WO2019010619A1 - Dérivé pyrimidine de 2-(aniline 2,4,5-substituée) - Google Patents

Dérivé pyrimidine de 2-(aniline 2,4,5-substituée) Download PDF

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Publication number
WO2019010619A1
WO2019010619A1 PCT/CN2017/092415 CN2017092415W WO2019010619A1 WO 2019010619 A1 WO2019010619 A1 WO 2019010619A1 CN 2017092415 W CN2017092415 W CN 2017092415W WO 2019010619 A1 WO2019010619 A1 WO 2019010619A1
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methyl
compound
deuterium atoms
substituted
methoxy
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English (en)
Chinese (zh)
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焦玉奇
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

  • This application relates generally to the field of medicinal chemistry.
  • the present application relates to EGFR and/or EGFR mutant inhibitors.
  • EGFR Epidermal growth factor receptor
  • HER1 ErbB1, EGFR
  • HER2 ErbB2, neu
  • HER3 ErbB3
  • HER4 ErbB4
  • the HER family plays an important regulatory role in the process of cell physiology.
  • EGFR is a receptor for epidermal growth factor (EGF) cell proliferation and signaling, and its mutation or overexpression generally triggers tumors.
  • EGFR is a glycoprotein, a tyrosine kinase receptor, with a cell membrane that penetrates and has a molecular weight of 170 kDa.
  • EGFR is located on the surface of the cell membrane and is activated by binding to ligands, including EGF and TGF ⁇ (Transforming Growth Factor ⁇ ). Upon activation, EGFR is converted from a monomer to a dimer, although there is also evidence that a dimer is present prior to activation. EGFR may also be activated by polymerization with other members of the ErbB receptor family, such as ErbB2/HER2/neu.
  • the application relates to a compound of formula (I) and pharmaceutically acceptable salts thereof:
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • the present application relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • the method comprises:
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting epidermal growth factor receptor (Her):
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer and/or tumor:
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • the present application relates to a method of treating a tumor and/or cancer comprising administering to a subject in need of such a method a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • references throughout the specification to "an embodiment,” “an embodiment,” “in another embodiment,” or “in certain embodiments” are meant to include in at least one embodiment Relevant specific reference elements, structures or features.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • isotope refers to a different species of nuclei of the same element having the same number of protons and different numbers of neutrons.
  • the term "abundance” as used herein refers to the percentage of atoms of an isotope in the natural element to which it belongs.
  • isotopic natural abundance or “natural abundance” as used herein refers to the percentage of atoms in a natural element that are present in a natural element.
  • isotopic enrichment index refers to the ratio of the abundance of an isotope to the natural abundance of that isotope. For example, a helium atomic index with an isotopic enrichment index of 6000 Abundance is 90% of helium atoms.
  • hydrogen refers to hydrogen consisting of 1 H (99.985%) and 2 H (0.015%) having the natural abundance of isotopes.
  • ⁇ ("D” and “d" as used herein refers to an isotope of hydrogen (H) having a proton and a neutron in the nucleus of the nucleus with a natural abundance of 0.015%.
  • d xy refers to a substitution with x to y deuterium atoms.
  • methoxy-d 3 refers to CD 3 O-.
  • pharmaceutically acceptable salt includes both acid addition salts and base addition salts.
  • pharmaceutically acceptable acid addition salt refers to a salt that retains the biological effectiveness and properties of the free base, which is not biologically or otherwise undesirable, and which is associated with inorganic acids. Formation of organic or organic acids. Examples of exemplary inorganic acids that can be used in the present application include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Examples of exemplary organic acids that can be used in the present application include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4 -acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecyl sulfate, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, Glutamate, glutaric acid, 2-oxo-glutaric acid, glycer
  • pharmaceutically acceptable base addition salt refers to a salt that retains the biological effectiveness and properties of the free acid, which is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid.
  • exemplary inorganic base-derived salts that can be used in the present application include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, rhodium, copper, manganese, aluminum salts, and the like.
  • the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts.
