WO2019228330A1 - Composé de benzo[d]imidazole substitué et composition pharmaceutique associée - Google Patents

Composé de benzo[d]imidazole substitué et composition pharmaceutique associée Download PDF

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Publication number
WO2019228330A1
WO2019228330A1 PCT/CN2019/088749 CN2019088749W WO2019228330A1 WO 2019228330 A1 WO2019228330 A1 WO 2019228330A1 CN 2019088749 W CN2019088749 W CN 2019088749W WO 2019228330 A1 WO2019228330 A1 WO 2019228330A1
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Prior art keywords
compound
hydrogen
cancer
mmol
deuterium
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Chinese (zh)
Inventor
王义汉
任兴业
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a substituted benzo [d] imidazole compound, a pharmaceutical composition containing the compound, and use thereof. More specifically, the present invention relates to certain deuterated N- (2-((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5-((4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) amino) phenyl) acrylamide, these deuterated compounds and The composition can be used to treat EGFR-related diseases, and these deuterium-substituted compounds have more excellent pharmacokinetic properties.
  • the epidermal growth factor receptor (ie, EGFR, ErbB-1 or HER1) is a member of the ErbB receptor family.
  • the ErbB receptor family includes four closely related members of the receptor tyrosine kinase: EGFR (ErbB-1), Her2 / c-neu (ErbB-2), Her3 (ErbB-3) and Her4 (ErbB-4).
  • EGFR is a cell surface receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. Mutations that affect EGFR expression or activity may cause cancer. EGFR has been reported to be dysregulated in most solid tumors such as lung, breast, and brain tumors. It is estimated that 30% of epithelial cancers are associated with mutations, amplifications or disorders of EGFR or family members.
  • gefitinib and erlotinib Treatment methods based on the inhibition of EGFR by antibody drugs or small molecule inhibitor drugs such as gefitinib and erlotinib have been developed. In the case of non-small cell lung cancer (NSCLC), gefitinib and erlotinib are beneficial for 10% to 40% of patients. However, after a period of treatment, acquired resistance to gefitinib or erlotinib has become a major clinical problem. Studies have confirmed that one of the main causes of drug resistance is due to a new mutation in T790M, which is the "gatekeeper" of EGFR. researchers then developed inhibitors targeting T790M, such as BIBW2992, and showed advantages in clinical trials.
  • T790M which is the "gatekeeper" of EGFR.
  • WO2018019204 discloses a compound T having the following structure, and the chemical name is N- (2-((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5-((4- ( 4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] imidazol-6-yl) pyrimidin-2-yl) amino) phenyl) acrylamide, compound T not only effectively inhibits the T790M mutation Moreover, it is highly selective for the T790M mutation compared to the wild type.
  • ADME absorption, distribution, metabolism, and / or excretion
  • the present invention discloses a new deuterium-substituted benzo [d] imidazole compound, as well as a composition and use thereof, which has better EGFR kinase inhibitory activity, and is resistant to drug-resistant mutations T790M, L858R, and Both of them are highly selective, have lower side effects, and better pharmacokinetic properties, and can be used to treat, prevent, and alleviate EGFR kinase-mediated diseases.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 and Y 9 are each independently selected from hydrogen, deuterium, halogen, or trifluoromethyl;
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen or deuterium;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compounds contain at least one deuterium atom
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • a compound of the invention is provided in a therapeutically effective amount.
  • a compound of the invention is provided in a prophylactically effective amount.
  • the present invention provides a method for preparing a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention to form a pharmaceutical composition.
  • the present invention provides treatment of EGFR-caused cancers (including cancers caused by EGFR mutations, eg, cancers with T790M mutation, L858R mutation, and L858R / T790M double mutation) -related disorders in a subject in need thereof.
  • the cancer caused by the EGFR is selected from the group consisting of: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, Gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, etc.
  • the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In a specific embodiment, the compound is administered chronically.
  • deuterated refers to the replacement of one or more hydrogens in a compound or group with deuterium; deuteration may be mono-, di-, poly- or fully substituted.
