WO2011068187A1 - Dérivés de la quinazoline - Google Patents

Dérivés de la quinazoline Download PDF

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Publication number
WO2011068187A1
WO2011068187A1 PCT/JP2010/071645 JP2010071645W WO2011068187A1 WO 2011068187 A1 WO2011068187 A1 WO 2011068187A1 JP 2010071645 W JP2010071645 W JP 2010071645W WO 2011068187 A1 WO2011068187 A1 WO 2011068187A1
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group
methyl
cancer
trifluoromethyl
phenyl
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PCT/JP2010/071645
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English (en)
Japanese (ja)
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邦雄 和田
勇人 岩垂
雅浩 太田
秀昭 渡邉
志保 岩崎
尚 朝日
充 伊藤
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第一三共株式会社
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Publication of WO2011068187A1 publication Critical patent/WO2011068187A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound having an action of inhibiting the kinase activity of BRAF, or a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing these as active ingredients.
  • Ras / RAF / MEK / ERK pathway plays an important role in cell proliferation, differentiation, survival, immortalization, metastasis, angiogenesis, apoptosis, etc. Increased ERK phosphorylation has been reported in some cancer cell lines and human clinical tumors (see Non-Patent Document 1). When cells are stimulated by growth factors such as EGF and PDGF, Ras is activated and RAF protein recruited to the cell membrane is phosphorylated.
  • the activated RAF is activated by phosphorylation of downstream MEK1 / 2 (MAP protein kinase 1/2), and activated MEK1 / 2 is further downstream of ERK1 / 2 (extracellular signal-regulated kinase 1). / 2) is phosphorylated and activated. Phosphorylated ERK moves into the nucleus and promotes transcription of Elk-1, c-Myc, CREB and the like, thereby suppressing apoptosis and cell proliferation.
  • MEK1 / 2 MAP protein kinase 1/2
  • RAF is a Ser / Thr kinase discovered as a retrovirus oncogene, and three types of ARAF, BRAF, and CRAF (also referred to as RAF-1) have been identified in mammals.
  • ARAF ARAF
  • BRAF BRAF
  • CRAF CRAF
  • mutations were observed in the BRAF gene in 60 to 70% of human malignant melanoma (see Non-Patent Document 2). Similar mutations are also observed in clinical cancers such as papillary thyroid cancer (35-70%), bile duct cancer (22%), colon cancer (about 10%), ovarian cancer (14%) ( Non-Patent Documents 3 and 4).
  • BRAF mutations have been reported in cancer cell lines such as glioma, lung cancer, sarcoma, breast cancer and liver cancer.
  • Non-Patent Document 2 V600E active mutations in which the amino acid residue valine at position 600 is replaced with glutamic acid.
  • this mutant BRAF is forcibly expressed in mouse fibroblast cell line NIH3T3, transformation is observed (non- Patent Document 2), when forcedly expressed in normal melanocytes, it has been reported that cells are transformed to show tumorigenicity in nude mice (see Non-Patent Document 5).
  • Non-Patent Document 6 There is also a report that cell growth is suppressed when the expression level of mutant BRAF is reduced by RNA interference treatment for BRAF mutant malignant melanoma strains.
  • BRAF inhibitory action a compound having an action of inhibiting the kinase activity of BRAF (hereinafter referred to as BRAF inhibitory action) is expected to be an effective therapeutic agent for an antitumor agent, particularly a tumor having a BRAF mutation.
  • compound (I) As a result of intensive studies on a compound having BRAF inhibitory activity, the present inventors have found that the compound of the present invention represented by formula (I) (hereinafter sometimes referred to as “compound (I)”) is in. Shows strong BRAF inhibitory action and cell growth inhibitory effect in vitro, and also has excellent oral administration properties, pharmacokinetics, and metabolic stability in vivo, and shows excellent BRAF inhibitory action, antitumor effect, and safety As a result, the present invention has been completed.
  • an object of the present invention is to provide a compound having a BRAF inhibitory action, or a pharmacologically acceptable salt thereof.
  • Another object of the present invention is to provide a pharmaceutical, a pharmaceutical composition, an antitumor agent, particularly a BRAF mutant tumor pharmaceutical composition comprising the above compound or a pharmacologically acceptable salt thereof as an active ingredient. is there.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-4 alkyl group, or a halogeno C 1-4 alkyl group
  • R 3 represents a hydroxy group, a C 2-4 alkynyl group (the C 2-4 alkynyl group may have one hydroxy group or an acetoxy group as a substituent), —NR 5a R 5b , an azetidinyl group ( The azetidinyl group may have one C 1-4 alkyl group as a substituent), an oxazolidinyl group (the oxazolidinyl group may have one oxo group as a substituent), a pyrrolidinyl group (the pyrrolidinyl group)
  • the group may have one C 1-4 alkyl group as a substituent), a dioxanyl group, or a pyrazolyl group;
  • R 5a and R 5b
  • R 3 is a hydroxy group, ethynyl group, propynyl group, hydroxypropynyl group, acetoxypropynyl group, amino group, methylamino group, ethylamino group, isopropylamino group, dimethylamino group, (2-hydroxyethyl) ( (Methyl) amino group, azetidinyl group, methylazetidinyl group, ethylazetidinyl group, pyrrolidinyl group, methylpyrrolidinyl group, oxazolidinyl group, oxooxazolidinyl group, dioxany
  • the present invention provides the compound described in any one of (1) to (16) above, or a pharmacologically acceptable salt thereof, and any of the above (17) to (20) A method for treating a tumor, preferably a method for preventing or treating a BRAF mutant tumor, comprising administering the pharmaceutical composition described in any one of the above to a warm-blooded animal (preferably a human).
