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WO2023040914A1 - Utilisation pharmaceutique d'un inhibiteur de cdk4/6 - Google Patents

Utilisation pharmaceutique d'un inhibiteur de cdk4/6 Download PDF

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Publication number
WO2023040914A1
WO2023040914A1 PCT/CN2022/118817 CN2022118817W WO2023040914A1 WO 2023040914 A1 WO2023040914 A1 WO 2023040914A1 CN 2022118817 W CN2022118817 W CN 2022118817W WO 2023040914 A1 WO2023040914 A1 WO 2023040914A1
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Prior art keywords
breast cancer
cancer
compound
positive
pharmaceutically acceptable
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English (en)
Chinese (zh)
Inventor
尹磊
姚郑林
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Gan and Lee Pharmaceuticals Co Ltd
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Gan and Lee Pharmaceuticals Co Ltd
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Priority to CN202280052041.8A priority Critical patent/CN118119393A/zh
Publication of WO2023040914A1 publication Critical patent/WO2023040914A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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

Definitions

  • the application belongs to the field of medicine and relates to the medical use of a CDK4/6 inhibitor.
  • Breast cancer is one of the most common malignant tumors in women. Global statistics show that about 1.7 million people (accounting for 25% of all female cancer patients) are diagnosed with breast cancer each year, and about 520,000 people (accounting for 15% of all female cancer patients) %) died from the disease. Breast cancer is a systemic disease. In the middle and early stages of the disease, breast cancer cells can enter the circulatory system and metastasize throughout the body. At present, the treatment of breast cancer is still mainly based on surgery, chemoradiotherapy, and endocrine therapy, and the survival rate of patients with advanced breast cancer is low and it is difficult to cure.
  • the pathological types of breast cancer include luminal A type (Luminal A type), luminal B type (Luminal B type), normal breast-like type, human epidermal growth factor receptor 2 (HER-2) overexpression type and basal cell-like type, Among them, basal cell-like breast cancer and triple-negative breast cancer are a type of breast cancer that are negative for estrogen receptor (ER), progesterone receptor (PR), and HER-2, accounting for about all newly diagnosed cases of breast cancer. 15%-20%. Human epidermal growth factor receptor-2 (HER2), overexpression and amplification of HER2 are found in different types of solid tumors (including breast cancer, gastric cancer, etc.).
  • trastuzumab targeting HER2 has a significant effect.
  • chemotherapy is still the main treatment.
  • chemotherapy drugs commonly used in advanced breast cancer include anthracyclines (epirubicin, doxorubicin, doxorubicin), taxanes, etc. , vinorelbine, capecitabine, gemcitabine, platinum, etc.
  • anthracyclines epirubicin, doxorubicin, doxorubicin
  • taxanes etc.
  • vinorelbine doxorubicin
  • capecitabine ecitabine
  • platinum etc.
  • due to severe side effects the clinical application of chemotherapy drugs is limited, and patients often stop treatment because they cannot tolerate severe adverse reactions. Therefore, it is particularly important to develop therapeutic regimens with better efficacy and lower toxicity.
  • Colorectal cancer is a combination of colon cancer and rectal cancer. It is one of the most common malignant tumors in the world, and its incidence rate varies greatly in different regions of the world. It is highest in America and Oceania, in the middle in Europe, and lower in Asia and Africa. In the United States, the morbidity and mortality of colorectal cancer are at the forefront of all tumors; in China, the morbidity and mortality of colorectal cancer are also increasing , transverse colon, etc.
  • adenocarcinoma adenosquamous carcinoma
  • spindle cell carcinoma adenosquamous cell carcinoma
  • undifferentiated carcinoma adenocarcinoma is the most common and can be divided into cribriform comedotype adenocarcinoma, medullary carcinoma , micropapillary carcinoma, mucinous adenocarcinoma, serrated adenocarcinoma, and signet ring cell carcinoma.
  • Hepatocellular carcinoma (Hepatocellular Carcinoma, HCC) is the most common type of primary liver cancer. HCC mostly occurs on the basis of hepatitis cirrhosis, and it appears about 10 to 20 years after the original liver damage. Most liver cancers are asymptomatic in the early stage, and most patients have reached locally advanced stage or developed distant metastasis when diagnosed. There is no standard treatment for advanced liver cancer, and clinical treatment is facing severe challenges.