  • deuteration may be mono-, di-, poly- or fully substituted.
  • deuteration may be mono-, di-, poly- or fully substituted.
  • deuteration may be mono-, di-, poly- or fully substituted.
  • deuterated and “one or more deuterated” are used interchangeably.
  • non-deuterated compound refers to a compound containing a deuterium atomic proportion not higher than the natural deuterium isotope content (0.015%).
  • pharmaceutically acceptable salt means, within the scope of sound medical judgment, suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergies, etc., and with reasonable benefits / dangers Proportion of those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., Pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include salts derived from suitable inorganic and organic acids and bases.
  • the compounds of the invention may be in amorphous or crystalline form.
  • the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • crystalline form refers to different arrangements of chemical drug molecules, which generally appear as the existing form of the drug substance in a solid state.
  • a drug can exist in multiple crystalline substance states, and different crystal forms of the same drug may have different dissolution and absorption in the body, which will affect the dissolution and release of the preparation.
  • crystalline form refers to different arrangements of chemical drug molecules, which generally appear as the existing form of the drug substance in a solid state.
  • a drug can exist in multiple crystalline substance states, and different crystal forms of the same drug may have different dissolution and absorption in the body, which will affect the dissolution and release of the preparation.
  • the term "subject” includes, but is not limited to: a human (ie, a male or female of any age group, for example, a pediatric subject (eg, infant, child, adolescent) or an adult subject (eg, Young adults, middle-aged adults or older adults)) and / or non-human animals, for example, mammals, for example, primates (for example, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses , Sheep, goats, rodents, cats and / or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effect of a subject having a specific disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder, or condition. Or development of a condition ("therapeutic treatment”), and also includes effects that occur before a subject begins to suffer from a particular disease, disorder, or disease (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest.
  • the effective amount of a compound of the present invention can vary depending on factors such as the biological objective, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit during the treatment of a disease, disorder, or condition, or one or more of which is associated with the disease, disorder, or condition. Symptoms are delayed or minimized.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder, or condition.
  • the term "therapeutically effective amount” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of other therapeutic agents.
  • a prophylactically effective amount of a compound used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent a disease , The number of recurrences of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a preventative benefit in the prevention of a disease, disorder, or condition.
  • the term “prophylactically effective amount” may include an amount that improves overall prevention, or an amount that enhances the preventive efficacy of other preventive agents.
  • Combination and related terms refer to the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously in a single unit dosage form with another therapeutic agent.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 and Y 9 are each independently selected from hydrogen, deuterium, halogen, or trifluoromethyl;
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen or deuterium;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compound contains at least one deuterium atom.
  • the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably Ground is greater than 95%, and more preferably greater than 99%.
  • Y 1, Y 2, Y 3, Y 4, Y 5, Y 6, Y 7, Y 8 and Y 9 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y 1 is selected from hydrogen, deuterium, halogen, or trifluoromethyl
  • Y 2 is selected from hydrogen, deuterium, halogen, or trifluoromethyl
  • Y 3 is selected from hydrogen, deuterium, halogen, or trifluoromethyl
  • Y 9 is selected from the group consisting of hydrogen, deuterium, halogen or trifluoromethyl.
  • Y 1 is hydrogen, Y 1 is deuterium, Y 1 is halogen (F, Cl, Br, or I) or Y 1 is trifluoromethyl
  • Y 2 is hydrogen, Y 2 is deuterium, and Y 2 is Halogen (F, Cl, Br or I) or Y 2 is trifluoromethyl
  • Y 3 is hydrogen, Y 3 is deuterium, Y 3 is halogen (F, Cl, Br or I) or Y 3 is trifluoromethyl
  • Y 9 is hydrogen, Y 9 is deuterium, Y 9 is halogen (F, Cl, Br or I) or Y 9 is trifluoromethyl.
