TW201124398A - Quinazoline derivatives - Google Patents

Abstract

The present invention provides a compound having BRAF inhibition activity, represented by the following formula (I), or the pharmacologically acceptable salt thereof, [wherein R1 and R2 are, same or different, hydrogen atom, halogen atom, C1-4 alkyl, or halo C1-4 alkyl; R3 is hydroxyl, C2-4 alkynyl(the said C2-4 alkynyl optionally has one hydroxyl or acetoxy as substituent), - NR5aR5b, azetidinyl(the said azetidinyl optionally has one C1-4 alkyl as substituent), oxazolidinyl(the said oxazolidinyl optionally has one oxo as substituent), pyrrolidinyl(the said pyrrolidinyl optionally has one C1-4 alkyl as substituent), dioxanyl, or pyrazolyl; R5a and R5b are, same or different, hydrogen atom, C1-4 alkyl, or hydroxy C1-4 alkyl; R4 is hydrogen or C1-4 alkyl; n is 1 or 2; Y is C-R6 or nitrogen atom; R6 is hydrogen atom or halogen atom].

Description

[Technical Field] 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 the same as an active ingredient. [Prior Art] Classical MAPK (mitogen-activated protein kinase) pathway has been reported

The Ras/RAF/MEK/ERK pathway plays an important role in cell proliferation, differentiation, survival, immortalization, metastasis, angiogenesis, apoptosis, etc., and is reported in a part of cancer cell lines and human clinical tumors. ERK phosphorylation is advanced (see Non-Patent Document 1). Once the cells are stimulated by a growth factor such as EGF or PDGF, Ras is activated, and the RAF protein recruited on the cell membrane is phosphorylated. In this way, the active RAF is activated by phosphorylation of the downstream Μ 1/2 1/2 (MAP protein kinase 1/2), and the active MEK 1/2 further regulates the downstream ERK1/2 (extracellular signal modulation). The kinase 1/2 (extracellular signal-regulated kinase 1/2) is phosphorylated and activated. Phosphorylated ERK migrates into the nucleus, promotes transcription of Elk-1, c-Myc, CREB, etc., and promotes inhibition of apoptosis or cell proliferation. The Ser/Thr kinase expressed by the RAF retrovirus oncogene has been identified in mammals as ARAF, BRAF, and CRAF (also known as RAF-1 in 201124398). In recent years, it has been reported that B RAF gene mutation is among 60 to 70% of human malignant melanoma (see Non-Patent Document 2). In addition, clinical cancers such as papillary thyroid carcinoma (35 to 70%), cholangiocarcinoma (22%), colorectal cancer (about 10%), and ovarian cancer (14%) are considered to have the same variation (see Non-patent documents 3, 4). In addition, BRAF mutations have also been reported in cancer cell lines such as glioma, lung cancer, sarcoma, breast cancer, and liver cancer. Approximately 90% of the variation is a V600E active variant in which the amino acid residue of the 600th amino acid is substituted with glutamic acid, and it has been reported that this variant BRAF is forcibly expressed in the mouse fibroblast cell line NIH3T3. In the case of the transformer (Non-Patent Document 2), the cells are transformed when they are forcibly expressed by normal melanocytes, and the tumorigenicity is exhibited in nude mice (see Non-Patent Document 5). In addition, it has been reported that cell proliferation is suppressed when the expression amount of the variant BR A F is decreased by RNA interference treatment in the B R A F variant malignant melanoma strain (see Non-Patent Document 6). From the above, it is suggested that B RAF plays an important role in tumors, and tumor proliferation is inhibited when the active variant BRAF is inhibited. Therefore, a compound having an action of inhibiting the kinase activity of BRAF (hereinafter referred to as B RAF inhibitory action) is expected to be an antitumor agent, and is particularly effective as a therapeutic drug for a tumor having BRAF mutation. A compound having a RAF kinase family inhibitory activity which is expected as an antitumor agent, for example, a diphenylurea compound (see Patent Documents 1 to 6) has been reported. -5- 201124398 PRIOR ART DOCUMENT Patent Document Patent Document 1 International Publication No. 00/420 1 2 Booklet Patent Document 2 International Publication Bulletin 2 0 0 5 / 0 0 9 9 6 Booklet 3 Patent Document 3 International Publication Bulletin No. 2 0 0 6 / 0 4 3 0 9 0 Booklet Patent Document 4 International Publication Bulletin 2 0 0 7 / 1 1 3 5 5 Booklet 7 • Patent Document 5 International Gazette No. 2007/ 1 1 905 Book No. 5 Patent Document 6 International Publication No. 2008/04468 No. 8 Booklet Non-Patent Document Non-Patent Document 1 Hoshino et al., Oncogene, vol. 18, 813-822, 19 99 Non-Patent Document 2 Davies et al., Nature , vol. 417, 949-954, 2002 Non-Patent Document 3 Tuveson et al., Cancer Cell vol. 4, 95-98, 20 03 Non-Patent Document 4 Tannapfel et al., Gut vol. 52, 706-7 1 2, 2003 Non-Patent Document 5 Wellbrock et al., Cancer Res., vol. 64, 2338-2342, 2004 Non-Patent Document 6 Sumimoto et al., Oncogene, vol. 23, 603 1 - 6039, 2004) 201124398 [Summary of the Invention] [Invention 槪[The subject to be solved by the invention] The present inventors focused on compounds having a BRAF inhibitory action. As a result of the investigation, it was found that the compound of the present invention represented by the formula (I) (hereinafter also referred to as "the compound (〇") exhibits potent BRAF inhibition and cell proliferation inhibitory effects in vitro, and is also excellent in vivo. The present invention is accomplished by oral administration, drug dynamics, metabolic stability, and exhibiting excellent BRAF inhibition, antitumor effect, and safety. Accordingly, the object of the present invention is to provide a compound having BRAF inhibition or A pharmacologically acceptable salt. The other object of the present invention is to provide a pharmaceutical, a pharmaceutical composition, an antitumor agent containing the above compound or a pharmacologically acceptable salt thereof as an active ingredient, in particular, a pharmaceutical composition for a BRAF variant tumor [Means for Solving the Problem] That is, the present invention relates to: (U) is a compound of the following formula (a compound represented by U or a pharmacologically acceptable salt thereof, ¢:

