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WO2019001307A1 - Composé amide, composition le contenant, et utilisation associée - Google Patents

Composé amide, composition le contenant, et utilisation associée Download PDF

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Publication number
WO2019001307A1
WO2019001307A1 PCT/CN2018/091829 CN2018091829W WO2019001307A1 WO 2019001307 A1 WO2019001307 A1 WO 2019001307A1 CN 2018091829 W CN2018091829 W CN 2018091829W WO 2019001307 A1 WO2019001307 A1 WO 2019001307A1
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compound
added
pharmaceutically acceptable
amide compound
mmol
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PCT/CN2018/091829
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English (en)
Chinese (zh)
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王义汉
赵九洋
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深圳市塔吉瑞生物医药有限公司
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Publication of WO2019001307A1 publication Critical patent/WO2019001307A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to an amide compound and a composition comprising the same and use thereof.
  • Protein tyrosine kinases play an important role in cell regulation, and abnormal expression or mutations have been observed in cancer cells or autoimmune diseases. Protein tyrosine kinases are enzymes that catalyze the transport of phosphate groups from ATP to tyrosine located on a protein substrate. Many growth factor receptor proteins function as tyrosine kinases to transmit cellular signals. The interaction between growth factors and their receptors usually controls cell growth, but abnormal signaling caused by mutation or overexpression of any of the receptors often induces a variety of cancers or autoimmune diseases (eg rheumatoid joints) inflammation).
  • autoimmune diseases eg rheumatoid joints
  • EGFR tyrosine kinase inhibitor is a molecularly targeted drug targeting EGFR, which binds to the EGFR tyrosine kinase catalytic domain binding site on the cell surface by competitively binding to ATP, blocking signaling into cells. Further delivery inhibits tumor cell growth and induces apoptosis.
  • EGFR-TKI such as erlotinib and gefitinib have been widely used in clinical practice.
  • EGFR inhibitors such as gefitinib and erlotinib have achieved remarkable results in EGFR-mutant advanced non-small cell lung cancer (NSCLC).
  • NSCLC EGFR-mutant advanced non-small cell lung cancer
  • AZD9291 is an oral, irreversible, third-generation EGFR inhibitor (EGFR-TKI) that has a better therapeutic effect in patients with NSCLC who are already resistant to EGFR-TKI and have T790M mutations.
  • EGFR-TKI oral, irreversible, third-generation EGFR inhibitor
  • patients taking AZD9291 will still develop symptoms of acquired resistance.
  • the mechanisms of AZD9291 acquired resistance mutations include: EGFR C797S mutation, FGFR1 amplification, HER2 amplification, c-Met amplification or MAPK alternative pathway activation, histological transformation (partial conversion to small cell lung cancer), or other genes mutation. (Reference: Oxnard et al. Nature Medicine, 2015, 21, 560-562)
  • AZD9291 forms a covalent bond with cysteine C797 at the ATP binding site, and the C797S mutation affects the binding of covalent bonds, similar to the resistance mechanism of the BTK inhibitor Ibrutinib.
  • “Nature” published a heavy article describing a new generation of targeted drug EAI045 that can overcome AZD9291 resistance, and combined EAI045 with Erbitux for mouse models for C797S mutation. Among them, the efficiency is as high as 80%. (Reference: M.J. Eck et al. Nature, 2016, 534, 129-132)
  • the present invention discloses an amide compound, a composition comprising the same, and a use thereof, which have protein kinase inhibitory activity and have better pharmacodynamic/pharmacokinetic properties.
  • the invention relates to an amide compound of formula (I), or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variation, hydrate or solvent compound thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl. With the proviso that the above amide compound contains at least one ruthenium atom.
  • the compound of the formula (I) contains at least one halogen atom, more preferably one germanium atom, more preferably two germanium atoms, more preferably three germanium atoms, more preferably four germanium atoms. More preferably, five helium atoms, more preferably six helium atoms, more preferably eight helium atoms.
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • the ytterbium isotope in each of the deuterated positions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The content is at least 5%, preferably more than 10%, more preferably more than 15%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably More than 40%, more preferably more than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably more than 70%, more preferably More than 75%, more preferably more than 80%, more preferably more than 85%, more preferably more than 90%, more preferably more than 95%, more preferably more than 99%.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 of the compound of formula (I) at least one of which contains bismuth, more preferably two ⁇ , more preferably three ⁇ , more preferably four ⁇ , more preferably five ⁇ , more preferably six ⁇ , more preferably Seven contain sputum, more preferably eight sputum, more preferably nine sputum, more preferably ten sputum, more preferably eleven sputum, more preferably twelve sputum.
