)-N-((5-fluoro-1a,6b-dihydro-1H-cyclopropeno[b]benzofuran-6 -Yl)methyl)pyrido[4,3-d]pyrimidin-5-amine
  • EED does not have enzymatic activity, but it plays an important role in the overall function of PRC2.
  • the effect of EED on PRC2 is specifically manifested in two aspects: 1) EED directly binds to the trimethylated H3K27Me3, which can locate the PCR2 complex on the chromatin that needs to be modified; 2) EED has the enzymatic catalytic function of EZH2 Great allosteric promotion. Therefore, the development of target compounds as the allosteric protein EED provides a new strategy to inhibit EZH2 enzyme activity. Moreover, such inhibitors have better or complementary advantages than EZH2 enzyme catalytic site inhibitors.
  • EED inhibitors when patients develop resistance to EZH2 enzyme inhibitors, EED inhibitors can also inhibit EZH2 enzyme activity.
  • the present invention discloses that the compound can be used as an EED target inhibitor, and has a therapeutic effect on diseases related to the mechanism of EED and/or PRC2.
  • the biological function of the compound disclosed in the present invention has been proved in biochemical and cellular level tests.
  • the compound disclosed in the present invention can have a strong competitive binding effect with the H3K27Me3 polypeptide that binds to the EED protein (IC 50 can reach ⁇ 10 nM).
  • the compound disclosed in the present invention can not only inhibit the methylation level of histone H3K27, but also inhibit the proliferation of cancer cells through this effect.
  • Example 54 Evaluation of the compound's effect on blocking the binding of EED and H3K27me3 by AlphaScreen (a-screen) method
  • the binding blocking reaction is performed. Dilute the full-length EED protein (441 amino acids) with His6 tag to 60 nM and the biotin-labeled polypeptide fragment H3K27me3 (amino acids 19-33) (Biotinylated-H3K27me3) to 75 nM with the above buffer. Transfer 5 ⁇ l of 75nM polypeptide fragment and 5 ⁇ l of 60nM protein to the detection well containing the compound, seal the detection plate with a film, and incubate at room temperature for 30 minutes.
  • the AlphaScreen method is tested.
  • the nickel chelated acceptor beads and the streptavidin donor beads were mixed in the above reaction buffer at a ratio of 1:1 (Perkin Elmer, product number 6760619M), and then 5 ⁇ l of the above pretreatment was added to each detection well.
  • the final concentration of the mixed detection solution, donor beads and acceptor beads are both 5 ⁇ g/mL. Cover the detection board with tin foil, and place it in the dark at room temperature for 1 hour. The signal was read using the AlphaScreen detector on Spectra max i3.
  • the compound was diluted in the same way, and the biotinylated peptide Biotinylated-(His) 6 was used to replace the EED and peptide H3K27me3 in the detection system. After incubating for the same time, in Spectra Read the signal value on max i3. Process the data in the same way.
  • the letter A represents IC 50 is less than 20nM
  • the letter B represents an IC 50 of 20 nM to 100 nM.
  • a representative compound of the present disclosure was diluted 3-fold in DMSO, 10 concentration gradients were detected for each compound, and the highest measured concentration was 10 ⁇ M.
  • the compound was diluted 200-fold into G401 cells cultured in 96-well plates (final concentration of DMSO was 0.5%). After 72 hours of incubation of the administered cells, the level of histone H3K27 trimethylation was detected by ELISA.
  • Histone extraction The cells treated with the compound in a 96-well plate were treated with 1x PBS (10x PBS buffer (80g NaCl (Sigma, product number S3014)), 2g KCl (Sigma, product number 60128), 14.4g Na 2 HP04 (Sigma, Product number S5136), 2.4g KH 2 P04 (Sigma, product number P9791) in 1L of water, pH to 7.4) wash three times, add 100 ⁇ L 0.4N HCl to each well, place at 4°C, gently shake for 2 hours to lyse cells.
  • 1x PBS 10x PBS buffer (80g NaCl (Sigma, product number S3014)), 2g KCl (Sigma, product number 60128), 14.4g Na 2 HP04 (Sigma, Product number S5136), 2.4g KH 2 P04 (Sigma, product number P9791) in 1L of water, pH to 7.4) wash three times, add 100 ⁇ L 0.4N HCl to each well, place at 4°C, gently shake
  • neutralize the lysate with 80 ⁇ L neutralization buffer 0.5M disodium hydrogen phosphate, pH12.5, 2.5mM DTT; 1% cocktail (Sigma, product number P8340)) (fully mix the cell lysate and neutralization buffer) .
  • ELISA detection method transfer the cell lysate in parallel to two 384-well detection plates (PerkinElmer, OptiPlate-384HB, product number 6007290), one plate is used to detect the level of H3K27 trimethylation, the other plate is used to determine H3
  • the final volume of PBS was adjusted to 50 ⁇ L/well and coated overnight at 4°C. The next day, discard the solution in the well, and use TBST buffer (l xTBS (10x TBS: 24.2g Tris (Sigma, product number T6066), 80g NaCl (Sigma, product number S3014)) into 1L of water, adjust the pH to 7.6 with HCl) , 0.1% Tween-20) wash 5 times, dry the water on absorbent paper.
  • TBST buffer l xTBS (10x TBS: 24.2g Tris (Sigma, product number T6066), 80g NaCl (Sigma, product number S3014)
  • human B cell non-Hodgkin lymphoma cells KARPAS-422S were cultured in culture flasks.
  • the medium is 15% fetal bovine serum (FBS, Invitrogen, product number 10099-141), 1% penicillin/streptomycin solution (P/S) RPMI-1640 (Invitrogen, product number 11875), and the culture flask is placed at a temperature Cultivate in a sterile incubator at 37°C, relative humidity 95%, and 5% CO2.
  • the counted cells each time were seeded into a new 96-well plate at the same density ( 1 ⁇ 10 4 cells/well), supplemented with fresh medium to 100 ⁇ L, and added compounds of different concentrations at the same time.
  • Incubate to the 13th day add 100 ⁇ L of CellTiter-Glo (CellTiter-GloCellTiter-GloCellTiter-GloCTG) (Promega, product number G7573) to each well, and place in the dark at room temperature for 10-20 minutes.
  • CellTiter-GloCellTiter-GloCellTiter-GloCTG CellTiter-GloCellTiter-GloCTG
  • Use Molecular Devices, SpectraMax i3X to read the luminescence signal.
  • GraphPad prisim5 was used to fit the data to a dose response curve to obtain the IC 50 value of the test compound.
  • the following table shows the IC 50 values of some compounds of the present invention.
  • the letter A represents IC 50 is less than 20nM;
  • the letter B represents an IC 50 of 20nM to 100nM
  • the letter C represents an IC 50 of 100nM or more.
  • the compounds disclosed in the present invention can be used to treat cancers related to the mechanism of action of the EED protein and/or PRC2 protein complex, including but not limited to lymphoma, leukemia, and multiple diseases such as diffuse large B-cell lymphoma, follicular lymphoma, etc.
  • Myeloma mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast cancer, brain tumors including neuroblastoma, 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, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma, etc.