201124398 [wherein R1 and R2 are the same or different from a hydrogen atom, a crypto atom, a Ci-4 alkyl group, or a halogen Cm alkyl group, and R3 is a hydroxyl group or a C2.4 alkynyl group (the C2.4 alkynyl group may have 1 hydroxy or ethoxylated as a substituent), NR5aR5b, azetidinyl (the azetidinyl group may have 1 Ci-4 alkyl group as a substituent), oxazolidinyl (the oxazolidinyl group may have 1) a pendant oxy group as a substituent), a pyrrolidinyl group (the pyrrolidinyl group may have 1 Ci-4 alkyl group as a substituent), a dioxanyl group or a pyrazolyl group, and the ruthenium 58 and R5b are the same or different in a hydrogen atom. , Cl. 4 alkyl or hydroxy (^-4 alkyl, R4 is a hydrogen atom or a Cu alkyl group, η is 1 or 2, Υ is C-R6 or a nitrogen atom, and R6 is a hydrogen atom or a halogen atom). And a pharmacologically acceptable salt thereof, wherein hydrazine is CH or CF. (3) A compound according to the above (1) or a pharmacologically acceptable salt thereof, wherein hydrazine is a nitrogen atom. The compound of any one of the above (1) to (3) or a pharmacologically acceptable salt thereof, wherein R3 is hydroxy, ethynyl, propynyl, hydroxypropynyl, ethoxypropynyl Amino group Methylamino, ethylamino, isopropylamino, dimethylamino '(2-hydroxyethyl)(methyl)amino, azetidinyl, methyl azetidinyl'ethylpyridinyl, pyrrole Pyridyl, methyl-8 - 201124398 pyrrolidinyl, oxazolidinyl, oxooxazolidinyl, dialkyl or pyrazolyl. (5) Any of the above (1) to (4) A compound or a pharmacologically acceptable salt thereof, wherein the substituent represented by the formula (CH2) n - R3 is 2-hydroxyethyl, prop-2-yn-1-yl, 4-hydroxybut-2- Alkyn-1-yl, 4-ethoxycarbonylbut-2-yn-1-yl, 2-(methylamino)ethyl, 2-(ethylamino)ethyl, 2-(isopropyl Amino)ethyl, 2-(dimethylamino)ethyl, 2-(2-hydroxyethyl)(methyl)aminoethyl, (1-methylazetidin-2-yl)-methyl , (1-ethyl卩f-butyl D-but-2-yl)methyl, 2-(卩仕略B疋-1-yl)ethyl, pyrrolidin-2-ylmethyl, (1-methyl Pyrrolidin-2-yl)methyl, 1,4-dioxan-2-ylmethyl, 2-(2-o-oxy-1,3-oxazolidin-3-yl)ethyl or 2- (1Η-pyrazol-1-yl)ethyl. (6) as in (1) to (5) above A compound or a pharmacologically acceptable salt thereof, wherein R1 is a hydrogen atom, a chlorine atom or a trifluoromethyl group. (7) A compound according to any one of the above (1) to (6) or a pharmacologically acceptable compound thereof And a pharmacologically acceptable salt thereof, wherein R4 is a methyl group. (9) 1 -{2-[2-(Dimethylamino)ethoxy]-5-(trifluoromethyl)pyridin-3-ylindole-3- { 3-[(3-methyl-4-lateral oxygen) Base - 3,4-dihydroquinazoline-6-yl)oxy]phenyl}urea. (10) 1- { 3-[( 3 -Methyl-4 -p-oxy-3,4-dihydrothiazoline-6-yl)oxy]phenyl} -3-[2-{[( 2S) -1-Methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)phenyl]urea. -9- 201124398 (11) 1-(4-Chloro-2-{[(2S) -1-methylpyrrolidin-2-yl]methoxy}phenyl)-3-{3-[(3- Methyl-4-oxo-3,4-dihydroquinazoline-6-yloxy]phenyl}urea. (12) 1-[2-{ [( 2S) -1-methylazetidin-2-yl]methoxy} -5-(trifluoromethyl)pyridin-3-yl]-3- { 3 -[(3-Methoxy-4-o-oxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea. (13) 1-[2-{ [( 2S) -1-ethylazetidin-2-yl]methoxy} -5-(trifluoromethyl)pyridine-3-yl]-3- { 3 -[(3-Methoxy-4-o-oxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea. (Μ) 1- { 3-[(3-Methyl-4-oxo- 3,4-dihydroquinazolin-6-yl)oxy]phenyl} -3-[2-{[( 2R) -1-methylpyrrolidin-2-yl]methoxy}-5-(dimethylmethyl)benzyl]. (15) 1-(4-Chloro-2-{[(2S)-1-methylazetidin-2-yl]methoxy}phenyl)-3-{ 3-[(3-methyl- 4_Sideoxy·3,4-dihydrothiazoline-6-yloxy]phenyl}urea. (1) A pharmacologically acceptable salt of the compound according to any one of the above items (9) to (5). (17) A pharmaceutical composition containing the above (1) to (16) The compound of any one of sS or a pharmacologically acceptable salt thereof is an active ingredient. (18) An antitumor agent which contains the compound as set forth in any one of the above items (1) to (16) or The pharmacologically acceptable salt is an active ingredient. -10-201124398 (1 9 ) A BRAF inhibitor comprising the compound according to any one of the above (1) to (6) or pharmacologically acceptable thereof (20) The antitumor agent according to (18) above, wherein the tumor is leukemia, lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendix cancer, large intestine Cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, digestive tract stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, renal pelvic cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer , uterine body cancer, cervical cancer, ovarian cancer, osteosarcoma, A sarcoma, a Kaposi's sarcoma, a muscle tumor, a renal pelvic cancer, a bladder cancer, and/or a ninth cancer. Further, the present invention provides the method according to any one of the above (1) to (16) A compound or a pharmacologically acceptable salt thereof, which is obtained by administering a pharmaceutical composition according to any one of the above (17) to (20) to a warm-blooded animal (preferably a human) In the present specification, "BRAF inhibition" means an action of inhibiting the kinase activity of BRAF, and "BRAF inhibitor" means a compound having the BRAF inhibitory effect, but the compound of the present invention It may also have other kinase inhibitory effects, and it is preferred to have a kinase activity which inhibits protein related to angiogenesis, and it is preferable to obtain a more excellent antitumor effect. In the present specification, "C, _4 alkyl group" Refers to a linear or branched alkyl group having 1 to 4 carbon atoms, which may be exemplified by methyl, ethyl, propyl, isopropyl, butyl 201124398, isobutyl, secondary butyl, and Butyl butyl, etc. "c2-4 alkynyl" And a monovalent group of one hydrogen atom of any one of the straight or branched chain alkane having 2 to 6 carbon atoms, and examples thereof include an ethynyl group, a 1-propynyl group, a 2-propynyl group, and the like. 1 - butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, etc. Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. "halogen C!-4 yard base" means a group in which the aforementioned Ci_4 yard group is substituted with 1 to 3 identical or different halogen atoms, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a chlorine group. Methyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 1,2-difluoroethyl, 2-trifluoroethyl, 2-chloroethyl, i,2-dichloroethyl, 1,1,2-trichloroethyl, 1,2,2-trichloroethyl and 2,2,2-trichloroethyl. "Hydroxy C!-4 alkyl" means a group in which the above Ci-4 alkyl group is substituted with 1 to 2 hydroxy groups, hydroxymethyl group, dihydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, I, 2- Dihydroxyethyl and the like. The "Cl_4 alkoxy group" means a group consisting of the above-mentioned "Cl-4 alkyl group" and an oxygen atom, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. The following is a description of the compound of the present invention represented by the formula (I). R1 and R2 are the same or different and are a hydrogen atom, a halogen atom, a Cl_4 alkyl group, or a halogen Ci_4 alkyl group. R1 is preferably a hydrogen atom or a chlorine atom 'methyl group or trifluoromethyl group'. More preferably, it is a hydrogen atom, a chlorine atom or a trifluoromethyl group, and particularly preferably a trifluoromethyl group. R2' is preferably a hydrogen atom, a chlorine atom or a methyl group, more preferably a hydrogen atom or a chlorine atom. A preferred combination of R1 and R2, when Ri is a hydrogen atom, a chlorine atom or a trifluoromethyl group, R2 is a hydrogen atom, a chlorine atom or a methyl group. A more preferred combination of Ri and R2 When R1 is a trifluoromethyl group, R2 is a hydrogen atom or a chlorine atom. 201124398 R stomach@yl, c2_4 alkynyl (the C2-4 alkynyl group may have 1 hydroxy or ethoxylated group as a substituent), a NR5aR5b, azetidinyl group (the azetidine g W_1 C 1 ·4 alkane) a group as a substituent), an oxazolidinyl group (the one of the oxazolidinyl group W as a substituent), a pyrrolidinyl group (the pyrrolidinyl group may have one (^_4 alkyl group as a substituent), two噚alkyl or pyrazolyl. The definition of NR5aR5b in the definition of r3 means that the amine group is substituted by 1153 and R5b. R5a and R5b are the same or different in hydrogen atom, Ci 4 alkyl or hydroxyCl.4 Preferably, the same or different is a hydrogen atom, a methyl group, an ethyl group or a hydroxyethyl group. As a NR5aR5b, an amine group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamine is preferred. Or (2-hydroxyethyl)(methyl)amino group. R3' is preferably hydroxy, ethynyl, propynyl, hydroxypropynyl, ethoxypropynyl, amine, methylamine. , ethylamino, isopropylamino, dimethylamino, (2-hydroxyethyl) (methyl) amine, azetidinyl, methyl azetidinyl, ethyl azetidinyl, pyrrole Methyl pyrrolidinyl, oxazolidinyl, oxooxazolidinyl, dialkyl or pyrazolyl, more preferably dimethylamino, azetidinyl, methyl azetidinyl, ethyl hydrazine Butyryl, pyrrolidinyl or methylpyrrolidinyl, particularly preferably dimethylamino, 丨-methylazetidine-2-yl, 1-ethylazetidin-2-yl or 1-methylpyrrole Acridine-2-yl. η is 1 or 2. The substituent represented by the formula -(CH2)n-R3 is preferably 2-hydroxyethyl, 2-(methylamino)ethyl or propyl-2. -alkyn-1-yl, 4-hydroxybut-2-yn-1-yl, 4-ethoxycarbonylbut-2-yn-1-yl, 2-(ethylamino)ethyl, 2-( Isopropylamino)ethyl, 2-(dimethylamino)ethyl, 2-(2--13- 201124398 hydroxyethyl)(methyl)aminoethyl, (1-methyl-methyl) Pyridin-2-yl)methyl, (1-ethylazetidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl, pyrrolidin-2-ylmethyl, (1- Methyl pyrrolidin-2-yl)methyl, 1,4-dioxan-2-ylmethyl, 2-(2-o-oxy-1,3-oxazolidin-3-yl)ethyl or 2-( 1H-pyrazol-1-yl)ethyl, more preferably 2-(methylamino)ethyl, 2- (ethylamino)ethyl, 2-(isopropylamino)ethyl, 2-(dimethylamino)ethyl, 2-(2-hydroxyethyl)(methyl)aminoethyl , (1-methylazetidin-2-yl)methyl, (1-ethylazetidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl, pyrrolidine-2 -ylmethyl, (1-methylpyrrolidin-2-yl)methyl, 1,4-dioxan-2-ylmethyl, 2-(2- oxo-1,3-oxazolidine 3-yl)ethyl or 2-(1Η-pyrazol-1-yl)ethyl, particularly preferably 2-(dimethylamino)ethyl, (1-methylazetidin-2-yl )methyl, (1-ethylazetidin-2-yl)methyl or (1-methylpyrrolidin-2-yl)methyl. R4 is a hydrogen atom or a Cb4 alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a methyl group. Y is C-R6 or a nitrogen atom. R6 is a hydrogen atom or a halogen atom, preferably a hydrogen atom or a fluorine atom, more preferably a hydrogen atom. Y is preferably C-H, C-F or a nitrogen atom, more preferably a C.-hydrazine or a nitrogen atom. In the formula (I), R1, R2, -(CH2) n - a preferred combination of R3, R4, and Y are: R1 is a hydrogen atom, a chlorine atom or a trifluoromethyl group, and R2 is a hydrogen atom, a chlorine atom or a Base, -14- 201124398 -(CH2) n-R3 is 2-(methylamino)ethyl, 2-(ethylamino)ethyl, 2-(isopropylamino)ethyl, 2- (Dimethylamino)ethyl, 2-(2-hydroxyethyl)(methyl)aminoethyl, (1-methylazetidin-2-yl)methyl, (1-ethyl hydrazine) Adenyl-2-yl)methyl '2-(indolebi B疋-1-yl) ethyl, pyrrolidine-2-ylmethyl, (1-methylpyrrolidin-2-yl) A 1,1,2-dioxan-2-ylmethyl, 2-(2-o-oxy-1,3-oxazolidin-3-yl)ethyl or 2-(1Η-pyrazole-1- Ethyl), R4 is a hydrogen atom, a methyl group or an ethyl group, and Y is a nitrogen atom. In the formula (I), a preferred combination of R1, R2, -(CH2)n_R3, R4 and Y is · R1 is a hydrogen atom, a chlorine atom or a trifluoromethyl group, and R2 is a hydrogen atom, a chlorine atom or a methyl group, (CH2) n—R3 is 2-(methylamino)ethyl, 2-(ethylamino)ethyl, 2-(isopropylamino)ethyl, 2-(dimethylamino) Ethyl, 2-(2-hydroxyethyl)(methyl)aminoethyl '(1-methylazetidin-2-yl)methyl, (1-ethylindole D疋-2- Methyl, 2-(indolyl)-ethyl, pyrrolidin-2-ylmethyl, (1-methylpyrrolidin-2-yl)methyl, 1,4-di噚-alkyl-2-ylmethyl, 2-(2-o-oxy-1,3-oxazolidin-3-yl)ethyl or 2-(1 Η-pyrazol-1-yl)ethyl, R4 It is a hydrogen atom, a methyl group or an ethyl group, and Υ is CH. -15- 201124398 In the formula (I), R1, R2, - (CH2) The most preferable combination of n-R3, R4 and Y is · R1 is a trifluoromethyl group, R2 is a hydrogen atom or a chlorine atom, _ (CH2) n-R3 is 2-(dimethylamino)ethyl, 1-methylazetidin-2-yl)methyl, (1-ethylazetidin-2-yl)methyl, 2- ( Pyrrrolidin-1 -yl)ethyl, pyrrolidin-2-ylmethyl or (1-methylpyrrolidin-2-yl)methyl, R4 is methyl and Y is a nitrogen atom. In the formula (I), R1, R2, -(CH2) n - R3, R4 and Y are other preferred combinations: R1 is a trifluoromethyl group, R2 is a hydrogen atom or a chlorine atom, and -(CH2)n_R3 is 2 -(dimethylamino)ethyl, 1-methylazetidin-2-yl)methyl, (1-ethylazetidin-2-yl)methyl, 2-(pyrrolidin-1- Ethyl, pyrrolidin-2-ylmethyl or (1-methylpyrrolidin-2-yl)methyl, R4 is methyl and Y is CH. Further, the compound (I) is preferably a compound of any one of the examples or a pharmacologically acceptable salt thereof, and particularly preferably a 1-{2-[2-(dimethylamino)ethoxy group. ]-5-(trifluoromethyl)pyridin-3-yl}-3-{3-[(3-methyl-16- 201124398 -4- oxo- 3,4-dihydroquinazoline-6 -yl)oxy]phenyl}urea, b { 3_[( 3 - methyl-4-oxooxy-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-dihydroquinazolin-6 -yl)oxy]phenyl}urea, 1-[2-{[(2S)-1-methylazetidin-2-yl]methoxy}-5-(trifluoromethyl)pyridine-3 -yl]-3-{ 3-[(3-methyl-4-o-oxo-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea, 1-[2-{ [(23)-1-ethylazetidin-2-yl]methoxy}-5-(trifluoromethyl)pyridin-3-yl]-3-{ 3-[(3-methyl-4) -Sideoxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea, 1-{3-[(3-methyl-4- oxo-3,4-di Hydrothiazoline-6-yl)oxy]phenyl} -3-[2-{ [( 2R) -1- Methyl pyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)phenyl]urea, or 1-(4-chloro-2-{[(2S)-1-methylazetidine -2-yl]methoxy}phenyl)-3-{ 3-[(3-methyl-4-o-oxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl Urea or a pharmacologically acceptable salt thereof. In the present invention, the "pharmaceutically acceptable salt" means a compound having a nitrogen atom or a basic substituent among the compounds (I), and it can be used as a salt according to a usual method, so it is called These salts. As such salts, for example, salts of inorganic acids such as hydrochlorides, hydrogen bromides, sulfates, nitrates, phosphates, and the like; acetates, fumarates, maleates, and the like are exemplified. a salt of a carboxylic acid such as an oxalate, a malonate, a succinate, a citrate or a malate; a methanesulfonate, an ethanesulfonate, a besylate or a tosylate; a salt of a sulfonic acid; a salt of an amino acid such as glutamate or aspartic acid hydrochloride. -17- 201124398 The compound (I) or a pharmacologically acceptable salt thereof is placed in the atmosphere or recrystallized, and it may absorb water, adhere to adsorbed water, or become a hydrate. These hydrates are also included in the present invention. . The compound (I) or a pharmacologically acceptable salt thereof may be a solvate by being placed in a solvent or recrystallized, and such solvates are also included in the present invention. The compound (I), a salt thereof or a solvate thereof may contain a geometric isomer, a tautomer or a d-body or a body of a cis, a trans form or the like via a type or a combination of the substituents. And other isomers such as optical isomers, but the compounds of the present invention include such all isomers, stereoisomers, and any ratio of such isomers, unless otherwise specified Stereo isomer mixture. In addition, the present invention also includes a compound which is an active ingredient of the pharmaceutical composition of the present invention, which is converted to an active ingredient of the pharmaceutical composition of the present invention by a reaction such as an enzyme or a gastric acid under physiological conditions in a living body, that is, an enzyme-induced oxidation, reduction, hydrolysis, or the like. The compound which is a compound (I) or a "pharmaceutically acceptable prodrug compound which changes to the compound (I) by hydrolysis or the like by gastric acid or the like. In the case of the above-mentioned prodrug, where the amine group is present in the compound (I), a compound which is thiolated, alkylated, or phosphorylated is exemplified (for example, the amine group is thiolated, Alanyl thiolation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl Methylation, trimethylacetoxymethylation, tertiary butylation, etc., etc., in the case where a hydroxyl group is present in the compound (I), 18-201124398 can be exemplified by the hydroxy group, alkane A compound that is phosphorylated, phosphorylated, or borated (for example, this hydroxyl group is acetylated, hexadecanylated, propylated) trimethylacetylated, amber thiolated, antibutene A compound, a propylamine thiolated, a dimethylaminomethylcarbonylated compound, etc.). The prodrug of the compound of the present invention can be produced from the compound (I) by a known method. Further, the prodrug of the compound of the present invention is also included as a compound (I) under physiological conditions in the manner described in the ninth page of the molecular design of the "Development of Pharmaceutical Products", published in the 1990 issue of Hirokawa Shoten. )By. Further, the present invention also encompasses compounds which are identified by various radioactive or non-radioactive isotopes. [Effect of the Invention] The compound of the formula (I) or a pharmacologically acceptable salt thereof of the present invention is substituted by a substitution represented by the formula -(CH2)n-R3 based on a urea-binding terminal aromatic ring, and then substituted The position is made into the ortho position of the urea group, which shows strong BRAF inhibition and cell proliferation inhibition effect in vitro, and has good oral administration, drug dynamics, metabolic stability, and excellent B RAF inhibition even in vivo. Function, anti-tumor effect, safety. Therefore, the pharmaceutical composition containing the compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is used as an anti-leukemia, lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, large intestine Cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, digestive tract stromal tumor, lung cancer, liver cancer, mesothelioma 'thyroid cancer, renal pelvic cancer, prostate cancer, neuroendocrine tumor, malignant melanoma, breast cancer, uterus Body cancer, cervical -19- 201124398 Cancer, ovarian cancer, osteosarcoma, soft sarcoma, Kaposi's sarcoma, muscle tumor, renal pelvic cancer, bladder cancer, and sputum cancer are effective, especially It is considered to be effective as a therapeutic drug for tumors caused by B RAF mutation. As a tumor which is considered to be caused by the BRAF mutation, for example, malignant melanoma, colon cancer, ovarian cancer, thyroid cancer, cholangiocarcinoma, glioma, lung cancer, sarcoma, breast cancer, and hepatic carcinoma can be exemplified. [Embodiment] [Best aspect for carrying out the invention] The compound of the invention having the general formula (I) can be easily produced according to the method described below. In the description of the solvent in the present specification, examples of the aliphatic hydrocarbons include hexane, Gengyuan, ligroin, and petroleum ether. Examples of the acid include diethyl ether, diisopropyl ether, and tetrahydrofuran. , dioxane, dimethoxyethane, monoethylol monomethyl acid, etc., as aromatic hydrocarbons, for example, toluene, benzene, xylene, etc., as halogenated hydrocarbons, methylene chloride, chloroform, Carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, etc., as the ketones, may be exemplified by acetone, methyl ethyl ketone, etc., and as the lower alkyl nitriles, acetonitrile, propionitrile or the like, may be exemplified as hydrazine. Examples of the amines include formazan, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, trimethylamine hexamethylphosphate, and the like. Examples of the fluorenes include dimethyl hydrazine and the like. Examples of the hydrazines include cyclazone, and the like, and examples of the alcohols include methanol, ethanol, η-propanol, isopropanol, η-butanol, and isobutylene. Alcohol, t-butanol, isodecyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve, etc., as lower alkyl alcohols For example, methanol, ethanol, propanol, butanol, and the like can be exemplified. -20- 201124398 In the description of the base in the present specification, examples of the alkali metal carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and carbonic acid planing. Examples of the alkali metal bicarbonate include lithium hydrogencarbonate and carbonic acid. Examples of the alkali metal hydrides include lithium hydride, sodium hydride, potassium hydride, and the like. Examples of the metal alkoxides include lithium methoxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide. The organic metal salt may, for example, be butyl lithium, lithium diisopropyl decylamine (LD A ) or lithium bis(trimethyldecyl) decylamine. Examples of the organic amines include triethylamine. , tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine, 4-(N,N-dimethylamino)pyridine, N, N-dimethylaniline, N,N-diethylaniline, anthracene, 5 _diindole bicyclo[4.3_0]non-5-ene, 1,4-dioxabicyclo[2.2.2] 辛院(〇八8(:〇), 1,8-diindolebicyclo[5_4·0]-7-undecene (DBU), etc. Further, as a base, the above base may be used in combination. The following describes the related method. Method for producing compounds (la), (lb), (Id), and (If) ο

Step A2

-2 1 - 201124398

Step A4a

R3/(CH2)n

(8)