  • R 1, R 2, R 3, R 4 and R 5 are each independently selected from hydrogen or deuterium” includes R 1 is selected hydrogen or deuterium, R 2 is selected from hydrogen or deuterium, R 3 is selected from hydrogen or deuterium, and so on until R 5 is selected from hydrogen or deuterium. More particularly, R 1 is hydrogen comprising, R 1 is deuterium, R 2 is hydrogen, R 2 is deuterium, R 3 is hydrogen, R 3 is deuterium, and so on, until R 5 is hydrogen, deuterium, R 5 is Technical solutions.
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D" including X 1 X 3 is selected from CH 3 , CD 3 , CHD 2 or CH 2 D, X 2 is selected from CH 3 , CD 3 , CHD 2 or CH 2 D, X 3 is selected from CH 3 , CD 3 , CHD 2 or CH 2 D, and By analogy, until X 7 is selected from the technical schemes of CH 3 , CD 3 , CHD 2 or CH 2 D.
  • X 1 is CH 3
  • X 1 is CD 3
  • X 1 is CHD 2 or X 1 is CH 2 D
  • X 2 is CH 3
  • X 2 is CD 3
  • X 2 is CHD 2 or X 2 Is CH 2 D
  • X 3 is CH 3
  • X 3 is CD 3
  • X 3 is CHD 2 or X 3 is CH 2 D
  • X 7 is CHD 2 or X 7 is a technical solution of CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, wherein Y 1 to Y 9 are each independently selected from hydrogen or deuterium, and R 1 to R 5 and X 1 to X 7 are as defined above, with the proviso that the above compound contains at least one deuterium atom.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, wherein Y 3 to Y 9 are hydrogen, Y 1 and Y 2 are each independently selected from hydrogen or deuterium, R 1 to R 5 are each independently selected from hydrogen or deuterium, and X 1 to X 7 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • Y 3 to Y 9 are hydrogen
  • Y 1 and Y 2 are each independently selected from hydrogen or deuterium
  • R 1 to R 5 are each independently selected from hydrogen or deuterium
  • X 1 to X 7 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • Y 1 is hydrogen
  • X 1 and X 2 are the same.
  • X 1 and X 2 are each independently selected from CH 3 or CD 3 .
  • X 3 and X 4 are each independently selected from CH 3 or CD 3 .
  • X 6 and X 7 are each independently selected from CH 3 , CD 3 or CHD 2 .
  • X 5 is CH 3 .
  • R 2 , R 3 , R 4 and R 5 are hydrogen.
  • R 1 is deuterium
  • R 1 is hydrogen
  • Y 2 is deuterium
  • Y 2 is hydrogen
  • the compound has any one of the following structures, or a pharmaceutically acceptable salt thereof, but is not limited to the following structures:
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and / or diastereomeric forms.
  • the compounds of the invention may be individual enantiomers, diastereomers or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, This includes racemic mixtures and mixtures rich in one or more stereoisomers.
  • Isomers can be separated from a mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • organic compounds can form complexes with solvents that react in the solvent or precipitate or crystallize from the solvent. These complexes are called “solvates”. When the solvent is water, the complex is called a "hydrate”. The invention encompasses all solvates of the compounds of the invention.
  • solvate refers to the form of a compound or a salt thereof in combination with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • the "solvate” includes a solvate in a solution state and a separable solvate. Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, for example, hydrates of the compounds may be used on behalf of the general formula Rx H 2 O, where R is the compound, and x is a number greater than 0.
  • a given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R0.5H 2 O )) and a multi-hydrate (x is greater than 1, e.g., dihydrate (R2H 2 O) and hexahydrate (R6H 2 O)).
  • the compounds of the invention may be in an amorphous or crystalline form (polymorphic form).
  • the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to a crystalline form (or a salt, hydrate, or solvate) of a compound in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the predominance of a crystalline form.
  • Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically-labeled compounds, which are equivalent to those described in formula (I), but one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of the present invention.
  • Certain isotopically-labeled compounds of the invention, such as those incorporating radioisotopes such as 3 H and 14 C, can be used for drug and / or substrate tissue distribution assays. Thallium, i.e. 3 H and carbon-14, i.e. 14 C isotopes, are particularly preferred because they are easy to prepare and detect.