  • HCC human cancer
  • treatment methods generally include surgery (hepatectomy, liver transplantation, and palliative surgery), non-surgical treatment (local therapy, arterial chemoembolization, chemotherapy, radiotherapy, biological therapy, and molecular targeted therapy) and Other treatments (including participation in clinical research).
  • surgery hepatectomy, liver transplantation, and palliative surgery
  • non-surgical treatment local therapy, arterial chemoembolization, chemotherapy, radiotherapy, biological therapy, and molecular targeted therapy
  • Other treatments including participation in clinical research.
  • Many cancers that are also found in the liver are not true liver cancers but arise from secondary liver cancers elsewhere in the body that have spread to the liver (ie, metastases).
  • the starting site is the gastrointestinal tract because of the liver's proximity to many of these metabolically active, blood-rich organs near blood vessels and lymph nodes (eg, pancreatic cancer, gastric cancer, colon cancer, and carcinoid tumors primarily of the appendix (carcinoid tumor)).
  • these metabolically active, blood-rich organs near blood vessels and lymph nodes (eg, pancreatic cancer, gastric cancer, colon cancer, and carcinoid tumors primarily of the appendix (carcinoid tumor)).
  • Secondary liver cancers can also arise from metastatic breast, ovarian, lung, kidney, and prostate cancers.
  • the present invention provides 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl
  • 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-nitrogen-(5-(1-methylpiperidine -4-yl)pyridin-2-yl)pyrimidin-2-amine is a highly selective CDK4/6 inhibitor, the inventors unexpectedly found that this compound, compared to other drugs with the same target Breast, colorectal, and liver cancers had unexpectedly better outcomes.
  • One aspect of the present invention provides a method for treating breast cancer, colorectal cancer or liver cancer, the method comprising administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject in need, preferably the subject
  • the subject is a mammal, more preferably said subject is a human,
  • Another aspect of the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer, colorectal cancer or liver cancer.
  • Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the cancer is breast cancer, colorectal cancer or liver cancer.
  • the pharmaceutically acceptable salt is a fumarate.
  • the breast cancer is hormone receptor (HR) positive breast cancer; preferably, the hormone receptor (HR) positive breast cancer is estrogen receptor positive (ER + ) breast cancer , progesterone receptor positive (PR + ) breast cancer, or ER + PR + breast cancer; more preferably, the hormone receptor (HR) positive breast cancer is estrogen receptor positive (ER + ) and HER2 negative breast cancer, breast cancer that is progesterone receptor positive (PR + ) and HER2 negative, or breast cancer that is ER + PR + and HER2 negative.
  • HR hormone receptor
  • the hormone receptor (HR) positive breast cancer is estrogen receptor positive (ER + ) breast cancer , progesterone receptor positive (PR + ) breast cancer, or ER + PR + breast cancer
  • the hormone receptor (HR) positive breast cancer is estrogen receptor positive (ER + ) and HER2 negative breast cancer
  • breast cancer that is progesterone receptor positive (PR + ) and HER2 negative or breast cancer that is ER + PR + and HER2 negative.
  • compound of the present invention refers to the compound of formula (I) and its salt, including the pharmaceutically acceptable salt of the compound and all stereoisomers (including but not limited to diastereoisomers) and enantiomers), tautomers, isotopic compounds, prodrugs, solvates, and hydrates thereof.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound without adverse biological effects.
  • pharmaceutically acceptable salts include, but are not limited to: salts formed between compound (I) and any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, Heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, formic acid Sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-
  • the prodrugs of the compounds of the present invention are included in the protection scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted in vivo to the desired compound. Therefore, the term "administering" in the treatment method provided by the present invention includes administering the compound disclosed in the present invention, or although not explicitly disclosed but can be converted into the compound disclosed in the present invention after administration to the subject to treat the described compound. various diseases. Routine methods for selecting and preparing suitable prodrug derivatives are described, for example, in such books as Design of Prodrugs, H. Bundgaard, Elsevier, 1985.
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers.
  • the present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the above formula I does not exactly define the stereostructure of a certain position of the compound.
