WO2011068187A1

WO2011068187A1 - Quinazoline derivatives

Info

Publication number: WO2011068187A1
Application number: PCT/JP2010/071645
Authority: WO
Inventors: 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
Original assignee: 第一三共株式会社
Priority date: 2009-12-04
Filing date: 2010-12-03
Publication date: 2011-06-09
Also published as: TW201124398A

Abstract

Compounds represented by general formula (I), exhibiting BRAF-inhibitory activity; or pharmacologically acceptable salts thereof. In general formula (I), R¹ and R² are each H, halogen, C_1-4 alkyl, or halogeno C_1-4 alkyl; R³ is hydroxy, C_2-4 alkynyl (which may have hydroxy or acetoxy), -NR^5aR^5b, azetidinyl (which may have C_1-4 alkyl), oxazolidinyl (which may have oxo), pyrrolidinyl (which may have C_1-4 alkyl), dioxanyl, or pyrazolyl; R^5a and R^5b are each H, C_1-4 alkyl, or hydroxy C_1-4 alkyl; R⁴ is H or C_1-4 alkyl; n is 1 or 2; Y is C-R⁶ or N; and R⁶ is H or halogen.

Description

Quinazoline derivatives

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.

The classic MAPK (mitogen-activated protein kinase) pathway 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.

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. In recent years, it was reported that 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). In addition, BRAF mutations have been reported in cancer cell lines such as glioma, lung cancer, sarcoma, breast cancer and liver cancer. About 90% of the mutations are V600E active mutations in which the amino acid residue valine at position 600 is replaced with glutamic acid. When 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). 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 (see Non-Patent Document 6).

From the above, it was suggested that BRAF plays an important role in tumors and that tumor growth is suppressed by suppressing active mutant BRAF. Therefore, 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.

Currently, for example, diphenylurea compounds (see Patent Documents 1 to 6) and the like have been reported as compounds having RAF kinase family inhibitory activity expected to be effective as antitumor agents.

International Publication No. 00/42012 Pamphlet International Publication No. 2005/009961 Pamphlet International Publication No. 2006/043090 Pamphlet International Publication No. 2007/113557 Pamphlet International Publication No. 2007/119055 Pamphlet International Publication No. 2008/044688 Pamphlet

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.

Therefore, 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.

That is, the present invention
(1) The following formula (I)

[Wherein, 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 are the same or different and each represents a hydrogen atom, a C _1-4 alkyl group, or a hydroxy C _1-4 alkyl group,
R ⁴ is a hydrogen atom or a C _1-4 alkyl group,
n is 1 or 2,
Y is C—R ⁶ or a nitrogen atom;
R ⁶ is a hydrogen atom or a halogen atom. ]
Or a pharmacologically acceptable salt thereof,
(2) The compound of the above (1), wherein Y is CH or CF, or a pharmacologically acceptable salt thereof,
(3) The compound of the above (1), wherein Y is a nitrogen atom, or a pharmacologically acceptable salt thereof,
(4) 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, dioxanyl group, or pyrazolyl group, 1) The compound according to any one of (3) or a pharmacologically acceptable salt thereof,
(5) The substituent represented by the formula — (CH ₂ ) _n —R ³ is a 2-hydroxyethyl group, a prop-2-yn-1-yl group, or a 4-hydroxybut-2-yn-1-yl. Group, 4-acetoxybut-2-yn-1-yl group, 2- (methylamino) ethyl 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-1,3-oxazolidine -3-yl) Eth Group, or 2-(1H-pyrazol-1-yl) compound according to any one of an ethyl group (1) to (4), or, a pharmacologically acceptable salt thereof,
(6) R ¹ is a hydrogen atom, a chlorine atom or a trifluoromethyl group, or the compound according to any one of claims 1 to 5, or a pharmacologically acceptable salt thereof,
(7) R ² is a hydrogen atom or a methyl group, or the compound according to any one of claims 1 to 6, or a pharmacologically acceptable salt thereof,
(8) The compound according to any one of claims 1 to 7, or a pharmacologically acceptable salt thereof, wherein R ⁴ is a methyl group.
(9) 1- {2- [2- (Dimethylamino) ethoxy] -5- (trifluoromethyl) pyridin-3-yl} -3- {3-[(3-methyl-4-oxo-3,4 -Dihydroquinazolin-6-yl) oxy] phenyl} urea,
(10) 1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- [2-{[(2S) -1-methylpyrrolidine- 2-yl] methoxy} -5- (trifluoromethyl) phenyl] urea,
(11) 1- (4-Chloro-2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} phenyl) -3- {3-[(3-methyl-4-oxo-3,4 -Dihydroquinazolin-6-yl) oxy] phenyl} urea,
(12) 1- [2-{[(2S) -1-Methylazetidin-2-yl] methoxy} -5- (trifluoromethyl) pyridin-3-yl] -3- {3-[(3- Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} urea,
(13) 1- [2-{[(2S) -1-ethylazetidin-2-yl] methoxy} -5- (trifluoromethyl) pyridin-3-yl] -3- {3-[(3- Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} urea,
(14) 1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- [2-{[(2R) -1-methylpyrrolidine- 2-yl] methoxy} -5- (trifluoromethyl) phenyl] urea,
(15) 1- (4-Chloro-2-{[(2S) -1-methylazetidin-2-yl] methoxy} phenyl) -3- {3-[(3-methyl-4-oxo-3, 4-dihydroquinazolin-6-yl) oxy] phenyl} urea,
(16) A pharmacologically acceptable salt of the compound according to any one of (9) to (15) above,
(17) A pharmaceutical composition comprising as an active ingredient the compound according to any one of (1) to (16) above, or a pharmacologically acceptable salt thereof,
(18) An antitumor agent comprising the compound according to any one of (1) to (16) above or a pharmacologically acceptable salt thereof as an active ingredient,
(19) A BRAF inhibitor comprising the compound according to any one of (1) to (16) above or a pharmacologically acceptable salt thereof as an active ingredient,
(20) Tumor is leukemia, lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendix cancer, colon cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal stromal tumor, lung cancer , Liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer, endometrial cancer, cervical cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, Kaposi sarcoma, myoma, kidney The antitumor agent according to the above (18), which is cancer, bladder cancer, and / or testicular cancer.

In addition, 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).

In the present specification, “BRAF inhibitory action” refers to an action that inhibits the kinase activity of BRAF, and “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.

In the present specification, the “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. The “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.

Hereinafter, the compound of the present invention represented by the formula (I) will be described.

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. is there. R ² is preferably a hydrogen atom, a chlorine atom, or a methyl group, and more preferably a hydrogen atom or a chlorine atom. A preferred combination of R ¹ and R ² is 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.

—NR ^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, a pyrrolidinyl group, or a methylpyrrolidinyl group, particularly preferably a dimethylamino group, 1-methylazetidin-2-yl Group, 1-ethylazetidin-2-yl group Or a 1-methylpyrrolidin-2-yl 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-1,3-oxazolidine -3- E) ethyl group or 2- (1H-pyrazol-1-yl) ethyl group, more preferably 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-ethylazetidine-2- Yl) methyl group, 2- (pyrrolidin-1-yl) ethyl group, pyrrolidin-2-ylmethyl group, (1-methylpyrrolidin-2-yl) methyl group, 1,4-dioxane-2-ylmethyl group, 2- A (2-oxo-1,3-oxazolidin-3-yl) ethyl group or a 2- (1H-pyrazol-1-yl) ethyl group, particularly preferably 2- (dimethylamino) ethyl Group, (1-methylazetidin-2-yl) methyl group, (1-ethylazetidin-2-yl) methyl group, or (1-methylpyrrolidin-2-yl) methyl group.

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.

In formula (I), preferred combinations of R ¹ , R ² , — (CH ₂ ) _n —R ³ , R ⁴ , and Y are:
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-2-yl) methyl group, 1,4-dioxane-2-ylmethyl group, 2- (2-oxo-1,3-oxazolidine-3-yl) An ethyl group or a 2- (1H-pyrazol-1-yl) ethyl group,
R ⁴ is a hydrogen atom, a methyl group, or an ethyl group,
Y is a nitrogen atom.

In formula (I), other preferred combinations of R ¹ , R ² , — (CH ₂ ) _n —R ³ , R ⁴ , and Y are:
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-2-yl) methyl group, 1,4-dioxane-2-ylmethyl group, 2- (2-oxo-1,3-oxazolidine-3-yl) An ethyl group or a 2- (1H-pyrazol-1-yl) ethyl group,
R ⁴ is a hydrogen atom, a methyl group, or an ethyl group,
Y is C—H.

In formula (I), particularly preferred combinations of R ¹ , R ² , — (CH ₂ ) _n —R ³ , R ⁴ , and Y are:
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.

In formula (I), other particularly preferred combinations of R ¹ , R ² , — (CH ₂ ) _n —R ³ , R ⁴ , and Y are:
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.

Further, 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-[(3-methyl- 4-oxo-3,4-dihydroquina Rin-6-yl) oxy] phenyl} urea, 1- [2-{[(2S) -1-methylazetidin-2-yl] methoxy} -5- (trifluoromethyl) pyridin-3-yl]- 3- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} urea, 1- [2-{[(2S) -1-ethylazetidine-2 -Yl] methoxy} -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-{[(2R) -1-methylpyrrolidine-2 -Yl] methoxy} -5- (trifluoromethyl ) Phenyl] urea or 1- (4-chloro-2-{[(2S) -1-methylazetidin-2-yl] methoxy} phenyl) -3- {3-[(3-methyl-4-oxo -3,4-dihydroquinazolin-6-yl) oxy] phenyl} urea or a pharmacologically acceptable salt thereof.

In the present invention, 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.

Examples of such 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.

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). .

As 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. In the case where 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). , Propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethyl Is nil of compounds, and the like.), And the like.

The prodrug of the compound of the present invention can be produced from compound (I) by a known method. In addition, 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. Therefore, 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. Cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor, malignant melanoma, breast cancer, endometrium Effective as an anti-tumor agent for cancer, cervical cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma, myoma, kidney cancer, bladder cancer, testicular cancer, etc., especially for tumors with BRAF mutation is there. Examples of 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.

In the description of the solvent in the present specification, examples of aliphatic hydrocarbons include hexane, heptane, ligroin, petroleum ether and the like, and 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. , Acetone, methyl ethyl ketone, etc., lower alkyl nitriles as acetonitrile, propionitrile, etc., amides as formamide, N, N-dimethylform Amide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, hexamethylphosphoric triamide and the like. Examples of the sulfoxides include dimethyl sulfoxide and the like. Examples of the sulfones include sulfolane and the alcohols. , Methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve, etc., and lower alkyl alcohols such as methanol, ethanol , Propanol, butanol and the like.

In the description of the base in the present specification, examples of the alkali metal carbonates include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, and 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. Examples of the organic amines 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. Moreover, the combination of the said base can also be used as a base.

The following describes the manufacturing method.

Method A is a method for producing compounds (Ia), (Ib), (Id) and (If).

In the above formula, 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 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. For example, aliphatic hydrocarbons, ethers, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles. Amides, lower alkyl alcohols, or water, preferably amides, and most preferably N, N-dimethylformamide. *

The base used in the reaction is not particularly limited. For example, 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
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. For example, 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 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. For example, 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. For example, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal water Oxides, alkali metal alkoxides, or organic amines, preferably alkali metal hydroxides, and most preferably sodium hydroxide.

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
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. For example, ethers, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles, amides, lower Examples thereof include alkyl alcohols, and preferably no solvent. *

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
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. For example, ethers, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles, amides, lower Examples thereof include alkyl alcohols, preferably lower alkyl alcohols, and most preferably 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. For example, 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.

While the 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.
While the 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
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. For example, 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. For example, 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
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).

In the isocyanate 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. For example, aliphatic hydrocarbons, ethers, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles. 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. 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.

In the carbamate method, 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. For example, 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. *

Step A7a
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. For example, ethers, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles, amides, lower 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 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
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. For example, 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 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.

While the reaction time varies depending on the reaction temperature, raw material compound, reagent, and solvent, it is generally 1 hour to 72 hours, preferably 3 hours to 24 hours.
Method B is a method for producing compound (8) which is an intermediate of compound (I) of the present invention.

In the above formula, R ¹ , R ² , R ³ , Y and n have the same meaning as described above.

Step B1
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. For example, aliphatic hydrocarbons, ethers, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles. And 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. *

While the 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
Step B2 is a step of producing a compound having the general formula (8). Preferably, 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. For example, 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 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 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. For example, aliphatic hydrocarbons, ethers, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles. Amides, water, or a mixed solvent of the above solvent and water, preferably a mixed solvent of ethers and water, and most preferably a mixed solvent of dioxane and water. *

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. For example, 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. . *

The 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).