-22 201124398 In the above formula, R1, R2, R3, R4, R5a, R5b, γ and η have the same meanings as defined above, X represents a halogen atom, m represents 2 or 3, and Rule 7 represents a hydrogen atom or a Cw alkyl group. Step A1 The step A1 is a step of producing the compound (3), which is carried out by reacting 3-aminophenol (1) with an organohalogen (2) in the presence of a solvent. The solvent to be used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aliphatic hydrocarbons, ethers, aromatic hydrocarbons, halogenated hydrocarbons, and lower alkyl nitriles. And guanamines, lower alkyl alcohols or water, preferably guanamines, most preferably N,N-dimethylformamide. The solvent used in the above reaction is not particularly limited, but examples thereof include alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, metal alkanols, organic amines, and organometallic bases. Or a combination of the above bases is preferably an alkali metal carbonate, particularly preferably potassium carbonate. The reaction temperature varies depending on the type of the starting compound, the reagent, the solvent, etc., and is usually carried out at 〇 ° C to 200 ° C, but it is from 50 ° C to 15 ° C. The reaction time varies depending on the reaction temperature, the starting compound, the reagent, and the solvent, and is usually from 1 hour to 72 hours, preferably from 3 hours to 24 hours. Step A2 The step A2 is a step of producing the compound (4) by catalytic reduction of the nitro group of the compound (3) in a solvent. -23- 201124398 The solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aliphatic hydrocarbons, aromatic hydrocarbons, esters, ethers, and alcohols. An organic acid such as acetic acid, hydrochloric acid, water or a mixed solvent of the above solvent and water is preferably an alcohol, more preferably methanol. The catalyst used for the catalytic reduction is not particularly limited as long as it is a reaction which is usually a reaction for reducing a nitro group, but is preferably palladium-calcium carbonate, palladium-alumina, palladium-carbon, palladium-sulfuric acid. Palladium such as ruthenium or ruthenium such as ruthenium-alumina is more preferably palladium-carbon. The hydrogen pressure is not particularly limited, but is usually carried out at 1 to 10 atmospheres, preferably 1 atmosphere. The reaction temperature varies depending on the type of the catalyst, the solvent, and the like, but is usually -2 (TC to 100 ° C, preferably 20 ° C. The reaction time varies depending on the reaction temperature, the catalyst, the type of the solvent, and the like. , but usually from 30 minutes to 48 hours, preferably from 1 hour to 24 hours. Step A3 Step A3 is a step of producing compound (5) in a solvent, in the presence of a base, via The solvent to be used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include ethers, alcohols, guanamines, water, or the like. The mixed solvent of the solvent or the mixed solvent of the above solvent and water is preferably a mixed solvent of an alcohol and water, and is preferably a mixed solvent of methanol and water. -24- 201124398 As the base used in the above reaction, as long as it is usual The base to be used for the hydrolysis can be 'not particularly limited', for example, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal hydride, an alkali metal hydroxide, an alkali metal alkoxide or an organic amine. Preferred is an alkali metal hydroxide, preferably Sodium hydroxide. The reaction temperature varies depending on the solvent, the type of the base, etc., and is usually -78 ° C to 150 ° C, preferably -5 0 ° C to 1 0 0 t: most preferably 2 0 ° C. The reaction time varies depending on the reaction temperature, the solvent, the kind of the base, etc., and is usually from 30 minutes to 48 hours, preferably from 1 hour to 24 hours. Step A4a Step A4a is a step of producing the compound (6), The hydrazine is used as a solvent to be used in the above reaction by reacting the compound (5) with formamide in the presence or absence of a solvent, and is not particularly limited as long as it does not inhibit the reaction. For example, an ether can be exemplified. Examples, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles, guanamines, lower alkyl alcohols, preferably solvent-free. The reaction temperature varies depending on the solvent, etc., usually from 20 ° C to 200 ° It is carried out in C, but preferably from 100 ° C to 150 ° C. The reaction time varies depending on the reaction temperature, the solvent, etc., but is usually from 1 hour to 72 hours, preferably from 3 hours to 24 hours. 25- 201124398 Step A4b Step A4b is the step of producing a compound (1〇) in the presence of a dissolved acid. The solvent to be used in the above reaction is not particularly limited as long as it does not inhibit the present reaction, and the ether (A) is exemplified as the solvent. Hydrocarbonated hydrocarbons, lower alkyl nitriles, decylamines, lower alkyl alcohols, lower alkyl alcohols, preferably methanol. As the acid used in the above reaction, as long as the acid catalyst is usually used in the reaction The reaction is not particularly limited, and examples thereof include inorganic acids such as hydrochloric acid and sulfur; organic acids such as acetic acid and P-toluenesulfonic acid; and organic acids, preferably P-toluenesulfonic acid. The reaction temperature depends on the solvent and the type of the acid. Equally, it is usually carried out at 0 ° c 3 , preferably 5 (TC to 100 ° C). The reaction time varies depending on the reaction temperature, the solvent, the kind of the acid, etc., from 1 hour to 72 hours, preferably from 3 hours to 24 hours. Step A5, step A5 is a step of producing compound (7), which is used as a solvent used in the above reaction by removing the formazan group of compound (6) in the presence of a solvent, as long as the reaction is not inhibited. It is not particularly limited, and examples thereof include a solvent mixture of an ether, an aromatic hydrocarbon hydrocarbon, a lower alkyl nitrile, a guanamine, and a lower alkyl alcohol, preferably a cyclized hydrocarbon. The solvent is mixed with a lower alkyl group, preferably a mixed solvent of dichloromethane and methanol. The amine in the agent, that is, the halogen is preferably used as the acid, preferably ΐ 150 ° C, usually in the middle, the acid is the class, the halogen, or the alcohol -26- 201124398 The acid to be used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction, and examples thereof include inorganic acids such as hydrochloric acid; and organic acids such as acetic acid and P-toluenesulfonic acid are preferred. The inorganic acid 'best is hydrochloric acid. The reaction temperature varies depending on the solvent, the type of the acid, etc., and is usually -1 50 ° C, preferably -5 〇 ° C to 100 ° C, most preferably 20 ° C. The reaction time varies depending on the solvent, the acid, the reaction temperature and the like, and is usually from 24 hours to 12 hours, preferably from 1 hour to 12 hours. Step A6 Step A6 is a step of producing a general formula (la) to (lb) by reacting the compound (7) to the compound (1) with an amine having (8) (isocyanate method, amine group A) The acid ester method is an isocyanate method which produces an isocyanate with an amine of the general formula (8) and phosgene, via the isocyanate and the compound (7) (10) in a solvent, in the presence of a base or in the absence of a base. The reaction is carried out by a lower (preferably) reaction. The solvent to be used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aliphatic hydrocarbons, ether aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles, and decylamines. The mixed solvent of the above solvent is preferably a mixture of an ether and a guanamine. A mixed solvent of tetrahydrofuran and N,N-dimethylformamide is not particularly limited as the base to be used in the above reaction, but for example Alkali metal carbonates, alkali metal bicarbonates, organic amines, organic amines, particularly preferably pyridine and triethylamine. The use of acid, sulfuric acid, 7 8 〇 C to 30 minutes of the compound - as usual. For example, the phosgene system used in the above reaction is, for example, phosgene, diphosgene, and triphosgene, preferably in the presence of a compound, a aryl ester or a solvent, preferably -27-201124398. For three phosgenes. The reaction temperature varies depending on the kind of the starting compound, the reagent, the solvent, etc., and is usually -78 ° C to 120 ° C, preferably -20 ° C to 60 ° C. The reaction time varies depending on the reaction temperature, the starting compound, the reagent, the solvent, and the like, and is usually from 1 hour to 48 hours, preferably from 2 hours to 24 hours. The carbamide method allows the compound (7) to the compound (10). And reacting with a halogenated formate to produce a carbamate by reacting the carbamate with an amine of the general formula (8) in a solvent, in the presence or absence of a base (preferably present) The next step is to carry out the reaction. The solvent to be used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, and lower alkyl nitriles. , guanamines, flavonoids, ring Dingfeng, preferably low-grade yard-based nitriles, especially acetonitrile +. The base to be used in the above reaction is, for example, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal hydroxide, an alkali metal alkoxide or an organic amine, preferably an organic amine, particularly preferably a pyridine. And triethylamine. The halogenated formate used in the above reaction is, for example, ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate or p-nitrophenyl chloroformate, preferably phenyl chloroformate. The reaction temperature varies depending on the kind of the starting compound, the reagent, the solvent, etc., and is usually 〇 ° C to 120 ° C, preferably 60 ° C. -28- 201124398 The reaction time varies depending on the reaction temperature, starting materials, reagents, solvents, etc., and is usually from 1 hour to 48 hours, preferably from 2 hours to 〇A7a. Step A7 a is manufactured in the general formula ( The compound of Id) is carried out by condensing a compound having (Ic) with an aldehyde having the general formula (11) in a solvent, in the presence or absence of an acid, and reducing the imine with a hydrogenating agent. The solvent to be used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include ethers, aromatic hydrocarbon hydrocarbons, lower alkyl nitriles, guanamines, and lower alkyl alcohols. The mixed solvent of the solvent is preferably a lower alkyl nitrile, and is preferably an acid used as the above reaction, and is not particularly limited as long as it is a usual reaction acid catalyst. For example, sulfuric acid can be exemplified. A class of inorganic acids; acetic acid, P-toluenesulfonic acid or the like, preferably inorganic acids, most preferably hydrochloric acid. The hydrogenating agent used in the above reaction is, for example, sodium borohydride, sodium borate or sodium triethoxy hydride hydride, preferably sodium triethoxy hydride. The reaction temperature varies depending on the starting compound, the reagent, the solvent and the acid, but is usually -78 ° C to 120 ° C, preferably CTC to 2 (TC. The reaction time depends on the reaction temperature, the starting compound, the reagent, and the type of the solvent. The difference is usually from minute to 48 hours, preferably 1 hour. The 24 hour step of the agent, the general formula is the type, halogen, or acetonitrile. The hydrochloric acid, organic acid cyanohydrogenation Boron or the like, acid to 24 -29- 201124398 A7b step A7b step is a step of producing a compound of the general formula (If), in the presence of a solvent, in the presence of a base, by having the general formula (Ie) The compound to be reacted with the alkyl halide having the general formula (12) is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aliphatic hydrocarbons and ethers. Ketones, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles, decylamines, lower alkyl alcohols, preferably ketones, preferably acetone. The base used in the above reaction is not particularly Limited, for example, The alkali metal carbonates, the alkali metal bicarbonates, the alkali metal hydrides, the metal alkanols, the organic amines, the organometallic bases or the combination of the above bases are preferably alkali metal carbonates, particularly preferably Potassium carbonate. The reaction temperature varies depending on the type of the starting compound, the reagent, the solvent, etc., and is usually carried out at 0 ° C to 200 ° C, preferably 5 〇»c to i 〇 (^c. The reaction time depends on the reaction temperature, The type of the raw material compound, the reagent, and the solvent varies from 1 hour to 72 hours, preferably from 3 hours to 24 hours. The B method is a compound (8) which is an intermediate of the compound (I) of the present invention. Method -30- 201124398 Method B

O R2

^ Step B1 vo -1 X

RzAYA〇 R3^(CH2)n (15) η0/(Ί

R1' NH, (13)

(15a)

(14) O

Step B2 (15b)

B'crB' (16) R3^(CH2)n 8a ) In the above formula, 'R1, R2, R3, Y and n have the same meanings as defined above. Step B1 Step Step B1 is a step of producing a compound of the general formula (is) by reacting an organohalide having the general formula (13) with an alcohol having the general formula (14) in a solvent in the presence of a base Come on. The solvent to be used in the above reaction is not particularly limited as long as it does not inhibit the reaction. For example, aliphatic hydrocarbons, ethers, aromatic hydrocarbons, halogenated hydrocarbons, lower alkyl nitriles, and guanamines can be exemplified. Preferably, it is an ether or a decylamine, preferably tetrahydrofuran or hydrazine, hydrazine-dimethylformamide. The base to be used in the above reaction is not particularly limited, and examples thereof include alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, metal alkanols, organic amines, and organometallic bases. Preferred are alkali metal hydrides or metal alkanols, particularly sodium hydride or potassium butoxide. The reaction temperature varies depending on the kind of the starting compound, the reagent, the solvent, etc., and is usually carried out at -78 ° C to 150 ° C, but preferably - 20 ° C to 120 ° C, more

The temperature is preferably 20 ° C or 80 ° C -3 1 - 201124398. The reaction time varies depending on the reaction temperature, the starting compound, the reagent, the solvent, etc., and is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours. Step B 2 Step Step B 2 is a step of producing a compound of the general formula (8) in which a nitro group having a compound of the general formula (15) is reduced, preferably via catalytic reduction or metal reduction. . The solvent to be used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, esters, ethers, alcohols, and acetic acid. The organic acid of the kind, hydrochloric acid, water, or a mixed solvent of the above solvent and water is preferably an alcohol, more preferably methanol or aqueous ethanol. The catalyst used for the catalytic reduction is usually not particularly limited as long as it is a reaction for reducing the nitro group, but is preferably palladium-calcium carbonate 'palladium-alumina, palladium-carbon, palladium-sulfuric acid. Palladium such as ruthenium or ruthenium such as ruthenium-alumina is more preferably palladium-carbon. The hydrogen pressure is not particularly limited, but is usually carried out at a pressure of from 1 to 10, preferably 1 atm. The metal used for the metal reduction is usually not particularly limited as long as it is a reaction for reducing the nitro group, but is preferably iron or zinc, more preferably iron. The reaction temperature varies depending on the starting compound, the catalyst or the metal, the kind of the solvent, etc., and is usually -20 ° C to 150 ° C, preferably 20 ° C or 80. (: -32- 201124398 The reaction time varies depending on the reaction temperature, the starting compound 'catalyst or metal, the type of solvent, etc., and is usually from 30 minutes to 48 hours', preferably from 1 hour to 24 hours. Step B3 is a step of producing a compound of the general formula (15b) in the presence of a solvent, a base and a palladium catalyst, via an organohalide having the general formula (15a) and trimethylboroxine. (trimethyl boroxin) (1 6 ) The solvent to be used in the above reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aliphatic hydrocarbons, ethers, aromatic hydrocarbons, and halogens. a hydrocarbon, a lower alkyl nitrile, a guanamine, water, or a mixed solvent of the above solvent and water, preferably a mixed solvent of an ether and water, preferably a mixed solvent of dioxane and water. The base to be used in the reaction is not particularly limited, and examples thereof include alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, metal alkanols, organic amines, and organometallic bases, preferably alkalis. Metal carbonates The palladium catalyst used in the above reaction is not particularly limited as long as it is usually used in a cross-coupling reaction, and examples thereof include (dibenzylideneacetone)palladium and ruthenium (triphenylphosphine). Palladium, palladium acetate, preferably ruthenium (triphenylphosphine) palladium. The reaction temperature varies depending on the type of the starting compound, the reagent, the solvent, etc., and is carried out at 0C to 200C, preferably 20 ° C to 150 ° C. °C, more preferably 100 °c. -33- 201124398 The reaction time varies depending on the reaction temperature, the starting compound, the reagent, the solvent, and the like, and is usually from 1 hour to 72 hours, preferably from 3 hours to 2 hours. The 4-hour C method is a method for producing the compound (13a).

