WO2022257568A1 - Composé hétérocyclique d'azaindole pyrimidinamine, son procédé de préparation et son utilisation - Google Patents

Composé hétérocyclique d'azaindole pyrimidinamine, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2022257568A1
WO2022257568A1 PCT/CN2022/084057 CN2022084057W WO2022257568A1 WO 2022257568 A1 WO2022257568 A1 WO 2022257568A1 CN 2022084057 W CN2022084057 W CN 2022084057W WO 2022257568 A1 WO2022257568 A1 WO 2022257568A1
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cancer
hydrogen
compound
synthesis
yield
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PCT/CN2022/084057
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English (en)
Chinese (zh)
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杨鹏
袁凯
陈玮娇
邝文彬
姬明慧
王晓
王丽萍
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中国药科大学
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    • 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
    • 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

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to an azaindopyrimidine amine heterocyclic compound and a preparation method and application thereof.
  • CDKs Cyclin-dependent kinases
  • the present invention provides an azaindopyrimidine amine heterocyclic compound, which can inhibit CDK6.
  • the invention also provides the preparation method and application of the compound.
  • the X is selected from C(O) or (CH 2 ) n ; n is 0-8;
  • R 1 is selected from hydrogen or halogen
  • the R 2 is selected from hydrogen, C 1 -C 8 alkyl or C 3 -C 6 cycloalkyl;
  • the R 3 is selected from hydrogen, halogen or C 1 -C 3 alkoxy
  • the R 4 is selected from hydrogen, C 1 -C 8 alkyl, -S(O) 2 C 1 -C 3 alkyl or -C(O)OC 1 -C 6 alkyl.
  • the X is C(O) or (CH 2 ) n ; n is 0-4.
  • said R 1 is hydrogen or fluorine.
  • the R 2 is hydrogen, C 1 -C 4 alkyl, cyclopentyl or cyclohexane; in some specific embodiments, the R 2 is hydrogen, methyl radical, ethyl, isopropyl, isobutyl or cyclopentyl.
  • the R 3 is hydrogen, fluoro or methoxy.
  • the R 4 is hydrogen, C 1 -C 3 alkyl, -S(O) 2 C 1 -C 3 alkyl or -C(O)OC 1 -C 4 alkyl ; In some more specific embodiments, said R 4 is hydrogen, methyl, ethyl, isopropyl or tert-butoxycarbonyl.
  • said X is selected from: (CH 2 ) n or C(O), n is 0 or 1; said R 1 is selected from: hydrogen, fluorine; said R 2 Selected from: hydrogen, methyl, ethyl, isopropyl, isobutyl, cyclopentyl; said R3 is selected from: hydrogen, fluorine or methoxy ; said R4 is selected from: hydrogen, methyl , ethyl, isopropyl or tert-butoxycarbonyl.
  • the present invention also provides compounds selected from S-1 to S-44 or pharmaceutically acceptable salts thereof:
  • compositions wherein the acid used for salt formation includes inorganic acid and organic acid, and described inorganic acid comprises: hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, Organic acids include acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid and tartaric acid.
  • organic acids include acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid and tartaric acid.
  • the pharmaceutically acceptable salt described in the present invention is hydrochloride.
  • the preparation method of the compound of general formula (S) of the present invention prepares compound (S) through coupling reaction by compound (A) and compound (B) under the effect of palladium catalyst:
  • the X is selected from C(O) or (CH 2 ) n ; n is 0-8;
  • R 1 is selected from hydrogen or halogen
  • the R 2 is selected from hydrogen, C 1 -C 8 alkyl or C 3 -C 6 cycloalkyl;
  • the R 3 is selected from hydrogen, halogen or C 1 -C 3 alkoxy
  • the R 4 is selected from hydrogen, C 1 -C 8 alkyl, -S(O) 2 C 1 -C 3 alkyl or -C(O)OC 1 -C 6 alkyl.
  • the reaction system of compound (A) and compound (B) is as follows: the reaction reagents are Pd 2 (dba) 3 , BINAP and cesium carbonate, under an inert gas atmosphere, the reaction temperature is 95-105°C, and the reaction time is 10-24h.
  • the reaction reagents are Pd 2 (dba) 3 , BINAP and cesium carbonate, under an inert gas atmosphere, the reaction temperature is 95-105°C, and the reaction time is 10-24h.
  • the present invention also provides a pharmaceutical composition of the compound as described in formula (S) or its pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug, and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound.
  • the present invention also provides the use of a compound of formula (S) or its pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug or the composition described in the present invention in the preparation of medicine.
  • the present invention also provides a compound of formula (S) or its pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug or the use of the composition described in the present invention in the preparation of CDK6 inhibitors;
  • the CDK6 kinase inhibitor is used for treating cancer or tumor-related diseases.
  • Cancer or tumor related diseases including but not limited to multiple myeloma, leukemia, breast cancer, prostate cancer, lung cancer, liver cancer, stomach cancer, bone cancer, brain cancer, head and neck cancer, bowel cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer cancer and endometrial cancer.
  • the compound of the general formula (S) or the pharmaceutically acceptable salt thereof in the present invention has CDK6 target inhibitory activity, and has a therapeutic effect on cell malignant proliferation tumors.
  • Me is methyl
  • Et is ethyl
  • Boc is tert-butoxycarbonyl
  • alkyl means a straight or branched chain saturated hydrocarbon group having the stated number of carbon atoms.
  • C 1 -C 8 alkyl refers to a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms.
  • C 1 -C 8 Alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl base, isohexyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl, etc.
  • C 3 -C 6 cycloalkane includes cyclopropanyl, cyclobutanyl, cyclopentyl and cyclohexyl.
  • C 1 -C 3 alkyl refers to a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms.
  • alkoxy means O-alkyl.
  • C 1 -C 3 alkoxy means having an O C 1 -C 3 alkyl group.
  • halogen means fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine, bromine.