In the above formula, R ¹ and R ² have the same meaning as described above.
Step C1
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. For example, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, or a mixed solvent of the above solvents Is mentioned.

The chlorinating agent used in the above reaction is not particularly limited as long as it is usually used in a chlorination reaction. For example, 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.

After completion of the reaction, the target compound in each step is collected from the reaction mixture according to a conventional method. For example, 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. If necessary, 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. Column adsorption method using CFD; carrier such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent, such as partition column chromatography using silica gel, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably high performance liquid chromatography). ) Are combined as appropriate and separated and purified by eluting with an appropriate eluent. Rukoto can.

When 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.

These formulations include 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; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate Silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, And compounds similar to the dosage form), disintegrants (eg, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose) A chemically modified starch / cellulose such as carboxymethyl starch, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone), stabilizers (paraoxybenzoates such as methyl paraben and propyl paraben); chlorobutanol Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.), Flavoring agents (for example, Commonly used sweeteners, acidulants, fragrances, and the like can be used.), And additives such as diluents are used to produce them by a known method.

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. When a compound of the present invention is administered to a human, 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. When administered to a human, it is preferably administered once a day, or divided into 2 to 4 times, and repeated at appropriate intervals. In addition, 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. 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.

More specifically, as the alkylating agent, for example, 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 Examples include 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.

Examples of various 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.

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.

Examples of the antineoplastic plant component include vinca alkaloids such as vindesine, vincristine and vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide and teniposide.

Examples of BRM include tumor necrosis factor or indomethacin.

Examples of the hormone include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, phosfestol, ethinylestradiol, chlormadinone, or medroxyprogesterone.

Examples of vitamins 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.

Other 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.

Furthermore, the present invention includes the use of the compound of the present invention and a salt thereof for producing the medicine.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.
Example 1
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

29.7 mg (0.10 mmol) of triphosgene was dissolved in anhydrous tetrahydrofuran (10 ml), and 2-{[(2S) -1-methylazetidin-2-yl] methoxy obtained in Reference Example 46 was stirred with ice cooling. } An anhydrous tetrahydrofuran solution (5 ml) containing 78.0 mg (0.30 mmol) of 5- (trifluoromethyl) aniline and 47.4 mg (0.60 mmol) of pyridine was added dropwise. After 15 minutes, 80.1 mg (0.30 mmol) of 6- (3-aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 and 60.6 mg (0.60 mmol) of triethylamine were added. An anhydrous N, N-dimethylformamide solution (5 ml) was added dropwise, followed by stirring with ice cooling for 30 minutes and further stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: triethylamine / methanol / ethyl acetate = 1/2/17) to give 33.6 mg (yield 20%) of the title compound. Got.
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 9.76 (s, 1H), 8.43 (s, 1H), 8.35
(s, 1H), 8.32 (s, 1H), 7.74 (d, 1H, J = 9.0Hz), 7.58 (dd, 1H, J = 9.0Hz,
2.9Hz), 7.51 (d, 1H, J = 2.9Hz), 7.39 (t, 1H, J = 2.2Hz), 7.36 (d, 1H, J =
8.1Hz), 7.30 (dd, 1H, J = 8.8Hz, 1.7Hz), 7.25-7.18 (m, 2H), 6.75 (ddd, 1H, J =
8.1Hz, 2.2Hz, 0.9Hz), 4.3-4.2 (m, 2H), 3.5-3.2 (m, 1H), 3.48 (s, 3H), 3.0-2.7
(m, 1H), 2.32 (s, 3H), 2.2-2.0 (m, 3H).
IR spectrum, ν _max cm ^-1 (KBr): 3353,
2959, 1675, 1606, 1548, 1483, 1443, 1341, 1271, 1201, 1131.
Mass spectrum (FAB ⁺ ), m / z: 554 ((M + H) ⁺ ).
(Example 2)
1- {2- [2- (Dimethylamino) ethoxy] -5- (trifluoromethyl) phenyl} -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl ) Oxy] phenyl} urea

Starting materials: 2- [2- (dimethylamino) ethoxy] -5- (trifluoromethyl) aniline and 6- (3-aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 In the same manner as in Example 1, the title compound was obtained (yield 24%).
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 9.69 (s, 1H), 8.46 (d, 1H, J =
2.1Hz), 8.32 (s, 1H), 8.31 (s, 1H), 7.74 (d, 1H, J = 8.8Hz), 7.58 (dd, 1H, J =
8.8Hz, 3.0Hz), 7.52 (d, 1H, J = 3.0Hz), 7.39-7.35 (m, 2H), 7.29 (dd, 1H, J =
8.6Hz, 1.7Hz), 7.24 (s, 1H), 7.21 (ddd, 1H, J = 8.1Hz, 2.1Hz, 0.9Hz), 6.75
(ddd, 1H, J = 8.1Hz, 2.4Hz, 0.9Hz), 4.26 (t, 2H, J = 6.2Hz), 3.48 (s, 3H), 2.74
(t, 2H, J = 6.2Hz), 2.24 (s, 6H).
IR spectrum, ν _max cm ^-1 (KBr): 3352,
1676, 1605, 1550, 1483, 1444, 1345, 1270, 1201, 1132.
Mass spectrum (FAB ⁺ ), m / z: 542 ((M + H) ⁺ ).
(Example 3)
1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- [2- (2-pyrrolidin-1-ylethoxy) -5- (tri Fluoromethyl) phenyl] urea

2- (2-Pyrrolidin-1-ylethoxy) -5- (trifluoromethyl) aniline obtained in Reference Example 29 and 6- (3-aminophenoxy) -3-methylquinazoline-4 obtained in Reference Example 1 The title compound was obtained according to the method described in Example 1 using (3H) -one as a starting material (yield 26%).
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 9.71 (s, 1H), 8.47 (d, 1H, J =
2.1Hz), 8.35 (s, 1H), 8.33 (s, 1H), 7.74 (d, 1H, J = 8.8Hz), 7.58 (dd, 1H, J =
8.8Hz, 2.9Hz), 7.52 (d, 1H, J = 2.9Hz), 7.39-7.35 (m, 2H), 7.29 (dd, 1H, J = 9.1Hz,
2.3Hz), 7.23 (d, 1H, J = 8.3Hz), 7.20 (dd, 1H, J = 2.1Hz, 0.9Hz), 6.75 (ddd,
1H, J = 8.3Hz, 2.3Hz, 0.9Hz), 4.28 (t, 2H, J = 6.24Hz), 3.48 (s, 3H), 2.95-2.85
(m, 2H), 2.60-2.45 (m, 4H), 1.77-1.65 (m, 4H).
IR spectrum, ν _max cm ^-1 (KBr): 3362,
2959, 1672, 1606, 1550, 1483, 1444, 1346, 1270, 1201, 1131.
Mass spectrum (FAB ⁺ ), m / z: 568 ((M + H) ⁺ ).
Example 4
1- {2- [2- (dimethylamino) ethoxy] -5- (trifluoromethyl) pyridin-3-yl} -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazoline -6-yl) oxy] phenyl} urea

2- [2- (Dimethylamino) ethoxy] -5- (trifluoromethyl) pyridin-3-amine obtained in Reference Example 3 and 6- (3-aminophenoxy) -3-amine obtained in Reference Example 1 The title compound was obtained according to the method described in Example 1 using methylquinazolin-4 (3H) -one as a starting material (yield 30%).
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 9.72 (s, 1H), 8.66 (d, 1H, J =
2.2Hz), 8.52 (s, 1H), 8.33 (s, 1H), 8.15 (dd, 1H, J = 2.2Hz, 0.9Hz), 7.74 (d,
1H, J = 8.7Hz), 7.58 (dd, 1H, J = 8.7Hz, 3.0Hz), 7.52 (d, 1H, J = 3.0Hz),
7.40-7.36 (m, 2H), 7.20 (ddd, 1H, J = 8.3Hz, 2.1Hz, 0.9Hz), 6.77 (ddd, 1H, J =
8.3Hz, 2.4Hz, 0.9Hz), 4.57 (t, 2H, J = 6.2Hz), 3.48 (s, 3H), 2.71 (t, 2H, J =
6.2Hz), 2.22 (s, 6H).
IR spectrum, ν _max cm ^-1 (KBr): 3358,
3075, 1675, 1610, 1554, 1533, 1484, 1459, 1348, 1276, 1147, 1121.
Mass spectrum (FAB ⁺ ), m / z: 543 ((M + H) ⁺ ).
(Example 5)
1- {2-[(2S) -azetidin-2-ylmethoxy] -5- (trifluoromethyl) pyridin-3-yl} -3- {3-[(3-methyl-4-oxo-3,4- Dihydroquinazolin-6-yl) oxy] phenyl} urea dihydrochloride

(2S) -2-({[3-Amino-5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) azetidine-1-carboxylic acid t-butyl ester obtained in Reference Example 5 and Reference Example Using 6- (3-aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in 1 as a starting material, the reaction and post-treatment were carried out according to the method described in Example 1, followed by 4N Deprotection (detert-butoxycarbonylation) was performed using hydrochloric acid / 1,4-dioxane to obtain the title compound (43% yield).
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 10.71 (s, 1H), 9.31 (s, 1H),
8.71 (d, 1H, J = 2.2Hz), 8.38 (s, 1H), 8.16 (dd, 1H, J = 2.0Hz, 1.0Hz), 7.75
(d, 1H, J = 8.9Hz), 7.58 (dd, 1H, J = 8.9Hz, 2.9Hz), 7.50 (d, 1H, J = 2.9Hz),
7.45 (d, 1H, J = 2.3Hz), 7.37 (d, 1H, J = 8.2Hz), 7.28 (ddd, 1H, J = 8.2Hz,
2.0Hz, 1.0Hz), 6.75 (ddd, 1H, J = 8.2Hz, 2.3Hz, 1.0Hz), 4.89-4.80 (m, 2H), 4.55
(dd, 1H, J = 11.8Hz, 2.5Hz), 4.04-3.81 (m, 2H), 3.48 (s, 3H), 2.46-2.42 (m, 2H).
IR spectrum, ν _max cm ^-1 (KBr): 3435,
2933, 1714, 1606, 1541, 1487, 1452, 1264, 1157, 906, 778, 688.
Mass spectrum (FAB ⁺ ), m / z: 541 ((M + H) ⁺ ).
(Example 6)
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

2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} -5- (trifluoromethyl) aniline obtained in Reference Example 7 and 6- (3-aminophenoxy obtained in Reference Example 1 ) -3-Methylquinazolin-4 (3H) -one was used as a starting material and the title compound was obtained according to the method described in Example 1 (yield 41%).
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 9.71 (s, 1H), 8.44 (d, 1H, J =
2.1Hz), 8.33 (s, 1H), 8.23 (s, 1H), 7.74 (d, 1H, J = 8.7Hz), 7.58 (dd, 1H, J =
8.7Hz, 2.7Hz), 7.52 (d, 1H, J = 2.7Hz), 7.38 (d, 1H, J = 2.1Hz), 7.35 (s, 1H),
7.29 (dd, 1H, J = 8.7Hz, 2.3Hz), 7.23 (d, 1H, J = 8.7Hz), 7.21 (ddd, 1H, J =
8.2Hz, 2.1Hz, 0.9Hz), 6.76 (ddd, 1H, J = 8.2Hz, 2.3Hz, 0.9Hz), 4.21 (dd, 1H, J
= 10.1Hz, 5.0Hz), 3.99 (dd, 1H, J = 10.1Hz, 6.7Hz), 3.48 (s, 3H), 2.99-2.94 (m,
1H), 2.72-2.65 (m, 1H), 2.36 (s, 3H), 2.24-2.17 (m, 1H), 2.09-2.00 (m, 1H),
1.75-1.59 (m, 3H).
IR spectrum, ν _max cm ^-1 (KBr): 3351,
2956, 1678, 1606, 1549, 1483, 1443, 1343, 1270, 1201, 1131.
Mass spectrum (FAB ⁺ ), m / z: 568 ((M + H) ⁺ ).
(Example 7)
1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- [2-{[(2S) -1-methylpyrrolidin-2-yl ] Methoxy} -5- (trifluoromethyl) pyridin-3-yl] urea