In the above formula, R1 and R2 have the same meanings as described above. Step C1 Step C1 is a step of producing a compound of the general formula (13a), which is carried out by reacting the compound (17) with a chlorinating agent in the presence or absence of a solvent (preferably in the absence of a solvent). . The solvent to be used in the above reaction is not particularly limited as long as it does not inhibit the reaction. For example, an aliphatic hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon or a mixed solvent of the above solvent can be exemplified. The chlorinating agent to be used in the above reaction is usually not particularly limited as long as it is a user of the chlorination reaction, and examples thereof include phosphorus oxychloride, phosphorus trichloride, and phosphorus pentachloride 'sulfur sulphide'. A small amount of sulfinium chloride of N,N-dimethylformamide is preferably a thionium chloride added with a small amount of N,N-dimethylformamide. The reaction temperature varies depending on the starting compound, the reaction reagent, the solvent to be used, etc., and is usually 20 ° C to 15 (TC, preferably 80 ° C. -34 - 201124398 Reaction time depending on the reaction temperature, starting compound, reaction reagent The type of solvent to be used varies from 30 minutes to 48 hours, preferably from 1 hour to 24 hours. After the end of the reaction, the compound of each step can be recovered from the reaction mixture by a usual method. For example, 'appropriate neutralization The reaction mixture, in the case where the insoluble matter is present, is removed by filtration, and an organic solvent such as ethyl acetate which is not mixed with water is added, and after washing with water or the like, the organic layer containing the objective compound is separated to have no water. After drying over magnesium sulfate, anhydrous sodium sulfate, etc., it is obtained by distilling off the solvent. The obtained target compound can be isolated and purified if necessary by the following methods: conventional recrystallization, reprecipitation, or separation and purification of an organic compound. A conventional method, such as adsorption column chromatography of a carrier such as tannin extract, alumina, or magnesium-ruthenium-based Florisil; using Sephadex L Η - 2 0 (P ha Method for synthesizing adsorbent, such as distribution of column chromatography, such as Amberlite X AD-1 1 (manufactured by Rohm and Haas Co., Ltd.), Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation), etc. The method of exchange chromatography, or a suitable combination of sulfhydryl or alkylated tannin by cis-phase reverse phase column chromatography (preferably high-speed liquid chromatography), is dissolved by a suitable dissolving agent. Further, the compound of the present invention (I), in the case where R3 is a hydroxyl group or an amine group, as necessary, for example, as described in "Green's PROTECTING GROUPS in ORGANIC SYNTHESIS 4th Edition" (WIL E Y-IN TERSC IEN CE 2007) The method of producing a target substance by applying a detachment of a protecting group. -35- 201124398 A case where the compound of the formula (I) or a pharmacologically acceptable salt thereof of the present invention is used as the above-mentioned therapeutic or prophylactic agent, Mixing with excipients, diluents, and the like, as appropriate, or by appropriate pharmacologically acceptable excipients, such as tablets, capsules, granules, powders, syrups, etc., or by injection or suppository, etc. These preparations It can be produced by a known method using any of the following: excipients (for example, sugar derivatives such as milk, sugar, sugar, glucose, mannitol, sorbitol, etc.; corn starch, potato starch, alpha starch, dextrin) Starch derivatives such as cellulose derivatives; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; pullulan (Pul lul an) and other organic excipients: and, light anhydrous citric acid, conversion 矽a citrate derivative such as aluminosilicate, calcium citrate or magnesium metasilicate aluminate; a phosphate such as calcium hydrogen phosphate; a carbonate such as calcium carbonate; an inorganic excipient such as a sulfate such as calcium sulfate; And a lubricant (for example, a stearic acid metal salt of stearic acid, calcium stearate, magnesium stearate, etc.; talc; colloidal vermiculite; beeswax, cetyl wax, etc.; boric acid; adipic acid; Sulfate such as sodium sulfate; diol; fumaric acid; sodium benzoate; DL leucine: fatty acid sodium salt; lauryl sulfate of sodium lauryl sulfate, lauryl sulfate, etc.; An acid such as a hydrate; and the above-mentioned starch derivative), a binding agent (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macro gol, and a compound similar to the aforementioned excipient), a breaker (For example, a cellulose derivative having a low degree of substitution of hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internal crosslinked carboxymethylcellulose sodium, or the like; carboxy-36-201124398 Chemically modified starch, cellulose, etc., based on base source powder, sodium thiomethyl starch or crosslinked polyvinylpyrrolidone, and stabilizer (for example, methylparaben, propylparaben) a paraben such as an ester; an alcohol such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; a benzalkonium chloride; a phenol such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid; A flavoring agent (for example, 'can be exemplified by commonly used sweeteners, sours, flavors, etc.), a diluent, and the like. The compounds of the present invention are useful in the treatment of cancer in mammals, especially humans. The amount of administration and the interval of administration depending on the location of the disease, the height, weight, sex or condition of the patient' can be appropriately selected by a physician. The case where the compound of the present invention is administered to humans is administered in an amount ranging from about 0.1 mg/kg body weight to about 500 mg/kg body weight per day, preferably about ln.lnig/kg body weight to about 100 mg/kg. body weight. When it is administered to humans, it is preferably once every 1 day or divided into 2 to 4 times, and it is preferred to repeat at appropriate intervals. In addition, the amount of one day can be determined by the physician to exceed the above amount as necessary. The compounds of the invention can be used with other anti-tumor agents. For example, an antitumor antibiotic anti-tumor botanical component, BRM (biologically reactive control substance), a hormone, a vitamin, an antitumor antibody, a molecular standard drug, and other antitumor agents can be exemplified. More specifically, as the alkylating agent, for example, a hospitalization agent such as Nitrogen Mustard, nitrogen mustard N-oxide or chloram butyl can be exemplified, and Carbofuran ( An aziridine-based alkylating agent such as carboquone or Thiotepa, an epoxide-based alkylating agent such as dibromomannitol or dibromogalactitol , carmustine, lomustinum, semustine, nimustine hydrochloride, streptozocin, chlorozotocin Or a nitrosourea-based compounding agent such as ranimustine, Busulfanum, improsulfan tosilate or dacarbazine. As various metabolic antagonists, for example, a metabolite antagonist such as 6-mercaptopurine, 6-sulfoguanine or thioinosine, fluorouracil D, and tegafur can be exemplified. , tegafur, uranium steep, carmofur, dexifluridine, bromodeoxyuridine: g: (bromodeoxyuridine), cytarabine or ilinoside (enocitabin) And other pyrimidine metabolism antagonists, methotrexate or trimetrexate and other folate metabolism antagonists. As the antitumor antibiotic, for example, mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin can be exemplified. Doxorubicin's onion rings (pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin) Anthracycline ) antibiotic antitumor agent, chromomycin A3 or actinomycin D. -38- 201124398 As an anti-tumor botanical component, for example, vinca alkaloid (vinca alkaloid) such as vindesine, vincristine or vinblastine, and paclitaxel can be exemplified. ), taxanes such as docetaxel, or epipodophyllotoxins such as etoposide or teniposide. As the B RM, for example, a tumor sudden death factor or indomethacin or the like can be exemplified. As the hormone, for example, hydrocortisone, dexamethasone, methylprednisolone, prednisolone, prasteronum, betamethasone can be exemplified. ), triamcinolone, B 哩 oxymetholone, nandrolone, metenolone, fosfestrol, ethinylestradiol, Chlormadinone or medroxyprogesterone. As the vitamin, for example, vitamin C or vitamin A can be exemplified. Examples of the antitumor antibody and the molecular standard include trastuzumab, rituximab, cetuximab, nimotuzumab, and denosmab. Bevacizumab, infliximab, imatinib mesilate, gefitinib, erlotinib, sultanide 39- 201124398 Anti-sunitinib, lapatinib, sorafenib, etc. as other anti-tumor agents, for example, cisplatin, carboplatin, Saliplatin (〇xaiipiatin), tamoxifen, camptothecin derivatives, ifosfamide, CyCi〇ph〇sphamide, melphalan ( Melphalan), L-asparaginase, aceglatone, siZ0firan, Picibanil, procarbazine, berberine Hospital (pipobroma), neocarcinoma (neocarzinostatin), hydroxyl Urea, ubenimex or krestin, etc. The present invention also encompasses a method of preventing and/or treating cancer characterized by administration of a compound of the present invention or a salt thereof. Furthermore, the present invention also encompasses the use of the compound of the present invention for the manufacture of the aforementioned medicine, and the use thereof. [Examples] Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. However, the scope of the present invention is not limited thereto. (Example 1) l-[2- { [( 2S) -1-methyl B-buten-t-yl]methoxy} -5-(trifluoromethyl)phenyl]-3 - { 3 -[ ( 3 -Methyl-4-oxooxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea-40- 201124398

Dissolved in anhydrous tetrahydrogen 11 fucant 4 6 obtained 2 - 丨 [(2 S ) fluoromethyl) aniline 78.0 mg III phosgene 29.7 mg (0.10 mmol) (10 ml), under ice-cooling, the anhydrous Tetrahydrofuran-1-methyl Iff butyl-2-yl]methoxy}-5-(dimethyl (0-30 mmol) and pyridine 47.4 mg (0.60 mm 〇l) solution (5 ml) were dropped. After I5 minutes, it will contain Reference Example 1 6-(3-Aminophenoxy)-3-methylquinazoline·4(3H)·ketone 8〇.lmg (0-30 mmol: 1 and triethylamine 60.6 mg (0.60 mmol) in anhydrous A solution of N,N-dimethylformamide (5 ml) was added dropwise, followed by stirring under ice-cooling for 3 hrs, and then further stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The extract was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by methylene chloride column chromatography (solvent solvent: triethylamine/methanol/ethyl acetate = 1/2/17). Compound 33.6 mg (yield 20%). 'HNMR 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 .5 1 (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, 1.7 Hz), 7.25-7.18 (m, 2H), 6.75 (ddd, 1 H, J = 8.1 Hz, 2.2 Hz, 0.9 Hz), 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) -4 1 - 201124398 IR spectrum, vmax cm·1 (KBr) : 3353,2 9 5 9, 1675,1606, 1 5 48, 1 48 3, 1 443, 1 34 1, 1 27 1 , 1 20 1 , 1 1 3 1 ° Mass spectrometry (FAB+), m/z: 554 ((M + H ))) (Example 2) l-{2-[2-(Dimethylamino)ethoxy]-5-(trifluoromethyl)phenyl} -3 - {3-[( 3- Methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea

2-(2-(Dimethylamino)ethoxy]-5-(trifluoromethyl)aniline and 6-(3-aminophenoxy)-3-methylsoxazoline obtained in Reference Example 1 4 (3H)-ketone was used as a starting material, and the title compound (yield 24%) was obtained according to the method described in Example 1. H NMR spectrum (DMSOd6, 400 ΜΗζ), δ: 9.69 (s, 1H), 8.46 (d, 1H, J = 2.1 Hz), 8.32 (s, 1H), 8.31 (s, 1H), 7.74 (d, 1H, J = 8.8 Hz), 7.58 (dd, 1H, J = 8.8 Hz, 3.0 Hz), 7.52 (d, 1H, J = 3.0 Hz), 7.3 9-7.3 5 (m, 2H), 7.29 (dd, 1H, J = 8.6 Hz, 1.7 Hz), 7.24 (s, 1H), 7.21 (ddd, 1H, J = 8.1 Hz, 2.1 Hz, 0.9 Hz), 6.75 (ddd, 1H, J = 8.1 Hz, 2.4 Hz, 0.9 Hz ), 4.26 (t, 2H, J = 6.2Hz), 3.48 (s, 3H), 2.74 (t, 2H, J = 6.2Hz), 2.24 (s, 6H). -42- 201124398 IR spectrum ' Vmax cm'1 (KBr) : 3 3 5 2,1 6 76,1 605,1 5 5 0, 1 48 3, 1 444, 1 345, 1 270, 1 20 1, 1 1 32° 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-(trifluoromethyl)phenyl]urea

2-(2-pyridyl-1-ylethoxy)-5-(trifluoromethyl)aniline obtained in Reference Example 29 and 6-(3-aminophenoxy)-3- obtained in Reference Example 1. The title compound (yield 2 6 %) was obtained according to the procedure of Example 1 using methyl quinazoline-4 (3 Η )-one as a starting material. 1H NMR spectrum (DMSOd6, 400 ΜΗζ), δ: 9.71 (s, 1 Η), 8.47 (d, 1H, J = 2.1 Hz), 8.35 (s, 1H), 8.33 (s, 1H), 7.74 (d, 1H, J = 8.8 Hz), 7.58 (dd, 1 H, J = 8.8 H z , 2.9 H z ), 7.5 2 ( d,1 H, J =2.9 Hz), 7.3 9 -7.3 5 (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 -2.8 5 (m, 2H), 2.60-2.45 (m, 4H), 1. 7 7 - 1 .6 5 (m, 4H). -43- 201124398 IR spectrum, vmax cm·1 (KBr) : 3 3 62,2959,1 672,1 606, 1550,1 48 3, 1444, 1346, 1 270, 1 20 1, 113 mass spectrometry (FAB+) > m/z: 568 ((M + H)+). (Example 4) l-{2-[2-(Dimethylamino)ethoxy]-5-(trifluoromethyl)pyridin-3-yl}-3-{3-[(3-A) 4-yloxy-3,4-dihydrothiazoline-6-yl)oxy]phenyl}urea

2-[2-(Dimethylamino)ethoxy]-5-(trifluoromethyl)pyridin-3-amine obtained in Reference Example 3 and 6-(3-aminophenoxyl) obtained in Reference Example 1 The title compound (yield 30%) was obtained according to the method described in Example 1 using 3-methyl quinazolin-4(3H)-one as a starting material. NMR spectrum (DMSOd6' 400 MHz), δ: 9.72 (s, 1H), 8.66 (d, 1H, J = 2.2 Hz), 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), 7.40-7.3 6 (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 > vmax cm·1 (KBr) : 3 3 5 8, 3 075, 1 675, 1 6 1 0, 1 5 54, 1 53 3, 1 484, 1 459, 1 348, 1 276, 1 1 47, 1 1 2 1 ° -44- 201124398 Mass spectrum (FAB+), m/z: 543 ((M + H)+). (Example 5) l-{ 2-[(2S)-Azetidin-2-ylmethoxy]-5-(trifluoromethyl)pyridine-3-yl}· 3 - { 3 - [( 3 -methyl-4-o-oxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea dihydrochloride

