WO2023005280A1 - Préparation et utilisation d'un dérivé d'aminopyrimidine ciblant de manière sélective cdk9 - Google Patents

Préparation et utilisation d'un dérivé d'aminopyrimidine ciblant de manière sélective cdk9 Download PDF

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WO2023005280A1
WO2023005280A1 PCT/CN2022/088154 CN2022088154W WO2023005280A1 WO 2023005280 A1 WO2023005280 A1 WO 2023005280A1 CN 2022088154 W CN2022088154 W CN 2022088154W WO 2023005280 A1 WO2023005280 A1 WO 2023005280A1
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compound
acid
pharmaceutically acceptable
cancer
acceptable salt
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PCT/CN2022/088154
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English (en)
Chinese (zh)
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李志裕
卞金磊
吴体智
喻彬
杜泽坤
张立翱
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中国药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention relates to the field of medicinal chemistry, and specifically includes aminopyrimidine derivatives capable of effectively inhibiting CDK9 protein activity, a preparation method and application thereof.
  • CDKs Cyclin-dependent kinases
  • CDKs are key protein kinases in cell cycle regulation, which can effectively regulate DNA synthesis and mitosis. Combining with the corresponding chaperones to form a complex is a necessary condition for CDK protein function.
  • CDKs can be divided into periodic CDKs (including CDK1, CDK2, CDK3, CDK4, and CDK6) and transcriptional CDKs (including CDK7, CDK8, CDK9, CDK11, CDK12, CDK13, CDK19, etc.).
  • CDK9 protein is widely involved in the initiation, elongation and termination stages of transcription.
  • CDK9 can effectively promote RNA transcription elongation by phosphorylating the CTD end of RNA polymerase II, and is a key factor in regulating RNA transcription. Effectively regulates downstream protein levels, including anti-apoptotic proteins MCL-1 and MYC.
  • Many studies have shown that the imbalance of CDK9 protein appears in the occurrence and development of various tumors, including various types of leukemia, prostate cancer, lung cancer, liver cancer, gastric cancer, breast cancer and so on.
  • an article published in the journal Cell pointed out that the inhibition of CDK9 protein can activate genes that are suppressed by tumors, and promote the expression of tumor suppressor genes and cell differentiation.
  • the above studies show that finding small molecule drugs that target and inhibit CDK9 may be an effective strategy for the development of anti-tumor drugs.
  • CDK9 inhibitors are in the clinical research stage, but most of them are non-selective, which leads to many unpredictable toxic and side effects. Even the clinical trials of some drugs were terminated because of this. Due to the high homology of CDK family members, it is difficult to obtain highly selective CDK9 inhibitors. However, in view of the current clinical research situation and the need to further study the biological role of CDK9, the development of selective CDK9 inhibitors is very important. Therefore, in the past two years, selective CDK9 inhibitors have continuously entered clinical research, and BAY-1143572 is the first selective CDK9 inhibitor developed by Bayer to enter clinical trials.
  • BAY-1251152 is the second-generation selective CDK9 inhibitor launched by Bayer. At present, the drug has been transferred to a pharmaceutical company named Vincerx, and the compound is in the clinical research center. At the same time, around 2017, AZD-4573 developed by AstraZeneca also entered clinical research. This is a highly selective CDK9 inhibitor, which has extremely significant in vivo anti-tumor effects in the MV4-11 mouse xenograft model active.
  • the main purpose of the present invention is to search for CDK9 small molecule inhibitors with aminopyrimidine or aminotriazine structure, high selectivity and good druggability.
  • the present invention provides a compound as shown in general formula I or formula II or a pharmaceutically acceptable salt thereof:
  • Ar is selected from the following groups:
  • X is selected from hydrogen, deuterium, halogen, cyano, methyl or trifluoromethyl
  • M and Y are independently selected from nitrogen or carbon
  • L is a bond or CH2 ;
  • R 1 is selected from the following groups:
  • the present invention also provides a compound represented by general formula III or a pharmaceutically acceptable salt thereof,
  • the pharmaceutically acceptable salt forms in the present invention refer to the salts formed by the compounds represented by general formulas I, II and III and pharmaceutically acceptable acids, including inorganic acid salts and organic acid salts.
  • Inorganic acid salts include: hydrochloric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, nitric acid, monohydrogen phosphate, dihydrogen phosphate, hydrobromic acid or hydroiodic acid; organic acids include: maleic acid, tartaric acid, citric acid , Methanesulfonic acid, succinic acid, acetic acid, p-toluenesulfonic acid, mandelic acid, isobutyric acid, malonic acid, etc.
  • the present invention provides any of the following compounds or pharmaceutically acceptable salts thereof:
  • the present invention also discloses a synthetic method of the compound of the present invention, which is selected from any of the following:
  • the present invention also provides a pharmaceutical composition, comprising the compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof.
  • the present invention also provides the application of the compound of the present invention or its pharmaceutically acceptable salt form in the preparation of CDK9 inhibitor drugs.
  • the inventors found that the compound of the present invention or its pharmaceutically acceptable salt form can effectively inhibit CDK9 protein Activity or application in the discovery of small molecule drugs targeting CDK9.
  • the present invention also provides the application of the compound of the present invention or a pharmaceutically acceptable salt form thereof in the preparation of antiviral drugs or antitumor drugs.
  • the viruses include: HIV virus, cytomegalovirus, Epstein-Barr virus, adenovirus, herpes, and human T-cell lymphoblastic virus.
  • the tumors include glioma, various types of leukemia, lymphoma, liver cancer, gastric cancer, prostate cancer, ovarian cancer, breast cancer, and lung cancer.
  • the compound described in the present invention is a seed compound with better CDK9 inhibitory activity.
  • the evaluation of biological activity shows that the designed compound has significant CDK9 inhibitory activity, good selectivity to CDK family members, and good anti-proliferation activity on MV4-11, MCF7, MOLM13 and other tumor cells.
  • Examples 1-17 can be prepared by the method of Route 1. Unless otherwise specified, the synthetic steps of the intermediates will not be repeated.
  • Embodiment 5 Compound LW-005
  • Embodiment 6 Compound LW-006
  • Embodiment 7 Compound LW-007
  • Embodiment 10 Compound LW-010
  • the preparation of the compounds described in Examples 24-29 can refer to the synthetic method of route 1, only need to replace the p-aminobenzoic acid (intermediate 2) of route one with p-aminophenylacetic acid (embodiment 24) or 3-aminobenzene Formic acid (Example 25) or 3-aminophenylacetic acid (Examples 26-29) will suffice.
  • Example 30 The preparation of the compound described in Example 30 can refer to the synthesis method of Route 1, only need to replace 4-fluoro-2-methoxyphenylboronic acid in Route 1 with 5-fluoro-2-methoxyphenylboronic acid.
  • Examples 31-40 can refer to the synthesis method of Route 2.
  • the synthesis of the compound described in Example 41 can refer to the synthesis method of Route 1.
  • the synthesis of intermediate 12 can refer to the preparation method provided in Scheme 2.
  • the synthesis of intermediate 13 can be prepared by referring to the synthesis method provided by Waleed Minzel et al. (doi:10.1016/j.cell.2018.07.045).
  • the synthesis of LW-046 uses intermediates 6 and 13 as starting materials, and the synthesis method can refer to the route provided in the route.
  • the preparation of the compounds described in Examples 50-53 can refer to the synthesis method of Route 2, only need to replace p-aminobenzoic acid in Route 2 with 6-aminonicotinic acid.
  • the experimental method is as follows:
  • the cytotoxicity of the compound to tumor cells with high expression of CDK9 was determined by MTT method: the cells were seeded in 96-well plate at 2000 cells/well, after the cells adhered to the wall, the culture medium was aspirated and added 200uL of the diluted drug was incubated at 37°C with 5% CO2 for 72h, and then 10uL/well of MTT was added. Incubate at 37°C for 4 hours, remove the supernatant, add 150uL of DMSO to each well, and detect the absorbance at 492nm with a multi-functional microplate reader. IC50 was calculated with GraphPad and the cell growth curve was plotted.
  • the experimental method is as follows:
  • the kinase reaction process is as follows:
  • test compound test concentration is 5nM, 20nM or 100nM, and repeated well detection.
  • Compounds were prepared at 100-fold final concentration in a 384-well plate. Then use Echo550 to transfer 250nl to 384 reaction plate for later use. Add 250 nl of 100% DMSO to negative control wells and positive control wells respectively.
  • Conversion%_sample is the conversion rate reading of the sample
  • Conversion%_min the average value of negative control wells, representing the conversion rate readings of wells without enzyme activity
  • Conversion%_max the average value of positive control wells, representing the conversion rate readings of wells without compound inhibition.
  • the concentration of the compound is indicated in the brackets, and the unit is nM, such as 90 (20) indicates that the inhibition rate of the compound to the enzyme is 90% at a concentration of 20 nM.
  • the compounds of the present invention show effective inhibitory activity to CDK9, and most of the compounds have an inhibitory rate of more than 70% to CDK9 at a concentration of 20 nM.
  • the compound of the present invention shows better CDK9 inhibitory activity and cell activity, such as compound LW-010.
  • compounds LW-008 and LW-030 also showed better or similar selectivity than positive drugs while maintaining CDK9 activity.