2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} -5- (trifluoromethyl) pyridin-3-amine obtained in Reference Example 4 and 6- ( The title compound was obtained according to the method described in Example 1 using 3-aminophenoxy) -3-methylquinazolin-4 (3H) -one as a starting material (yield 32%).
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 9.75 (s, 1H), 8.65 (d, 1H, J =
2.4Hz), 8.45 (s, 1H), 8.33 (s, 1H), 8.15 (dd, 1H, J = 2.2Hz, 1.2Hz), 7.74 (d,
1H, J = 8.8Hz), 7.58 (dd, 1H, J = 8.8Hz, 2.9Hz), 7.52 (d, 1H, J = 2.9Hz), 7.40-7.34
(m, 2H), 7.20 (ddd, 1H, J = 8.1Hz, 2.2Hz, 0.9Hz), 6.78 (ddd, 1H, J = 8.1Hz,
2.4Hz, 0.9Hz), 4.47 (dd, 1H, J = 10.9Hz, 5.2Hz), 4.39 (dd, 1H, J = 10.9Hz,
6.3Hz), 3.48 (s, 3H), 2.99-2.93 (m, 1H), 2.70-2.63 (m, 1H), 2.34 (s, 3H),
2.24-2.15 (m, 1H), 2.02-1.94 (m, 1H), 1.76-1.61 (m, 3H).
IR spectrum, ν _max cm ^-1 (KBr): 3348,
2957, 1669, 1607, 1550, 1483, 1344, 1264, 1152, 945, 913.
Mass spectrum (FAB ⁺ ), m / z: 569 ((M + H) ⁺ ).
(Example 8)
1- [2- (1,4-Dioxane-2-ylmethoxy) -5- (trifluoromethyl) phenyl] -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazoline-6 -Yl) oxy] phenyl} urea

2- (1,4-Dioxane-2-ylmethoxy) -5- (trifluoromethyl) aniline obtained in Reference Example 39 and 6- (3-aminophenoxy) -3-methylquinazoline obtained in Reference Example 1 The title compound was obtained according to the method described in Example 1 using -4 (3H) -one as a starting material (yield 58%).
¹ H NMR spectrum (DMSOd6, 400MHz), δ: 9.73 (s,
1H), 8.46 (d, 1H, J = 1.8Hz), 8.33 (s, 1H), 8.24 (s, 1H), 7.75 (d, 1H, J =
9.2Hz), 7.59 (dd, 1H, J = 8.9Hz, 2.9Hz), 7.52 (d, 1H, J = 2.9Hz), 7.41-7.35 (m,
2H), 7.30 (dd, 1H, J = 8.9Hz, 1.8Hz), 7.25-7.19 (m, 2H), 6.79-6.74 (m, 1H),
4.19 (dd, 1H, J = 11.00Hz, 5.96Hz), 4.12 (dd, 1H, J = 10.55Hz, 4.58Hz),
4.03-3.92 (m, 2H), 3.83-3.76 (m, 1H), 3.72-3.61 (m, 2H), 3.58-3.50 (m, 1H),
3.48 (s, 3H), 3.47-3.38 (m, 1H).
Example 9
1- [2- (2-hydroxyethoxy) -5- (trifluoromethyl) phenyl] -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] Phenyl} Urea

2- (2-{[t-Butyl (dimethyl) silyl] oxy} ethoxy) -5- (trifluoromethyl) aniline obtained in Reference Example 37 and 6- (3-aminophenoxy obtained in Reference Example 1 ) -3-Methylquinazolin-4 (3H) -one was used as a starting material for the reaction and post-treatment according to the method described in Example 1, followed by deprotection using tetrabutylammonium fluoride [det. -Butyl (dimethyl) silylation] to give the title compound (yield 34%).
¹ H NMR spectrum (DMSOd6, 400MHz), δ: 9.70 (s,
1H), 8.48 (d, 1H, J = 2.3Hz), 8.41 (br s, 1H), 8.33 (s, 1H), 7.75 (d, 1H, J =
9.2Hz), 7.59 (dd, 1H, J = 8.71Hz, 2.8Hz), 7.52 (d, 1H, J = 2.8Hz), 7.41-7.34
(m, 2H), 7.31-7.26 (m, 1H), 7.25-7.18 (m, 2H), 6.78-6.73 (m 1H), 4.98 (br s,
1H), 4.20 (t, 2H, J = 5.2Hz), 3.82 (dd, 2H, J = 10.1Hz, 5.2Hz), 3.48 (s, 3H).
(Example 10)
1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- {2- [2- (1H-pyrazol-1-yl) ethoxy] -5- (trifluoromethyl) phenyl} urea

2- [2- (1H-pyrazol-1-yl) ethoxy] -5- (trifluoromethyl) aniline obtained in Reference Example 31 and 6- (3-aminophenoxy) -3 obtained in Reference Example 1 The title compound was obtained according to the method described in Example 1 using -methylquinazolin-4 (3H) -one as a starting material (yield 63%).
¹ H NMR spectrum (DMSOd6, 400MHz), δ: 9.63 (s,
1H), 8.43 (d, 1H, J = 2.3Hz), 8.33 (s, 1H), 8.30 (s, 1H), 7.86 (d, 1H, J =
2.3Hz), 7.75 (d, 1H, J = 8.8Hz), 7.59 (dd.1H, J = 8.8Hz, 2.9Hz), 7.53 (d, 1H,
J = 2.9Hz), 7.47 (d, 1H, J = 1.9Hz), 7.42-7.35 (m, 2H), 7.27 (dd, 1H, J =
8.8Hz, 1.9Hz), 7.24-7.20 (m, 1H), 7.16 (d, 1H, J = 8.8Hz), 6.80-6.74 (m, 1H),
6.23 (t, 1H, J = 2.1Hz), 4.59 (t, 2H, J = 5.2Hz), 4.52 (t, 2H, J = 5.2Hz), 3.48
(s, 3H).
(Example 11)
1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- {4-methyl-2-[(2S) -pyrrolidin-2-ylmethoxy ] -5- (Trifluoromethyl) phenyl] urea

(2S) -2-{[2-Amino-5-methyl-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine-1-carboxylic acid t-butyl ester obtained in Reference Example 44 and Reference Example 1 Using the obtained 6- (3-aminophenoxy) -3-methylquinazolin-4 (3H) -one as a starting material, the reaction and post-treatment were carried out according to the method described in Example 1, and then trifluoroacetic acid was added. Was used for deprotection (de-t-butoxycarbonylation) to give the title compound (57% yield).
¹ H NMR spectrum (DMSOd6, 400MHz), δ: 9.59 (s,
1H), 8.41 (s, 1H), 8.33 (s, 1H), 8.24 (br s, 1H), 7.74 (d, 1H, J = 8.8Hz), 7.58
(dd, 1H, J = 8.8Hz, 2.9Hz), 7.51 (d, 1H, J = 2.9Hz), 7.41-7.33 (m, 2H), 7.21
(dd, 1H, J = 8.3Hz, 1.4Hz), 7.09 (s, 1H), 6.78-6.72 (m, 1H), 4.03 (dd, 1H, J =
9.5Hz, 5.0Hz), 3.91 (dd, 1H, J = 9.5Hz, 7.6Hz), 3.52-3.47 (m, 1H), 3.48 (s,
3H), 2.90-2.79 (m, 2H), 2.37 (s, 3H), 1.95-1.84 (m, 1H), 1.78-1.59 (m, 2H),
1.49-1.37 (m, 1H).
(Example 12)
1- {4-Chloro-2- [2- (methylamino) ethoxy] -5- (trifluoromethyl) phenyl} -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazoline -6-yl) oxy] phenyl} urea

{2- [2-Amino-5-chloro-4- (trifluoromethyl) phenoxy] ethyl} methylcarbamic acid t-butyl ester obtained in Reference Example 13 and 6- (3-Amino acid obtained in Reference Example 1 Using phenoxy) -3-methylquinazolin-4 (3H) -one as a starting material, the reaction and post-treatment were carried out according to the method described in Example 1, followed by removal with 4N hydrochloric acid / 1,4-dioxane. Protection (de-t-butoxycarbonylation) gave the title compound (yield 40%).
¹ H NMR spectrum (CDCl ₃
, 400MHz), δ: 8.68 (s,
1H), 8.52 (br s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.77 (d, 1H, J = 2.8Hz), 7.70
(d, 1H, J = 9.2Hz), 7.47 (dd, 1H, J = 8.9Hz, 3.0Hz), 7.31 (t, 1H, J = 2.1Hz),
7.27 (t, 1H, J = 8.0Hz), 7.18 (d, 1H, J = 8.3Hz), 6.91 (s, 1H), 6.72 (dd, 1H, J
= 8.3Hz, 2.1Hz), 4.12 (t, 2H, J = 4.8Hz), 3.57 (s, 3H), 3.03 (t, 2H, J =
4.8Hz), 2.50 (s, 3H).
Mass spectrum (ESI ⁺ ), m / z: 562 ((M + H) ⁺ ).
(Example 13)
1- {2- [2- (ethylamino) ethoxy] -3-fluoro-5- (trifluoromethyl) phenyl} -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazoline -6-yl) oxy] phenyl} urea

{2- [2-Amino-6-fluoro-4- (trifluoromethyl) phenoxy] ethyl} ethylcarbamic acid t-butyl ester obtained in Reference Example 18 and 6- (3- Aminophenoxy) -3-methylquinazolin-4 (3H) -one was used as a starting material, followed by reaction and post-treatment according to the method described in Example 1, followed by 4N hydrochloric acid / 1,4-dioxane. Deprotection (de-t-butoxycarbonylation) was performed to give the title compound (35% yield).
¹ H NMR spectrum (CDCl ₃
, 400MHz), δ: 9.51 (br s,
1H), 8.42 (s, 1H), 7.98 (s, 1H), 7.79 (d, 1H, J = 2.8Hz), 7.71 (d, 1H, J =
9.2Hz), 7.48 (dd, 1H, J = 8.7Hz, 2.8Hz), 7.34 (t, 1H, J = 2.3Hz), 7.30 (t, 1H,
J = 8.3Hz), 7.18-7.13 (m, 2H), 6.99 (dd, 1H, J = 10.1Hz, 2.3Hz), 6.75 (dd, 1H,
J = 8.3Hz, 2.3Hz), 4.19 (t, 2H, J = 4.8Hz), 3.58 (s, 3H), 2.99 (t, 2H, J =
4.8Hz), 2.83 (q, 2H, J = 7.1Hz), 1.24 (t, 3H, J = 7.1Hz).
Mass spectrum (ESI ⁺ ), m / z: 560 ((M + H) ⁺ ).
(Example 14)
1- {4-Chloro-2- [2- (isopropylamino) ethoxy] -5- (trifluoromethyl) phenyl} -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazoline -6-yl) oxy] phenyl} urea

{2- [2-Amino-5-chloro-4- (trifluoromethyl) phenoxy] ethyl} isopropylcarbamic acid t-butyl ester obtained in Reference Example 24 and 6- (3- Aminophenoxy) -3-methylquinazolin-4 (3H) -one was used as a starting material, followed by reaction and post-treatment according to the method described in Example 1, followed by 4N hydrochloric acid / 1,4-dioxane. Deprotection (de-t-butoxycarbonylation) gave the title compound (yield 28%).
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 10.61 (s, 1H), 9.29 (s, 1H),
9.15 (br s, 1H), 8.71 (s, 1H), 8.39 (s, 1H), 7.75 (d, 1H, J = 9.2Hz), 7.59 (dd,
1H, J = 9.2Hz, 2.9Hz), 7.49 (d, 1H, J = 2.9Hz), 7.45 (t, 1H, J = 2.0Hz), 7.40
(s, 1H), 7.37 (t, 1H, J = 8.3Hz), 7.26 (d, 1H, J = 7.4Hz), 6.74 (dd, 1H, J =
8.0Hz, 1.7Hz), 4.42 (t, 2H, J = 4.6Hz), 3.42-3.51 (m, 6H), 1.35 (d, 6H, J =
6.3Hz).
Mass spectrum (ESI ⁺ ), m / z: 590 ((M + H) ⁺ ).
(Example 15)
1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- [2- (prop-2-yn-1-yloxy) -5 (Trifluoromethyl) phenyl] urea