(2S)-2-({[3-Amino-5-(trifluoromethyl)pyridine-2-yl]oxy}methyl)azetidine-1-carboxylic acid t-butyl obtained in Reference Example 5 The ester and the obtained 6-(3-aminophenoxy)-3-methylquinazolin-4(3H)-one as a starting material were subjected to the post-treatment after the reaction according to the method described in Example 1. Then, deprotection (de-butoxycarbonylation) was carried out using 4N hydrochloric acid / 1,4-dioxane to give the title compound (yield 43%). 'HNMR spectrum (DMSOd6, 400MHz), δ: 10.71 (s, 1H), 9.31 (s, 1H), 8.71 (d, 1H, J = 2.2Hz), 8.38 (s, 1 H), 8.16 (dd, 1H) , J = 2.0Hz, 1.0Hz), 7.75 (d, 1H, J = 8.9Hz), 7.58 (dd, 1 H, J = 8.9Hz, 2.9Hz), 7.50 (d, 1H, J = 2.9Hz), 7.45 (d, 1 H, J -2.3Hz), 7.37 (d, 1H, J = 8.2Hz), 7.28 (ddd, 1H, J = 8.2Hz, 2.0Hz, 1.00Hz), 6.75 (ddd, 1H, J = 8.2 Hz, 2.3 Hz, 1.0 Hz), 4.8 9-4.8 0 (m, 2H), 4.55 (dd, 1H, J = 11.8 Hz, 2.5 Hz), 4.04-3.81 (m, 2H), 3_48 (s , 3H), 2.46-2.42 (m, 2H). -45- 201124398 IR spectrum, vmax cm·1 (KBr) : 3 43 5, 2 9 3 3, 1 7 1 4, 1 6 06, 1 54 1, 1 48 7, 1 452, 1 264, 1 1 57 , 906, 778, 68 8 ° 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-amino group) obtained in Reference Example 1. The title compound (yield 41%) was obtained according to the method described in Example 1 using phenoxy)-3-methylquinazoline-4(3H)-one as a starting material. 4 NMR spectra (DMSOd6, 400MHz), 5: 9.71 (s, 1H), 8.44 (d, 1H, J = 2.1Hz), 8.33 (s, 1H), 8.23 (s, 1H), 7.74 (d, 1H, J = 8.7 Hz), 7.58 (dd, 1H, J = 8.7 Hz, 2.7 Hz), 7.52 (d, 1H, J = 2.7 Hz), 7.38 (d, 1H, J = 2.1 Hz), 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. 7 5 - 1 .5 9 (m, 3H). -46- 201124398 IR spectrum, Vmax cm'1 (KBr) : 3 3 5 1, 295 6, 1 6 7 8, 1 606, 1 549,1 48 3,1 443,1 343, 1 270, 1 20 1 , 1 1 3 1. 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 - (obtained in Reference Example 1) 3-aminophenoxy)-3-methylquinazoline-4(3H)-one was used as a starting material to give the title compound (yield 32%). 'H NMR spectrum (DMSOd6, 400MHz), 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 = 10.9 Hz, 5.2 Hz), 4.39 (dd, 1H, J = 10.9 Hz, 6.3 Hz), 3.48 (s, 3H), 2.99-2.93 (m, 1H), 2.7 0-2.6 3 (m, 1H) , 2.34 (s, 3H), 2.24-2.15 (m, 1H), 2.02-1.94 (m, 1H), 1.7 6-1.61 (m, 3H). -47- 201124398 IR spectrum, vmax cm.1 (KBr) : 3348,2957,1 669,1 607, 1 5 5 0,1 483,1 3 44,1 264,1152,945, 9 1 3 ° Mass spectrometry ( FAB+), m/z: 569 ((M + H)+). (Example 8) [2-( 1,4-dioxan-2-ylmethoxy)-5-(trifluoromethyl)phenyl]_3_ {3-[(3-methyl-4-) Sideoxy-3,4-dihydrooxazoline-6-yl)oxy]phenyl}urea

2-(1,4-dioxan-2-ylmethoxy)-5-(trifluoromethyl)aniline obtained in Reference Example 39 and 6-(3-aminophenoxy)_3-methyl obtained as a reference example The quinazoline-4(3H)-one was used as a starting material to give the title compound (yield: 58%) according to the method described in Example 1. NMR spectrum (DMSOd6,400 ΜΗζ), δ: 9.73 (s, 1H), 8.46 (d, 1H, J = 1.8 Hz), 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 · 8 H z), 7.2 5 - 7.1 9 (m, 2 H), 6 · 7 9 - 6 · 7 4 (m, 1 H), 4.1 9 (dd, 1 H, J = 11.00Hz, 5.96 Hz), 4.12 (dd, 1H, J = 10.55Hz, 4.58Hz), 4.03 -3.92 (m, 2H), 3.8 3 -3.7 6 (m, 1H), 3.72-3.61 (m, 2H), 3.5 8 - 3.5 0 (m, 1H), 3.48 (s, 3H), 3.47-3.3 8 (m, 1H). -48- 201124398 (Example 9) 1-[2-(2-Hydroxyethoxy)-5-(trifluoromethyl)phenyl]-3-{ 3-[(3-methyl_4· side Oxy-3,4-dihydrothiazoline-6-yl)oxy]phenyl}urea

2-(2-{[t-butyl(dimethyl)decyl)oxy}ethoxy)-5-(trifluoromethyl)aniline obtained in Reference Example 37 and 6-(3) obtained in Reference Example 1. -Aminophenoxy)-3-methylquinazoline-4(3H)-one as a starting material, followed by post-treatment after the reaction according to the method described in Example 1, followed by using tetrabutylammonium fluoride Deprotection [de-t-butyl(dimethyl)decanelation] gave the title compound (yield 34%). 1H NMR spectrum (DMSOd6, 400 ΜΗζ), δ: 9.70 (s, 1 Η), 8.48 (d, 1H, J = 2.3 Hz), 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), 6.7 8 -6.7 3 (m 1H), 4.98 (br s, 1H), 4.20 (t, 2H, J = 5.2Hz), 3.82 (dd, 2H, J = 10.1 Hz, 5.2 Hz), 3.48 (s 3H). (Example 1 〇) 1-{3-[(3-Methyl-4-oxooxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl}-3-{2- [2-(lH-pyrazol-1-yl)ethoxy]-5-(trifluoromethyl)phenyl}urea-49- 201124398

2-[2-( 1 Η-pyrazol-1-yl)ethoxy]-5-(trifluoromethyl)aniline obtained in Reference Example 31 and 6-(3-aminophenoxyl) obtained in Reference Example 1. The title compound (yield 63%) was obtained according to the procedure of Example 1 as the starting material. 'Η NMR spectrum (DMSOd6,400ΜΗζ), δ : 9 · 6 3 (s,1 Η), 8.43 (d, 1Η, J = 2.3Hz), 8.33 (s, 1 H), 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), 7.42-7.3 5 (m, 2H), 7.27 (dd, 1H, J = 8.8Hz, 1.9Hz), 7.24-7.20 (m, 1H), 7.16 (d ,1H,J = 8.8Hz), 6.8 0-6.74 (m, 1H), 6.23 (t, 1H, J - 2.1Hz), 4.59 (t, 2H, J = 5.2Hz), 4.52 (t, 2H, J = 5.2 Hz), 3.48 (s, 3H). (Example 11) 1-{3-[(3-Methyl-4-oxo-3,4-dihydroquinazoline-6-yl)oxy]phenyl}-3-{4-A 2-[(2S)-pyrrolidin-2-ylmethoxy]-5-(trifluoromethyl)phenyl]urea

-50- 201124398 (2S ) -2 - { [2-Amino-5-methyl-4-(trifluoromethyl)phenoxy]methyl}pyrrolidine-1-carboxylic acid t_ The base ester and the 6-(3-aminophenoxy)-3-methylsoxazoline-4(3H)-one obtained in Reference Example 1 were used as a starting material, and the reaction was carried out according to the method described in Example 1. Treatment, followed by deprotection (de-butoxycarbonylation) using trifluoroacetic acid afforded the title compound (yield: 57%). 'H NMR spectrum (DMSOd6,400ΜΗζ), δ: 9.59 (s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 8.24 (br s, 1H), 7.74 (d, 1H, J = 8.8 Hz), 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), 1.9 5 - 1.8 4 (m, 1H), 1.7 8 - 1.5 9 (m , 2H), 1.49- 1.3 7 (m, 1H). (Example 1 2 ) l-{4-Chloro-2-[2-(methylamino)ethoxy]-5-(trifluoromethyl)phenyl} -3 - {3-[( 3- Methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea

The 2-(2-amino-5-chloro-4-(trifluoromethyl)phenoxy]ethyl}methylaminecarboxylic acid t-butyl ester obtained in Reference Example 13 and the 6-( 3--51 - 201124398 Aminophenoxy)-3-methylquinazolin-4 (3H)-one as a starting material, followed by the method described in Example 1, followed by post-treatment, followed by 4N Hydrochloric acid / 1,4-dioxane was subjected to deprotection (de-butoxycarbonylation) to give the title compound (yield 40%). NMR spectrum (CDC13, 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 = 4.8 Hz), 2.50 (s, 3H). Mass Spectrum (ESI+), m/z: 562 ( (M + H)+). (Example 1 3 ) l-{2-[2-(ethylamino)ethoxy]-3-fluoro-5-(trifluoromethyl)phenyl}-3-丨3-[ (3- Methyl-4-oxo-3,4-dihydroquinazoline-6-yl)oxy]phenyl}urea

The 2-(2-amino-6-fluoro-4-(trifluoromethyl)phenoxy]ethyl}ethylamine formate t-butyl ester obtained in Reference Example 18 and the 6-(3) obtained in Reference Example 1 -Aminophenoxy)-3-methylquinazolin-4(3H)-one as a starting material, followed by the method described in Example 1, followed by post-treatment, and then -4N for -52-201124398 Hydrochloric acid / I,4-dioxane was subjected to deprotection (t-butoxycarbonylation) to give the title compound (yield 35%). HNMR spectrum (CDC13 > 400MHz) > δ : 9.51 (br s, 1H), 8.42 (s, 1 H), 7.98 (s, 1 H), 7.79 (d, 1 H, J = 2 · 8 H z), 7.7 1 (d, 1H, J - 9.2Hz), 7.48 (dd, 1H, J = 8.7Hz, 2.8Hz), 7.34 (t, 1 H, J = 2.3Hz), 7.30 (t, 1 H , J = 8.3Hz), 7.1 8-7. 1 3 (m, 2H), 6.99 (dd, 1H, J = 10.1 Hz, 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 = 7.1 Hz) ° Mass Spectrum (ESI+), m/z: 560 ((M + H)+). (Example 1 4 ) l-{4·Chloro-2-[2-(isopropylamino)ethoxy]-5-(trifluoromethyl)phenyl} -3- { 3-[ ( 3 -Methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea

The t-butyl {2-[2-amino-5-chloro-4-(trifluoromethyl)phenoxy]ethyl}isopropylaminecarboxylate obtained in Reference Example 24 and 6- obtained in Reference Example 1 (3-Aminophenoxy)-3-methylquinazoline-4(3H)-one as a starting material, followed by the method described in Example 1, followed by post-treatment, followed by '4N hydrochloric acid/1 The 4-dioxane was subjected to deprotection (t-butoxycarbonylation) to give the title compound (yield 28%). -53- 201124398 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 = 9.2 H z, 2.9 H z), 7.49 (d, 1H, J = 2.9Hz), 7.45 (t, 1H, J = 2.0 Hz), 7.40 (s, 1H), 7.37 (t, 1H, J = 8.3Hz), 7.26 (d, 1H, J = 7.4Hz), 6.74 (dd, 1H, J = 8.〇hz> 1.7Hz) , 4.42 (t, 2H, J = 4.6Hz), 3.42-3.51 (m, 6H), 135 (d, 6H, j = 6 3Hz). Mass Spectrum (ESI+), m/z: 590 ( (M + H) + ). (Example 1 5 ) 1- ί 3-[ c 3-methyl-4_sideoxy-3,4-dihydroquinazolin-6-yl)oxy]phenylindole_3_[2-( Prop-2-yn-1-yloxy)-5-(trifluoromethyl)phenyl]urea

The 6-(3-aminophenoxy)-3-methylquinazolin-4(3H)-one obtained in Reference Example 1 was dissolved in anhydrous acetonitrile (5 ml), and chloroformic acid was added. 54.9 mg (O.351 mmol) of vinegar and B=40.1 mg (0.5 08 mmo1) of D are stirred under ice cooling. After 2 hours, 2-(prop-2-yn-1-yloxy)-5-(trifluoromethyl)aniline 74 2 mg (0.345 mmol) and triethylamine 72.6 mg (0.719 mmol) obtained in Reference Example 33 were added. ), stirring at 60 degrees for one night. A saturated aqueous solution of ammonium chloride was added to the mixture, and ethyl acetate was evaporated. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified eluted eluted eluted elution elution iHNMR spectrum (DMSOd6' 400MHz)' 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 -7.3 2 (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 1 6 ) 1- { 3-[ ( 3 -Methyl-4-oxooxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl}·3-{ 2- [2·(2-Sideoxy-1,3-oxazolidin-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-(4-) obtained in Reference Example 41 Trifluoromethyl)phenoxy]ethyl}-1,3-oxazolidin-2-one was used as a starting material to give the title compound (yield: 31%). Ifi NMR spectrum (DMSOd6,400ΜΗζ), 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 = 8.9 Hz), 7.59 (dd, 1H, J = 8.9 Hz, 2.8 Hz), 7.52 (d, 1H, J = 2.8 Hz), 7.42-7.3 4 (m, 2H), 7.30 (d, 1H, J = 2.1Hz), 7.25 -55- 201124398,, ,J = 8.2Hz), 7.20 (dt,1H,J = 8.2Hz,1.0Hz), 6.79- 6.73 (m,1H),4.36 (t,2H,J = 5.5 Hz), 4.25 (dd, 2H, J = 8.7 Hz, 7 3 Hz), 3 7 〇 _3 59 (m, 4H), 3_48 (s, 3H). (Example 丨7) 4-{2_[({3_[(3_methyl-4_ pendantoxy-3,4-dihydroquinazoline-6-S)oxy]phenyl)amine) Amino]-4-(trifluoromethyl)phenoxy}butyl-2-yne·丨-yl ester

6-(3-Aminophenoxy)-3-methylquinazoline-4 (3H)_Flour 1 obtained in Reference Example 1 and Reference Example 35 obtained 4-[2-amino-4-(3) The fluoromethyl)phenoxyl-yl]but-2-yn-1-yl ester was prepared as the starting material. The title compound (yield: 44%) was obtained according to the procedure H NMR spectrum (DMSOd6, 400 MHz), δ: 9 · 6 3 (s, 1 Η), 8.49 (d, 1 Η, j = 2.3 Hz), 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) 〇 (Example 18) 1-{2-[(4-Hydroxybut-2-yn-1-yl)oxy]-5-(trifluoromethyl Phenyl} -3- { 3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea-56- 201124398

The 4-{2-[({3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)amine obtained in Example 17 was obtained. Mercapto)amino]_4_(trifluoromethyl)phenoxy}but-2-yn-1-yl ester 97.8mg (0.168mm〇l) is dissolved in tetrahydrofuran (1. 〇m 1 ), under ice cooling, A 3 N aqueous solution of sodium hydroxide (0.30 ml) was added and stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the mixture. After the filtration, the solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjj NMR spectrum (DMSOd6, 400MHz), δ: 9.65 (s, 1H), 8.5 2 - 8.4 7 (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 1 9 ) 1- { 2-[2-(Isopropylamino)ethoxy]-5-(trifluoromethyl)phenyl} -3- {3-[(3-methyl- 4-sided oxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl hydrazide-57- 201124398