  • BRAF inhibitory action refers to an action that inhibits the kinase activity of BRAF
  • BRAF inhibitor refers to a compound having the BRAF inhibitory action, but the compound of the present invention is not limited to other compounds. It may have a kinase inhibitory action and preferably has an action of inhibiting the kinase activity of a protein involved in angiogenesis in order to obtain a more excellent antitumor effect.
  • C 1-4 alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms, and includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group. , Sec-butyl group, tert-butyl group and the like.
  • the “C 2-4 alkynyl group” is a monovalent group obtained by removing one hydrogen atom from any carbon atom of a linear or branched alkyne having 2 to 6 carbon atoms, such as an ethynyl group, 1- Examples include propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group and the like.
  • Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • halogeno C 1-4 alkyl group is a group in which 1 to 3 identical or different halogen atoms are substituted on the C 1-4 alkyl group, and includes a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group.
  • Chloromethyl group dichloromethyl group, trichloromethyl group, 2-fluoroethyl group, 1,2-difluoroethyl group, 2-trifluoroethyl group, 2-chloroethyl group, 1,2-dichloroethyl group, 1,1 , 2-trichloroethyl group, 1,2,2-trichloroethyl group, 2,2,2-trichloroethyl group and the like.
  • the “hydroxy C 1-4 alkyl group” is a group obtained by substituting one or two hydroxy groups for the C 1-4 alkyl group, and includes a hydroxymethyl group, a dihydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxy group, Examples thereof include a hydroxyethyl group and a 1,2-dihydroxyethyl group.
  • the “C 1-4 alkoxy group” is a group composed of the “C 1-4 alkyl group” and an oxygen atom, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group.
  • R 1 and R 2 are the same or different and are a hydrogen atom, a halogen atom, a C 1-4 alkyl group, or a halogeno C 1-4 alkyl group.
  • R 1 is preferably a hydrogen atom, a chlorine atom, a methyl group or a trifluoromethyl group, more preferably a hydrogen atom, a chlorine atom or a trifluoromethyl group, particularly preferably a trifluoromethyl group.
  • R 2 is preferably a hydrogen atom, a chlorine atom, or a methyl group, and more preferably a hydrogen atom or a chlorine atom.
  • R 1 and R 2 are that when R 1 is a hydrogen atom, a chlorine atom, or a trifluoromethyl group, R 2 is a hydrogen atom, a chlorine atom, or a methyl group. In a more preferred combination of R 1 and R 2 , R 2 is a hydrogen atom or a chlorine atom when R 1 is a trifluoromethyl group.
  • R 3 represents a hydroxy group, a C 2-4 alkynyl group (the C 2-4 alkynyl group may have one hydroxy group or an acetoxy group as a substituent), —NR 5a R 5b , an azetidinyl group ( The azetidinyl group may have one C 1-4 alkyl group as a substituent), an oxazolidinyl group (the oxazolidinyl group may have one oxo group as a substituent), a pyrrolidinyl group (the pyrrolidinyl group) The group may have one C 1-4 alkyl group as a substituent), a dioxanyl group, or a pyrazolyl group.
  • R 5a R 5b in the definition of R 3 indicates that R 5a and R 5b are substituted on the amino group.
  • R 5a and R 5b are the same or different and are a hydrogen atom, a C 1-4 alkyl group, or a hydroxy C 1-4 alkyl group, preferably the same or different, a hydrogen atom, a methyl group, an ethyl group, Or it is a hydroxyethyl group.
  • —NR 5a R 5b is preferably an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group, or a (2-hydroxyethyl) (methyl) amino group.
  • R 3 is preferably a hydroxy group, an ethynyl group, a propynyl group, a hydroxypropynyl group, an acetoxypropynyl group, an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group, (2-hydroxyethyl) ( Methyl) amino group, azetidinyl group, methylazetidinyl group, ethylazetidinyl group, pyrrolidinyl group, methylpyrrolidinyl group, oxazolidinyl group, oxooxazolidinyl group, dioxanyl group, or pyrazolyl group, more preferably Is a dimethylamino group, an azetidinyl group, a methylazetidinyl group, an ethylazetidinyl group
  • N is 1 or 2.
  • the substituent represented by the formula — (CH 2 ) n —R 3 is preferably 2-hydroxyethyl group, 2- (methylamino) ethyl group, prop-2-yn-1-yl group, 4-hydroxy But-2-yn-1-yl group, 4-acetoxybut-2-yn-1-yl group, 2- (ethylamino) ethyl group, 2- (isopropylamino) ethyl group, 2- (dimethylamino) ethyl 2- (2-hydroxyethyl) (methyl) aminoethyl group, (1-methylazetidin-2-yl) methyl group, (1-ethylazetidin-2-yl) methyl group, 2- (pyrrolidine- 1-yl) ethyl group, pyrrolidin-2-ylmethyl group, (1-methylpyrrolidin-2-yl) methyl group, 1,4-dioxane-2-ylmethyl group, 2- (2-oxo-1
  • R 4 is a hydrogen atom or a C 1-4 alkyl group, preferably a hydrogen atom, a methyl group, or an ethyl group, and more preferably a methyl group.