  • the compound of formula (I) contains at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve deuterium atoms. .
  • R 1 and R 2 are each independently hydrazine or hydrogen.
  • R 1 is deuterium
  • R 2 is deuterium
  • R 1 and R 2 are deuterium.
  • R 3 and R 4 are each independently hydrazine or hydrogen.
  • R 3 is deuterium
  • R 3 and R 4 are deuterium.
  • R 5 , R 6 , R 7 and R 8 are each independently hydrazine or hydrogen.
  • R 5 , R 6 , R 7 and R 8 are deuterium.
  • R 9 , R 10 and R 11 are each independently hydrazine or hydrogen.
  • R 9 is deuterium
  • R 10 is deuterium
  • R 11 is hydrazine
  • R 9 , R 10 and R 11 are deuterium.
  • R 12 is deuterium
  • the present invention also discloses a process for the preparation of an amide compound of the formula (I), characterized in that it comprises a substituted or unsubstituted The step of reacting as an intermediate with a substituted or unsubstituted 2-aminothiazoline under basic conditions.
  • the base used in the production method is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N-di At least one of isopropylethylamine, 4-N,N-lutidine or pyridine.
  • the present invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an amide compound as described above, or a polymorphic form thereof, a pharmaceutically acceptable salt, or a prodrug , stereoisomers, isotopic variations, hydrates or solvates.
  • the present invention also discloses a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: pharmaceutically acceptable excipients with an amide compound as described above, or a polymorph thereof
  • pharmaceutically acceptable salts, prodrugs, stereoisomers, isotopic variations, hydrates or solvates are combined to form a pharmaceutical composition.
  • the pharmaceutical composition is an injection, a sachet, a tablet, a pill, a powder or a granule.
  • the pharmaceutical composition further comprises an additional therapeutic agent, which is cancer, cardiovascular disease, inflammation, infection, immune disease, cell proliferative disease, viral disease. , a metabolic disease, or a drug for organ transplantation.
  • an additional therapeutic agent which is cancer, cardiovascular disease, inflammation, infection, immune disease, cell proliferative disease, viral disease. , a metabolic disease, or a drug for organ transplantation.
  • the invention provides a compound of the first aspect of the invention, or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variation, hydrate or solvent thereof Use of the compound for the preparation of a medicament for the treatment and/or prevention of a disease associated with a protein kinase.
  • the invention provides a method of treating and/or preventing a protein kinase-associated disease in a subject, the method comprising administering to the subject an amide of formula (I) A compound having a polymorphic form, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotope variant, a hydrate or a solvent compound, or a pharmaceutical composition thereof.
  • the present invention provides a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variation, hydrate or solvent compound of the amide compound of formula (I), or A pharmaceutical composition for treating and/or preventing a disease associated with a protein kinase.
  • the compound or pharmaceutical composition is for treating and/or preventing a disease: cancer, cell proliferative disease, inflammation, infection, immune disease, organ transplantation, viral disease, cardiovascular disease Or metabolic disease.
  • the cancer includes, but is not limited to, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer , osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.
  • the immune disease or inflammation includes, but is not limited to, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, pouch Sexual fibrosis.
  • the cell proliferative disorder refers to lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer. , osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • the present invention provides a kit comprising: a first container comprising an amide compound of the formula (I), a polymorph, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, An isotope variant, hydrate or solvent compound; and, optionally, a second container containing other therapeutic agent; and, optionally, a third container containing for diluting or suspending the compound and/or other therapeutic agent A pharmaceutically acceptable excipient.
  • the invention also discloses the use of an amide compound as described above for the preparation of a pharmaceutical composition for inhibiting protein kinases.
  • a pharmaceutical composition for inhibiting protein kinases Preferably, it is used to prepare a pharmaceutical composition that inhibits EGFR kinase.