6-(3-Aminophenoxy)-3-methylquinazolin-4(3H)-one obtained in Reference Example 1 and {2-[2-amino-4-(trifluoro) obtained in Reference Example 9 The methyl t) phenoxy]ethyl} isopropyl amide t-butyl ester was used as a starting material, followed by the method described in Example 15, followed by post-treatment, followed by 4N hydrochloric acid / 1,4-di The decane was subjected to deprotection (t-butoxycarbonylation) to give the title compound (yield: 5%). 4 NMR spectrum (CDC13, 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), 7.3 0-7.20 (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) l-[5-Chloro-2-(2-pyrrolidin-1-ylethoxy)phenyl]_3_丨3·[(3-methyl-4-oxooxy-3, 4-Dihydrothiazoline-6-yl)oxy]phenyl}urea-58- 201124398

6-(3-Aminophenoxy)-3-methylsoxazoline-4 (3H)-oxime obtained in Reference Example 1 and 5-chloro-2-(2-pyrenepyrene) obtained by Dream Test 11 The title compound (yield 73%) was obtained according to the method described in Example 15. *H NMR spectrum (CDC13 >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 -7.6 6 (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 = 5.3 Hz), 3.58 (s, 3H), 2.87 (t, 2H, J = 5.0 Hz), 2.69 -2.6 3 (m, 4H), 1.91-1.84 (m, 4H). Mass Spectrum (ESI+), m/z: 534 ((M + H)+). (Example 2 1 ) 1-(4-Chloro-2-{[(28)-1-methyl) 11-but-2-yl]methoxy}phenyl)-3- {3-[( 3 -Methyl-4-oxooxy-3,4-dihydrothiazolin-6-yl)oxy]phenyl}urea-59- 201124398 ο

6-(3-Aminophenoxy)-3-indole (3Η)-one obtained in Reference Example 1 and 4-chloro-2-{[(2S)pyridin-2-yl]methoxy group obtained in Reference Example 20. The title compound (yield 5 5 %) was obtained according to the method. 1 H NMR spectrum (CDC13 > 400 MHz ) > δ : 8.55 (d, 1 H, J = 8·7 Ηζ), 7.97 (s, 1 Η), 7.83 (s, 1 Η), J = 2·8 Ηζ) , 7.69 (d, 1Η, J = 8·7Ηζ), 7.46 (dd, 1 2·8Ηζ), 7.34 (t, 1Η, J = 2·3Ηζ), 7.27 (t, 1Η, 7.18 (d, 1 Η, J = 8_7Ηζ), 6.95 (dd, 1 Η, J = 8: 6.86 (d, 1 Η, J = 2.3Ηζ), 6.70 (dd, 1 Η, J = 7. 4.04 (d, 2Η, J = 3.2Ηζ) ), 3.57 (s, 3Η), 3.21-3 2.62-2.54 (m, 1Η), 2.42-2.32 (m, 4H), 1.98-1. Mass Spectrum (ESI+)> m/z: 534 ((M + H ))) (Example 2 2 ) 1-( 4,5-Dichloro-2-{ [( 2S ) -1-methylpyrrolidine-2 phenyl)-3- { 3-[ ( 3- 4--4-oxo-3,4-dihydroquinoxy]phenyl}urea P-quinazoline-4 -1 -methylpyrrol Example 1 5 (s, 1 H), 8.19 7.79 (d, 1H, H, J = 8.7Hz, J = 8.3Hz), 7Hz, 2.3Hz), 6Hz, 2.1Hz), .13 (m, 1 H), 79 (m, 4H). 1-Base] Methoxy}oxazoline-6-yl) -60- 201124398

6-(3-Aminophenoxy)-3-methylsoxazoline-4 (3H)-one obtained in Reference Example 1 and 4,5-dichloro-2-{[(2S) obtained in Reference Example 22. The title compound (yield 28%) was obtained according to the procedure described in Example 15 as the starting material of -1-methylpyrrolidin-2-yl]methoxy}aniline. NMR spectrum (CDC13, 400MHz), δ: 8.70 (s, 1H), 8.45 (s, 1H), 7.98 (s, 1H), 7.82 - 7.7 5 (m, 2H), 7.70 (d, 1H, J = 9.2 Hz), 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 - 9.7 Hz), 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 -2.5 5 (m, 1H), 2.44-2.3 5 (m, 4H), 1.9 7 - 1.8 0 (m, 4H). Mass Spectrum (ESI+), m/z: 5 6 8 ( (M + H) + ). (Example 23) l-[2-{[(2S)-1-methylpyrrolidin-2-yl]methoxyindole-5-(trifluoromethyl)phenyl]-3- { 3- [(4-Sideoxy-3,4-dihydrothiazolin-6-yl)oxy]phenyl}urea

;〇201124398 6-(3·Aminophenoxy)quinazoline-4(3H)-one obtained in Reference Example 2 and 2-{[(2S)-1-methylpyrrolidine-2 obtained in Reference Example 7; The title compound (yield 5 2%) was obtained according to the procedure of Example 15 as the starting material. Spectrum (CD3OD, 400MHz), S: 8.39 (brs, lH), 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 = 10.5 Hz, 4.2 Hz), 3.34-3.24 (m, 1H), 2.89-2.76 (m, 1H), 2.52 (s, 3H), 2.5 5-2.40 (m, 1H), 2.14-2.05 (m, 1H), 1.96-1.81 (m, 3H). Mass Spectrum (ESI+) > m/z: 554 ((M + H)+). (Example 24) l-[2-{[(2S)-1-methylazetidin-2-yl]methoxy}-5-(trifluoromethyl)pyridin-3-yl]-3 - { 3-[(3-Methyl-4-o-oxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl sulfonamide

The 1-{2-[(2S)-azetidin-2-ylmethoxy]-5-(trifluoromethyl)pyridin-3-yl}-3-{3-[ (3) obtained in Example 5 -Methyl-4-oxo- 3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea. Dihydrochloride 184 mg (0.30 mmol) was suspended in acetonitrile (10 mL). % Formaldehyde solution (l. 〇ml) -62- 201124398 and sodium acetoxylated sodium 127 mg (0-60 mmol) were stirred at room temperature for 1 hour. The reaction mixture was concentrated, washed with EtOAc EtOAc EtOAc. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc %). [HNMR spectrum (DMSOd6, 400MHz), δ: 9.77 (s, 1H), 8.66 (d, 1H, J = 2.2Hz), 8.54 (s, 1H), 8.33 (s, 1 H), 8.14 (dd, 1 H, J = 2.2 Hz, 1.1 Hz), 7.74 (d, 1H, J = 8.8 Hz), 7.58 (dd, 1H, J = 8.8 Hz, 2.9 Hz), 7.52 (d, 1H, J = 2.9 Hz) ), 7.40-7.3 6 (m, 2H), 7.19 (ddd, 1H, J = 8.2Hz, 1 · 9 H z , 0.9 H z), 6.7 7 (ddd, 1H, J = 8.2Hz, 2.4Hz, 0.9 Hz), 4.60 (dd, 1H, J = 11.4Hz, 4.3Hz), 4.44 (dd, 1H, J = 11.4Hz, 5.8Hz), 3.48 (s, 3H), 3.3 8 -3.3 0 (m, 2H) , 2.75 - 2.67 (m, 1H), 2.23 (s, 3H), 2.05-1.91 (m, 2H). IR spectrum, vmax cm.1 (KBr): 3 3 5 7,1678,1 608,1 5 47, 1483, 1345, 1265, 1206, 1151, 942° mass spectrum (FAB+)> m/z : 555(( M + H)+). (Example 25) l-[2- { [( 2S ) -1-ethylazetidin-2-yl]methoxy} -5-(trifluoromethyl)pyridine-3-yl]-3- { 3-[(3-Methyl-4-o-oxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea-63- 201124398

N 1 - { 2 - [( 2 S )-吖丁啤酒-2 _ methoxy] 5 5 (trifluoromethyl)pyridin-3-yl} - 3 - { 3 - [ (3 _Methyl-4 _sideoxy_ 3,4 _ dihydrosalin-6-yl)oxy]phenyl}urea dihydrochloride and acetic acid as starting materials 'described in accordance with Example 24 The title compound was obtained (yield: 27%). 4 NMR spectra (DMSOd6'40〇MHz), 5: 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), 7.40-7.3 6 (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 = 7.3 Hz). IR spectrum, vmax cm'1 (KBr): 3 3 48,2 967, 1 6 73,1 60 8, 1548, 1483, 1452, 1345, 1269, 1205, 1151, 1122. Mass spectrum (FAB+), m/z: 569 ((M + H)+). -64- 201124398 (Example 2 6 ) 1- { 3-[( 3 -Methyl-4-oxooxy-3,4-dihydrothiazolin-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) pyrrolidin-2-ylmethoxy]-5-(trifluoromethyl)phenyl}urea hydrochloride as the starting material, the title compound was obtained according to the method of Example 24 (yield 26 %). NMR spectrum (CDC13, 400 MHz), δ: 8.65 (s, 1H), 8.61 (d, 1H, J = 2.3 Hz), 7.98 (s, 1H), 7.79 (d, 1H, J = 2.8 Hz), 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), 7.23-7.1 8 (m, 2H) , 6.93 (d, 1 H, J = 8.7 Hz), 6.73 (dd, 1H, J = 7.8 Hz, 2.3 Hz), 4.14-4.04 (m, 2H), 3.58 (s, 3 H), 3.25-3.15 ( m, 1H), 2.70-2.5 9 (m, 1H), 2.49-2.3 6 (m, 4H), 2.00- 1.80 (m, 4H). Mass Spectrum (ESI+), m/z: 568 ( (M + H)+). (Example 2 7 ) 1-(4-Chloro-2-{[(2S)-1-methylazetidin-2-yl]methoxy}phenyl)-3-{3-[(3- Methyl-4-oxooxy-3,4- 嗤哩[嗤哩嗤哩-6-yl)oxy]phenyl}urea-65- 201124398

1-{2-[(2S)-Azetidin-2-ylmethoxy]-4-chlorophenyl}-3-{3-[(3-methyl-4- side oxygen) obtained in Reference Example 27 The title compound (yield 48%) was obtained according to the procedure of Example 24 as the starting material of the title compound (3, 4-dihydroquinazolin-6-yl)oxy]phenyl}urea hydrochloride. 1H NMR spectrum (CDC13 > 400 ΜΗζ) > δ : 8.84 (s, 1H), 8.19 (d, 1H, J = 8.7 Hz), 7.97 (s, 1H), 7.79 (d, 1H, J = 2.8 Hz) , 7.70 (d, 1H, J = 9.2Hz), 7.51 (s, 1H), 7.47 (dd, 1H, J = 8.7Hz, 2.8Hz), 7.3 5 (t, 1H, J = 2.1Hz), 7.27 ( t, 1H, J = 8.3Hz), 7.14 (dd, 1 H, J = 7.6Hz, 1 ,6Hz), 6.99 (dd, 1 H, J = 8.7Hz, 2.3Hz), 6.91 (d, 1H, J = 2.3Hz), 6.71 (dd, 1H, J = 7.8Hz, 1. 8Hz), 3.98 (dd, 1 H, J = 1 1 .0Hz, 4.1Hz), 3.90 (dd, 1H, J = 11.0Hz, 2.8 Hz), 3.57 (s, 3H), 3.5 6-3.5 0 (m, 1 H), 3.47-3.3 9 (m, 1H), 2.99 (dd, 1H, J = 1 7.0Hz, 7.8Hz), 2.43 (s, 3H), 2.3 6-2.27 (m, 1H), 2.10-2.03 (m, 1H). (Example 2 8 ) l-[4-Chloro-2-{2-[(2-hydroxyethyl)(methyl)amino]ethoxy}-5-(trifluoromethyl)phenyl]- 3-{3-[(3-Methyl-4-oxooxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl sulfoxime-66- 201124398

1 -{ 4 -Chloro-2 -[ 2 (methylamino)ethoxy]-5 -(trifluoromethyl)phenyl} -3- { 3-[ (3 - A) obtained in Example 12. 31-4 (3,4-dihydroquinoxalin-6-yl)oxy]phenyl}urea 31 mg (0.055 mmol) was dissolved in acetone (5 ml), and sodium iodide 3.0 mg (0.020 mmol) was added. ), potassium carbonate 23 mg (0.167 mmol) and 2-chloroethanol hydrazine 〇 ml ll ml (〇. 164 min 〇 l), and heated to reflux for one night. After concentrating the reaction mixture, water was added, extracted with dichloromethane and dried over anhydrous sodium sulfate. After the filtration, the solvent was evaporated, and the residue was purified (jjjjjjjjjjjjjj NMR spectrum (CDC13, 4〇〇μΗζ), δ: 8.72 (s, 1H), 8.41 (br s, 1Η), 8.18 (br s,1Η), 7.98 (s,1Η), 7.79 (d,1Η,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 = 7.8 Hz), 7.24-7.20 (m, 1H), 6.91 (s, ih), 6.70 (d, 1H, J = 7.8 Hz), 4.07 (t, 2H, J = 4.6 Hz), 3.82 (t, 2H, J = 5.0 Hz), 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: 6 〇 6 ((M + H) +). (Example 2 9 ) 1- { 3-[( 3 -Methyl-4-oxo- 3,4-dihydroquinazolin-6-yl)oxy]phenyl} -3-[2- { [(2S) q•Methyl pyrrolidine-2-yl]methoxy} -5-(trifluoromethyl)phenyl]urea hydrochloride-6 7-201124398

ο F F

• HC1

1-{3-[(3-Methyl-4-oxo- 3,4-dihydrosoxazolyl-6-yl)oxy]phenyl}-3-[2-{ [(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl)phenyl]urea 100 mg (0.176 mmol) dissolved in methanol (4.0 ml), 4N hydrochloric acid / Dioxane (2.0 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and methanol and isopropyl ether were added to the residue. *11 NMR spectrum (DMSOd6, 400 MHz), δ: 10.4 (br s, 1H), 10.2 (br s, 1H), 8.60- 8.48 (m, 1H), 8.3 9-8.3 3 (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), 4.5 8-4.5 0 (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), 2.3 0- 1.94 (m, 4H). (Example 30) 1-{ 3-[(3-Methyl-4-oxooxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl}-3-[2- { [( 2S) -1-methylpyrrolidin-2-yl]methoxy} -5-(trifluoromethyl)phenyl]urea·dimethanesulfonate-68- 201124398