  • An isotope-labeled compound of the formula (I) of the present invention and a prodrug thereof can generally be prepared in such a manner that, when performing the processes disclosed in the following schemes and / or examples and preparation examples, non-isotope-labeled reagents are replaced with readily available isotopically-labeled reagents Labeled reagent.
  • prodrugs are also included in the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted into its active form with a medical effect in vivo by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs Novel Delivery Systems, ACSSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D.Fleisher, S. Ramon, and H. Barbra, "Improved, or drug, delivery: solubility, limitation, overcome, and use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each article This article is for reference.
  • a prodrug is any covalently bonded compound of the invention, and when such a prodrug is administered to a patient, it releases the parent compound in vivo.
  • Prodrugs are usually prepared by modifying functional groups, and the modification is performed in a manner such that the modification can be performed by routine manipulation or cleavage in vivo to produce the parent compound.
  • Prodrugs include, for example, compounds of the invention in which a hydroxyl, amino, or thiol group is bonded to an arbitrary group, and when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group.
  • prodrugs include, but are not limited to, acetate, amide, formate / amide, and benzoate / amide derivatives of hydroxyl, thiol, and amino functional groups of the compound of formula (I).
  • a carboxylic acid -COOH
  • an ester such as methyl ester, ethyl ester, or the like can be used.
  • the esters themselves can be active and / or can be hydrolyzed under conditions in the human body.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups that readily break down in the human body to release the parent acid or its salt.
  • the compounds of the invention can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic pathways, such as those in the schemes below.
  • the reaction for preparing the compound of the present invention can be performed in a suitable solvent, and those skilled in the art of organic synthesis can easily select a solvent.
  • Suitable solvents may be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is performed (eg, a temperature in the range of the solvent freezing temperature to the solvent boiling temperature).
  • a given reaction may be performed in one solvent or a mixture of more than one solvent.
  • the skilled person can select a solvent for a specific reaction step depending on the specific reaction step.
  • the preparation of the compounds of the invention may involve the protection and removal of different chemical groups. Those skilled in the art can easily determine whether protection and removal of protection are needed and the selection of an appropriate protecting group.
  • the chemical properties of protecting groups can be found, for example, in Wuts and Greene, Protective Groups, Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.
  • the reaction can be monitored according to any suitable method known in the art.
  • spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible light), mass spectrometry (MS)), or by chromatography Methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) to monitor product formation.
  • NMR nuclear magnetic resonance
  • IR infrared
  • MS mass spectrometry
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • compositions preparations and kits
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of an active ingredient.
  • the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient.
  • the pharmaceutical composition comprises a prophylactically effective amount of an active ingredient.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compounds formulated together.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin ), Buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substance, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-embe
  • kits eg, pharmaceutical packaging.
  • the provided kits can include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other Suitable container).
  • the provided kit may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and / or other therapeutic agent.
  • a compound of the invention and other therapeutic agents are provided in a first container and a second container to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, and sternal administration , Cerebrospinal spinal membrane administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician .
  • a compound provided herein is administered to a subject at risk of developing the condition, typically based on and under the supervision of a physician, at a dosage level as described above.
  • Subjects at risk for developing a particular disorder typically include subjects with a family history of the disorder, or those who are determined by genetic testing or screening to be particularly sensitive to the development of the disorder.
  • the pharmaceutical compositions provided herein can also be administered chronically ("long-term administration").
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can be continued indefinitely, For example, the remainder of a subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within a therapeutic window.
  • the pharmaceutical composition may be administered by bolus, for example, to rapidly increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient, for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, whereas a bolus delivered directly to a vein (e.g., by IV intravenous drip) can be more Rapid delivery allows the concentration of the active ingredient in the blood to rise quickly to an effective level.
  • the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV infusion, to provide a steady state concentration of the active ingredient in the subject's body.