  • the present invention includes all stereoisomers of the compound represented by formula I and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During the synthesis of such compounds, or during the use of racemization or epimerization procedures well known to those of ordinary skill in the art, the products obtained may be mixtures of stereoisomers.
  • the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent forming a solvate is not particularly limited as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone, and the like can be used.
  • the invention also includes all pharmaceutically acceptable isotopic compounds which are identical to the compounds of the invention except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass or mass prevailing in nature Atomic substitution of numbers.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 13C and 14C ); Isotopes (such as 37 Cl); isotopes of iodine (such as 125 I); isotopes of nitrogen (such as 13 N and 15 N); isotopes of oxygen (such as 17 O and 18 O); isotopes of phosphorus (such as 32 P); Isotopes of sulfur (eg 34 S).
  • isotopes of hydrogen e.g., deuterium ( 2H ), tritium ( 3H
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie arresting its development; or (b) relieving the symptoms of the disease, ie causing regression of the disease or symptoms.
  • an effective amount refers to an amount or dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an amount or dose of endocrine therapy that provides an effective response in a patient under diagnosis or treatment.
  • treatment failure refers to intolerable side effects, disease progression during treatment, or recurrence after treatment.
  • subject is a mammal, preferably a human.
  • the compound of the present invention has a significant inhibitory effect on human breast cancer, and compared with the positive control drug Abemaciclib, it shows a better tumor inhibitory effect.
  • the compound of the present invention has a significant inhibitory effect on human colorectal cancer, and compared with the positive control drugs Palbociclib and Abemaciclib, it shows a better tumor inhibitory effect.
  • the compound of the present invention does not show obvious drug toxicity and side effects, has good tolerance, and has good clinical application prospects for treating colorectal cancer.
  • the compound of the present invention has a significant inhibitory effect on human liver cancer, and compared with the positive control drugs Palbociclib and Abemaciclib, it shows a better tumor inhibitory effect.
  • the compound of the present invention does not show obvious drug toxicity and side effects, has good tolerance, and has good clinical application prospects for treating liver cancer.
  • Figure 1 Changes in body weight of each administration group in the human-derived colorectal cancer xenograft mouse model.
  • Figure 2 Changes in body weight of each administration group in the human-derived liver cancer xenograft mouse model.
  • the above solution was filtered through a microporous filter, and transferred to the reactor, stirred, dichloromethane and ethanol were evaporated at normal pressure, and then the temperature of the reactor was kept at 80 ⁇ 5 degrees Celsius, and the fumaric acid ( 1.0eq) of ethanol solution (12 volumes) was slowly dropped into the reaction kettle through a microporous filter, and kept stirring overnight. Cool down to 20-30 degrees Celsius, continue to stir for at least 1 hour, centrifuge, and collect the filter cake.
  • Embodiment 2 The compounds of the present invention inhibit the proliferation of breast cancer cell lines
  • Abemaciclib and Compound A were dissolved in DMSO to prepare a 10 mM stock solution. And put it in a -80°C refrigerator for long-term storage; take 5 ⁇ L of 10 mM Abemaciclib and Compound A stock solutions, and dilute them into 60 ⁇ M working solutions respectively, starting at 60 ⁇ M, and diluting 10 points five times.
  • the test results are shown in Table 2. The results show that Compound A has obvious growth inhibitory activity on four breast cancer cells T47D, MCF-7, 4T1, and Du4475. Compared with the positive control drug Abemaciclib, Compound A has higher growth inhibitory activity. .
  • Table 2 The inhibitory activity of test substance on the proliferation of different breast cancer cell lines
  • the test was divided into Compound A 5.0mg/kg, 10.0mg/kg and 50.0mg/kg groups, Abemaciclib25.0mg/kg group, and Vehicle group.
  • the preparations of the above test and reference substances are shown in Table 3.
  • the positive control drug Abemaciclib was prepared by the inventors according to the synthesis method described in WO2010075074A1.
  • mice in each group were administered orally orally, once a day, for a total of 28 days. Changes in tumor volume and body weight were observed regularly, and curative effect was evaluated based on relative tumor proliferation rate (T/C) and relative tumor inhibition rate (TGI).