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 100 mg (0.176 mmol) dissolved in dichloromethane (2.0 ml), methane The sulfonic acid was 22.8 μl (0.35 2 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was evaporated to ethyl ether. iH NMR spectrum (DMSOd6, 400 MHz), δ: 9.62 (br s, 1H), 9.51 (br s, 1H), 8.6 0 - 8.3 0 (m, 1H), 8.28-8.19 (m, 1H), 7.7 8 - 7.7 2 (m, 1H), 7.62 - 7.5 7 (m, 1H), 7.51-7.48 (m, 1H), 7.44-7.3 5 (m, 3H), 7.30-7.16 (m, 2H), 6.81-6.73 4.5 3 -4.3 4 (m, 2H), 3.91-3.80 (m, 1 H), 3.47 (s, 3 H), 3.2 3 -3.09 (m, 1 H), 2.99 (br s, 3 H), 2.69- 2.65 (m, 1 H), 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 3-aminophenol 4.91 g (45 mmol), 5-chloro-2-nitro A mixture of methyl benzoate 9.70 g (45 mmol), potassium carbonate 12-4 g (45 mmol) and anhydrous hydrazine, hydrazine-dimethylformamide (10 ml) was stirred at 120 ° C for 3 hours. After the reaction mixture was concentrated under reduced pressure -6 9 - 201124398, water was added, and ethyl acetate was evaporated and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, and methanol (1 〇 〇 m 1 ) and 1 〇 % palladium carbon (2.5 2 g ) were placed under a hydrogen atmosphere and stirred at room temperature for 4 hours. After the insoluble material was filtered off from the reaction mixture, the solvent was evaporated, and then, 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, washed with EtOAc EtOAc. After filtration, the solvent was distilled off, and methylamine [40% methanol solution] 9.181111 (9〇111111〇1), triethyl orthoformate 13.3 g (90 mmol), p-toluenesulfonic acid monohydrate 171 mg (0.90 mmol) was added. And methanol (100 ml), heated to reflux for 23 hours. The reaction mixture was concentrated, washed with EtOAc EtOAcjEtOAc After filtration, the solvent was evaporated, ethyl acetate and isopropyl ether were added, and crystals which crystallised were collected by filtration, and washed with isopropyl ether to give the title compound 4.47 g (37%). H NMR spectrum (DMSOd6, 400 MHz), δ: 8.28 (s, 1H), 7.72 (d, 1 H, J = 8.8 Hz), 7.53 (dd, 1 Η, J = 8.8 Hz, 2.8 Hz), 7.48 (d , 1Η, 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 = 8.8 Hz, 0.9Hz), 5.28 (br s, 2H), 3.48 (s, 3H). IR spectrum, vmax cm·1 (KBr): 3 3 3 2,3217,1661,1 607, 1481, 1348, 1151, 832° mass spectrum (EI+ ), m/z: 267 (M +, base), 250, 238, 222, 209, 182 〇-70- 201124398 (Reference Example 2) 6-(3-Aminophenoxy)quinazolin-4(3H)-one The synthetic intermediate 2 of the compound of Reference Example 1 A mixture of -amino-5-(3-aminophenoxy)benzoic acid 1.0 g (4.1 mmol) and formamide (10 ml) was stirred at 150 ° C for 15 hours. Sodium bicarbonate water was added to the reaction mixture, which was extracted with ethyl acetate. After filtration, the solvent was evaporated. EtOAc (EtOAc m. After concentrating the reaction mixture, methanol and ether were added, and the crystals which precipitated were collected by filtration, and washed with ether to give 1.19 g (yield: 100%) of the title compound. The obtained hydrochloride salt (500 mg, 1.73 mmol) was dissolved in EtOAc. After filtration, the solvent was evaporated, ethyl acetate and EtOAc (hexane) were evaporated. WNMR spectrum (CDC13, 400MHz), 5: 9.69 (brs, lH), 7.96 (s, 1H), 7.77 (d, 1H, J = 2.9 Hz), 7.74 (d, 1H, J = 8.8 Hz), 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 = 8.0 Hz, 1.7 Hz), 6.39 (dd, 1H, J - 1.7 Hz, 1.7 Hz), 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-7 1-201124398 3-Nitro-5-(III A mixture of fluoromethyl) batch of tert-2-ol 7.52 § (36.2111111 〇 1), thionyl chloride (30 ml) and N,N-dimethylformamide (0.50 ml) was heated under reflux for 60 hours. After concentrating the reaction mixture, dehydrated toluene was added, the solvent was evaporated under reduced pressure, and anhydrous tetrahydrofuran (20 ml) was added. Anhydrous tetrahydrofuran (40 m 1 ) containing 3.86 g (43.4 mmol) of 2-(dimethylamino)ethanol and 1.89 g (4 3 · 4 m m ο 1 ) of 55% sodium hydride was added, and the mixture was heated under reflux for 8 hours. After concentrating the reaction mixture, water was added, and ethyl acetate was evaporated. After filtration, the solvent was distilled off, and the residue was applied to a hexane column chromatography (solvent solvent: ethyl acetate), and the solvent was evaporated. The obtained N,N-dimethyl-2-{[3-nitro-5-(trifluoromethyl)pyridin-2-yl]oxy}ethaneamine was dissolved in methanol (50 ml), i. Palladium on carbon (〇.56 g) was stirred at room temperature for 90 minutes under a hydrogen atmosphere. After the palladium carbon was filtered off from the reaction mixture, the solvent was evaporated. NMR spectrum (DMS0d6, 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 = 6·0Ηζ), 2.21 (s, 6H). IR spectrum, vmax cm:1 (liquid film): 3331,3199, 2953, 1604, 1 442, 1 3 40, 1 25 9,1 1 2 0, 1 02 7, 8 96, 7 6 3, 648 ° mass spectrometry (FAB+), m/z: 250((M + H)+ ) · (Reference Example 4) 2-{ [(2S)-Temethylpyrrolidin-2-yl]methoxy}-5-(trifluoromethyl) Pyridyl-3-amine-72- 201124398 Starting from 3-nitro-5-(trifluoromethyl)pyridine-2-ol and [(2S)-1-methylpyrrolidin-2-yl]methanol Starting from the starting material, the title compound (yield 30%) was obtained. H NMR spectrum (DMSOd6, 400 ΜΗζ), δ: 7.09 (d, 1H, J - 2.5 Hz), 6.49 (d, 1H, J = 2.5 Hz), 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), 2.3 8 - 2.1 4 (m, 2 H), 1 _ 6 6 -1 · 4 7 (m , 3 H). IR spectrum, vmax cm_1 (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 The ester is based on 3-nitro-5-(trifluoromethyl)pyridin-2-ol and (2S)-2-(hydroxymethyl)azetidine-1-carboxylic acid t-butyl ester as a starting material. The title compound (yield 49%) was obtained by the method of the title compound.