  • the bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
  • Oral compositions can take the form of a liquid solution or suspension in bulk or a powder in bulk. However, more generally, to facilitate accurate dosing, the composition is provided in unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined number of active substances and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect.
  • Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.
  • the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is each useful for forming a desired administration form A carrier or excipient and processing aid.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides about 0.01 to about 20 mg / kg of a compound of the invention, and preferred doses each provide about 0.1 to about 10 mg / kg, especially about 1 to about 5 mg / kg.
  • transdermal doses are usually selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 To about 10% by weight, and more preferably about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 0.1 mg / kg / hour to at least 10 mg / kg / hour.
  • a preloaded bolus of about 0.1 mg / kg to about 10 mg / kg or more can also be given.
  • the maximum total dose cannot exceed about 2 g / day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles and buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or compounds having similar properties: a binder, such as microcrystalline cellulose, tragacanth, or gelatin; an excipient, such as starch or lactose, a disintegrant, For example, alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as mint, water Methyl salicylate or orange flavor.
  • a binder such as microcrystalline cellulose, tragacanth, or gelatin
  • an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing an active ingredient.
  • the active ingredient When formulated as an ointment, the active ingredient is typically combined with a paraffin or a water-miscible ointment base.
  • the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and generally include other components for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
  • transdermal administration can be achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques are described in Section 8 of Remington's Pharmaceuticals, Science, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
  • the compounds of the invention may also be administered in a sustained release form or from a sustained release delivery system.
  • sustained-release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to a pharmaceutically acceptable formulation of a compound of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ -, and ⁇ -cyclodextrin consisting of 6, 7, and 8 ⁇ -1,4-linked glucose units, respectively, which optionally include one on the linked sugar moiety Or more substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, for example, a sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the present invention provides a method for inhibiting a protein tyrosine kinase (such as EGFR kinase) or treating a disease (such as cancer, cell proliferative disease, inflammation, infection, immune disease, organ transplant, viral disease, cardiovascular disease or Method of metabolic disease), which comprises the step of administering to a subject in need of treatment a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystalline form, prodrug thereof Or an isotope derivative, or a pharmaceutical composition according to the invention.
  • a protein tyrosine kinase such as EGFR kinase
  • a disease such as cancer, cell proliferative disease, inflammation, infection, immune disease, organ transplant, viral disease, cardiovascular disease or Method of metabolic disease
  • the compounds of the invention are useful for treating cancer caused by EGFR.
  • the compounds are useful in the treatment of cancers caused by EGFR expressing EGFR mutants and in the treatment of cancers of EGFR refractory to RTKI therapy (eg, erlotinib or gefitinib).
  • the compounds of the present invention are inhibitors of at least one mutant of EGFR and are therefore suitable for use in treatment with one or more EGFR mutants (e.g., deletion mutations, activation mutations, resistance mutations, or combinations thereof, specific examples including T790M mutations, L858R mutation and L858R / T790M double mutation) activity related to one or more disorders.
  • EGFR mutants e.g., deletion mutations, activation mutations, resistance mutations, or combinations thereof, specific examples including T790M mutations, L858R mutation and L858R / T790M double mutation
  • the present invention provides a method for treating a mutant EGFR-mediated disorder, which comprises administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, A solvate, a hydrate, a crystalline form, a prodrug or an isotope derivative, or a step of administering a pharmaceutical composition according to the present invention.
  • Cancers treatable by the compounds of the present invention include, but are not limited to, non-small cell lung cancer (NSCLS), small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, Gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma and other hyperproliferative diseases.
  • NSCS non-small cell lung cancer
  • small cell lung cancer small cell lung cancer
  • lung adenocarcinoma lung squamous cell carcinoma
  • pancreatic cancer breast cancer
  • prostate cancer liver cancer
  • skin cancer epithelial cell cancer
  • Gastrointestinal stromal tumor Gastrointestinal stromal tumor
  • leukemia histiocytic lymphoma
  • nasopharyngeal carcinoma other hyperproliferative diseases.