  • Y is C—R 6 or a nitrogen atom.
  • R 6 is a hydrogen atom or a halogen atom, preferably a hydrogen atom or a fluorine atom, and more preferably a hydrogen atom.
  • Y is preferably C—H, C—F or a nitrogen atom, and more preferably C—H or a nitrogen atom.
  • R 1 is a hydrogen atom, a chlorine atom, or trifluoromethyl group
  • R 2 is a hydrogen atom, a chlorine atom, or a methyl group
  • — (CH 2 ) n —R 3 is a 2- (methylamino) ethyl group, 2- (ethylamino) ethyl group, 2- (isopropylamino) ethyl group, 2- (dimethylamino) ethyl group, 2- ( 2-hydroxyethyl) (methyl) aminoethyl group, (1-methylazetidin-2-yl) methyl group, (1-ethylazetidin-2-yl) methyl group, 2- (pyrrolidin-1-yl) ethyl Group, pyrrolidin-2-ylmethyl group, (1-methylpyrrolidin-1-yl) ethyl Group, pyrrolidin-2-ylmethyl group, (1-methylpyrrolidin-1-yl)
  • R 1 is a hydrogen atom, a chlorine atom, or trifluoromethyl group
  • R 2 is a hydrogen atom, a chlorine atom, or a methyl group
  • — (CH 2 ) n —R 3 is a 2- (methylamino) ethyl group, 2- (ethylamino) ethyl group, 2- (isopropylamino) ethyl group, 2- (dimethylamino) ethyl group, 2- ( 2-hydroxyethyl) (methyl) aminoethyl group, (1-methylazetidin-2-yl) methyl group, (1-ethylazetidin-2-yl) methyl group, 2- (pyrrolidin-1-yl) ethyl Group, pyrrolidin-2-ylmethyl group, (1-methylpyrrolidin-1-yl) ethyl Group, pyrrolidin-2-ylmethyl group, (1-methylpyrrolidin-1-yl)
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom or a chlorine atom
  • — (CH 2 ) n —R 3 is a 2- (dimethylamino) ethyl group, 1-methylazetidin-2-yl) methyl group, (1-ethylazetidin-2-yl) methyl group, 2- ( Pyrrolidin-1-yl) ethyl group, pyrrolidin-2-ylmethyl group, or (1-methylpyrrolidin-2-yl) methyl group
  • R 4 is a methyl group
  • Y is a nitrogen atom.
  • R 1 is a trifluoromethyl group
  • R 2 is a hydrogen atom or a chlorine atom
  • — (CH 2 ) n —R 3 is a 2- (dimethylamino) ethyl group, 1-methylazetidin-2-yl) methyl group, (1-ethylazetidin-2-yl) methyl group, 2- ( Pyrrolidin-1-yl) ethyl group, pyrrolidin-2-ylmethyl group, or (1-methylpyrrolidin-2-yl) methyl group
  • R 4 is a methyl group
  • Y is C—H.
  • the compound (I) is preferably a compound described in any of the examples or a pharmacologically acceptable salt thereof, particularly preferably 1- ⁇ 2- [2- (dimethylamino) ethoxy] -5. -(Trifluoromethyl) pyridin-3-yl ⁇ -3- ⁇ 3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl ⁇ urea, 1- ⁇ 3- [(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl ⁇ -3- [2- ⁇ [(2S) -1-methylpyrrolidin-2-yl] methoxy ⁇ -5 -(Trifluoromethyl) phenyl] urea, 1- (4-chloro-2- ⁇ [(2S) -1-methylpyrrolidin-2-yl] methoxy ⁇ phenyl) -3- ⁇ 3
  • the “pharmacologically acceptable salt” means that a compound having a nitrogen atom or a basic substituent in the compound (I) is converted into a salt according to a usual method, if desired. It refers to such a salt.
  • salts include salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, fumarate, maleate, oxalate, malonic acid Salts of carboxylic acids such as succinate, citrate, malate; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate; glutamate, asparagine Examples include salts of amino acids such as acid salts.
  • inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, fumarate, maleate, oxalate, malonic acid Salts of carboxylic acids such as succinate, citrate, malate; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, tol
  • Compound (I) or a pharmacologically acceptable salt thereof may absorb moisture, adsorb water, or become a hydrate when left in the air or by recrystallization. Such hydrates are also encompassed by the present invention.
  • Compound (I) or a pharmacologically acceptable salt thereof may become a solvate by being left in a solvent or recrystallized, and such a solvate is also included in the present invention. Is included.
  • Compound (I), a salt thereof or a solvate thereof may be a geometric isomer such as cis isomer or trans isomer, tautomer or optical isomer such as d isomer, l isomer, etc., depending on the type or combination of substituents.
  • the compounds of the present invention include all isomers, stereoisomers, and any ratios of these isomers and stereoisomer mixtures, unless otherwise specified. It is.