92.1 mg (0.345 mmol) of 6- (3-aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 was dissolved in anhydrous acetonitrile (5 ml), and phenyl chloroformate 54 .9 mg (0.351 mmol) and 40.1 mg (0.508 mmol) of pyridine were added and stirred under ice cooling. After 2 hours, 74.2 mg (0.345 mmol) of 2- (prop-2-yn-1-yloxy) -5- (trifluoromethyl) aniline obtained in Reference Example 33 and 72.6 mg (0.719 mmol) of triethylamine were obtained. ) And stirred at 60 degrees overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel column chromatography (elution solvent: ethyl acetate) to obtain 72.7 mg (42% yield) of the title compound.
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 9.64 (s, 1H), 8.50 (d, 1H, J =
2.3Hz), 8.48 (s, 1H), 8.33 (s, 1H), 7.75 (d, 1H, J = 9.2Hz), 7.59 (dd, 1H, J =
8.7Hz, 2.8Hz), 7.52 (d, 1H, J = 2.8Hz), 7.42-7.32 (m, 3H), 7.28 (d, 1H, J =
8.7Hz), 7.22-7.17 (m, 1H), 6.77-6.74 (m, 1H), 5.04 (d, 2H, J = 2.3Hz), 3.71 (t,
1H, J = 2.3Hz), 3.48 (s, 3H).
(Example 16)
1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- {2- [2- (2-oxo-1,3-oxazolidine- 3-yl) ethoxy] -5- (trifluoromethyl) phenyl} urea

6- (3-Aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 and 3- {2- [2-amino-4- (trifluoro) obtained in Reference Example 41 The title compound was obtained according to the method described in Example 15 using (methyl) phenoxy] ethyl} -1,3-oxazolidine-2-one as the starting material (yield 31%).
¹ H NMR spectrum (DMSOd6, 400MHz), δ: 9.52 (s,
1H), 8.45 (d, 1H, J = 2.1Hz), 8.34 (s, 1H), 8.33 (s, 1H), 7.75 (d, 1H, J =
8.9Hz), 7.59 (dd, 1H, J = 8.9Hz, 2.8Hz), 7.52 (d, 1H, J = 2.8Hz), 7.42-7.34 (m,
2H), 7.30 (d, 1H, J = 2.1Hz), 7.25 (d, 1H, J = 8.2Hz), 7.20 (dt, 1H, J = 8.2Hz,
1.0Hz), 6.79-6.73 (m, 1H), 4.36 (t, 2H, J = 5.5Hz), 4.25 (dd, 2H, J = 8.7Hz,
7.3Hz), 3.70-3.59 (m, 4H), 3.48 (s, 3H).
(Example 17)
Acetic acid 4- {2-[({3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} carbamoyl) amino] -4- (trifluoromethyl) phenoxy} But-2-yn-1-yl ester

6- (3-Aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 and acetic acid 4- [2-amino-4- (trifluoromethyl) obtained in Reference Example 35 The title compound was obtained according to the method described in Example 15 using phenoxy] but-2-yn-1-yl ester as a starting material (yield 44%).
¹ H NMR spectrum (DMSOd6, 400MHz), δ: 9.63 (s,
1H), 8.49 (d, 1H, J = 2.3Hz), 8.48 (s, 1H), 8.33 (s, 1H), 7.75 (d, 1H, J =
8.7Hz), 7.59 (dd, 1H, J = 8.7Hz, 2.8Hz), 7.52 (d, 1H, J = 2.8Hz), 7.41-7.31 (m,
3H), 7.26 (d, 1H, J = 8.7Hz), 7.19 (d, 1H, J = 9.6Hz), 6.76 (dd, 1H, J = 8.7Hz,
2.3Hz), 5.12 (s, 2H), 4.76 (s, 2H), 3.48 (s, 3H), 2.01 (s, 3H).
(Example 18)
1- {2-[(4-Hydroxybut-2-in-1-yl) oxy] -5- (trifluoromethyl) phenyl} -3- {3-[(3-methyl-4-oxo-3, 4-Dihydroquinazolin-6-yl) oxy] phenyl} urea

Acetic acid 4- {2-[({3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} carbamoyl) amino] -4- obtained in Example 17 97.8 mg (0.168 mmol) of (trifluoromethyl) phenoxy} but-2-yn-1-yl ester was dissolved in tetrahydrofuran (1.0 ml), and 3N aqueous sodium hydroxide solution (0.30 ml) was added under ice cooling. ) And stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel column chromatography (elution solvent: ethyl acetate) to obtain 58.9 mg (yield 65%) of the title compound.
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 9.65 (s, 1H), 8.52-8.47 (m, 2H),
8.33 (s, 1H), 7.75 (d, 1H, J = 9.1Hz), 7.59 (dd, 1H, J = 9.1Hz, 2.9Hz), 7.52
(d, 1H, J = 2.9Hz), 7.41-7.31 (m, 3H), 7.27 (d, 1H, J = 8.5Hz), 7.19 (dt, 1H, J
= 8.5Hz, 1.3Hz), 6.76 (dt, 1H, J = 7.2Hz, 1.3Hz), 5.25 (t, 1H, J = 6.0Hz), 5.08
(br s, 2H), 4.12 (d, 2H, J = 6.0Hz), 3.48 (s, 3H).
(Example 19)
1- {2- [2- (Isopropylamino) ethoxy] -5- (trifluoromethyl) phenyl} -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl ) Oxy] phenyl} urea

6- (3-Aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 and {2- [2-amino-4- (trifluoromethyl) obtained in Reference Example 9 Phenoxy] ethyl} isopropylcarbamic acid t-butyl ester was used as a starting material for the reaction and workup according to the method described in Example 15, followed by deprotection (deprotection using 4N hydrochloric acid / 1,4-dioxane. t-butoxycarbonylation) to give the title compound (yield 50%).
¹ H NMR spectrum (CDCl ₃
, 400MHz), δ: 8.54-8.41
(m, 2H), 8.52 (d, 1H, J = 1.8Hz), 7.96 (s, 1H), 7.73-7.68 (m, 2H), 7.48 (dd,
1H, J = 8.7Hz, 2.8Hz), 7.41 (t, 1H, J = 2.1Hz), 7.30-7.20 (m, 2H), 7.11 (dd,
1H, J = 8.3Hz, 1.8Hz), 6.77-6.70 (m, 2H), 4.13 (t, 3H, J = 5.0Hz), 3.55 (s,
3H), 3.18-3.04 (m, 1H), 1.29-1.18 (m, 1H), 1.22 (d, 6H, J = 6.4Hz).
Mass spectrum (ESI ⁺ ), m / z: 556 ((M + H) ⁺ ).
(Example 20)
1- [5-Chloro-2- (2-pyrrolidin-1-ylethoxy) phenyl] -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl } Urea

6- (3-Aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 and 5-chloro-2- (2-pyrrolidin-1-ylethoxy) obtained in Reference Example 11 The title compound was obtained according to the method described in Example 15 using aniline as a starting material (yield 73%).
¹ H NMR spectrum (CDCl ₃
, 400MHz), δ: 8.74 (s,
1H), 8.32 (d, 1H, J = 2.8Hz), 7.97 (s, 1H), 7.79 (d, 1H, J = 3.2Hz), 7.72-7.66
(m, 2H), 7.46 (dd, 1H, J = 8.7Hz, 2.8Hz), 7.35 (t, 1H, J = 2.3Hz), 7.27 (t, 1H,
J = 8.3Hz), 7.20-7.15 (m, 1H), 6.87 (dd, 1H, J = 8.7Hz, 2.8Hz), 6.76 (d, 1H, J
= 8.7Hz), 6.76-6.69 (m, 1H), 4.09 (t, 2H, J = 5.3Hz), 3.58 (s, 3H), 2.87 (t,
2H, J = 5.0Hz), 2.69-2.63 (m, 4H), 1.91-1.84 (m, 4H).
Mass spectrum (ESI ⁺ ), m / z: 534 ((M + H) ⁺ ).
(Example 21)
1- (4-Chloro-2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} phenyl) -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazoline -6-yl) oxy] phenyl} urea

6- (3-Aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 and 4-chloro-2-{[(2S) -1-methyl obtained in Reference Example 20 The title compound was obtained according to the method described in Example 15 using pyrrolidin-2-yl] methoxy} aniline as a starting material (yield 55%).
¹ H NMR spectrum (CDCl ₃
, 400MHz), δ: 8.55 (s,
1H), 8.19 (d, 1H, J = 8.7Hz), 7.97 (s, 1H), 7.83 (s, 1H), 7.79 (d, 1H, J =
2.8Hz), 7.69 (d, 1H, J = 8.7Hz), 7.46 (dd, 1H, J = 8.7Hz, 2.8Hz), 7.34 (t, 1H,
J = 2.3Hz), 7.27 (t, 1H, J = 8.3Hz), 7.18 (d, 1H, J = 8.7Hz), 6.95 (dd, 1H, J =
8.7Hz, 2.3Hz), 6.86 (d, 1H, J = 2.3Hz), 6.70 (dd, 1H, J = 7.6Hz, 2.1Hz), 4.04
(d, 2H, J = 3.2Hz), 3.57 (s, 3H), 3.21-3.13 (m, 1H), 2.62-2.54 (m, 1H),
2.42-2.32 (m, 4H), 1.98-1.79 (m, 4H).
Mass spectrum (ESI ⁺ ), m / z: 534 ((M + H) ⁺ ).
(Example 22)
1- (4,5-dichloro-2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} phenyl) -3- {3-[(3-methyl-4-oxo-3,4- Dihydroquinazolin-6-yl) oxy] phenyl} urea

6- (3-Aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 and 4,5-dichloro-2-{[(2S) -1 obtained in Reference Example 22 The title compound was obtained according to the method described in Example 15 using -methylpyrrolidin-2-yl] methoxy} aniline as a starting material (yield 28%).
¹ H NMR spectrum (CDCl ₃
, 400MHz), δ: 8.70 (s,
1H), 8.45 (s, 1H), 7.98 (s, 1H), 7.82-7.75 (m, 2H), 7.70 (d, 1H, J = 9.2Hz),
7.47 (dd, 1H, J = 9.2Hz, 2.9Hz), 7.35 (t, 1H, J = 2.0Hz), 7.27 (t, 1H, J =
8.0Hz), 7.17 (d, 1H, J = 9.7Hz), 6.93 (s, 1H), 6.72 (dd, 1H, J = 8.0Hz, 2.3Hz),
4.02 (d, 2H, J = 2.9Hz), 3.58 (s, 3H), 3.21-3.13 (m, 1H), 2.63-2.55 (m, 1H),
2.44-2.35 (m, 4H), 1.97-1.80 (m, 4H).
Mass spectrum (ESI ⁺ ), m / z: 568 ((M + H) ⁺ ).
(Example 23)
1- [2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} -5- (trifluoromethyl) phenyl] -3- {3-[(4-oxo-3,4-dihydroquinazoline -6-yl) oxy] phenyl} urea

6- (3-Aminophenoxy) quinazolin-4 (3H) -one obtained in Reference Example 2 and 2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} obtained in Reference Example 7 The title compound was obtained according to the method described in Example 15 using -5- (trifluoromethyl) aniline as a starting material (yield 52%).
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 8.39 (br s, 1H), 8.03 (s, 1H),
7.75 (d, 1H, J = 8.6Hz), 7.68 (m, 1H), 7.58 (m, 1H), 7.40-7.20 (m, 4H), 7.15
(d, 1H, J = 8.6Hz), 6.80-6.73 (m, 1H), 4.25 (dd, 1H, J = 10.5Hz, 4.2Hz), 4.21
(dd, 1H, J = 10.5Hz, 4.2Hz), 3.34-3.24 (m, 1H), 2.89-2.76 (m, 1H), 2.52 (s,
3H), 2.55-2.40 (m, 1H), 2.14-2.05 (m, 1H), 1.96-1.81 (m, 3H).
Mass spectrum (ESI ⁺ ), m / z: 554 ((M + H) ⁺ ).
(Example 24)
1- [2-{[(2S) -1-methylazetidin-2-yl] methoxy} -5- (trifluoromethyl) pyridin-3-yl] -3- {3-[(3-methyl-4 -Oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} urea