  • the compound of formula (I) of the present invention can treat or prevent abnormally activated B lymphocytes A cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease caused by cells, T lymphocytes, or both. Accordingly, the present invention also provides a pharmaceutical composition for treating and/or preventing cancer, a tumor, an inflammatory disease, an autoimmune disease or an immune-mediated disease, comprising the compound of the formula (I) of the present invention or Polymorphic forms, pharmaceutically acceptable salts, prodrugs, stereoisomers, isotopic variations, hydrates or solvates are included as active ingredients.
  • the invention also includes isotopically labeled compounds (also referred to as "isotopic variants"), equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes. In addition, heavier isotopic substitutions such as guanidine, or 2 H, are preferred in certain therapies due to their good metabolic stability, such as increased half-life or reduced dosage in vivo, and therefore may be preferred in certain circumstances. Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • the beneficial effects of the present invention are as follows: First, the amide compound using the technical scheme of the present invention has excellent inhibitory effect on protein kinase. Second, the metabolism of the compound in the organism is improved, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability. Third, the drug concentration of the compound in the animal is increased, and the drug efficacy is improved. Fourth, certain metabolites are inhibited and the safety of the compounds is increased.
  • C 1 -C 6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 - C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 C 4 -C 6 , C 4 -C 5 and C 5 -C 6 alkyl.
  • Halogen means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • polymorph refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state.
  • a drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • pharmaceutically acceptable salt means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate.
  • 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 those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • non-toxic acid addition salts examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using conventional methods in the art, for example, ion exchange methods.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Subjects for administration include, but are not limited to, humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young Adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, 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.
  • the terms "person,” “patient,” and “subject” are used interchangeably herein.
  • treating includes the effect that occurs when a subject has a particular disease, disorder or condition that reduces the severity of the disease, disorder or condition, or delays or slows the progression of the disease, disorder or condition.
  • prevention includes the effect that occurs before a subject begins to have a particular disease, disorder or condition.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound which is converted in vivo to an active form thereof having a medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as 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 oral drug delivery: Solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each This article is incorporated herein by reference.
  • a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of the invention in vivo.
  • Prodrugs are typically prepared by modifying functional groups that cleave the prodrug in vivo to yield the parent compound.
  • Prodrugs include, for example, a compound of the invention wherein a hydroxy, amino or thiol group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amino or thiol group.
  • representative examples of prodrugs include, but are not limited to, covalent derivatives of the compounds of the invention formed by the hydroxyl, amino or thiol functional groups thereof with acetic acid, formic acid or benzoic acid.
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable esters include those which readily decompose in the human body to release the parent acid or its salt.
  • “Pharmaceutically acceptable excipient” as used in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound 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 (eg, human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxyprop
  • the present invention relates to an amide compound of the formula (I), or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotope variant, hydrate or solvent compound thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl. With the proviso that the above amide compound contains at least one ruthenium atom.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen and deuterium.
  • halogen or trifluoromethyl includes R 1 selected from hydrogen, deuterium, halogen or trifluoromethyl, R 2 is selected from hydrogen, deuterium, halogen or trifluoromethyl, and R 3 is selected from hydrogen, deuterium, halogen or tri fluoromethyl, and so on until 20 is selected from hydrogen, deuterium, halogen or trifluoromethyl aspect R.
  • R 1 is hydrogen, R 1 is deuterium, R 1 is halogen (F, Cl, Br or I) or R 1 is trifluoromethyl
  • R 2 is hydrogen, R 2 is deuterium, and R 2 is Halogen (F, Cl, Br or I) or R 2 is trifluoromethyl
  • R 3 is hydrogen, R 3 is deuterium, R 3 is halogen (F, Cl, Br or I) or R 3 is trifluoromethyl
  • R 20 is hydrogen, R 20 is deuterium, R 20 is halogen (F, Cl, Br or I) or R 20 is a trifluoromethyl group.
  • the invention relates to an amide compound of formula (I), or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variation, hydrate or solvent compound thereof, Wherein R 2 , R 9 and R 11 are hydrogen, and R 1 , R 3 -R 8 , R 10 and R 12 are each independently selected from hydrogen or hydrazine.
  • the invention relates to an amide compound of formula (I), or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variation, hydrate or solvent compound thereof, Wherein R 2 , R 9 and R 11 are hydrogen, R 1 is hydrazine, and R 3 to R 8 , R 10 and R 12 are each independently selected from hydrogen or hydrazine.
  • R 3 and R 4 are the same.