  • the present invention also relates to a compound that is converted into compound (I), which is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, Also included in the present invention is a compound that undergoes hydrolysis or the like and is converted to compound (I), or a “pharmaceutically acceptable prodrug compound” that undergoes hydrolysis or the like by gastric acid or the like and is changed to compound (I). .
  • the prodrug when an amino group is present in the compound (I), a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated, alanylated, pentylamino Carbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.
  • the amino group is eicosanoylated, alanylated, pentylamino Carbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.
  • the compound (I) has a hydroxyl group
  • a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated for example, the hydroxyl group is acetylated, palmitoyl.
  • the prodrug of the compound of the present invention can be produced from compound (I) by a known method.
  • the prodrug of the compound of the present invention is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. Is also included.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound having the formula (I) of the present invention or a pharmacologically acceptable salt thereof substitutes the substituent represented by the formula — (CH 2 ) n —R 3 on the urea-bonded terminal aromatic ring, Furthermore, by making the substitution position the ortho position of the urea group, it exhibits a strong BRAF inhibitory action and cell growth inhibitory effect in vitro, and also has good oral administration properties, pharmacokinetics, and metabolic stability in vivo. And showed excellent BRAF inhibitory action, antitumor effect, and safety.
  • the pharmaceutical composition containing the compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is leukemia, lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, large intestine.
  • tumors in which such BRAF mutation is observed include malignant melanoma, colon cancer, ovarian cancer, thyroid cancer, bile duct cancer, glioma, lung cancer, sarcoma, breast cancer, liver cancer and the like.
  • the compound having the general formula (I) of the present invention can be easily produced according to the method described below.
  • examples of aliphatic hydrocarbons include hexane, heptane, ligroin, petroleum ether and the like
  • examples of ethers include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like.
  • examples of aromatic hydrocarbons include toluene, benzene, xylene, and the like.
  • Examples of halogenated hydrocarbons include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, etc., and ketones.
  • sulfoxides include dimethyl sulfoxide and the like.
  • sulfones include sulfolane and the alcohols.
  • examples of the alkali metal carbonates include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like
  • examples of the alkali metal bicarbonates include lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like.
  • examples of the alkali metal hydrides include lithium hydride, sodium hydride, and potassium hydride.
  • examples of the metal alkoxides include lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like.
  • examples of the organic metal bases include butyl lithium, lithium diisopropylamide (LDA), and lithium bis (trimethylsilyl) amide.
  • organic amines examples include triethylamine, tributylamine, and diisopropyl ether.
  • Ruamine N-methylmorpholine, pyridine, 2,6-lutidine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3 .0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), and the like.
  • the combination of the said base can also be used as a base.
  • Method A is a method for producing compounds (Ia), (Ib), (Id) and (If).
  • R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , Y and n are as defined above, X is a halogen atom, m is 2 or 3 R 7 represents a hydrogen atom or a C 1-3 alkyl group.
  • Step A1 is a step for producing compound (3), and is carried out by reacting 3-aminophenol (1) with organic halide (2) in the presence of a base in a solvent. .
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • the base used in the reaction is not particularly limited.
  • alkali metal carbonates alkali metal bicarbonates, alkali metal hydrides, metal alkoxides, organic amines, organometallic bases, or the above bases.
  • the alkali metal carbonates are preferable, and potassium carbonate is particularly preferable.
  • the reaction temperature varies depending on the types of raw material compounds, reagents, solvents and the like, but is usually 0 ° C. to 200 ° C., but is preferably 50 ° C. to 150 ° C.
  • the reaction time varies depending on the reaction temperature, the raw material compound, the reagent, and the solvent, but is usually 1 hour to 72 hours, preferably 3 hours to 24 hours.
  • Step A2 is a step for producing compound (4), and is carried out by catalytic reduction of the nitro group of compound (3) in a solvent.
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • aliphatic hydrocarbons, aromatic hydrocarbons, esters, ethers, alcohols, acetic acid Organic acids such as, hydrochloric acid, water, or a mixed solvent of the above solvent and water, preferably alcohols, and more preferably methanol.
  • the catalyst used for the catalytic reduction is not particularly limited as long as it is usually used for the reaction for reducing the nitro group, but preferably palladium-calcium carbonate, palladium-aluminum oxide, palladium-carbon.
  • Palladium such as palladium-barium sulfate or rhodium such as rhodium-aluminum oxide, more preferably palladium-carbon.
  • the hydrogen pressure is not particularly limited, but is usually 1 to 10 atm, preferably 1 atm. *
  • the reaction temperature varies depending on the type of catalyst and solvent, but is usually ⁇ 20 ° C. to 100 ° C., preferably 20 ° C. *
  • the reaction time varies depending on the reaction temperature, the catalyst, the type of the solvent, etc., but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • Step A3 is a step for producing compound (5), and is carried out by hydrolyzing the ester of compound (4) in the presence of a base in a solvent.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • ethers, alcohols, amides, water, a mixed solvent of the above solvents, or the above solvent and water A mixed solvent of alcohols and water is preferable, and a mixed solvent of methanol and water is most preferable.
  • the base used in the above reaction is not particularly limited as long as it is a base usually used for hydrolysis.
  • the reaction temperature varies depending on the type of solvent, base, etc., but is usually ⁇ 78 ° C. to 150 ° C., preferably ⁇ 50 ° C. to 100 ° C., and most preferably 20 ° C.