1- {2-[(2S) -azetidin-2-ylmethoxy] -5- (trifluoromethyl) pyridin-3-yl} -3- {3-[(3-methyl-4) obtained in Example 5 -Oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} urea dihydrochloride 184 mg (0.30 mmol) was suspended in acetonitrile (10 ml), 37% formaldehyde solution (1.0 ml) and triacetoxy 127 mg (0.60 mmol) of sodium borohydride was added and stirred at room temperature for 1 hour. The reaction solution was concentrated, water was added, neutralized with sodium bicarbonate, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: triethylamine / methanol / ethyl acetate = 1/2/17) to give 63.5 mg (38% yield) of the title compound. Got.
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 9.77 (s, 1H), 8.66 (d, 1H, J =
2.2Hz), 8.54 (s, 1H), 8.33 (s, 1H), 8.14 (dd, 1H, J = 2.2Hz, 1.1Hz), 7.74 (d,
1H, J = 8.8Hz), 7.58 (dd, 1H, J = 8.8Hz, 2.9Hz), 7.52 (d, 1H, J = 2.9Hz),
7.40-7.36 (m, 2H), 7.19 (ddd, 1H, J = 8.2Hz, 1.9Hz, 0.9Hz), 6.77 (ddd, 1H, J =
8.2Hz, 2.4Hz, 0.9Hz), 4.60 (dd, 1H, J = 11.4Hz, 4.3Hz), 4.44 (dd, 1H, J =
11.4Hz, 5.8Hz), 3.48 (s, 3H), 3.38-3.30 (m, 2H), 2.75-2.67 (m, 1H), 2.23 (s,
3H), 2.05-1.91 (m, 2H).
IR spectrum, ν _max cm ^-1 (KBr): 3357,
1678, 1608, 1547, 1483, 1345, 1265, 1206, 1151, 942.
Mass spectrum (FAB ⁺ ), m / z: 555 ((M + H) ⁺ ).
(Example 25)
1- [2-{[(2S) -1-ethylazetidin-2-yl] methoxy} -5- (trifluoromethyl) pyridin-3-yl] -3- {3-[(3-methyl-4 -Oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} urea

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 %).
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 9.75 (s, 1H), 8.65 (d, 1H, J =
2.3Hz), 8.52 (s, 1H), 8.32 (s, 1H), 8.13 (dd, 1H, J = 2.3Hz, 1.1Hz), 7.74 (d,
1H, J = 8.8Hz), 7.58 (dd, 1H, J = 8.8Hz, 2.9Hz), 7.52 (d, 1H, J = 2.9Hz),
7.40-7.36 (m, 2H), 7.19 (ddd, 1H, J = 8.2Hz, 2.1Hz, 0.93Hz), 6.77 (ddd, 1H, J =
8.2Hz, 2.4Hz, 0.9Hz), 4.56 (dd, 1H, J = 11.3Hz, 5.0Hz), 4.45 (dd, 1H, J =
11.3Hz, 5.6Hz), 3.48 (s, 3H), 3.44-3.40 (m, 1H), 3.29-3.25 (m, 1H), 2.70-2.56
(m, 2H), 2.29-2.24 (m, 1H), 2.05-1.90 (m, 2H), 0.84 (t, 3H, J = 7.3Hz).
IR spectrum, ν _max cm ^-1 (KBr): 3348,
2967, 1673, 1608, 1548, 1483, 1452, 1345, 1269, 1205, 1151, 1122.
Mass spectrum (FAB ⁺ ), m / z: 569 ((M + H) ⁺ ).
(Example 26)
1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- [2-{[(2R) -1-methylpyrrolidin-2-yl ] Methoxy} -5- (trifluoromethyl) phenyl] urea

1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- {2-[(2R) -pyrrolidine- obtained in Reference Example 16 The title compound was obtained according to the method described in Example 24 using 2-ylmethoxy] -5- (trifluoromethyl) phenyl} urea hydrochloride as a starting material (yield 26%).
¹ H NMR spectrum (CDCl ₃
, 400MHz), δ: 8.65 (s, 1H), 8.61 (d, 1H, J =
2.3Hz), 7.98 (s, 1H), 7.79 (d, 1H, J = 2.8Hz), 7.74-7.60 (m, 2H), 7.47 (dd, 1H,
J = 8.7Hz, 2.8Hz), 7.34 (s, 1H), 7.29 (t, 1H, J = 8.0Hz), 7.23-7.18 (m, 2H),
6.93 (d, 1H, J = 8.7Hz), 6.73 (dd, 1H, J = 7.8Hz, 2.3Hz), 4.14-4.04 (m, 2H),
3.58 (s, 3H), 3.25-3.15 (m, 1H), 2.70-2.59 (m, 1H), 2.49-2.36 (m, 4H),
2.00-1.80 (m, 4H).
Mass spectrum (ESI ⁺ ), m / z: 568 ((M + H) ⁺ ).
(Example 27)
1- (4-Chloro-2-{[(2S) -1-methylazetidin-2-yl] methoxy} phenyl) -3- {3-[(3-methyl-4-oxo-3,4-dihydro Quinazolin-6-yl) oxy] phenyl} urea

1- {2-[(2S) -azetidin-2-ylmethoxy] -4-chlorophenyl} -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazoline obtained in Reference Example 27 The title compound was obtained according to the method described in Example 24 using -6-yl) oxy] phenyl} urea hydrochloride as a starting material (yield 48%).
¹ H NMR spectrum (CDCl ₃
, 400MHz), δ: 8.84 (s,
1H), 8.19 (d, 1H, J = 8.7Hz), 7.97 (s, 1H), 7.79 (d, 1H, J = 2.8Hz), 7.70 (d,
1H, J = 9.2Hz), 7.51 (s, 1H), 7.47 (dd, 1H, J = 8.7Hz, 2.8Hz), 7.35 (t, 1H, J =
2.1Hz), 7.27 (t, 1H, J = 8.3Hz), 7.14 (dd, 1H, J = 7.6Hz, 1.6Hz), 6.99 (dd, 1H,
J = 8.7Hz, 2.3Hz), 6.91 (d, 1H, J = 2.3Hz), 6.71 (dd, 1H, J = 7.8Hz, 1.8Hz),
3.98 (dd, 1H, J = 11.0Hz, 4.1Hz), 3.90 (dd, 1H, J = 11.0Hz, 2.8Hz), 3.57 (s,
3H), 3.56-3.50 (m, 1H), 3.47-3.39 (m, 1H), 2.99 (dd, 1H, J = 17.0Hz, 7.8Hz),
2.43 (s, 3H), 2.36-2.27 (m, 1H), 2.10-2.03 (m, 1H).
(Example 28)
1- [4-Chloro-2- {2-[(2-hydroxyethyl) (methyl) amino] ethoxy} -5- (trifluoromethyl) phenyl] -3- {3-[(3-methyl-4- Oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} urea

1- {4-Chloro-2- [2- (methylamino) ethoxy] -5- (trifluoromethyl) phenyl} -3- {3-[(3-methyl-4-oxo obtained in Example 12 -3,4-Dihydroquinazolin-6-yl) oxy] phenyl} urea 31 mg (0.055 mmol) was dissolved in acetone (5 ml), sodium iodide 3.0 mg (0.020 mmol), potassium carbonate 23 mg (0. 167 mmol) and 0.011 ml (0.164 mmol) of 2-chloroethanol were added and heated to reflux overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with methylene chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 95/5 → 90/10) to obtain 20 mg (yield 60%) of the title compound.
¹ H NMR spectrum (CDCl ₃
, 400MHz), δ: 8.72 (s,
1H), 8.41 (br s, 1H), 8.18 (br s, 1H), 7.98 (s, 1H), 7.79 (d, 1H, J = 2.8Hz),
7.70 (d, 1H, J = 8.7Hz), 7.47 (dd, 1H, J = 8.7Hz, 2.8Hz), 7.38 (t, 1H, J =
1.8Hz), 7.28 (t, 1H, J = 7.8Hz), 7.24-7.20 (m, 1H), 6.91 (s, 1H), 6.70 (d, 1H,
J = 7.8Hz), 4.07 (t, 2H, J = 4.6Hz), 3.82 (t, 2H, J = 5.0Hz), 3.58 (s, 3H),
2.91-2.85 (m, 2H), 2.87-2.76 (m, 2H), 2.50 (s, 3H).
Mass spectrum (ESI ⁺ ), m / z: 606 ((M + H) ⁺ ).
(Example 29)
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 hydrochloride

1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- [2-{[(2S) -1 obtained in Example 6 -Methylpyrrolidin-2-yl] methoxy} -5- (trifluoromethyl) phenyl] urea (100 mg, 0.176 mmol) was dissolved in methanol (4.0 ml), and 4N hydrochloric acid / dioxane (2.0 ml) was added. And stirred at room temperature for 1 hour. The reaction mixture was concentrated, methanol and isopropyl ether were added to the residue, and the precipitated crystals were collected by filtration and washed with isopropyl ether to obtain 110 mg (yield 100%) of the title compound.
¹ H NMR spectrum (DMSOd6, 400 MHz), δ: 10.4 (br s, 1H), 10.2 (br s,
1H), 8.60-8.48 (m, 1H), 8.39-8.33 (m, 1H), 7.79-7.71 (m, 1H), 7.60-7.54 (m,
1H), 7.51-7.42 (m, 2H), 7.40-7.18 (m, 4H), 6.78-6.71 (m, 1H), 4.58-4.50 (m,
2H), 3.90-3.80 (m, 1H), 3.77-3.67 (m, 1H), 3.47 (s, 3H), 3.21-3.09 (m, 1H),
2.93 (br s, 3H), 2.30-1.94 (m, 4H).
(Example 30)
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 dimethanesulfonate