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Abstract

L'invention concerne un composé azaaryle substitué par un cyclopropène et un benzofurane, et un intermédiaire, un procédé de préparation et une application de celui-ci. L'invention concerne également un procédé de préparation d'un tel composé, une composition contenant un tel composé, et l'utilisation d'un tel composé dans la préparation d'un médicament pour le traitement d'une maladie ou d'un trouble lié à un mécanisme d'action du complexe protéine EED et/ou protéine PRC2.
PCT/CN2020/073978 2019-02-02 2020-01-23 Composé azaaryle substitué par un cyclopropène et un benzofurane, et intermédiaire, procédé de préparation et application de celui-ci WO2020156479A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021032004A1 (fr) * 2019-08-22 2021-02-25 上海青煜医药科技有限公司 Composé d'azahétéroaryle et son utilisation
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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118652256A (zh) * 2019-11-01 2024-09-17 上海科技大学 Eed抑制剂及其制备方法和用途
CN116514897B (zh) * 2023-05-09 2024-03-29 暨南大学 环丙烷或者环丙烯类化合物及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103012343A (zh) * 2011-09-26 2013-04-03 上海恒瑞医药有限公司 稠合环类衍生物、其制备方法及其在医药上的应用
WO2015089842A1 (fr) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Nouveaux antagonistes tricycliques du récepteur sensible au calcium pour le traitement de l'ostéoporose
WO2016103155A1 (fr) * 2014-12-23 2016-06-30 Novartis Ag Composés triazolopyrimidine et leurs utilisations
WO2017219948A1 (fr) * 2016-06-20 2017-12-28 Novartis Ag Formes cristallines d'un composé de triazolopyrimidine
WO2018170290A1 (fr) * 2017-03-15 2018-09-20 Fulcrum Therapeutics, Inc. Compositions et méthodes pour renforcer l'expression de fmr1

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103012343A (zh) * 2011-09-26 2013-04-03 上海恒瑞医药有限公司 稠合环类衍生物、其制备方法及其在医药上的应用
WO2015089842A1 (fr) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Nouveaux antagonistes tricycliques du récepteur sensible au calcium pour le traitement de l'ostéoporose
WO2016103155A1 (fr) * 2014-12-23 2016-06-30 Novartis Ag Composés triazolopyrimidine et leurs utilisations
WO2017219948A1 (fr) * 2016-06-20 2017-12-28 Novartis Ag Formes cristallines d'un composé de triazolopyrimidine
WO2018170290A1 (fr) * 2017-03-15 2018-09-20 Fulcrum Therapeutics, Inc. Compositions et méthodes pour renforcer l'expression de fmr1

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021032004A1 (fr) * 2019-08-22 2021-02-25 上海青煜医药科技有限公司 Composé d'azahétéroaryle et son utilisation
CN112409385A (zh) * 2019-08-22 2021-02-26 上海青煜医药科技有限公司 氮杂芳基化合物及其应用
AU2020332462B2 (en) * 2019-08-22 2023-08-17 Shanghai Blueray Biopharma Co., Ltd. Azaheteroaryl compound and application thereof
CN112409385B (zh) * 2019-08-22 2024-08-13 上海青煜医药科技有限公司 氮杂芳基化合物及其应用
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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