  • the compounds of the present invention are also useful for maintaining the
  • an effective amount of a compound of the present invention is usually administered in a single or multiple doses at an average daily dose of 0.01 to 50 mg of the compound per kg of the patient's body weight, preferably 0.1 to 25 mg of the compound per kg of the patient's body weight.
  • the compound of the present invention can be administered to the patient in need of such treatment at a daily dose range of about 1 mg to about 3500 mg per patient, preferably 10 mg to 1000 mg.
  • the daily dose per patient may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000mg.
  • Administration can be one or more times daily, weekly (or several days apart), or on an intermittent schedule.
  • the compound can be administered one or more times per day on an weekly basis (e.g., every Monday), indefinitely or for several weeks, such as 4-10 weeks.
  • the compound can be administered daily for several days (e.g., 2-10 days), and then the compound is not administered for several days (e.g., 1-30 days), the cycle is repeated indefinitely, or a given number of times, such as 4-10 Cycles.
  • a compound of the invention may be administered daily for 5 days, then intermittently for 9 days, and then daily for 5 days, then intermittently for 9 days, and so on, the cycle may be repeated indefinitely or a total of 4-10 times.
  • EGFR-TKI eg, erlotinib or gefitinib
  • the components of the combination therapy can be administered at their monotherapy dose levels and schedules.
  • erlotinib has been administered orally at 150 mg per day for the treatment of non-small cell lung cancer, and it has been administered orally at 100 mg per day for pancreatic cancer.
  • gefitinib has been administered orally at 250 mg per day for the treatment of non-small cell lung cancer.
  • EGFR-TKI eg, erlotinib or gefitinib
  • the dosage level of one or both of its components is reduced compared to when used alone.
  • each reaction is usually performed in an inert solvent at room temperature to reflux temperature (for example, 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • the gray solid (220 mg, 0.48 mmol) obtained above was dispersed uniformly by adding acetonitrile (5 mL), and then N 1 , N 1 , N 2 -trimethylethane-1,2-diamine (59 mg, 0.57 mmol), and potassium carbonate were added. (132 mg, 0.96 mmol), heated to reflux at 90 ° C for 2 hours. The reaction solution was cooled to room temperature, and the insoluble solid was removed by filtration. The filtrate was evaporated to dryness to obtain Compound 5 as a red oil (126 mg).
  • the red oily compound 5 (126 mg) was dissolved in a mixed solution of ethanol-water (4 mL + 1 mL), and reduced iron powder (106 mg) and ammonium chloride (34 mg) were added, and the mixture was heated under reflux at 90 ° C for 5 hours to react. The reaction was cooled to room temperature, the insoluble solid was removed by filtration, and the filtrate was evaporated to dryness. The obtained oil was dissolved by adding 10 mL of DCM, 5 mL of a saturated aqueous sodium hydrogen carbonate solution was added, and the solution was cooled in an ice bath.
  • step 1 in Example 1 is replaced by the following steps:
  • Trifluoroacetic acid (10 mL) was added to a solution of compound 21 (1.70 g, 2.79 mmol) in dichloromethane (20 mL), and the reaction was stirred in a greenhouse for 1 hr.
  • the reaction solution was concentrated under reduced pressure to remove the reaction solution, and the pH was adjusted to be alkaline with a saturated sodium bicarbonate solution.
  • Water (30 mL) was added and stirred overnight.
  • the solid was filtered, the solid was washed with water, and then washed with cold ethanol (3 mL x 2), and dried under vacuum at 55 ° C to obtain 1.1 g of a red solid, yield: 77.44%.
  • LC-MS (APCI): m / z 509.2 (M + 1) + .
  • test compound was dissolved in DMSO to prepare a 20 mM mother liquor. Then, a 3-fold dilution in DMSO was performed ten times. When adding medicine, dilute it with buffer 10 times.