1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- [2-{[(2S) -1 obtained in Example 6 -Methylpyrrolidin-2-yl] methoxy} -5- (trifluoromethyl) phenyl] urea 100 mg (0.176 mmol) was dissolved in methylene chloride (2.0 ml), and methanesulfonic acid 22.8 μl (0.352 mmol) was dissolved. And stirred at room temperature for 2 hours. The reaction mixture was concentrated, methanol and isopropyl ether were added to the residue, and the precipitated crystals were collected by filtration and washed with isopropyl ether and ether to obtain 118 mg (yield 88%) of the title compound.
¹H NMR spectrum (DMSOd6, 400MHz), δ: 9.62 (br s, 1H), 9.51 (br s,
1H), 8.60-8.30 m (m, 1H), 8.28-8.19 (m, 1H), 7.78-7.72 (m, 1H), 7.62-7.57 (m,
1H), 7.51-7.48 (m, 1H), 7.44-7.35 (m, 3H), 7.30-7.16 (m, 2H), 6.81-6.73 (m, 1H),
4.53-4.34 (m, 2H), 3.91-3.80 (m, 1H), 3.47 (s, 3H), 3.23-3.09 (m, 1H), 2.99 (br
s, 3H), 2.69-2.65 (m, 1H), 2.34-2.31 (m, 1H), 2.31 (s, 3H), 2.30 (s, 3H),
2.17-1.84 (m, 3H).
(Reference Example 1)
6- (3-Aminophenoxy) -3-methylquinazolin-4 (3H) -one
A mixture of 4.91 g (45 mmol) of 3-aminophenol, 9.70 g (45 mmol) of methyl ester of 5-chloro-2-nitrobenzoic acid, 12.4 g (45 mmol) of potassium carbonate and anhydrous N, N-dimethylformamide (100 ml) Was stirred at 120 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, methanol (100 ml) and 10% palladium carbon (2.52 g) were added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. After removing insolubles from the reaction solution by filtration, the solvent was distilled off, 3.60 g (90 mmol) of sodium hydroxide, water (20 ml) and methanol (60 ml) were added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated, water was added, neutralized with acetic acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, methylamine [40% methanol solution] 9.18 ml (90 mmol), orthoformic acid triethyl ester 13.3 g (90 mmol), p-toluenesulfonic acid monohydrate 171 mg (0. 90 mmol) and methanol (100 ml) were added, and the mixture was heated to reflux for 23 hours. The reaction mixture was concentrated, water was added, extracted with ethyl acetate and tetrahydrofuran, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, ethyl acetate and isopropyl ether were added, and the precipitated crystals were collected by filtration and washed with isopropyl ether to obtain 4.47 g (37%) of the title compound.
¹H-NMR spectrum (DMSOd6,
400MHz), δ: 8.28 (s, 1H), 7.72 (d, 1H, J = 8.8Hz),
7.53 (dd, 1H, J = 8.8Hz, 2.8Hz), 7.48 (d, 1H, J = 2.8Hz), 7.08 (t, 1H, J =
8.0Hz), 6.43 (ddd, 1H, J = 8.0Hz, 2.1Hz, 0.9Hz), 6.28 (d, 1H, J = 2.1Hz), 6.23
(dd, 1H, J = 8.8Hz, 0.9Hz), 5.28 (br s, 2H), 3.48 (s, 3H).
IR spectrum, ν_max cm^-1(KBr): 3332,
3217, 1661, 1607, 1481, 1348, 1151, 832.
Mass spectrum (EI⁺), M / z: 267 (M⁺, Base), 250, 238, 222,
209, 182.
(Reference Example 2)
6- (3-Aminophenoxy) quinazolin-4 (3H) -one
A mixture of 1.0 g (4.1 mmol) of 2-amino-5- (3-aminophenoxy) benzoic acid, which is a synthetic intermediate of the compound shown in Reference Example 1, and formamide (10 ml) was stirred at 120 ° C. for 15 hours. . Sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated, methanol (10 ml), methylene chloride (5.0 ml) and 4N dioxane / hydrochloric acid (5.0 ml) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, methanol and ether were added, and the precipitated crystals were collected by filtration and washed with ether to obtain 1.19 g (yield 100%) of the hydrochloride of the title compound. 500 mg (1.73 mmol) of the obtained hydrochloride was dissolved in sodium bicarbonate water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, ethyl acetate and n-hexane were added, and the precipitated crystals were collected by filtration and washed with n-hexane to obtain 401 mg (yield 92%) of the title compound.
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 9.69 (br s, 1H), 7.96 (s, 1H), 7.77 (d,
1H, J = 2.9Hz), 7.74 (d, 1H, J = 8.8Hz), 7.50 (dd, 1H, J = 8.8Hz, 2.9Hz), 7.15
(dd, 1H, J = 8.0Hz, 8.0Hz), 6.50 (dd, 1H, J = 8.0Hz, 1.7Hz), 6.45 (dd, 1H, J =
8.0Hz, 1.7Hz), 6.39 (dd, 1H, J = 1.7Hz, 1.7Hz), 3.74 (br s, 2H).
Mass spectrum (EPCI⁺), M / z: 254 ((M + H)⁺).
(Reference Example 3)
2- [2- (Dimethylamino) ethoxy] -5- (trifluoromethyl) pyridin-3-amine
A mixture of 7.52 g (36.2 mmol) of 3-nitro-5- (trifluoromethyl) pyridin-2-ol, thionyl chloride (30 ml) and N, N-dimethylformamide (0.50 ml) was heated to reflux for 60 hours. . The reaction mixture was concentrated, dehydrated toluene was added, the solvent was distilled off under reduced pressure, and anhydrous tetrahydrofuran (20 ml) was added. Anhydrous tetrahydrofuran (40 ml) containing 3.86 g (43.4 mmol) of 2- (dimethylamino) ethanol and 1.89 g (43.4 mmol) of 55% sodium hydride was added, and the mixture was heated to reflux for 8 hours. The reaction mixture was concentrated, water was added, the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate), and the solvent was distilled off. The obtained 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.
¹H-NMR spectrum (DMSOd6,
400MHz), δ: 7.68 (d, 1H, J = 2.2Hz), 7.06 (d, 1H, J =
2.2Hz), 5.38 (br s, 2H), 4.41 (t, 2H, J = 6.0Hz),) 2.65 (t, 2H, J = 6.0Hz), 2.21
(s, 6H).
IR spectrum, ν_max cm^-1Li (Liquid film):
3331, 3199, 2953, 1604, 1442, 1340, 1259, 1120, 1027, 896, 763, 648.
Mass spectrum (FAB⁺), M / z: 250 ((M + H)⁺).
(Reference Example 4)
2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} -5- (trifluoromethyl) pyridin-3-amine
The title compound according to the method described in Reference Example 3 using 3-nitro-5- (trifluoromethyl) pyridin-2-ol and [(2S) -1-methylpyrrolidin-2-yl] methanol as starting materials (Yield 30%).
¹H-NMR spectrum (DMSOd6,
400MHz), δ: 7.09 (d, 1H, J = 2.5Hz), 6.49 (d, 1H, J =
2.5Hz), 5.49 (br s, 2H), 4.39-4.15 (m, 2H), 3.05-2.98 (m, 1H), 2.61-2.51 (m,
1H), 2.50 (s, 3H), 2.38-2.14 (m, 2H), 1.66-1.47 (m, 3H).
IR spectrum, ν_max cm^-1Li (Liquid film):
3335, 1660, 1603, 1445, 1346, 1261, 1119, 954, 868, 827.
Mass spectrum (FAB⁺), M / z: 276 ((M + H)⁺).
(Reference Example 5)
(2S) -2-({[3-Amino-5- (trifluoromethyl) pyridin-2-yl] oxy} methyl) azetidine-1-carboxylic acid t-butyl ester
3-Nitro-5- (trifluoromethyl) pyridin-2-ol and (2S) -2- (hydroxymethyl) azetidine-1-carboxylic acid t-butyl ester were used as the starting material and the method described in Reference Example 3 was followed. The title compound was obtained accordingly (yield 49%).
¹H-NMR spectrum (DMSOd6,
400MHz), δ: 7.68 (d, 1H, J = 2.2Hz), 7.09 (d, 1H, J =
2.2Hz), 5.42 (br s, 2H), 4.67-4.51 (m, 1H), 4.50-4.47 (m, 1H), 4.37-4.32 (m,
1H), 3.93-3.67 (m, 2H), 2.35-2.14 (m, 2H), 1.32 (s, 9H).
IR spectrum, ν_max cm^-1Li (Liquid film):
3481, 3350, 2977, 1687, 1442, 1394, 1367, 1258, 1157, 1121, 941, 887, 763.
Mass spectrum (FAB⁺), M / z: 348 ((M + H)⁺).
(Reference Example 6)
(2S) -1-methyl-2-{[2-nitro-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine
1.05-g (5.0 mmol) of 1-fluoro-2-nitro-4- (trifluoromethyl) benzene, 0.69 g (6.0 mmol) of [(2S) -1-methylpyrrolidin-2-yl] methanol, potassium A mixture of 0.67 g (6.0 mmol) of t-butoxide and anhydrous N, N-dimethylformamide (20 ml) was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate = 1/9) to obtain 0.20 g (yield 13%) of the title compound.
¹H-NMR spectrum (DMSOd6,
400MHz), δ: 8.30 (d, 1H, J = 2.3Hz), 8.02 (dd, 1H, J =
8.8Hz, 2.3Hz), 7.59 (d, 1H, J = 8.8Hz), 4.25-4.16 (m, 1H), 4.01-3.91 (m, 1H),
2.99-2.94 (m, 1H), 2.73-2.68 (m, 1H), 2.38 (s, 3H), 2.30-2.18 (m, 1H),
1.99-1.83 (m, 1H), 1.74-1.59 (m, 3H).
IR spectrum, ν_max cm^-1Li (Liquid film):
2952, 2787, 1740, 1628, 1542, 1328, 1287, 1129, 1016, 897, 824, 689.
Mass spectrum (FAB⁺), M / z: 305 ((M + H)⁺).
(Reference Example 7)
2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} -5- (trifluoromethyl) aniline
(2S) -1-methyl-2-{[2-nitro-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine 188 mg (0.62 mmol) was dissolved in methanol (5 ml),
10% palladium carbon (44 mg) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. After palladium carbon was removed from the reaction solution by filtration, the solvent was distilled off under reduced pressure to obtain 144 mg (yield 85%) of the title compound.
¹H-NMR spectrum (DMSOd6,
400MHz), δ: 6.94 (d, 1H, J = 8.2Hz), 6.91 (d, 1H, J =
2.2Hz), 6.82 (dd, 1H, J = 8.2Hz, 2.2Hz), 5.07 (br s, 2H), 4.03 (dd, 1H, J =
9.7Hz, 5.4Hz), 3.84 (dd, 1H, J = 9.7Hz, 6.0Hz), 2.98-2.94 (m, 1H), 2.63-2.56
(m, 1H), 2.36 (s, 3H), 2.34-2.16 (m, 1H), 2.05-1.96 (m, 1H), 1.73-1.56 (m, 3H).
IR spectrum, ν_max cm^-1Li (Liquid film):
3343, 2953, 2792, 1735, 1622, 1521, 1449, 1334,4491223, 1159, 1114, 1028, 920,
867, 804.
Mass spectrum (FAB⁺), M / z: 275 ((M + H)⁺).
(Reference Example 8)
Isopropyl {2- [2-nitro-4- (trifluoromethyl) phenoxy] ethyl} carbamic acid t-butyl ester
Starting from 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and (2-hydroxyethyl) isopropylcarbamic acid t-butyl ester [patent description compound: WO2003 / 105845A1 (2003/12/24)] The title compound was obtained according to the method described in Reference Example 6 (yield 62%).
Mass spectrum (ESI⁺), M / z: 415 ((M + Na)⁺).
(Reference Example 9)
{2- [2-Amino-4- (trifluoromethyl) phenoxy] ethyl} isopropylcarbamic acid t-butyl ester
The title compound was obtained according to the method described in Reference Example 7 using isopropyl {2- [2-nitro-4- (trifluoromethyl) phenoxy] ethyl} carbamic acid t-butyl ester as a starting material according to the method described in Reference Example 7 (yield) 100%).
(Reference Example 10)
1- [2- (4-Chloro-2-nitrophenoxy) ethyl] pyrrolidine
The title compound was obtained according to the method described in Reference Example 6 using 5-chloro-2-fluoro-1-nitrobenzene and 1- (2-hydroxyethyl) pyrrolidine as starting materials (yield 83%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 7.83 (d, 1H, J = 2.6Hz), 7.48 (dd, 1H, J =
9.0Hz, 2.9Hz), 7.05 (d, 1H, J = 9.2Hz), 4.23 (t, 2H, J = 5.7Hz), 2.98-2.94 (m,
2H), 2.68-2.60 (m, 4H), 1.83-1.78 (m, 4H).
Mass spectrum (ESI⁺), M / z: 271 ((M + H)⁺).
(Reference Example 11)
5-Chloro-2- (2-pyrrolidin-1-ylethoxy) aniline
The title compound was obtained according to the method described in Reference Example 13 using 1- [2- (4-chloro-2-nitrophenoxy) ethyl] pyrrolidine as a starting material (yield 78%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.70 (d, 1H, J = 8.5Hz), 6.68 (d, 1H, J =
2.3Hz), 6.63 (dd, 1H, J = 8.5Hz, 2.3Hz), 4.10 (t, 2H, J = 6.0Hz), 4.01 (br s,
2H), 2.89 (t, 2H, J = 6.0Hz), 2.66-2.58 (m, 4H), 1.84-1.78 (m, 4H).
Mass spectrum (ESI⁺), M / z: 271 ((M + H)⁺).
(Reference Example 12)
{2- [5-Chloro-2-nitro-4- (trifluoromethyl) phenoxy] ethyl} methylcarbamic acid t-butyl ester
The title compound was obtained according to the method described in Reference Example 6 using 2,4-dichloro-5-nitrobenzotrifluoride and (2-hydroxyethyl) methylcarbamic acid t-butyl ester as starting materials (yield 49 %).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 8.26 (s, 1H), 7.24 (s, 1H), 4.34-4.21 (m,
2H), 3.68 (t, 2H, J = 5.0Hz), 3.01 (s, 3H), 1.47 (s, 9H).
Mass spectrum (ESI⁺), M / z: 421 ((M + Na)⁺).
(Reference Example 13)
{2- [2-Amino-5-chloro-4- (trifluoromethyl) phenoxy] ethyl} methylcarbamic acid t-butyl ester
{2- [5-Chloro-2-nitro-4- (trifluoromethyl) phenoxy] ethyl} carbamic acid t-butyl ester 1.13 g (2.84 mmol), iron 950 mg (17.0 mmol), ammonium chloride 30. A mixture of 0 mg (0.560 mmol), ethanol (20 ml) and water (5 ml) was heated to reflux for 2.5 hours. The reaction mixture was filtered through celite, the solvent was evaporated, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/2) to give 772 mg (yield 74%) of the title compound. It was.
(Reference Example 14)
(2R) -2-{[2-Nitro-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine-1-carboxylic acid t-butyl ester
Starting from 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and (2R) -2- (hydroxymethyl) pyrrolidine-1-carboxylic acid t-butyl ester, the method described in Reference Example 6 was applied. The title compound was obtained accordingly (yield 74%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 8.13, 8.10 (each s, total 1H), 7.79, 7.76
(each d, total 1H, J = 2.3Hz), 7.40, 7.37 (each s, total 1H), 4.38-4.25 (m,
2H), 4.20-4.00 (m, 1H), 3.50-3.28 (m, 2H), 2.15-1.80 (m, 4H), 1.55, 1.46 (each
s, total 9H).
Mass spectrum (ESI⁺), M / z: 413 ((M + Na)⁺).
(Reference Example 15)
(2R) -2-{[2-Amino-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine-1-carboxylic acid t-butyl ester
(2R) -2-{[2-Nitro-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine-1-carboxylic acid t-butyl ester was used as a starting material according to the method described in Reference Example 7. The compound was obtained (yield 99%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.98-6.85 (m, 3H), 4.31-4.11 (m, 2H),
4.06-3.82mm (m, 3H), 3.51-3.31mm (m, 2H), 2.08-1.86mm (m, 4H), 1.55mm (s, 9H).
Mass spectrum (ESI⁺), M / z: 383 ((M + Na)⁺).
(Reference Example 16)
1- {3-[(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} -3- {2-[(2R) -pyrrolidin-2-ylmethoxy] -5 (Trifluoromethyl) phenyl} urea hydrochloride
6- (3-Aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 and (2R) -2-{[2-amino-4- ( Trifluoromethyl) phenoxy] methyl} pyrrolidine-1-carboxylic acid t-butyl ester was used as a starting material for the reaction and post-treatment according to the method described in Example 15, followed by 4N hydrochloric acid / 1,4-dioxane. Was used for deprotection (de-t-butoxycarbonylation) to give the title compound (yield 100%).
(Reference Example 17)
Ethyl {2- [2-fluoro-6-nitro-4- (trifluoromethyl) phenoxy] ethyl} carbamic acid t-butyl ester
In accordance with the method described in Reference Example 6, starting from 1,2-difluoro-3-nitro-5- (trifluoromethyl) benzene and ethyl (2-hydroxyethyl) carbamic acid t-butyl ester, the title compound (Yield 63%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 7.87 (s, 1H), 7.60 (d, 1H, J = 10.5Hz),
4.52-4.33 (m, 2H),) 3.60 (t, 2H, J = 5.7Hz), 3.40-3.26 (m, 2H), 1.46 (s, 9H),
1.12 (t, 3H, J = 6.9Hz).
Mass spectrum (ESI⁺), M / z: 419 ((M + Na)⁺).
(Reference Example 18)
{2- [2-Amino-6-fluoro-4- (trifluoromethyl) phenoxy] ethyl} ethylcarbamic acid t-butyl ester