  • the compound represented by the general formula (S) of the present invention can inhibit the malignant proliferation of cancer, has good therapeutic effect, low toxicity, has good drug metabolism characteristics, and is not easy to produce drug resistance, and can be used to prepare and treat cancer or tumor-related diseases drug.
  • Reactants (ZA) and reactants (ZB) can be purchased directly or developed independently, which can significantly reduce costs.
  • the specific preparation methods of the self-developed reactant (ZA) and reactant (ZB) are as follows:
  • 3-Bromo-7-azaindole (3.94g, 20mmol) was dissolved in DMF (100mL), and NaH (1.6g, 40mmol) was added under ice-bath conditions, and after 30 minutes of reaction, iodoisopropane (1.36 g, 80 mmol), reacted at room temperature for 8 hours, quenched with water in an ice bath, extracted with dichloromethane, filtered and concentrated the solvent, and purified by flash silica gel column to obtain compound ZA9 (4.21 g, yield 88%).
  • Step 1 the synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate: Weigh 5-bromo-2-nitropyridine (0.41g, 2.0mmol), tert Butylpiperazine-1-carboxylate (0.48g, 2.6mmol) and triethylamine (0.41g, 4.0mmol) were dissolved in DMSO (5mL), heated to 60°C, and reacted for 18 hours. Concentrated by cold filtration and flash silica gel column purification to obtain compound tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (0.49 g, yield 80%).
  • Step 2 the synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate: Weigh tert-butyl 4-(6-nitropyridin-3-yl)piperazine -1-carboxylate (0.31g, 1.0mmol), reduced iron powder (0.17g, 3.0mmol) and ammonium chloride (0.49g, 9.0mmol) were dissolved in 70% ethanol (10mL), heated to 70°C, and reacted 6 hours. Concentrated by cold filtration and flash silica gel column purification to obtain compound ZB8 (0.24 g, yield 85%).
  • Example 3 The compound of Example 3 (120 mg) was dissolved in dichloromethane (40 mL), and HCl gas was passed through at 0° C. for 2 h. After the reaction was completed, it was concentrated to obtain compound S4 with a yield of 100% as a pale yellow solid.
  • Eu can transfer energy to the adjacent fluorescent substance Ulight acceptor, and then detect the emitted light.
  • the compound was dissolved and diluted to 2 mM with DMSO, and then 3-fold diluted to 10 concentrations, so that the compound concentration in the final experimental plate was 10 ⁇ M to 0.508 nM.
  • CDK6/cyclinD1 Life Technologies
  • Ulight-4E-BPI-peptide substrate PerkinElmer
  • reaction buffer 50mM Hepes pH 7.5, 10mM MgCl 2 , 0.01% Birj-35, 1mM EDTA, 2mM DTT
  • 5 ⁇ l of polypeptide and kinase mixture was mixed with 100 ⁇ L of compounds of different concentrations in an OptiPlate-384 microwell plate. After incubation at room temperature for 15 minutes, 5 ⁇ L of 350 ⁇ M ATP solution was added and incubated at room temperature for 90 min.
  • the measured IC 50 values are shown in Table 1 below. From the experimental results, it can be seen that the example compounds of the present invention have strong inhibitory activity on CDK6 kinase activity.
  • Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) 1 130 16 30 31 32 2 120 17 10 32 42 3 >10000 18 >10000 33 27 4 251 19 33 34 45 5 >10000 20 35 35 36 6 56 twenty one 25 36 2622 7 46 twenty two 38 37 2200 8 440 twenty three >1000 38 1869 9 >10000 twenty four 18 39 36 10 905 25 >10000 40 46 11 >10000 26 86 41 25 12 445 27 53 42 >1000 13 113 28 45 43 69 14 126 29 40 44 twenty four 15 87 30 >1000 / /
  • the compounds of the present invention have very good inhibitory activity on CDK6 kinase, among which Example 17 has the strongest inhibitory activity on CDK6, and it will be further evaluated for in vivo activity.
  • Test animals ICR mice (provided by Shanghai Slack Experimental Animal Co., Ltd.); 18-22 g; female; 20 in total.
  • Group dose setting There are four groups in total, control group; 1000mg/kg group; Group 5 mice, observed for 14 days;
  • Test sample Example 17 and positive drug Palbociclib
  • embodiment 17 dosage is 100mg/kg, every day is given intragastric administration 1 time, when administration 23 days, to human multiple myeloma cell PRMI8226 nude mouse transplanted tumor T/C (%) is 58.3%, The tumor inhibition rate is 34.1%; the dose of embodiment 17 is 200mg/kg, administered by intragastric administration 1 time every day, and when administered for 23 days, the T/C (%) to human multiple myeloma cell PRMI8226 nude mouse transplanted tumor is 33.8%, tumor inhibition rate was 61.5%.
  • the dose of the positive drug Palbociclib is 100mg/kg, administered once a day by intragastric administration, and when administered for 23 days, the T/C (%) of the human multiple myeloma cell PRMI8226 nude mouse transplanted tumor was 37.9%, and the tumor inhibition rate was 55.6%.
  • the experimental results showed that the body weight of the nude mice in each group did not decrease significantly during the administration period.
  • Example 17 has a significant inhibitory effect on the growth of human multiple myeloma cells PRMI8226 xenograft tumors in nude mice, and the high dose group of Example 17 has strong anti-tumor activity on human multiple myeloma PRMI8226 xenograft tumors in nude mice In the positive drug Palbociclib group.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé hétérocyclique d'azaindole pyrimidinamine tel que représenté dans la formule (S), son procédé de préparation et son utilisation. Le composé selon la présente invention peut inhiber la prolifération maligne de cancers, a un bon effet thérapeutique et une faible toxicité, présente de bonnes caractéristiques de métabolisme de médicament, ne génère pas facilement une résistance aux médicaments, et peut être utilisé pour préparer un médicament destiné au traitement de maladies associées à des cancers ou des tumeurs, les maladies associées aux cancers ou aux tumeurs comprenant le myélome multiple, la leucémie, le cancer du sein, le cancer de la prostate, le cancer du foie, le cancer de l'estomac, le cancer de l'os, le cancer du cerveau, le cancer de la tête et du cou, le cancer intestinal, le cancer du pancréas, le cancer de la vessie, le cancer des testicules, le cancer de l'ovaire et le cancer de l'endomètre.
PCT/CN2022/084057 2021-06-10 2022-03-30 Composé hétérocyclique d'azaindole pyrimidinamine, son procédé de préparation et son utilisation WO2022257568A1 (fr)