  • T/C relative tumor proliferation rate
  • TGI relative tumor inhibition rate
  • T/C Relative tumor proliferation rate
  • TGI relative tumor inhibition rate
  • compound A exhibits obvious tumor suppressive effect in the xenograft mouse model of human breast cancer, and has a good clinical application prospect in the treatment of breast cancer.
  • Embodiment 4 The compound of the present invention is to the proliferation inhibitory determination of liver cancer cell line
  • the positive control drug Abemaciclib was prepared by the inventor according to the synthesis method recorded in WO2010075074A1.
  • the cell detection equipment was In Cell Analyzer 2200 (GE Healthcare) , the reagents or consumables used in the experiment are shown in Table 5 below:
  • Abemaciclib and Compound A were dissolved in DMSO to prepare a 10 mM stock solution. And put it in a -80°C refrigerator for long-term storage; take 5 ⁇ L of 10 mM Abemaciclib and Compound A stock solutions, and dilute them into a 60 ⁇ M working solution, starting at 60 ⁇ M, three-fold dilution of Abemaciclib by 10 points, and six-fold dilution of Compound A 10 points.
  • the test results are shown in Table 6, the results show that: compound A showed proliferation inhibitory activity on 31 kinds of liver cancer cells; among them, compound A had inhibitory activity on 21 kinds of liver cancer cell lines SNU-761, PLC/PRF/5, SK-HEP-1 , SNU-475, SNU-739, SNU-368, HCCC9810, SNU-423, SNU-449, SNU-387, MHCC97L, MHCC97H, SNU-398, HLE, SNU-886, MHCC97, Hepa1-6, Huh-1 , Huh-7, JHH-7, and Li-7 have obvious growth inhibitory activity (IC 50 ⁇ 1 ⁇ M); compared with the positive control drug Abemaciclib, compound A has inhibitory effect on 20 liver cancer cell lines SNU-761, PLC/PRF/5 , SNU-475, SNU-739, SNU-368, HCCC9810, SNU-423, SNU-449, SNU-387, MHCC97L, MHCC97H, S
  • liver cancer xenograft model LI1088 (Crown Biotechnology Co., Ltd.) tumor-bearing mice were harvested from tumor tissues, cut into 2-3mm diameter tumor pieces and inoculated subcutaneously at the right anterior scapula of Balb/c nude mice. 117.61mm 3 , randomly grouped according to tumor size.
  • the positive control drugs were Palbociclib and Abemaciclib, Palbociclib was prepared by the inventor according to the synthesis method described in WO2003062236A1, and Abemaciclib was prepared by the inventor according to the synthesis method described in WO2010075074A1.
  • test is divided into compound A 10.0mg/kg, 25.0mg/kg and 50.0mg/kg groups, Palbociclib 25.0mg/kg group, Abemaciclib 25.0mg/kg group, and Vehicle group. 7.
  • mice in each group were administered orally orally, once a day, for a total of 28 days. Changes in tumor volume and body weight were observed regularly, and curative effect was evaluated based on relative tumor proliferation rate (T/C) and relative tumor inhibition rate (TGI).
  • T/C relative tumor proliferation rate
  • TGI relative tumor inhibition rate
  • T/C Relative tumor proliferation rate
  • TGI relative tumor inhibition rate
  • the results are shown in Table 8 and Figure 1.
  • the relative tumor proliferation rate (T/C) of the compound A (25mg/kg, 50mg/kg) treatment group on the 25th day was significantly higher than that of the positive drug Palbociclib (25mg/kg) and Abemaciclib (25mg/kg) groups. Better tumor suppressive effect.
  • compound A 25mg/kg, 50mg/kg
  • compound A has shown obvious tumor inhibitory effect in human liver cancer xenograft mouse model, and the compound has no obvious toxic and side effects, and has good clinical efficacy in the treatment of liver cancer. Application prospects.
  • P value is to compare each group with Vehicle group by T test.
  • Example 6 Determination of the inhibition of the proliferation of colorectal cancer cell lines by the compounds of the present invention
  • the positive control drug Abemaciclib was prepared by the inventor according to the synthesis method recorded in WO2010075074A1.
  • the cell detection equipment was In Cell Analyzer 2200 (GE Healthcare).