  • the reaction time varies depending on the reaction temperature, solvent, base type and the like, but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • Step A4a is a step for producing compound (6), and is performed by reacting compound (5) with formamide in the presence or absence of a solvent.
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • the reaction temperature varies depending on the solvent and the like, but is usually 20 ° C. to 200 ° C., and preferably 100 ° C. to 150 ° C. While the reaction time varies depending on the reaction temperature, solvent, etc., it is generally 1 hour to 72 hours, preferably 3 hours to 24 hours.
  • Step A4b is a step for producing compound (10), and is carried out by reacting compound (5) with an amine having general formula (9) and orthoformate in the presence of an acid in a solvent. It is.
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • the acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction.
  • inorganic acids such as hydrochloric acid and sulfuric acid; acetic acid and p-toluenesulfonic acid are used.
  • Organic acids can be mentioned, organic acids are preferred, and p-toluenesulfonic acid is most preferred.
  • reaction temperature varies depending on the type of solvent, acid, etc., it is usually 0 ° C. to 150 ° C., preferably 50 ° C. to 100 ° C.
  • reaction time varies depending on the reaction temperature, solvent, acid type, etc., it is generally 1 hour to 72 hours, preferably 3 hours to 24 hours.
  • Step A5 is a step for producing compound (7), and is performed by removing the formyl group of compound (6) in the presence of an acid in a solvent.
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • ethers, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles, amides, lower Examples include alkyl alcohols or mixed solvents of the above solvents, preferably mixed solvents of halogenated hydrocarbons and lower alkyl alcohols, and most preferably mixed solvents of methylene chloride and methanol. . *
  • the acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction.
  • inorganic acids such as hydrochloric acid and sulfuric acid; acetic acid and p-toluenesulfonic acid are used.
  • Organic acids can be mentioned, preferred are inorganic acids, and most preferred is hydrochloric acid.
  • the reaction temperature varies depending on the type of solvent, acid, etc., but is usually ⁇ 78 ° C. to 150 ° C., preferably ⁇ 50 ° C. to 100 ° C., and most preferably 20 ° C.
  • the reaction time varies depending on the solvent, acid, reaction temperature, etc., but is usually 30 minutes to 24 hours, preferably 1 hour to 12 hours.
  • Step A6 is a step of producing a compound having the general formulas (Ia) to (Ib).
  • the compound (7) to the compound (10) is reacted with an amine having the general formula (8) (isocyanate method, Carbamate method).
  • an amine having the general formula (8) is reacted with phosgene to produce an isocyanate, and the isocyanate and the compounds (7) to (10) are mixed in a solvent in the presence or absence of a base.
  • the reaction is carried out under (preferably in the presence).
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • Amides, esters, or a mixed solvent of the above solvents preferably a mixed solvent of ethers and amides, particularly preferably a mixture of tetrahydrofuran and N, N-dimethylformamide. It is a solvent.
  • the base used in the above reaction is not particularly limited, and examples thereof include alkali metal carbonates, alkali metal bicarbonates, and organic amines, preferably organic amines, particularly preferable.
  • alkali metal carbonates alkali metal bicarbonates
  • organic amines preferably organic amines, particularly preferable.
  • pyridine and triethylamine are pyridine and triethylamine.
  • the phosgene used in the above reaction is, for example, phosgene, diphosgene or triphosgene, and preferably triphosgene.
  • the reaction temperature varies depending on the raw material compound, reagent, type of solvent, etc., but is usually ⁇ 78 ° C. to 120 ° C., and preferably ⁇ 20 ° C. to 60 ° C. *
  • the reaction time varies depending on the reaction temperature, the raw material compound, the reagent, the type of the solvent, and the like, but is usually 1 hour to 48 hours, preferably 2 hours to 24 hours.
  • compound (7) to compound (10) are reacted with halogenated formate to produce carbamate, and the carbamate and amine having the general formula (8) are present in a solvent in the presence of a base.
  • the reaction is carried out under or in the absence (preferably in the presence).
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, Lower alkyl nitriles, amides, sulfoxides and sulfolanes can be mentioned, and lower alkyl nitriles are preferred, and acetonitrile is particularly preferred.
  • the base used in the above reaction is, for example, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal alkoxides, organic amines, preferably organic amines, Particularly preferred are pyridine and triethylamine.
  • the halogenated formate used in the above reaction is, for example, ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate, p-nitrophenyl chloroformate, and preferably phenyl chloroformate. . *
  • the reaction temperature varies depending on the raw material compound, reagent, type of solvent, etc., but is usually 0 ° C. to 120 ° C., preferably 60 ° C. *
  • the reaction time varies depending on the reaction temperature, the raw material compound, the reagent, the type of the solvent, and the like, but is usually 1 hour to 48 hours, preferably 2 hours to 24 hours.
  • Step A7a is a step of producing a compound having the general formula (Id), and a compound having the general formula (Ic) and an aldehyde having the general formula (11) in a solvent in the presence or absence of an acid
  • the imine produced by the condensation of is reduced by a hydrogenating agent.
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • An alkyl alcohol or a mixed solvent of the above-mentioned solvents can be mentioned, and preferred are lower alkyl nitriles, and most preferred is acetonitrile.