  • Detection of WT EGFR and EGFR [L858R / T790M] kinase In 5x kinase buffer A, mix WT EGFR or EGFR [L858R / T790M] kinase with a compound of different concentration prepared in a pre-diluted form for 10 minutes, and duplicate the wells at each concentration . Add the corresponding substrate and ATP, and react at room temperature for 20 minutes (wherein a negative positive control is set: a negative is a blank control and a positive is erlotinib). After the reaction, add detection reagents (reagents in the HTRF Kinase TK kit), and incubate for 30 minutes at room temperature.
  • detection reagents reagents in the HTRF Kinase TK kit
  • the compound of the present invention was tested in the above kinase inhibition experiment, and it was found that the compound of the present invention has a potent activity on EGFR [L858R / T790M] and an excellent selectivity over WT EGFR compared to the non-deuterated compound T.
  • the results for representative example compounds are summarized in Table 1 below.
  • the anti-proliferative activity of the compound of the present invention on three tumor cells cultured in vitro was detected by the MTS method.
  • the experimental results show that the compound of the present invention has an inhibitory effect on the in vitro proliferation of cancer cells cultured in vitro; wherein the inhibitory effect on the proliferation of lung cancer cells in vitro is stronger than the inhibitory effect on the proliferation of skin cancer cells in vitro.
  • Skin cancer cells A431 purchased from the American Standard Biological Collection (ATCC)
  • lung cancer cells NCI-H1975 purchased from the American Standard Biological Collection (ATCC)
  • HCC827 purchased from the American Standard Biological Collection (ATCC))
  • All were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U / ml penicillin, and 100 ⁇ g / ml streptomycin.
  • RPMI-1640 (GIBCO, catalog number A10491-01); fetal bovine serum (GIBCO, catalog number 10099141); 0.25% trypsin-EDTA (GIBCO, catalog number 25200); penicillin-streptomycin, liquid (GIBCO, catalog number 15140-122); DMSO (Sigma, catalog number D2650); MTS test kit (Promega, catalog number G3581), 96-well plate (Corning, catalog number 3365).
  • test compound preparation The test compound was dissolved in DMSO to prepare a 20 mM mother liquor, and stored at -20 ° C. When using, dilute with DMSO and other gradients 3 times, 10 times. At the time of dosing, it was diluted 4 times with cell culture medium RPMI-1640.
  • MTS cell viability test 0.25% trypsin-EDTA digested cells in logarithmic growth phase, inoculated 150 ⁇ l in a 96-well plate according to the optimized density, 24 hours after adding the medium to dilute the compound 4 times, 50 ⁇ l / well Concentration: 100, 33.3, 11.1, 3.70, 1.23, 0.412, 0.137, 0.0457, 0.0152, 0.00508 ⁇ M). As a control, the same volume of 0.5% DMSO was added. After the cells were cultured for 72 hours, MTS was used to detect cell viability.
  • adherent cells discard the culture medium, and add a mixed solution containing 20 ⁇ L MTS and 100 ⁇ L culture medium to each well. Put it in the incubator and continue to incubate for 1-4 hours to detect OD490, and use the OD650 value as a reference. Using GraphPad Prism software to make dose-response curves and calculate IC 50.
  • the compound of the present invention was tested in the above cytotoxicity experiment, and it was found that the compound of the present invention has strong activity on lung cancer cells NCI-H1975 and HCC827 and an excellent choice better than skin cancer cell A431 compared with the non-deuterated compound T. Sex.
  • the results of representative example compounds are summarized in Table 2 below.
  • Microsomal experiments human liver microsomes: 0.5mg / mL, Xenotech; rat liver microsomes: 0.5mg / mL, Xenotech; coenzyme (NADPH / NADH): 1mM, Sigma Life Science; magnesium chloride: 5mM, 100mM phosphate buffered Agent (pH 7.4).
  • Preparation of the stock solution A certain amount of powder of the example compound and the reference compound was precisely weighed, and dissolved to 5 mM with DMSO, respectively.
  • phosphate buffer solution 100 mM, pH 7.4.