  • An exemplary salt derived from an organic base that can be used in the present application Examples include, but are not limited to, the following salts: primary, secondary and tertiary amines, substituted amines including naturally substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, Triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine , procaine, baibamin, choline, betaine, phenylethylbenzylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, hydrazine, Piperazine, piperidine, N-ethylpiper
  • pharmaceutical composition refers to a formulation of a compound of the present application and a medium generally accepted in the art for delivering a biologically active compound to a mammal, such as a human.
  • the medium includes all pharmaceutically acceptable carriers for its use.
  • the pharmaceutical composition facilitates administration of the compound to the organism.
  • methods for administering compounds in the art including, but not limited to, oral administration, injectable administration, aerosol administration, parenteral administration, and topical administration.
  • a pharmaceutical composition can also be obtained by reacting a compound with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid or the like.
  • an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid or the like.
  • carrier as used herein is defined to mean a compound that facilitates the introduction of a compound into a cell or tissue.
  • DMSO dimethyl sulfoxide
  • carrier because it is easy to introduce certain organic compounds into cells or tissues of an organism.
  • tumor refers to a neogrowth formed by local tissue cell proliferation under the action of various tumorigenic factors. According to the cell characteristics of the new organism and the degree of harm to the body, the tumor is divided into two major categories: benign tumor and malignant tumor.
  • cancer refers to a generic term for malignant tumors.
  • terapéuticaally effective amount means that when administered to a mammal, preferably to a human, the compound of the present application is sufficient to effectively treat (as defined below) the amount of a tumor, and/or cancer of a mammal, preferably a human.
  • the amount of the compound of the present application which constitutes a “therapeutically effective amount” will vary depending on the compound, the state of the disease and its severity, and the age of the mammal to be treated, but those skilled in the art can, based on their own knowledge and the present disclosure, According to Conventional determination of the amount of the compound of the present application
  • treating encompasses a mammal having a related disease or condition, preferably a treatment-related disease or condition in a human, and includes:
  • disease and “disease state” may be used interchangeably or may be different, as a particular disease or condition may not have a known causative agent (and therefore cannot be explained by etiology). Therefore, it is not recognized as a disease, but is considered to be an undesired disease state or condition in which the clinician has identified more or less specific series of symptoms.
  • In vivo administration can be carried out in a single administration, continuous or intermittent administration (e.g., administration at appropriate intervals in divided doses) throughout the course of treatment.
  • Methods for determining the most effective mode of administration and dosage are well known to those skilled in the art and will vary with the formulation used for the treatment, the purpose of the treatment, the target cells being treated, and the individual being treated. Single or multiple administrations can be performed, and the dosage level and mode are selected by the attending physician.
  • the application relates to a compound of formula (I) and pharmaceutically acceptable salts thereof:
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • R 1 is selected from -CH 2 D, -CHD 2, or -CD 3 .
  • R 2 is selected from -CH 2 D, -CHD 2, or -CD 3 .
  • R 3 is selected from -CHD- or -CD 2 -.
  • R 4 is selected from -CHD- or -CD 2 -.
  • R 5 is selected from -CH 2 D, -CHD 2, or -CD 3 .
  • R 6 is selected from -CH 2 D, -CHD 2, or -CD 3 .
  • R 1 is —CD 3 .
  • R 2 is —CD 3 .
  • R 3 is —CD 2 —.
  • R 4 is -CD 2 -.
  • R 5 or R 6 is —CD 3 .
  • both R 5 and R 6 are -CD 3 .
  • R 1 is -CD 3
  • R 2 is -CH 3
  • R 3 is -CH 2 -
  • R 4 is -CH 2 -
  • R 5 is -CD 3
  • R 6 is -CH 3 .
  • R 1 is -CD 3
  • R 2 is -CH 3
  • R 3 is -CH 2 -
  • R 4 is -CH 2 -
  • R 5 is -CD 3
  • R 6 is -CD 3 .
  • R 1 is -CD 3
  • R 2 is -CD 3
  • R 3 is -CD 2 -
  • R 4 is -CD 2 -
  • R 5 is -CD 3
  • R 6 is -CD 3 .
  • R 1 is —CH 3
  • R 2 is —CH 3
  • R 3 is —CH 2 —
  • R 4 is —CH 2 —
  • R 5 is —CH 2 D
  • R 6 is — CH 3 .