Ethyl {2- [2-fluoro-6-nitro-4- (trifluoromethyl) phenoxy] ethyl} carbamic acid t-butyl ester is used as a starting material and the title compound is obtained according to the method described in Reference Example 7. (Yield 81%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.74-6.66 (m, 2H), 4.40-4.03 (m, 4H),
3.62-3.47 (m, 2H), 3.41-3.23 (m, 2H), 1.46 (s, 9H), 1.14 (t, 3H, J = 6.9Hz).
Mass spectrum (ESI⁺), M / z: 367 ((M + H)⁺).
(Reference Example 19)
(2S) -2-[(5-Chloro-2-nitrophenoxy) methyl] -1-methylpyrrolidine
The title compound was obtained according to the method described in Reference Example 6 using 4-chloro-2-fluoro-1-nitrobenzene and [(2S) -1-methylpyrrolidin-2-yl] methanol as starting materials. Rate 77%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 7.83 (d, 1H, J = 8.6Hz), 7.07 (d, 1H, J =
2.3Hz), 7.00 (dd, 1H, J = 8.6Hz, 1.7Hz), 4.06 (dd, 1H, J = 9.2Hz, 5.2Hz), 3.98
(dd, 1H, J = 9.2Hz, 5.2Hz), 3.13-3.07 (m, 1H), 2.81-2.74 (m, 1H), 2.50 (s, 3H),
2.37-2.31 (m, 1H), 2.12-2.01 (m, 1H), 1.89-1.67 (m, 3H).
Mass spectrum (ESI⁺), M / z: 271 ((M + H)⁺).
(Reference Example 20)
4-chloro-2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} aniline
(2S) -2-[(5-Chloro-2-nitrophenoxy) methyl] -1-methylpyrrolidi
The starting compound was obtained according to the method described in Reference Example 13 (yield 72%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.79-6.74 (m, 2H), 6.61 (d, 1H, J =
8.6Hz), 4.00 (dd, 1H, J = 9.2Hz, 5.7Hz), 3.87 (dd, 1H, J = 9.2Hz, 5.7Hz), 3.79
(br s, 2H), 3.13-3.07 (m, 1H), 2.71-2.64 (m, 1H), 2.48 (s, 3H), 2.35-2.28 (m,
1H), 2.08-1.99 (m, 1H), 1.90-1.68 (m, 3H).
Mass spectrum (ESI⁺), M / z: 241 ((M + H)⁺).
(Reference Example 21)
(2S) -2-[(4,5-Dichloro-2-nitrophenoxy) methyl] -1-methylpyrrolidine
The title compound was obtained according to the method described in Reference Example 6 using 4,5-dichloro-2-fluoro-1-nitrobenzene and [(2S) -1-methylpyrrolidin-2-yl] methanol as starting materials. (Yield 41%).
(Reference Example 22)
4,5-dichloro-2-{[(2S) -1-methylpyrrolidin-2-yl] methoxy} aniline
The title compound was obtained according to the method described in Reference Example 13 using (2S) -2-[(4,5-dichloro-2-nitrophenoxy) methyl] -1-methylpyrrolidine as a starting material (yield) 85%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.82 (s, 1H), 6.75 (s, 1H), 3.97 (dd, 1H,
J = 9.2Hz, 5.7Hz), 3.91 (br s, 2H), 3.85 (dd, 1H, J = 9.2Hz, 5.7Hz), 3.12-3.07
(m, 1H), 2.70-2.63 (m, 1H), 2.46 (s, 3H), 2.34-2.28 (m, 1H), 2.07-1.98 (m, 1H),
1.88-1.67 (m, 3H).
Mass spectrum (ESI⁺), M / z: 275 ((M + H)⁺).
(Reference Example 23)
{2- [5-Chloro-2-nitro-4- (trifluoromethyl) phenoxy] ethyl} isopropylcarbamic acid t-butyl ester
The title compound was obtained according to the method described in Reference Example 6 using 2,4-dichloro-5-nitrobenzotrifluoride and (2-hydroxyethyl) isopropylcarbamic acid t-butyl ester as starting materials (yield). 67%).
(Reference Example 24)
{2- [2-Amino-5-chloro-4- (trifluoromethyl) phenoxy] ethyl} isopropylcarbamic acid t-butyl ester
{2- [5-Chloro-2-nitro-4- (trifluoromethyl) phenoxy] ethyl} isopropylcarbamic acid t-butyl ester was used as a starting material and the title compound was obtained according to the method described in Reference Example 13. (94% yield).
(Reference Example 25)
(2S) -2-[(5-Chloro-2-nitrophenoxy) methyl] azetidine-1-carboxylic acid t-butyl ester
The title compound according to the method described in Reference Example 6 using 4-chloro-2-fluoro-1-nitrobenzene and (2S) -2- (hydroxymethyl) azetidine-1-carboxylic acid t-butyl ester as starting materials (Yield 80%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 7.86 (d, 1H, J = 8.7Hz), 7.14 (d, 1H, J =
1.8Hz), 7.02 (dd, 1H, J = 8.7Hz, 1.8Hz), 4.58-4.50 (m, 2H), 4.17-4.11 (m, 1H),
3.97-3.81 (m, 2H), 2.49-2.29 (m, 2H), 1.53 (s, 9H).
Mass spectrum (ESI⁺), M / z: 365 ((M + Na)⁺).
(Reference Example 26)
(2S) -2-[(2-Amino-5-chlorophenoxy) methyl] azetidine-1-carboxylic acid t-butyl ester
(2S) -2-[(5-Chloro-2-nitrophenoxy) methyl] azetidine-1-carboxylic acid t-butyl ester was used as a starting material, and the title compound was obtained according to the method described in Reference Example 13. (Yield 74%).
(Reference Example 27)
1- {2-[(2S) -azetidin-2-ylmethoxy] -4-chlorophenyl} -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl) oxy] Phenyl} urea hydrochloride
6- (3-Aminophenoxy) -3-methylquinazolin-4 (3H) -one obtained in Reference Example 1 and (2S) -2-[(2-amino-5-chloro obtained in Reference Example 26) Phenoxy) methyl] azetidine-1-carboxylic acid t-butyl ester was used as a starting material, followed by reaction and post-treatment according to the method described in Example 1, followed by removal with 4N hydrochloric acid / 1,4-dioxane. Protection (de-t-butoxycarbonylation) gave the title compound (78% yield).
(Reference Example 28)
1- {2- [2-Nitro-4- (trifluoromethyl) phenoxy] ethyl} pyrrolidine
The title compound was obtained according to the method described in Reference Example 6 using 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and 1- (2-hydroxyethyl) pyrrolidine as starting materials (yield) 71%).
(Reference Example 29)
2- (2-Pyrrolidin-1-ylethoxy) -5- (trifluoromethyl) aniline
The title compound was obtained according to the method described in Reference Example 7 using 1- {2- [2-nitro-4- (trifluoromethyl) phenoxy] ethyl} pyrrolidine as a starting material (yield 98%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.99-6.94 (m, 1H), 6.92 (d, 1H, J =
1.8Hz), 6.82 (d, 1H, J = 8.3Hz), 4.17 (t, 2H, J = 6.0Hz), 4.04 (br s, 2H), 2.93
(t, 2H, J = 6.0Hz), 2.66-2.60 (m, 4H), 1.85-1.78 (m, 4H).
Mass spectrum (ESI⁺), M / z: 275 ((M + H)⁺).
(Reference Example 30)
1- {2- [2-Nitro-4- (trifluoromethyl) phenoxy] ethyl} -1H-pyrazole
The title compound was obtained according to the method described in Reference Example 6 using 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and 2- (1H-pyrazol-1-yl) ethanol as starting materials. (Yield 59%).
(Reference Example 31)
2- [2- (1H-pyrazol-1-yl) ethoxy] -5- (trifluoromethyl) aniline
The title compound was obtained according to the method described in Reference Example 7 using 1- {2- [2-nitro-4- (trifluoromethyl) phenoxy] ethyl} -1H-pyrazole as a starting material (yield 85 %).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 7.55 (d, 1H, J = 1.7Hz), 7.49 (d, 1H, J =
2.0Hz), 6.97-6.88 (m, 2H), 6.76 (d, 1H, J = 8.3Hz), 6.29-6.26 (m, 1H),
4.59-4.54 (m, 2H), 4.44-4.39 (m, 2H), 3.86 (br s, 2H).
(Reference Example 32)
2-Nitro-1- (prop-2-yn-1-yloxy) -4- (trifluoromethyl) benzene
The title compound was obtained according to the method described in Reference Example 6 using 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and 2-propyn-1-ol as starting materials (yield: 67% ).
(Reference Example 33)
2- (prop-2-yn-1-yloxy) -5- (trifluoromethyl) aniline
The title compound was obtained according to the method described in Reference Example 13 using 2-nitro-1- (prop-2-yn-1-yloxy) -4- (trifluoromethyl) benzene as a starting material (yield) 99%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 7.02-6.90 (m, 3H), 4.77 (d, 2H, J =
2.4Hz), 3.97 (br s, 2H), 2.55 (tt, 1H, J = 2.4Hz, 0.7Hz).
(Reference Example 34)
Acetic acid 4- [-2-nitro-4- (trifluoromethyl) phenoxy] but-2-yn-1-yl ester
Using 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and 2-butyne-1,4-diol as starting materials, the reaction and post-treatment were carried out according to the method described in Reference Example 6, and then Then, the hydroxyl group was protected (acetylated) using acetyl chloride to obtain the title compound (yield 86%).
(Reference Example 35)
Acetic acid 4- [2-amino-4- (trifluoromethyl) phenoxy] but-2-yn-1-yl ester
Using the acetic acid 4- [に 2-nitro-4- (trifluoromethyl) phenoxy] but-2-yn-1-yl ester as a starting material, the title compound was obtained according to the method described in Reference Example 13 (yield). 83%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.97-6.91 (m, 3H), 4.80 (d, 2H, J =
1.9Hz), 4.71 (t, 2H, J = 1.9Hz), 3.97 (br s, 2H), 2.09 (s, 3H).
(Reference Example 36)
2- [2-Nitro-4- (trifluoromethyl) phenoxy] ethanol
The title compound was obtained according to the method described in Reference Example 6 using 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and acetic acid 2-hydroxyethyl ester as starting materials (yield 49%). .
(Reference Example 37)
2- (2-{[t-Butyl (dimethyl) silyl] oxy} ethoxy) -5- (trifluoromethyl) aniline
Using 2- [2-nitro-4- (trifluoromethyl) phenoxy] ethanol as a starting material, the reaction and post-treatment were performed according to the method described in Reference Example 7, followed by t-butyl (dimethyl) silyl chloride. Was used to protect the hydroxyl group [t-butyl (dimethyl) silylation] to give the title compound (yield 65%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.70-6.67 (m, 3H), 4.35 (br s, 2H), 4.12
(t, 2H, J = 4.33Hz), 3.90 (t, 2H, J = 4.33Hz), 0.91 (s, 9H), 0.10 (s, 6H).
(Reference Example 38)
2-{[2-nitro-4- (trifluoromethyl) phenoxy] methyl} -1,4-dioxane
The title compound was obtained according to the method described in Reference Example 6 using 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and 1,4-dioxane-2-ylmethanol as starting materials. 82%).
(Reference Example 39)
2- (1,4-Dioxane-2-ylmethoxy) -5- (trifluoromethyl) aniline
2-{[2-nitro-4- (trifluoromethyl) phenoxy] methyl} -1,4-dioxane was used as a starting material according to the method described in Reference Example 7 to obtain the title compound (yield 94 %).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.98-6.91 (m, 2H), 6.81 (d, 1H, J =
8.3Hz), 4.10-3.89 (m, 6H), 3.88-3.73 (m, 3H), 3.71-3.62 (m, 1H), 3.58-3.50 (m,
1H).
(Reference Example 40)
3- {2- [2-Nitro-4- (trifluoromethyl) phenoxy] ethyl} -1,3-oxazolidine-2-one
According to the method described in Reference Example 6, using 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and N, N-bis (2-hydroxymethyl) carbamic acid t-butyl ester as starting materials, The title compound was obtained (yield 53%).
(Reference Example 41)
3- {2- [2-Amino-4- (trifluoromethyl) phenoxy] ethyl} -1,3-oxazolidine-2-one
According to the method described in Reference Example 7, the title compound was prepared using 3- {2- [2-nitro-4- (trifluoromethyl) phenoxy] ethyl} -1,3-oxazolidine-2-one as a starting material. Obtained (yield 91%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 7.00-6.91 (m, 2H), 6.78 (d, 1H, J =
8.3Hz), 4.37-4.33 (m, 2H), 4.23-4.18 (m, 2H), 4.00 (s, 2H), 3.76-3.67 (m, 4H).
(Reference Example 42)
(2S) -2-{[5-Chloro-2-nitro-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine-1-carboxylic acid t-butyl ester
According to the method described in Reference Example 6, starting from 2,4-dichloro-5-nitrobenzotrifluoride and (2S) -2- (hydroxymethyl) pyrrolidine-1-carboxylic acid t-butyl ester The compound was obtained (76% yield).
¹H NMR spectrum (CDCl_Three
, 400MHz), δ: 8.23 (s, 1H), 7.40 (s, 1H), 4.35-4.02
(m, 3H), 3.42-3.33 (m, 2H), 2.13-1.80 (m, 4H), 1.46 (s, 9H).
Mass spectrum (ESI⁺), M / z: 447 ((M + Na)⁺).
(Reference Example 43)
(2S) -2-{[5-Methyl-2-nitro-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine-1-carboxylic acid t-butyl ester
(2S) -2-{[5-Chloro-2-nitro-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine-1-carboxylic acid t-butyl ester 603 mg (1.42 mmol) obtained in Reference Example 42 Was dissolved in a mixed solvent (3.3 ml) of 1,4-dioxane / water (10/1), 355 mg (2.84 mmol) of trimethylboroxine, 82.1 mg (0.07 mmol) of tetrakis (triphenylphosphine) palladium. And 392 mg (2.84 mmol) of potassium carbonate were added and heated to reflux overnight. The reaction mixture was filtered through celite, water was added, the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was purified by basic silica gel column chromatography (elution solvent: ethyl acetate) to obtain 467 mg (yield 81%) of the title compound.
(Reference Example 44)
(2S) -2-{[2-Amino-5-methyl-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine-1-carboxylic acid t-butyl ester
(2S) -2-{[5-Methyl-2-nitro-4- (trifluoromethyl) phenoxy] methyl} pyrrolidine-1-carboxylic acid t-butyl ester was used as a starting material and the method described in Reference Example 7 was followed. The title compound was obtained accordingly (yield 77%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.96 (br s, 1H), 6.73-6.60 (m, 1H),
4.30-4.07 (m, 2H), 4.01-3.69 (m, 3H), 3.52-3.32 (m, 2H), 2.35 (s, 3H),
2.10-1.81 (m, 4H), 1.48 (s, 9H).
(Reference Example 45)
[(2S) -1-methylazetidin-2-yl] methanol
(2S) -1-methylazetidine-2-carboxylic acid [Patent Document: WO2009 / 32326A1 (2009/03/12)] 10.0 g (86.9 mmol), lithium aluminum hydride 3.58 g (86.9 mmol) ) And anhydrous tetrahydrofuran (100 ml) were stirred at 80 ° C. for 24 hours. The reaction solution was ice-cooled, and 15% aqueous sodium hydroxide solution (10 ml) was added dropwise. After filtration through Celite, the solvent was distilled off, and the residue was purified by distillation under reduced pressure (80 ° C./50 mmHg) to obtain 8.0 g (yield 91%) of the title compound.
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 3.61-3.54 (m, 1H), 3.45-3.38 (m, 1H),
3.38-3.30 (m, 1H),) 3.21-3.12 (m, 1H), 2.86-2.77 (m, 1H), m2.29 (s, 3H),
2.22-2.11 (m, 1H), 1.94-1.83 (m, 1H).
Mass spectrum (EPCI⁺), M / z: 102 ((M + H)⁺).
(Reference Example 46)
2-{[(2S) -1-methylazetidin-2-yl] methoxy} -5- (trifluoromethyl) aniline
Reference Example 6 and Reference were made using 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and [(2S) -1-methylazetidin-2-yl] methanol obtained in Reference Example 45 as starting materials. The title compound was obtained according to the method described in Example 7 (yield 41%).
¹H NMR spectrum (CDCl_Three,
400MHz), δ: 6.95 (d, 1H, J = 8.3Hz), 6.92 (s, 1H),
6.81 (d, 1H, J = 8.3Hz), 4.14-4.02 (m, 2H), 3.56-3.45 (m, 2H), 2.98-2.88 (m,
1H), 2.43 (s, 3H), 2.17-2.08 (m, 2H).
Mass spectrum (EPCI⁺), M / z: 261 ((M + H)⁺).
(Test Example 1) Evaluation of BRAF kinase activity inhibitory action (in vitro)
The BRAF kinase activity inhibitory action of each example compound was evaluated. The evaluation was performed using purified human recombinant V600E active mutant BRAF kinase (Δ1-416, 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).