  • the acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction.
  • inorganic acids such as hydrochloric acid and sulfuric acid; acetic acid and p-toluenesulfonic acid are used.
  • Organic acids can be mentioned, preferred are inorganic acids, and most preferred is hydrochloric acid.
  • the hydrogenating agent used in the above reaction is, for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and preferably sodium triacetoxyborohydride.
  • the reaction temperature varies depending on the starting compound, reagent, solvent, acid type, etc., but is usually ⁇ 78 ° C. to 120 ° C., preferably 0 ° C. to 20 ° C.
  • the reaction time varies depending on the reaction temperature, raw material compound, reagent, solvent, type of acid, etc., but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • Step A7b is a step of producing a compound having the general formula (If), and reacting a compound having the general formula (Ie) with an alkyl halide having the general formula (12) in a solvent in the presence of a base. Is done.
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • aliphatic hydrocarbons, ethers, ketones, aromatic hydrocarbons, halogenated hydrocarbons examples thereof include lower alkyl nitriles, amides, and lower alkyl alcohols, preferably ketones, and most preferably acetone.
  • the base used in the reaction is not particularly limited.
  • alkali metal carbonates alkali metal bicarbonates, alkali metal hydrides, metal alkoxides, organic amines, organometallic bases, or the above bases.
  • the alkali metal carbonates are preferable, and potassium carbonate is particularly preferable.
  • the reaction temperature varies depending on the raw material compound, the reagent, the type of the solvent, etc., but is usually 0 ° C to 200 ° C, preferably 50 ° C to 100 ° C.
  • Method B is a method for producing compound (8) which is an intermediate of compound (I) of the present invention.
  • R 1 , R 2 , R 3 , Y and n have the same meaning as described above.
  • Step B1 is a step of producing a compound having the general formula (15), and reacting an organic halide having the general formula (13) and an alcohol having the general formula (14) in a solvent in the presence of a base. Is done.
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • ethers or amides are preferable, and tetrahydrofuran or N, N-dimethylformamide is most preferable.
  • the base used in the above reaction is not particularly limited, and examples thereof include alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, metal alkoxides, organic amines, and organometallic bases. Preferred are alkali metal hydrides or metal alkoxides, and particularly preferred is sodium hydride or potassium t-butoxide. *
  • reaction temperature varies depending on the kind of raw material compound, reagent, solvent and the like, it is usually carried out at ⁇ 78 ° C. to 150 ° C., preferably ⁇ 20 ° C. to 120 ° C., more preferably 20 ° C. Or it is 80 degreeC.
  • the reaction time varies depending on the reaction temperature, the raw material compound, the reagent, the type of the solvent, etc., but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • Step B2 is a step of producing a compound having the general formula (8).
  • catalytic reduction or metal reduction is performed by reducing the nitro group of the compound having the general formula (15) in a solvent. Is done.
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, esters, ethers examples include alcohols, organic acids such as acetic acid, hydrochloric acid, water, or a mixed solvent of the above solvent and water, preferably alcohols, and more preferably methanol or hydrous ethanol.
  • the catalyst used for the catalytic reduction is not particularly limited as long as it is usually used for the reaction for reducing the nitro group, but preferably palladium-calcium carbonate, palladium-aluminum oxide, palladium-carbon.
  • Palladium such as palladium-barium sulfate or rhodium such as rhodium-aluminum oxide, more preferably palladium-carbon.
  • the hydrogen pressure is not particularly limited, but is usually 1 to 10 atm, preferably 1 atm.
  • the metal used for the metal reduction is not particularly limited as long as it is usually used for the reaction for reducing the nitro group, but is preferably iron or zinc, more preferably iron. is there.
  • the reaction temperature varies depending on the raw material compound, catalyst or metal, type of solvent, etc., but is usually ⁇ 20 ° C. to 150 ° C., preferably 20 ° C. or 80 ° C. *
  • the reaction time varies depending on the reaction temperature, the raw material compound, the catalyst or metal, the type of the solvent, etc., but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • Step B3 is a step of producing a compound having the general formula (15b). In the presence of a base and a palladium catalyst in a solvent, an organic halide having the general formula (15a) and trimethylboroxine (16 ).
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • the base used in the above reaction is not particularly limited, and examples thereof include alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, metal alkoxides, organic amines, and organometallic bases. Preferred are alkali metal carbonates, and particularly preferred is potassium carbonate. *
  • the palladium catalyst used in the above reaction is not particularly limited as long as it is usually used in a cross-coupling reaction.
  • tris (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, Palladium acetate can be mentioned, and tetrakis (triphenylphosphine) palladium is preferable.
  • the reaction temperature varies depending on the raw material compound, reagent, type of solvent, etc., but is usually 0 ° C. to 200 ° C., preferably 20 ° C. to 150 ° C., more preferably 100 ° C. . *
  • reaction time varies depending on the reaction temperature, the raw material compound, the reagent, the type of the solvent, etc., but is usually 1 hour to 72 hours, preferably 3 hours to 24 hours.
  • Method C is a method for producing compound (13a).
  • Step C1 is a step of producing a compound having the general formula (13a), and reacting the compound (17) with a chlorinating agent in the presence or absence (preferably in the absence) of a solvent. Is done.