  • R 1 is —CH 3
  • R 2 is —CH 3
  • R 3 is —CH 2 —
  • R 4 is —CH 2 —
  • R 5 is —CHD 2
  • R 6 is —CH. 3 .
  • R 1 is -CH 2 D
  • R 2 is -CH 3
  • R 3 is -CH 2 -
  • R 4 is -CH 2 -
  • R 5 is -CD 3
  • R 6 is - CH 3 .
  • R 1 is —CHD 2
  • R 2 is —CH 3
  • R 3 is —CH 2 —
  • R 4 is —CH 2 —
  • R 5 is —CD 3
  • R 6 is —CH. 3 .
  • R 1 is -CD 3
  • R 2 is -CH 3
  • R 3 is -CHD-
  • R 4 is -CH 2 -
  • R 5 is -CD 3
  • R 6 is -CH 3 .
  • R 1 is -CD 3
  • R 2 is -CH 3
  • R 3 is -CH 2 -
  • R 4 is -CHD-
  • R 5 is -CD 3
  • R 6 is -CH 3 .
  • the ruthenium atom as a substituent has an isotopic enrichment index of 200, that is, the abundance of the ruthenium atom as a substituent is 3%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 400, that is, the abundance of the ruthenium atom as a substituent is 6%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 666.67, that is, the abundance of the ruthenium atom as a substituent is 10%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 1000, that is, the abundance of the ruthenium atom as a substituent is 15%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 2000, that is, the abundance of the ruthenium atom as a substituent is 30%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 3333.33, that is, the abundance of the ruthenium atom as a substituent is 50%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 4000, that is, the abundance of the ruthenium atom as a substituent is 60%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 5000, that is, the abundance of the ruthenium atom as a substituent is 75%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 6000, that is, the abundance of the ruthenium atom as a substituent is 90%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 6333.33, that is, the abundance of the ruthenium atom as a substituent is 95%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 6466.67, that is, the abundance of the ruthenium atom as a substituent is 97%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 6533.33, that is, the abundance of the ruthenium atom as a substituent is 98%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 6566.67, that is, the abundance of the ruthenium atom as a substituent is 98.5%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 6,600, that is, the abundance of the ruthenium atom as a substituent is 99%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 6633.33, that is, the abundance of the ruthenium atom as a substituent is 99.5%.
  • the ruthenium atom as a substituent has an isotopic enrichment index of 6,660, that is, the abundance of the ruthenium atom as a substituent is 99.9%.
  • the aze atom of the substituent is at least 60%, while other isotopes have their natural abundance.
  • the aze atom of the substituent has a abundance of at least 75%, while other isotopes have their natural abundance.
  • the aze atom of the substituent is at least 90%, while other isotopes have their natural abundance.
  • the atom atom as a substituent has an abundance of at least 95%, while other isotopes have their natural abundance.
  • the aze atom of the substituent has a abundance of at least 97%, while other isotopes have their natural abundance.
  • the aze atom of the substituent is at least 98%, while other isotopes have their natural abundance.
  • the compound of formula (I), and pharmaceutically acceptable salts thereof The abundance of the ruthenium atom as a substituent is at least 98.5%, while other isotopes have their natural abundance.
  • the aze atom of the substituent is at least 99%, while other isotopes have their natural abundance.
  • the aze atom of the substituent has a abundance of at least 99.5%, while other isotopes have their natural abundance.
  • the compound of formula (I) is selected from the group consisting of
  • the compounds of the present application have improved pharmacodynamic properties.
  • the compounds of the present application have epidermal growth factor receptor inhibitory activity.
  • the compounds of the present application have improved pharmacokinetic properties.
  • the compounds of the present application have improved in vivo metabolic properties.
  • the compounds of the present application have improved in vivo tumor suppressor activity.
  • the compounds of the present application have improved safety.
  • the compounds of the present application have improved tolerance.
  • a compound of the present application refers specifically to the following compounds:
  • the present application relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • the method comprises:
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • the compound of formula (II) is reacted with acryloyl chloride in the presence of a strong base to provide a compound of formula (I).
  • Examples of exemplary strong bases that can be used in the present application include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, and sodium t-butoxide.