Specifically, mutant BRAF 2 ng / well, ATP 100 μM, MEK 1100 ng / well, and a test compound (final concentration 0.01 nM to 30 μM) 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 μL / well and reacted at 30 ° C. for 60 minutes. Thereafter, 25 μL / 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.

* PBS solution composition: 60 mM EDTA (final concentration 20 mM), 1.2 M KF (final concentration 400 μM), 1 mg / mL BSA (final concentration 333 μg / mL), 630 ng / mL anti-rabbit IgG-Cryptate (Cisbiointernational, France, final) Concentration 210 ng / mL), 3 μg / mL anti-GST-XL665 (Cisbiointernational, France, final concentration 1 μg / mL), pH 7.0 to anti-phospho-MEK1 / 2 (finally 1/1000 dilution) Dissolved in PBS.

IC ₅₀ value is calculated as T / C% of each test compound addition group (T / C = test compound addition group / DMSO only addition group) with the average value of wells added only with DMSO as 100%. The 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 μL / 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 μL / well. The final DMSO concentration was adjusted to 0.1%. After culturing at 37 ° C. under 5% -CO ₂ conditions for 72 hours, Cell Titer-Glo solution (Promega, Madison, Wis.) Was added at 100 μL / well. After 10 minutes, luminescence was measured with a luminometer (WallacARVOTMSX), and living cells were measured. Number was measured. IC ₅₀ value is calculated by calculating T / C% of each test compound addition group (T / C = test compound addition group / DMSO only addition group) with the average value of wells added only with DMSO being 100%. The concentration at which C% is 50% was calculated by an approximate value from a linear function of two concentrations sandwiching it.

The IC ₅₀ value of each test compound is as shown in Table 2, and a strong cell growth inhibitory action was observed.

(Test Example 3) Antitumor effect in vivo BRAF mutant human cancer cell line A375 was transplanted subcutaneously into the right axillary region of nude mice. Transplantation can be performed by transplanting a 5 mm square tumor piece subcutaneously using a transplantation needle, or by suspending an appropriate number of tumor cells in physiological saline (Otsuka Pharmaceutical Co., Ltd.) and attaching a two-stage hypodermic needle. The tube was implanted subcutaneously. After confirming that the transplanted tumor was engrafted, grouping was performed using the tumor volume, and each test compound (compounds of Examples 4, 6, 21, 24, 25, 26, and 27) was 0.5% methylcellulose. The solution was dissolved or suspended in the solution and orally administered to mice. 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. At the same time, 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 ^*
*: Tumor volume is calculated by 1/2 × [tumor major axis] × [tumor minor axis] ² .

Since 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.

Claims

Formula (I)

[Wherein, 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 are the same or different and are a hydrogen atom, a C 1-4 alkyl group, or a hydroxy C 1-4 alkyl group,
R 4 is a hydrogen atom or a C 1-4 alkyl group,
n is 1 or 2,
Y is C—R 6 or a nitrogen atom;
R 6 is a hydrogen atom or a halogen atom. ]
Or a pharmacologically acceptable salt thereof.
The compound according to claim 1, wherein Y is CH or CF, or a pharmacologically acceptable salt thereof.
The compound of claim 1, wherein Y is a nitrogen atom, or a pharmacologically acceptable salt thereof.
R 3 is hydroxy group, ethynyl group, propynyl group, hydroxypropynyl group, acetoxypropynyl group, amino group, methylamino group, ethylamino group, isopropylamino group, dimethylamino group, (2-hydroxyethyl) (methyl) amino A group, an azetidinyl group, a methylazetidinyl group, an ethylazetidinyl group, a pyrrolidinyl group, a methylpyrrolidinyl group, an oxazolidinyl group, an oxooxazolidinyl group, a dioxanyl group, or a pyrazolyl group. Or a pharmacologically acceptable salt thereof.
The substituent represented by the formula — (CH 2 ) n —R 3 is a 2-hydroxyethyl group, a prop-2-yn-1-yl group, a 4-hydroxybut-2-yn-1-yl group, 4 -Acetoxybut-2-yn-1-yl group, 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-2-yl) methyl group, 1,4-dioxane-2-ylmethyl group, 2- (2-oxo-1,3-oxazolidine-3- Yl) ethyl group, Salt 2-(1H-pyrazol-1-yl) compound according to any one of claims 1 to 4 is an ethyl group, or, that is pharmacologically acceptable.
R 1 is a hydrogen atom, a compound according to any one of claims 1 to 5 is a chlorine atom or a trifluoromethyl group, or a pharmacologically acceptable salt thereof.
A compound according to any one of claims 1 to 6 R 2 is a hydrogen atom or a methyl group, or a pharmacologically acceptable salt thereof.
R 4 is A compound according to any one of claims 1 to 7 is a methyl group, or a pharmacologically acceptable salt thereof.
1- {2- [2- (dimethylamino) ethoxy] -5- (trifluoromethyl) pyridin-3-yl} -3- {3-[(3-methyl-4-oxo-3,4-dihydroquinazoline -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-[(3-methyl-4-oxo-3,4-dihydroquinazoline) -6-yl) oxy] phenyl} urea.
1- [2-{[(2S) -1-methylazetidin-2-yl] methoxy} -5- (trifluoromethyl) pyridin-3-yl] -3- {3-[(3-methyl-4 -Oxo-3,4-dihydroquinazolin-6-yl) oxy] phenyl} urea.
1- [2-{[(2S) -1-ethylazetidin-2-yl] methoxy} -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-{[(2R) -1-methylpyrrolidin-2-yl ] Methoxy} -5- (trifluoromethyl) phenyl] urea.
1- (4-Chloro-2-{[(2S) -1-methylazetidin-2-yl] methoxy} phenyl) -3- {3-[(3-methyl-4-oxo-3,4-dihydro Quinazolin-6-yl) oxy] phenyl} urea.
A pharmacologically acceptable salt of the compound according to any one of claims 9 to 15.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, or a pharmacologically acceptable salt thereof as an active ingredient.
An antitumor agent comprising the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient.
A BRAF inhibitor comprising the compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient.
Tumor is leukemia, lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendix cancer, colon cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer , Mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer, endometrial cancer, cervical cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, Kaposi sarcoma, muscle tumor, kidney cancer, bladder The antitumor agent according to claim 18, which is cancer and / or testicular cancer.