  • the reagents or consumables used in the experiment are shown in the following table:
  • Abemaciclib and Compound A were dissolved in DMSO to prepare a 10 mM stock solution. And put it in a -80°C refrigerator for long-term storage; take 5 ⁇ L of 10 mM Abemaciclib and Compound A stock solutions, and dilute them respectively to form a 60 ⁇ M working solution. With 60 ⁇ M as the initial concentration, Abemaciclib is three-fold diluted 10 points, and Compound A is six-fold diluted 10 points.
  • the test results are shown in Table 10.
  • the results show that Compound A exhibited anti-proliferation activity on 14 colorectal cancer cell lines, among which Compound A had inhibitory activity on 11 colorectal cancer cell lines DLD-1, HCT8, HCT15, Caco-2 , LOVO, HCT116, SW620, SW948, Colo205, HT29, LS174T have obvious growth inhibitory activity (IC 50 ⁇ 1 ⁇ M); compared with the positive control drug Abemaciclib, compound A has the effect on 8 kinds of colorectal cancer cell lines DLD-1, HCT8 , HCT15, LOVO, HCT116, SW948, Colo205, HT29 have higher proliferation inhibitory activity.
  • the test is divided into compound A 5.0mg/kg, 10.0mg/kg, 25.0mg/kg and 50.0mg/kg groups, positive control drugs are Palbociclib 25.0mg/kg and Abemaciclib 25.0mg/kg groups, and Vehicle group, the above test
  • the preparation of product and reference substance is shown in Table 11.
  • the positive control drug Palbociclib was prepared by the inventor according to the synthesis method described in WO2003062236A1
  • Abemaciclib was prepared by the inventor according to the synthesis method described in WO2010075074A1.
  • mice in each group were administered orally orally, once a day, for a total of 35 days. Changes in tumor volume and body weight were observed regularly, and curative effect was evaluated based on relative tumor proliferation rate (T/C) and relative tumor inhibition rate (TGI).
  • T/C relative tumor proliferation rate
  • TGI relative tumor inhibition rate
  • T/C Relative tumor proliferation rate
  • TGI relative tumor inhibition rate
  • the results are shown in Table 12 and Fig. 2.
  • the results show that: the compound A (5mg/kg, 10mg/kg, 25mg/kg, 50mg/kg) treatment groups all showed the effect of tumor suppression on the 35th day, and the relative tumor proliferation rate ( T/C) is 57%, 46%, 28%, 8%, relative to Vehicle group, statistically significant difference (p value is respectively 0.003, ⁇ 0.001, ⁇ 0.001, ⁇ 0.001); and compound A (25mg /kg, 50mg/kg) treatment group showed better tumor suppression effect than positive drug Palbociclib (25mg/kg) and Abemaciclib (25mg/kg) group.
  • compound A 25mg/kg, 50mg/kg
  • P value is to compare each group with Vehicle group by T test.

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Abstract

L'invention concerne une méthode de traitement du cancer avec un inhibiteur de CDK4/6 et une utilisation pharmaceutique correspondante. L'inhibiteur de CDK4/6 est la 5-fluoro-4-(7'-fluoro-2'-méthylspiro[cyclopentane-1, 3'-indole]-5'-yl)-azote-(5-(1-méthylpipéridin-4-yl)pyridin-2-yl)pyrimidin-2-amine, et ledit cancer comprend le cancer colorectal, le cancer du foie ou le cancer du sein. L'inhibiteur de CDK4/6 a un bon effet suppresseur de tumeur.
PCT/CN2022/118817 2021-09-14 2022-09-14 Utilisation pharmaceutique d'un inhibiteur de cdk4/6 Ceased WO2023040914A1 (fr)

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CN101001857A (zh) * 2002-01-22 2007-07-18 沃尼尔·朗伯有限责任公司 2－(吡啶－2－基氨基)－吡啶并[2,3－d]嘧啶－7－酮
CN102264725A (zh) * 2008-12-22 2011-11-30 伊莱利利公司 蛋白激酶抑制剂
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Title
LEI YIN, HENG LI, WENJIAN LIU, ZHENGLIN YAO, ZHENZHEN CHENG, HUABEI ZHANG, HUI ZOU: "A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy", EUROEPAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, pages 1 - 28, XP055766971, [retrieved on 20210120] *

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