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Abstract

La présente invention concerne la préparation et l'utilisation d'un dérivé d'aminopyrimidine ciblant de manière sélective la CDK9. La présente invention concerne également un procédé de préparation du composé et une utilisation du composé dans la prévention et/ou le traitement de maladies associées à une tumeur comprenant le gliome, diverses leucémies, le lymphome, le cancer du foie, le cancer de l'estomac, le cancer de la prostate, le cancer de l'ovaire, le cancer du sein, le cancer du poumon et similaires. Le composé peut inhiber efficacement et de manière sélective l'activité de la protéine CDK9, le composé ayant une activité antitumorale remarquable dans des cellules cancéreuses telles que MV4-11, MCF-7 et MOLM-13.
PCT/CN2022/088154 2021-07-27 2022-04-21 Préparation et utilisation d'un dérivé d'aminopyrimidine ciblant de manière sélective cdk9 WO2023005280A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024044757A1 (fr) * 2022-08-26 2024-02-29 Sanford Burnham Prebys Medical Discovery Institute Dérivés d'aminopyrimidine et d'aminotriazine utilisés en tant que modulateurs de la protéine myc

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113563275B (zh) * 2021-07-27 2024-05-03 中国药科大学 一种选择性靶向cdk9的氨基嘧啶类衍生物的制备及其应用
CN113999210B (zh) * 2021-12-03 2023-05-23 郑州大学第一附属医院 一组2-苯氨基-4-三氮唑基嘧啶类衍生物及其应用
CN115093397B (zh) * 2022-06-07 2023-09-05 自贡市第三人民医院 一种用于***的化合物、合成方法及应用

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CN102143953A (zh) * 2008-03-26 2011-08-03 诺丁汉大学 嘧啶、三嗪类化合物以及它们作为药剂的用途
CN105294655A (zh) * 2014-07-26 2016-02-03 广东东阳光药业有限公司 Cdk类小分子抑制剂的化合物及其用途
US20180244654A1 (en) * 2015-10-28 2018-08-30 Northwestern University Substituted aromatic n-heterocyclic compounds as inhibitors of mitogen-activated protein kinase interacting kinase 1 (mnk1) and 2 (mnk2)
WO2020202232A1 (fr) * 2019-03-29 2020-10-08 Virostatics Srl Composés ayant des activités enzymatiques anti-cdk4/6 et anti-cdk9 pour inhiber la prolifération du cancer et procédé de criblage associé pour leur détection
CN113563275A (zh) * 2021-07-27 2021-10-29 中国药科大学 一种选择性靶向cdk9的氨基嘧啶类衍生物的制备及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102143953A (zh) * 2008-03-26 2011-08-03 诺丁汉大学 嘧啶、三嗪类化合物以及它们作为药剂的用途
CN105294655A (zh) * 2014-07-26 2016-02-03 广东东阳光药业有限公司 Cdk类小分子抑制剂的化合物及其用途
US20180244654A1 (en) * 2015-10-28 2018-08-30 Northwestern University Substituted aromatic n-heterocyclic compounds as inhibitors of mitogen-activated protein kinase interacting kinase 1 (mnk1) and 2 (mnk2)
WO2020202232A1 (fr) * 2019-03-29 2020-10-08 Virostatics Srl Composés ayant des activités enzymatiques anti-cdk4/6 et anti-cdk9 pour inhiber la prolifération du cancer et procédé de criblage associé pour leur détection
CN113563275A (zh) * 2021-07-27 2021-10-29 中国药科大学 一种选择性靶向cdk9的氨基嘧啶类衍生物的制备及其应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024044757A1 (fr) * 2022-08-26 2024-02-29 Sanford Burnham Prebys Medical Discovery Institute Dérivés d'aminopyrimidine et d'aminotriazine utilisés en tant que modulateurs de la protéine myc

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