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CN202110645809.X 2021-06-10
CN202110645809.XA CN113248500B (zh) 2021-06-10 2021-06-10 氮杂吲哚嘧啶胺杂环化合物及其制备方法和应用

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CN113248500B (zh) * 2021-06-10 2021-10-19 中国药科大学 氮杂吲哚嘧啶胺杂环化合物及其制备方法和应用

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WO2020108661A1 (fr) * 2018-11-30 2020-06-04 杭州英创医药科技有限公司 Composé hétérocyclique utilisé en tant qu'inhibiteur de cdk-hdac à double canal
WO2021003517A1 (fr) * 2019-07-10 2021-01-14 Aucentra Therapeutics Pty Ltd Dérivés de 4-(imidazo [l, 2-a] pyridine-3-yl)-n-(pyridinyl) pyrimidine-2-amine en tant qu'agents thérapeutiques
CN112390793A (zh) * 2021-01-19 2021-02-23 中国药科大学 Cdk6/dyrk2双靶点抑制剂及其制备方法和应用
CN113248500A (zh) * 2021-06-10 2021-08-13 中国药科大学 氮杂吲哚嘧啶胺杂环化合物及其制备方法和应用

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CN1694705A (zh) * 2002-09-04 2005-11-09 先灵公司 用作依赖细胞周期蛋白激酶抑制剂的吡唑并嘧啶
CN101723936A (zh) * 2008-10-27 2010-06-09 上海睿星基因技术有限公司 激酶抑制剂及其在药学中的用途
CN105732615A (zh) * 2014-12-31 2016-07-06 山东轩竹医药科技有限公司 Cdk激酶抑制剂
CN107286134A (zh) * 2016-04-11 2017-10-24 上海勋和医药科技有限公司 2，4-二取代嘧啶衍生物作为cdk抑制剂及其应用
WO2018045957A1 (fr) * 2016-09-07 2018-03-15 江苏豪森药业集团有限公司 Inhibiteur de cdk4/6, son procédé de préparation et son application
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WO2020108661A1 (fr) * 2018-11-30 2020-06-04 杭州英创医药科技有限公司 Composé hétérocyclique utilisé en tant qu'inhibiteur de cdk-hdac à double canal
WO2021003517A1 (fr) * 2019-07-10 2021-01-14 Aucentra Therapeutics Pty Ltd Dérivés de 4-(imidazo [l, 2-a] pyridine-3-yl)-n-(pyridinyl) pyrimidine-2-amine en tant qu'agents thérapeutiques
CN112390793A (zh) * 2021-01-19 2021-02-23 中国药科大学 Cdk6/dyrk2双靶点抑制剂及其制备方法和应用
CN113248500A (zh) * 2021-06-10 2021-08-13 中国药科大学 氮杂吲哚嘧啶胺杂环化合物及其制备方法和应用

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