  • the solvent used in the above reaction is not particularly limited as long as it does not inhibit this reaction.
  • the chlorinating agent used in the above reaction is not particularly limited as long as it is usually used in a chlorination reaction.
  • phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, sulfuryl chloride, a small amount Thionyl chloride to which N, N-dimethylformamide is added, and thionyl chloride to which a small amount of N, N-dimethylformamide is added is preferable.
  • the reaction temperature varies depending on the raw material compound, the reaction reagent, the type of solvent used, and the like, but is usually 20 ° C. to 150 ° C., and preferably 80 ° C.
  • the reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent, and the type of solvent used, but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the target compound in each step is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained.
  • the organic layer is separated, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then the solvent is distilled off.
  • the obtained target compound is a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, a carrier such as silica gel, alumina, magnesium-silica gel type florisil.
  • the compound having the formula (I) of the present invention or a pharmacologically acceptable salt thereof, is used as the above therapeutic agent or prophylactic agent, it is itself or an appropriate pharmacologically acceptable excipient. It can be mixed with an agent, a diluent and the like, and can be administered orally, for example, by tablet, capsule, granule, powder or syrup, or parenterally by injection or suppository.
  • excipients eg, sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan: and silicate derivatives such as light anhydrous silicic acid, converted aluminum silicate, calcium silicate, magnesium metasilicate magnesium phosphate; phosphates such as calcium hydrogen phosphate; Carbonates such as calcium; inorganic excipients such as sulfates such as calcium sulfate; and lubricants (eg, stearic acid, calcium stearate, metal stearate such as magnesium stearate) Salt; Talc; Colloidal silica; Veagam Waxes such as gay wax; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; fume,
  • the compound of the present invention can be used for cancer treatment of mammals, particularly humans.
  • the dose and administration interval can be appropriately selected according to the judgment of the doctor according to the location of the disease, the height, weight, sex, or medical history of the patient.
  • the dosage range is from about 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably from about 0.1 mg / kg body weight to about 100 mg / kg body weight per day. It is.
  • it is preferably administered once a day, or divided into 2 to 4 times, and repeated at appropriate intervals.
  • the daily amount may exceed the above amount depending on the judgment of the doctor.
  • the compound of the present invention may be used in combination with other antitumor agents.
  • antitumor antibiotics for example, antitumor antibiotics, antitumor plant components, BRM (biological response control substances), hormones, vitamins, antitumor antibodies, molecular targeted drugs, other antitumor agents and the like can be mentioned.
  • BRM biological response control substances
  • hormones for example, vitamins, antitumor antibodies, molecular targeted drugs, other antitumor agents and the like can be mentioned.
  • an alkylating agent such as nitrogen mustard, nitrogen mustard N-sodium oxide or chlorambutyl, an aziridine alkylating agent such as carbocon or thiotepa, dibromomannitol or dibromodarsi
  • an alkylating agent such as nitrogen mustard, nitrogen mustard N-sodium oxide or chlorambutyl
  • an aziridine alkylating agent such as carbocon or thiotepa, dibromomannitol or dibromodarsi
  • epoxide-based alkylating agents such as Toll, carmustine, lomustine, semustine, nimustine hydrochloride
  • nitrosourea-based alkylating agents such as streptozocin, chlorozotocin or ranimustine, busulfan, improsulfan tosylate or dacarbazine.
  • antimetabolites include, for example, purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine, and pyrimidine metabolism antagonists such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine And antifolate inhibitors such as methotrexate or trimethrexate.
  • purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine
  • pyrimidine metabolism antagonists such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine
  • antifolate inhibitors such as methotrexate or trimethrexate.
  • Antitumor antibiotics include, for example, anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, pepromycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4′-epidoxorubicin or epirubicin, chromomycin A3 Or actinomycin D etc. are mentioned.
  • anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, pepromycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4′-epidoxorubicin or epirubicin, chromomycin A3 Or actinomycin D etc. are mentioned.
  • antineoplastic plant component examples include vinca alkaloids such as vindesine, vincristine and vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide and teniposide.
  • BRM examples include tumor necrosis factor or indomethacin.
  • hormones examples include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, phosfestol, ethinylestradiol, chlormadinone, or medroxyprogesterone.
  • vitamins examples include vitamin C and vitamin A.
  • Antitumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, sorafenib, etc.
  • antitumor agents include, for example, cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, pipobroman, neocartinostatin, Examples include hydroxyurea, ubenimex, and krestin.
  • the present invention also includes a method for preventing and / or treating cancer characterized by administering the compound of the present invention or a salt thereof.
  • the present invention includes the use of the compound of the present invention and a salt thereof for producing the medicine.
  • Example 1 [2- ⁇ [(2S) -1-methylazetidin-2-yl] methoxy ⁇ -5- (trifluoromethyl) phenyl] -3- ⁇ 3-[(3-methyl-4-oxo-3 , 4-Dihydroquinazolin-6-yl) oxy] phenyl ⁇ urea
  • Example 5 1- ⁇ 2-[(2S) -azetidin-2-ylmethoxy] -5- (trifluoromethyl) pyridin-3-yl ⁇ -3- ⁇ 3-[(3-methyl-4) obtained in Example 5
  • the title compound was obtained according to the method described in Example 24, starting from -oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl ⁇ urea dihydrochloride and acetaldehyde (yield 27 %).