  • the compound of formula (II) is reacted with acryloyl chloride in the presence of a polar solvent to provide a compound of formula (I).
  • exemplary polar solvents that can be used in the present application include, but are not limited to, water, formamide, trifluoroacetic acid, dimethyl sulfoxide (DMSO), acetonitrile, N,N-dimethylformamide (DMF). , hexamethylphosphoramide, methanol, ethanol, acetic acid, isopropanol, pyridine, tetramethylethylenediamine, acetone, triethylamine, n-butanol, dioxane and tetrahydrofuran (THF).
  • DMSO dimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • hexamethylphosphoramide hexamethylphosphoramide
  • methanol ethanol
  • acetic acid isopropanol
  • pyridine tetramethylethylenediamine
  • acetone triethylamine
  • n-butanol dioxane and tetrahydr
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • exemplary "pharmaceutically acceptable carriers” include, but are not limited to, any adjuvants, carriers, excipients, glidants approved by the National Drug Administration for acceptable use in humans or livestock. , sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting epidermal growth factor receptor (Her):
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • the epidermal growth factor receptor (Her) is EGFR (Her1).
  • EGFR (Her1) is wild type.
  • EGFR (Her1) is a mutant.
  • EGFR (Her1) is a single mutant or a double mutant.
  • the compounds of Formula (I), and pharmaceutically acceptable salts thereof have inhibitory activity against L858R EGFR mutants, T790M EGFR mutants, and Exon19 deletion activating mutants.
  • the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer and/or tumor:
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • the compound of the formula (I) of the present application and a pharmaceutically acceptable salt thereof have inhibitory activity against L858R EGFR mutant, T790M EGFR mutant and Exon19 deletion activating mutant, which can be used for mediated by EGFR mutant activity
  • the treatment of a disease or disease state such as cancer.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof of the present application are used to treat mediated by L858R EGFR mutants and/or T790M EGFR mutants and/or Exon19 deletion activating mutants The treatment of a disease or disease state such as cancer.
  • the cancer is selected from the group consisting of ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodge Gold lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia ( AML), multiple myeloma, melanoma, and mesothelioma.
  • AML acute myeloid leukemia
  • the lung cancer is selected from the group consisting of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the present application relates to a method of treating a tumor and/or cancer comprising administering to a subject in need of such a method a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
  • R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms
  • R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms
  • the condition is that at least one deuterium atom is contained in R 1 to R 6 .
  • the individual is a mammal.
  • the individual is a human.
  • the unit dosage of a compound of formula (I), or a pharmaceutically acceptable salt thereof is administered to an individual in need of treatment for a tumor and/or cancer, from 0.1 mg to 1000 mg.
  • the unit dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof, administered to an individual in need of treatment for a tumor and/or cancer is from 1 mg to 1000 mg.
  • N 1 ,N 1 ,N 2 -trimethyl-2,2-diindoleethane-1,2-diamine 80 mg, 0.79 mmol
  • N-(4-fluoro-2-methoxyl) -5-Nitrophenyl)-4-(1-H-indol-3-yl)pyrimidin-2-amine (Intermediate 11, 350 mg, 0.79 mmol) and DIPEA (0.342 mL, 1.97 mmol)
  • N 1 ,N 1 ,N 2 -trimethyl-1,1-dihaloethane-1,2-diamine 80 mg, 0.79 mmol
  • N-(4-fluoro-2-methoxyl) -5-Nitrophenyl)-4-(1-H-indol-3-yl)pyrimidin-2-amine (Intermediate 11, 350 mg, 0.79 mmol) and DIPEA (0.342 mL, 1.97 mmol)
  • p-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol) was added in one portion to 3-(2-chloropyrimidin-4-yl)-1-H-indole (intermediate 13, 24.27 g, 99.58 mmol). in 2-fluoro-2-pentanol (500 mL) of 5-nitroaniline (intermediate 15,18.54g, 99.58mmol) (methyloxy -d 3) in. The resulting mixture was stirred at 105 ° C for 2.5 hours. It was then cooled to room temperature.