  • NADPH regeneration system solution (containing 6.5mM NADP, 16.5mM G-6-P, 3U / mL G-6-PD, 3.3mM magnesium chloride), and place on wet ice before use.
  • stop solution an acetonitrile solution containing 50ng / mL propranolol hydrochloride and 200ng / mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer solution (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg / mL.
  • phosphate buffer solution pH 7.4
  • Determination of metabolic stability 300 ⁇ L of pre-cooled stop solution was added to each well of a 96-well deep well plate, and placed on ice as a stop plate. Place the 96-well incubation plate and NADPH regeneration system in a 37 ° C water bath, shake at 100 rpm, and pre-incubate for 5 minutes. Take 80 ⁇ L of the incubation solution from each well of the incubation plate and add it to the termination plate, mix well, and add 20 ⁇ L of the NADPH regeneration system solution as a 0min sample. Add 80 ⁇ L of NADPH regeneration system solution to each well of the incubation plate, start the reaction, and start timing.
  • the reaction concentration of the corresponding compound was 1 ⁇ M, and the protein concentration was 0.5 mg / mL.
  • 100 ⁇ L of each reaction solution was taken, added to the stop plate, and vortexed for 3 minutes to stop the reaction.
  • the stop plate was centrifuged at 5000 ⁇ g for 10 min at 4 ° C. Take 100 ⁇ L of the supernatant into a 96-well plate pre-added with 100 ⁇ L of distilled water, mix well, and use LC-MS / MS for sample analysis.
  • the compounds of the present invention and their non-deuterated compounds were tested and compared simultaneously to evaluate their metabolic stability in human and rat liver microsomes.
  • Undeuterated compound T was used as a reference.
  • the compounds of the present invention can significantly improve metabolic stability by comparison with the undeuterated compound T.
  • Table 3 The results for representative example compounds are summarized in Table 3 below.
  • Rats were raised on a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide.
  • Orbital blood was collected at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were anesthetized briefly after inhaling ether, and 300 ⁇ L of blood samples were collected in test tubes from the orbit.
  • the test tube contained 30 ⁇ L of a 1% heparin salt solution. Before use, test tubes were dried at 60 ° C overnight. After blood samples were collected at the last time point, rats were sacrificed after ether anesthesia.
  • the blood sample was centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate the plasma from the red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube with the name and time point of the compound. Plasma was stored at -80 ° C before analysis. LC-MS / MS was used to determine the concentration of a compound of the invention in plasma. Pharmacokinetic parameters were calculated based on the blood drug concentration of each animal at different time points.

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Abstract

La présente invention concerne un composé de benzo[d]imidazole substitué et une composition pharmaceutique associée, ainsi que ses utilisations ; le composé de benzo[d]imidazole est un composé représenté par la formule (I), ou un sel pharmaceutiquement acceptable, un promédicament, un hydrate ou un composé de solvant, une forme cristalline, un stéréoisomère ou un variant isotopique dudit composé. Le composé et la composition selon la présente invention peuvent être utilisés dans des méthodes de traitement de maladies liées au cancer provoquées par l'EGFR (y compris le cancer provoqué par des mutations d'EGFR, par exemple, le cancer ayant une mutation T790M, une mutation L858R, et une double mutation L858R/T790M).
PCT/CN2019/088749 2018-05-29 2019-05-28 Composé de benzo[d]imidazole substitué et composition pharmaceutique associée Ceased WO2019228330A1 (fr)

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CN107827875B (zh) * 2017-09-25 2021-07-09 文韬创新药物研究（北京）有限责任公司 一种苯并咪唑类衍生物作为周期蛋白依赖性激酶4/6抑制剂的应用

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WO2020151742A1 (fr) * 2016-07-26 2020-07-30 Shenzhen Targetrx, Inc. Composé aminé pyrimidinique pour l'inhibition de l'activité de la protéine tyrosine kinase
US11111233B2 (en) 2016-07-26 2021-09-07 Shenzhen Targetrx, Inc. Amino pyrimidine compound for inhibiting protein tyrosine kinase activity

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