  • N, N-dimethyl-2- ⁇ [3-nitro-5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ ethanamine was dissolved in methanol (50 ml) and 10% palladium on carbon (0.56 g ) And stirred at room temperature for 90 minutes under a hydrogen atmosphere. After removing palladium carbon from the reaction solution, the solvent was distilled off under reduced pressure to obtain 3.47 g (yield 39%) of the title compound.
  • the evaluation was performed using purified human recombinant V600E active mutant BRAF kinase ( ⁇ 1-416, GST fusion) and rabbit recombinant inactive MEK1 (full length, GST and His fusion, MEK1 unactive, Upstate, LakePlacid, NY) was used to detect the phosphorylation level of inactive MEK1 by the HTRF method (homogeneoustimersolvedfluorescence method).
  • mutant BRAF 2 ng / well, ATP 100 ⁇ M, MEK 1100 ng / well, and a test compound (final concentration 0.01 nM to 30 ⁇ M) were added to a kinase reaction buffer (50 mM Tris-HCl, 10 mM MgCl 2 , 2 mM EGTA, 1 mM Na 3 VO 4 , 0.1 mg / mL BSA, pH 7.4) and mixed so that the total reaction volume was 50 ⁇ L / well and reacted at 30 ° C. for 60 minutes. Thereafter, 25 ⁇ L / well of a PBS solution * containing the following was added and reacted at 4 ° C. overnight to stop the phosphorylation reaction and perform the HTRF reaction.
  • a kinase reaction buffer 50 mM Tris-HCl, 10 mM MgCl 2 , 2 mM EGTA, 1 mM Na 3 VO 4 , 0.1 mg / mL BSA
  • PBS solution composition 60 mM EDTA (final concentration 20 mM), 1.2 M KF (final concentration 400 ⁇ M), 1 mg / mL BSA (final concentration 333 ⁇ g / mL), 630 ng / mL anti-rabbit IgG-Cryptate (Cisbiointernational, France, final) Concentration 210 ng / mL), 3 ⁇ g / mL anti-GST-XL665 (Cisbiointernational, France, final concentration 1 ⁇ g / mL), pH 7.0 to anti-phospho-MEK1 / 2 (finally 1/1000 dilution) Dissolved in PBS.
  • concentration at which% is 50% was calculated by an approximation from a linear function of two concentrations sandwiching it.
  • the IC 50 value of each test compound is as shown in Table 1, and a strong BRAF kinase activity inhibitory action was observed.
  • Test Example 2 Cell growth inhibitory action (in vitro) The cell growth inhibitory action of each Example compound was evaluated.
  • a 96-well plate for cell culture was seeded with an appropriate amount of BRAF mutant human cancer cell line A375 (Dainippon Pharmaceutical Co., Ltd.) at 50 ⁇ L / well and pre-cultured overnight at 37 ° C. under 5% CO 2 conditions.
  • a test compound was dissolved in DMSO to prepare a dilution series, and the test compound solution was diluted with a medium on the day after cell seeding, and then added to the cells in a volume of 50 ⁇ L / well. The final DMSO concentration was adjusted to 0.1%. After culturing at 37 ° C.
  • the IC 50 value of each test compound is as shown in Table 2, and a strong cell growth inhibitory action was observed.
  • the administration period was 2 to 4 weeks, depending on the tumor, and was administered daily on weekends.
  • the major axis (mm) and the minor axis (mm) of the tumor were measured with electronic digital calipers over time, and evaluated by the tumor growth inhibition rate (GI%) on the determination date (in principle, the day after the final administration) by the following formula.
  • GI% tumor growth inhibition rate
  • body weight measurement and general condition were observed over time, and the effect at a dose at which no significant weight loss or appearance abnormality was observed was effective. All the test compounds showed a good antitumor effect.
  • GI (%) (1-A / B) ⁇ 100
  • A Mean tumor volume on the date of determination in the compound administration group *
  • B Average tumor volume on the day of determination in the untreated control group *
  • the compound of the present invention has a strong BRAF inhibitory activity and an excellent antitumor activity, it is useful as a pharmaceutical, particularly as an antitumor agent.

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Abstract

La présente invention a pour objet des composés représentés par la formule générale (I), présentant une activité inhibitrice de BRAF ; ou leurs sels pharmacologiquement acceptables. Dans la formule générale (I), R1 et R2 sont chacun H, un halogène, un alkyle en C1 à C4, ou un halogéno (alkyle en C1 à C4) ; R3 est un hydroxy, un alcynyle en C2 à C4 (qui peut avoir un hydroxy ou un acétoxy), -NR5aR5b, un azétidinyle (qui peut avoir un alkyle en C1 à C4), un oxazolidinyle (qui peut avoir un oxo), un pyrrolidinyle (qui peut avoir un alkyle en C1 à C4), un dioxanyle, ou un pyrazolyle ; R5a et R5b sont chacun H, un alkyle en C1 à C4, ou un hydroxy (alkyle en C1 à C4) ; R4 est H ou un alkyle en C1 à C4 ; n est 1 ou 2 ; Y est C-R6 ou N ; et R6 est H ou un halogène.
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