  • N-(2- ⁇ 2-dimethylaminoethyl-methylamino ⁇ -4-(methoxy-d 3 )-5- ⁇ [4-(1-H- ⁇ -3-) obtained in the above step 2 0.5 g (1.0 eq) of pyrimido-2-yl]amino ⁇ phenyl)-2-enamide was added to a 500 mL three-necked flask, dissolved in 120 mL of ethanol and 80 mL of ethyl acetate, and 4.1 g of methanesulfonic acid was added dropwise at room temperature.
  • the titrated test compound was added to the assay plate the next day using the Echo Liquid Handler, and the treated cells were incubated for an additional 72 hours at 37 ° C, 5% CO 2 .
  • Each compound was assayed by an 11-point dose reaction with a maximum concentration of 10 ⁇ M and a 1:3 dilution.
  • the day 0 plate parallel to the dosing assay plate was treated with Sytox Green and saponin, and the number of viable cells in each well was determined.
  • 5 ⁇ L of 2 ⁇ M of Sytox green was added to each well, and the plate was incubated at room temperature for 1 hour. The number of fluorescent cells per well was determined using Acumen.
  • Table 1 show that the compounds of Examples 1-6 and the compound of Example 7 (control) proliferated against cell lines expressing wild type EGFR and cell lines expressing mutant EGFR (Ex19del, L858R and/or T790M EGFR). The inhibition is equivalent.
  • Example 7 control group
  • compound group of Examples 1-6 were respectively 4 subjects.
  • the other example compounds were tested after re-grouping after a 7-day wash period. After the subject was fasted for 10 hours, the test substance was orally administered after the standard meal was taken the next morning. The dose was 0.4 mg/kg (this dose is about 1/50 of the acute toxicity dose of the animal, so there is no Potential side effects).
  • subjects were required to collect blood samples at the set 9 time points (before administration, 30 minutes after administration, 1, 2, 3, 6, 12, 24, 48, 72 hours after administration). Used to determine the concentration of a drug in plasma.
  • Inter-assay precision is 3.0% to 6.8%, intra-assay accuracy is between 96.0% and 108.0%, and inter-assay accuracy is 97.6% to 105.0%.
  • the plasma concentration was calculated using Watson LIMS v.7.3.0.01 (Thermo Scientific Inc.) software, and the pharmacokinetic parameters were analyzed using the non-compartmental model of WinNonLin v5.2.1 (Pharsight Inc.) software (the main pharmacokinetics in this study) The parameters are the area under the curve of the drug, AUC0-t and the elimination half-life, t1/2).
  • nude mice (Balb/c nude mice, 6-8 weeks old, 20-22 g) were subcutaneously inoculated with human cell line H1975 (L858R/T790M). After the tumors were grown to 100-300 mm 3 , the animals were randomly divided. There were 5 groups, of which 8 were in each group and 12 in the solvent group, female. There were three dose groups of Compounds 1-6, 2.5, 5, 10 mg/kg/d, a compound of Example 7 at a dose of 5 mg/kg/d, and a solvent control group. The above groups were given a total of 21 days of continuous gavage. In the experiment, the tumor volume was measured 2-3 times per week, and the tumor weight was called. Tumor volume (TV), relative tumor volume (RTV), tumor growth inhibition rate (TGI), and tumor growth rate (T/C) are as follows:
  • T/C% RTV treatment group / RTV control group ⁇ 100%
  • Tumor growth inhibition rate 100% ⁇ (1-(TVDt (treatment group) - TVD0 (treatment group)) / (TVDt (control group) - TVD0 (control group)))

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Abstract

La présente invention concerne un composé tel que présenté dans la formule (I) ou son sel pharmaceutiquement acceptable, un procédé de préparation du composé tel que présenté dans la formule (I) ou son sel pharmaceutiquement acceptable, une composition pharmaceutique comprenant le composé tel que présenté dans la formule (I) ou son sel pharmaceutiquement acceptable, et une utilisation du composé tel que présenté dans la formule (I) ou son sel pharmaceutiquement acceptable, où R1 à R6 sont tels que définis dans la description.
PCT/CN2017/092415 2017-07-10 2017-07-10 Dérivé pyrimidine de 2-(aniline 2,4,5-substituée) Ceased WO2019010619A1 (fr)

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