  • R 3 and R 4 are deuterium.
  • R 3 is deuterium
  • R 5 - R 8 are the same.
  • R 10 is deuterium.
  • the amide compound is any of the following structures, or a pharmaceutically acceptable salt thereof, but is not limited to the following structures:
  • formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention.
  • the invention is not limited to the following pharmaceutical compositions.
  • Exemplary Formulation 1 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 0.3-30 mg tablets (each tablet contains 0.1-10 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 2 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 30-90 mg tablet (each tablet contains 10-30 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 3 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 4-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 150-240 mg tablet (each tablet contains 50-80 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 5 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 240-270 mg tablets (each tablet contains 80-90 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 6-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into a 270-450 mg tablet (each tablet contains 90-150 mg of active compound) in a tablet press.
  • Exemplary Formulation 7-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 450-900 mg tablets (each tablet contains 150-300 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 8-Capsule The compound of the present invention in dry powder form can be mixed with a starch diluent in a weight ratio of about 1:1. The mixture was filled into 250 mg capsules (each capsule containing 125 mg of active compound).
  • Exemplary Formulation 9-Liquid The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended, passed through a No. 10 mesh U.S. sieve, and then It was mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then, sufficient water can be added to give a total volume of 5 mL.
  • Exemplary Formulation 10 - Injection The compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.
  • the pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration. , intracerebroventricular 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. .
  • the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.
  • long-term administration can also be administered chronically.
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject.
  • chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.
  • a pharmaceutical composition of the present invention can be further delivered using various methods of administration.
  • a pharmaceutical composition can be administered by bolus injection, for example, in order to rapidly increase the concentration of the compound in the blood to an effective level.
  • the bolus dose will depend on the target systemic level of the active ingredient, for example, an intramuscular or subcutaneous bolus dose will allow the active component to be slowly released, while a bolus delivered directly to the vein (eg, via IV IV drip) can be more Delivered rapidly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level.
  • the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.
  • Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration.
  • a carrier or excipient and a processing aid is provided in unit dosage form for ease of precise dosing.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as 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 a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, water Methyl salicylate or orange flavoring.
  • a binder for example, microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn star
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active component When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base.
  • the active ingredient can 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 ingredients for enhancing 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 accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials, as well as processing techniques, are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8, which is incorporated herein by reference.
  • the compounds of the invention may also be administered in sustained release form or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention further relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation comprises hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 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 compounds obtained in the above examples were subjected to biological evaluation to determine their biological activities.
  • anti-proliferative activity in some of these compounds was screened in human A431 skin cancer cells and human NCI-H1975 and HCC827 lung cancer cell lines, and the activity was demonstrated to be in the range of ⁇ 20 nM.
  • the cytotoxic or growth inhibitory effects of the compounds on the tumor cells of interest were evaluated.
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. The solution was diluted in DMSO to a final concentration of 100 times the dilution. Dilute to 10 times the final concentration of the dilution solution with the buffer.
  • EGFR and EGFR [T790M/L858R] kinase assay After buffer preparation, the enzyme was mixed with different concentrations of pre-diluted compounds for 10 minutes, each double well. The corresponding substrate and ATP were added and reacted at room temperature for 20 minutes (in which a negative positive control was set). After the reaction is completed, the detection reagent is added, and after incubation at room temperature for 30 minutes, the machine is detected and data is collected. Data analysis and mapping according to Graphpad 5.0 software.
  • EGFR [d746-750] Kinase Assay: After the buffer was prepared, the mixed solution of the enzyme and the antibody was mixed with the different concentrations of the compound prepared by pre-dilution for 10 minutes, and the concentration was doubled. Kinase tracer 199 was added and incubated for 60 minutes at room temperature (where a negative positive control was set). After the reaction is completed, the machine is tested, data is collected, and analysis and mapping are performed.
  • the anti-proliferative activity of the compound of the present invention against two tumor cells cultured in vitro was examined 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 inhibition of proliferation of lung cancer cells in vitro is stronger than that of skin cancer cells in vitro.
  • Cell lines skin cancer A431 (purchased from the American Standard Collection of Biological Products (ATCC)); lung cancer cells NCI-H1975 (purchased from the American Standard Collection of Biological Products (ATCC)) and HCC827 (purchased from the US Standard Collection of Biological Products) (ATCC)); both were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin.
  • ATCC American Standard Collection of Biological Products
  • ATCC827 purchased from the US Standard Collection of Biological Products
  • Reagents and consumables RPMI-1640 (GIBCO, catalog number A10491-01); fetal bovine serum (GIBCO, catalog number 10099141); 0.25% trypsin-EDTA (GIBCO, catalog number 25200); penicillin-streptomycin; GIBCO, Cat. No. 15140-122); DMSO (Sigma, Cat. No. D2650); MTS Test Kit (Promega, Cat. No. G3581), 96-well plate (Corning, Cat. No. 3365).
  • test compound preparation The test compound was dissolved in DMSO to prepare a 20 mM mother liquor and stored at -20 °C. Dilute 3 times with a gradient of DMSO and the like, and dilute 10 times. The drug medium was diluted 4 times with the drug.
  • MTS cell viability assay 0.25% trypsin-EDTA digested logarithmic growth phase cells, inoculated with 150 ⁇ l in 96-well plates at an optimized density, and added to the medium 4 times after dilution for 4 hours, 50 ⁇ l/well (generally 10 Concentrations: 100, 33.3, 11.1, 3.70, 1.23, 0.412, 0.137, 0.0457, 0.0152, 0.00508 ⁇ M). A well of the same volume of 0.5% DMSO was added as a control. After the cells were cultured for 72 hours, MTS was assayed for cell viability.
  • the compounds of Examples 1-8 were subjected to EGFR kinase inhibition and cytotoxicity experiments according to the above methods, and the results showed that the compounds of the present invention exhibited potent and excellent inhibitory activities against EGFR mutants and no expression of EGFR (WT) expressed in normal cells.
  • the inhibitory activity, so the compound of the present invention is an effective safe drug for patients with non-small cell lung cancer.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; mouse liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM , Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (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. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of each reaction solution was taken at 10, 30, and 90 min, respectively, and added to a stop plate, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of human and rat liver microsomes was evaluated by simultaneously testing the compounds of the present invention and their compounds without deuteration.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 1.
  • the undeuterated compound EAI045 was used as a control in Table 1.
  • the compound of the present invention can significantly improve metabolic stability by comparison with EAI045.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 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 briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

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Abstract

L'invention concerne un composé amide de formule (I), un polymorphe, un sel pharmaceutiquement acceptable, un promédicament, un stéréoisomère, un variant isotope, un hydrate ou un solvate de celui-ci, une composition pharmaceutique le contenant, et une utilisation pharmaceutique de celui-ci. Le composé et la composition pharmaceutique, selon l'invention possèdent une excellente activité inhibitrice de protéine kinase et présentent de bonnes propriétés pharmacocinétiques, peuvent augmenter les concentrations médicamenteuses du composé chez des animaux, et peuvent améliorer l'efficacité et la sécurité du médicament.
PCT/CN2018/091829 2017-06-26 2018-06-19 Composé amide, composition le contenant, et utilisation associée WO2019001307A1 (fr)

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WO2007143434A2 (fr) * 2006-05-31 2007-12-13 Takeda San Diego, Inc. Activateurs de glucokinase
WO2009080694A1 (fr) * 2007-12-20 2009-07-02 Novartis Ag Dérivés de thiazole utilisés comme inhibiteur de la pi 3 kinase
WO2017004383A1 (fr) * 2015-06-30 2017-01-05 Dana-Farber Cancer Institute, Inc. Inhibiteurs d'egfr et méthodes d'utilisation de ceux-ci

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WO2007143434A2 (fr) * 2006-05-31 2007-12-13 Takeda San Diego, Inc. Activateurs de glucokinase
WO2009080694A1 (fr) * 2007-12-20 2009-07-02 Novartis Ag Dérivés de thiazole utilisés comme inhibiteur de la pi 3 kinase
WO2017004383A1 (fr) * 2015-06-30 2017-01-05 Dana-Farber Cancer Institute, Inc. Inhibiteurs d'egfr et méthodes d'utilisation de ceux-ci

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JIANG, WENFENG ET AL.: "Application of Deuteration in Drug Research", QILU PHARMACEUTICAL AFFAIRS, vol. 29, no. 11, 31 December 2010 (2010-12-31), pages 682 - 684, XP008173943, ISSN: 1672-7738 *

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