*H 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), 4.3 7-4.3 2 (m, 1H), 3.93-3.67 (m, 2H), 2.35-2.14 (m, 2H), 1-32 (s, 9H) ° IR spectrum, vmax cm·1 (liquid film): 3 4 8 1,3 3 5 0, 2 9 7 7, 1 6 8 7, 1442,1 3 94,1 3 67,1 2 5 8,1157,&quot ;21,941,8 8 7,7 6 3 » Mass spectrum (FAB+), m/z: 348 ((M + H)+). -73- 201124398 (Reference Example 6) (2S)-1-methyl-2-{[2-nitro-4-(trifluoromethyl)phenoxy]methyl}pyrrolidine 1-fluoro-2 -nitro-4-(trifluoromethyl)benzene l.〇5g (5.0mmol), [(2S)-1-methylpyrrolidin-2-yl]methanol 0.69g (6.0mmol), tert-butanol A mixture of potassium 0.67 g (6.0 mmol) and anhydrous N,N-dimethylformamide (20 ml) was stirred at room temperature for 17 h. The reaction mixture was concentrated under reduced pressure. After the filtration, the solvent was evaporated, and the residue was purified (jjjjjjjjjjjj NMR spectrum (DMSOd6, 400MHz), δ: 8.30 (d, 1H, J = 2.3Hz), 8.02 (dd, 1 H, J = 8.8 H z, 2.3 H z), 7.5 9 (d,1H, J = 8.8 Hz), 4.25-4.16 (m,1H), 4.01-3.91 (m,1H), 2.99-2.94 (m, 1H), 2.73 -2.6 8 (m, 1H), 2.38 (s, 3H), 2.30-2.18 (m, 1H), 1.99-1.8 3 (m, 1 H), 1.74- 1.5 9 (m, 3H). IR spectrum, vmax cm·1 (liquid film): 2952, 278 7, 1 740, 1 628, 1 542, 1 328,1 287,1 1 29, 1 0 1 6, 897,824, 689° mass spectrometry (FAB+ ), m/z: 305 ((M + H)+). (Reference Example 7) 2 - {[ ( 2 S ) .- 1 -Methylpyrrolidin-2-yl]methoxyindole-5 -(trifluoromethyl)aniline (2S)-bumethyl-2-{ [2-Nitro- 4-(trifluoromethyl)phenoxy]methyl}pyrrolidine 188 mg (0.62 mmol) dissolved in methanol (5 ml) 'Add-74- 201124398 into 10% palladium on carbon (44 mg), hydrogen The mixture was stirred at room temperature for 3 hours under the environment. After the palladium carbon was filtered off from the reaction mixture, the solvent was evaporated. NMR spectrum (DMSOd6, 400 MHz), δ: 6.94 (d, 1H, J = 8.2 Hz), 6.9 1 (d, 1H, J = 2.2 Hz), 6.82 (dd, 1H, J - 8.2 Hz, 2.2 Hz), 5.07 (br s, 2H), 4.03 (dd, 1 H, J = 9.7 Hz, 5.4 Hz), 3.84 (dd, 1H, J = 9.7 Hz, 6.0 Hz), 2.98 -2.94 (m, 1H), 2.63 - 2.5 6 (m, 1H), 2.36 (s, 3H), 2.34-2.16 (m, 1H), 2.05 - 1.96 (m, 1 Η), 1. 7 3 - 1 . 5 6 (m, 3 H). IR spectrum 'vmax cm'1 (liquid film): 3343, 2953, 2792, 1735, 1 622, 1521, 1 449, 1 3 3 4, 1 223, 1159, 1114, 1 028, 920, 8 67, 8 04 ° Mass spectrum (FAB+), m/z: 275 ((M + H)+). (Reference Example 8) Isopropyl {2-[2-nitro-4-(trifluoromethyl)phenoxy]ethylguanidinic acid t-butyl ester as 1-fluoro-2-nitro-4_ (trifluoromethyl)benzene and (2-hydroxyethyl)isopropylaminecarboxylic acid t-butyl ester [patent compound: W02003/105845A 1 (2 003 / 1 2/24 )] as a starting material, based on The title compound (yield 62%) was obtained by the method of the procedure. Mass g (ESI+), m/z: 415 ((M + Na)+). (Reference Example 9) {2-[2-Amino_4_(trifluoromethyl)phenoxy]ethyl}isopropylaminecarboxylic acid t-butyl ester-75- 201124398 as isopropyl {2-[ The title compound (yield 100%) was obtained according to the method described in the title compound 7 m. (Reference Example 10) 1-[2-(4-Chloro-2-nitrophenoxy)ethyl]pyrrolidine as 5-chloro-2-fluoro-1-nitrobenzene and 1-(2-hydroxyl The title compound (yield: 83%) was obtained according to the method of the title compound 6 (ethyl). 'HNMR spectrum (CD.C13, 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 = 5.7 Hz), 2.98 - 2.94 (m, 2H), 2.6 8 - 2.6 0 (m, 4H), 1.8 3 - 1.7 8 (m, 4H). Mass Spectrum (ESI+), m/z: 271 ( (M + H)+). (Reference Example 1 1 ) 5-Chloro-2-(2-pyrrolidin-1-ylethoxy)aniline as 1-[2-(4-chloro-2-nitrophenoxy)ethyl]pyrrolidine The title compound (yield 78%) was obtained as the starting material from the method described in Reference Example 13. 4 NMR spectrum (CDC13, 400 MHz), δ: 6.70 (d, 1H, J = 8.5 Hz), 6.68 (d, 1H, J = 2.3 Hz), 6.63 (dd, 1H, J = 8.5 Hz, 2.3 Hz), 4.10 (t, 2H, J = 6.0Hz), 4.01 (br s, 2H), 2.89 (t, 2H, J = 6.0Hz), 2.66-2.5 8 (m, 4H), 1.84- 1.7 8 (m, 4H ). Mass Spectrum (ESI+), m/z: 271 ( (M + H)+). -76- 201124398 (Reference Example 1 2 ) {2-[5-Aromatic 2-nitro-4-(dimethylmethyl))oxy]ethyl}methylaminecarboxylic acid t-butyl ester as 2 , 4-dichloro-5-nitrobenzotrifluoride and (2-hydroxyethyl) 'methylamine formate t-butyl ester as starting materials' according to the method described in Reference Example 6, to obtain the title compound ( Yield 49%). NMR spectrum (CDC13, 40 〇 MHz), δ: 8.26 (s, 1H), 7.24 (s, 1 Η), 4.34-4.21 (m, 2 Η), 3.68 (t, 2 Η, J = 5.00 Ηζ), 3.01 ( s, 3H), 1.47 (s, 9H). Mass Spectrum (ESI+), m/z: 422 ( (M + Na)+). (Reference Example 1 3) {2-[2-Amino-5-chloro-4-(trifluoromethyl)phenoxy]ethyl}methylaminecarboxylic acid t-butyl ester {2-[5 - Chloro-2-nitro-4-(dimethylmethyl)-oxy]ethyl}aminecarboxylic acid t-butyl ester 1.13 g (2-84 mmol), iron 950 mg (17.0 mmol), ammonium chloride 30.0 mg (0.560 mmol) A mixture of ethanol (20 ml) and water (5 ml) was heated to reflux for 2.5 hours. After the reaction mixture was filtered through celite (c.), EtOAc (EtOAc) 74%). (Reference Example 1 4 ) (2R)-2-{[2-Nitro- 4-(trifluoromethyl)phenoxy]methyl}pyrrolidine-1-carboxylic acid t-butyl ester-77- 201124398 1-fluoro-2-nitro-4-(trifluoromethyl)benzene and (2R)-2-(hydroxymethyl)pyrrolidine-1 -carboxylic acid t-butyl ester as starting materials, according to Reference Example 6 The title compound was obtained by the method described (yield: 74%). iHNMR spectrum (CDC1 3, 400 MHz), 8: 8.13, 8.10 (each s, total 1H), 7.79, 7.76 (each d, total 1H, J = 2.3 Hz), 7.40, 7.37 (each s, total 1 H), 4.3 8-4.2 5 (m, 2H), 4.20-4.00 (m, 1H), 3.50-3.28 (m, 2H), 2.15-1.80 (m, 4H), 1.5 5, 1 .46 (each s , total 9 H) ° Mass Spectrum (ESI+), m/z: 413 ((M + Na)+). (Reference Example 1 5 ) (2R) -2-{[2-Amino-4-(trifluoromethyl)phenoxy]methyl}pyrrolidine-1-carboxylic acid t-butyl ester as (2R) - 2-{[2-Nitro-(trifluoromethyl)phenoxy]methyl}pyrrolidin-1-carboxylic acid t-butyl ester was used as a starting material, and the title was obtained according to the method described in Reference Example 7. Compound (yield 99%). NMR spectrum (CDC13, 400MHz), δ: 6.98-6.85 (m, 3H), 4.31-4.11 (m, 2H), 4.06-3.82 (m, 3H), 3.51-3.31 (m, 2H), 2.0 8 - 1.8 6 (m, 4H), 1.55 (s, 9H). Mass Spectrum (ESI+), m/z: 3 8 3 ( (M + Na) + ). (Reference Example 1 6) 1- { 3-[(3-Methyl-4-oxooxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl} -3-{2- [(2R)-pyrrolidin-2-ylmethoxy]-5-(trifluoromethyl)phenyl}urea hydrochloride-78- 201124398 6-(3-aminophenoxybenzene) obtained in Reference Example 1 (3-)-methylquinazoline-4(3H)-one and (2R)-2-{[2-amino-4-(trifluoromethyl)phenoxy]methyl} obtained in Reference Example 15. Pyrrolidine-1-carboxylic acid t-butyl ester was used as a starting material. According to the method described in Example 15, the reaction was post-treated, followed by deprotection using 4N hydrochloric acid / 1,4-dioxane ( De-butoxycarbonylation) gave the title compound (yield 100%). (Reference Example 1 7) Ethyl {2-[2-fluoro-6-nitro.4((trifluoromethyl)phenoxy]ethyl}-carbamic acid t-butyl ester as 1,2-difluoro -3-Nitro-5-(trifluoromethyl)benzene and ethyl (2-hydroxyethyl) carbamic acid t-butyl vinegar were used as starting materials, and the title compound was obtained according to the method described in Reference Example 6. Rate 63%). WNMR spectrum (CDC13, 400 MHz), 5: 7.87 (S, 1H), 7.60 (d, 1H, J = 10.5 Hz), 4.52-4.33 (m, 2H), 3.60 (t, 2H, J = 5.7 Hz), 3.40-3.26 (m, 2H), 1.46 (s, 9H), 1.12 (t, 3H, J = 6.9Hz). Mass Spectrum (ESI+), m/z: 495 ( (M + Na)+). (Reference Example 1 8 ) {2-[2·Amino-6-fluoro-4-(trifluoromethyl)phenoxy]ethyl}ethylaminecarboxylic acid t-butyl ester as ethyl { 2-[ 2-Fluoro-6-nitro-4-(trifluoromethyl)phenoxy]ethyl} amide t-butyl ester as a starting material, the title compound was obtained according to the method described in Reference Example 7 (yield 81%). -79- 201124398 4 NMR spectrum (CDC13, 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: 356 ( (M + H)+). (Reference Example 1 9 ) (2S) -2-[(5-Chloro-2-nitrophenoxy)methyl]-1-methylpyrrolidine as 4-chloro-2-fluoro-1-nitrobenzene And [(2S)-1-methylpyrrolidin-2-yl]methanol as a starting material, the title compound (yield: 77%) was obtained according to the method described in Reference 6. NMR spectrum (CDC13, 400 MHz), δ: 7 · 8 3 (d, 1 Η, J = 8.6 Hz), 7.07 (d, 1 Η, J = 2.3 Hz), 7.00 (dd, 1H, J - 8.6 Hz, 1.7 Hz), 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), 2.37-2.3 1 (m, 1H), 2.12-2.01 (m, 1 H), 1.89- 1.67 (m, 3H). Mass Spectrum (ESI+), m/z: 271 ((M + H)+). (Reference Example 2 0 ) 4 -Chloro-2- { [ ( 2S) -1-methylpyrrolidin-2-yl]methoxy}phenylamine as (2S) -2-[(5-chloro-2-nitro The title compound (yield 72%) was obtained as the starting material of the title compound. NMR spectrum (CDC13, 400MHz), δ: 6.79-6.74 (m, 2H), 6.61 (d, 1H, J = 8.6Hz), 4.00 (dd, 1H, J = 9.2Hz, 5.7Hz), -80- 201124398 3.87 (dd, 1H, J = 9.2Hz, 5.7Hz), 3.79 (br (m, 1H), 2.71-2.64 (m, 1H), 2.48 (s, 3H), 2.0 8 - 1.99 (m, 1H), 1.90- 1.68 (m, 3H) Mass Spectrum (ESI+), m/z: 241 ((M + H)+) (Reference Example 2 1 ) (23)-2-[(4,5-Dichloro-2) -Nitrophenoxy)pyrrolidine using 4,5-dichloro-2-fluoro-1-nitrobenzene and [(23)-yl]methanol as starting materials, according to the reference compound of Reference Example 6 (yield 41%) (Reference Example 22) 4,5-Dichloro-2-{[(23)-1-methylpyrrolidine-amine with (25)-2-[(4,5-dichloro-2- Nitrophenoxy-pyrrolidine was used as a starting material, and the title compound (yield 85%) was obtained according to Reference Example 13. iHNMR spectrum (CDC13, 400 MHz), 5: ((s, 1H), 3_97 (dd, 1H, J = 9.2 Hz, 5.7 Hz), 3.85 (dd, 1H, J = 9.2 Hz, 5.7 Hz), 3.1 2.7 0-2.63 (m, 1H), 2.46 (s, 3H), 2.3, 2.07- 1.9 8 (m, 1H), 1.8 8 - 1.6 7 (m, 3H) Mass Spectrum (ESI+), m/z: 275 ((M + H)+) -8 1- s, 2H), 3.13-3.07: .35-2.28 (m, 1H), methyl]-1 -methylpyridin-1-methylpyrrolidine- 2 - ; method, obtain the standard 2-yl] methoxy} benzene £) methyl]-1-methyl oxime method, obtain the standard. 82 (s, 1 H), 6.75 3.9 1 (br s, 2H), 2-3.07 (m, 1 Η), -2.28 (m, 1 Η), 201124398 (Reference Example 2 3 ) { 2-[5-Chloro-2-nitro-4-(trifluoromethyl) T-butyl phenoxy]ethyl}isopropylaminecarboxylate with 2,4-dichloro-5-nitrobenzotrifluoride and (2-hydroxyethyl)isopropylamine formate As a starting material, the title compound (yield: 67%) was obtained according to the method described in the title compound. (Reference Example 2 4 ) {2-[2-Amino-5-chloro-4-(trifluoromethyl)phenoxy]ethyl}isopropylaminecarboxylic acid t-butyl ester as {2-[5 -Chloro-2-nitro-4-(trifluoromethyl)phenoxy]ethyl hydrazide propyl propyl methacrylate as the starting material, the title compound was obtained according to the method described in Reference 13 (yield 94%). (Reference Example 2 5 ) (2S) -2-[(5-Gas-2-nitrophenoxy)methyl]indole steep-1_carboxylic acid t-butyl ester as 4-chloro-2-fluoro The title compound was obtained according to the method described in Reference Example 6 as the starting material of 1-nitrobenzene and (2S)-2-(methylidenemethyl)p-butidine-1-carboxylic acid t-butyl ester. The rate is 80%). 4 NMR spectra (QDClj, 400 MHz), δ ·· 7.86 (d, 1H, J = 8.7 Hz), 7.14 (d, 1H, J = 1.8 Hz), 7.02 (dd, 1H, J = 8.7 Hz, 1.8 Hz) , 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)+). -82- 201124398 (Reference Example 2 6 ) (2S) -2-[(2-Amino-5-chlorophenoxy)methyl]H-butyl-stirty-i-carboxylic acid t-butyl ester (2S) -2-[(5-Chloro-2-nitrophenoxy)methyl]-p-butylate-i-t-butyl formate as the starting material, the title compound was obtained according to the method described in Reference 13 74%). (Reference Example 2 7 ) 1-{ 2-[( 2S )-Azetidin-2-ylmethoxy]-4-chlorophenyl}-3-{ 3-[( 3-methyl-4- side Oxy-3,4-dihydroquinazolin-6-yl)oxy]phenyl}urea hydrochloride The 6-(3-aminophenoxy)-3-methylindole obtained in Reference Example 1 Oxazoline-4 (3H)-one and (2S)-2-[(2-amino-5-chlorophenoxy)methyl]azetidine-1 -carboxylic acid t-butyl ester obtained in Reference Example 26 as The starting material was subjected to post-treatment after the reaction according to the method described in Example 1, followed by deprotection (de-t-butoxycarbonylation) using 4N guanidine hydrochloride and 4-dioxadium to obtain the title compound. Rate 78%). (Reference Example 28) 1-{2-[2-Nitro-4(trifluoromethyl)phenoxy]ethyl}pyrrolidine as 1-fluoro-2-nitro-4-yl (trifluoromethyl) Benzene and hydrazine-(2-hydroxyethyl)pyrrolidine were used as starting materials, and the title compound (yield: 71%) was obtained according -83- 201124398 (Reference Example 29) 2-(2-Pyrrolidin-1-ylethoxy)-5-(trifluoromethyl)aniline as 1-{2-[2-nitro-4-(III The title compound (yield 98%) was obtained according to the procedure described in the title compound (yield: fluoromethyl)phenoxy]ethyl}pyrrole. 'H NMR spectrum (CDC13, 400 MHz), δ: 6.99-6.94 (m, 1H), 6.9 2 (d, 1 Η, J = 1 · 8 Η z), 6 · 8 2 (d, 1 Η, J = 8.3 Η z),4 · 1 7 (t, 2 Η, J = 6.0Hz), 4.04 (br s, 2H), 2.93 (t, 2H, J = 6.0Hz), 2.66-2.60 (m, 4H), 1.8 5 - 1.7 8 (m, 4H). Mass Spectrum (ESI+), m/z: 275 ( (M + H) + ). (Reference Example 3 0) 2-[2-Nitro- 4-(trifluoromethyl)phenoxy]ethyl} -1H-pyrazole as 1-fluoro-2-nitro-4-(trifluoromethyl) The title compound (yield 59%) was obtained according to the procedure described in the title compound (yield: benzene) and 2-(1 - pyrazol-1-yl)ethanol. (Reference Example 3 1) 2-[2-(1Η-pyrazol-1-yl)ethoxy]-5-(trifluoromethyl)aniline as 1-{2-[2-nitro-4-(() Trifluoromethyl)phenoxy]ethyl}-1 oxime-pyrazole was used as a starting material to give the title compound (yield: 85 %). iH NMR spectrum (CDC13, 400 MHz), δ: 7.55 (d, 1H, J = 1.7 Hz), 7.49 (d, 1 H, J = 2.0 Hz), 6.97-6.8 8 (m, 2H), 6.76 (d , 1H, J = 8.3Hz), 6.29-6.26 (m, 1H), 4.5 9-4.54 (m, 2H), 4.44-4.39 (m, 2H), 3.86 (br s, 2H). -84- 201124398 (Reference Example 3 2 ) 2-Nitro-1-(propan-2-indole-yl-yloxy)-4·(trifluoromethyl)benzene as 1-fluoro-2-nitro- 4-(Trifluoromethyl)benzene and 2-propyne-indole-alcohol were used as starting materials. The title compound was obtained (yield: 67%). (Reference Example 3 3 ) 2-(Propan-2-ynyl-1-yloxy)-5-(trifluoromethyl)aniline as 2-nitro-1-(propan-2-indole-buyloxy) -4_(Trifluoromethyl)benzene as a starting material 'The title compound was obtained according to the method described in Reference Example 13 (yield: 9 9 %). 4 NMR spectrum (CDC13, 400 ΜΗζ), δ: 7.02-6.90 (m, 3 Η), 4.77 (d, 2H, J = 2.4 Hz), 3.97 (br s, 2H), 2.55 (tt, 1H, J = 2.4Hz , 0.7Hz). (Reference Example 3 4 ) 4-[2-Nitro- 4-(trifluoromethyl)phenoxy]but-2-yn-1-yl acetate as 1-fluoro-2-nitro-4-( Trifluoromethyl)benzene and 2-butyne-1,4-diol were used as starting materials, and the reaction was followed by post-treatment according to the method described in Reference Example 6. Subsequently, the hydroxy group was used to protect the hydroxyl group. (Ethylation), the title compound was obtained (yield 86%). (Reference Example 3 5 ) 4-[2-Amino-4-(trifluoromethyl)phenoxy]but-2-yn-1-yl acetate-85- 201124398 4-[2-nitro-acetic acid 4-(Trifluoromethyl)phenoxy]but-2-yn-1-yl ester was used as a starting material to give the title compound (yield: 3%). 'H NMR spectrum (CDC13, 400MHz), δ · 6.97-6.91 (m, 3H), 4.80 (d, 2H, J = 1·9Ηζ), 4.71 (t, 2H, J = 1·9ΗΖ), 3_97 (br s, 2H), 2·09 (s, 3H). (Reference Example 3 6) 2-[2-Nitro-4-(trifluoromethyl)phenoxy]ethanol as 1-fluoro-2-nitro-4-(trifluoromethyl)benzene and 2-hydroxyacetic acid Ethyl ester was used as a starting material to give the title compound (yield: 49%). (Reference Example 3 7 ) 2 (2·{ [t-butyl(—methyl) litreyl]oxy}ethoxy)-5-(trifluoromethyl)aniline with 2-[2-nitro _4_(trifluoromethyl)phenoxy]ethanol was used as a starting material. According to the method described in Reference Example 7, the reaction was followed by post-treatment, followed by using t-butyl(dimethyl)decyl chloride. The hydroxy group was protected with < butyl ("methyl) oxime alkyl] to give the title compound (yield: 65%). 1 H NMR spectrum (cdC13, 400 MHZ), δ: 6.70-6.67 (m, 3H), 4.35 (br s, 2H), 4.12 (t, 2H, J = 4.33 Hz), 3.90 (t, 2H, J = 4 · 33Ηζ), 0.9! (s, 9H), 0.10 (s, 6H). -86- 201124398 (Reference Example 3 8) 2-{[2-Nitro- 4-(trifluoromethyl)phenoxy]methyl}-1,4-dioxane as 1-fluoro-2-nitrate The title compound (yield 82%) was obtained according to the method described in the title compound (yield: hexane). (Reference Example 3 9) 2-(1,4-Dioxan-2-ylmethoxy)-5-(trifluoromethyl)aniline as 2-{[ 2-nitro-4-(trifluoromethyl) The title compound (yield 94%) was obtained according to the method described in the title compound 7 as the starting material of phenyloxy]methylindole-1,4-dioxane. H NMR spectrum (CDC13, 400 MHz), δ: 6.98-6.91 (m, 2H), 6.81 (d, 1H, J = 8.3 Hz), 4.10--3.89 (m, 6H), 3.88-3.73 (m, 3 H), 3.7 1 - 3.6 2 ( m, 1 H ), 3 · 5 8 - 3 · 5 0 (m , 1 H ). (Reference Example 40) 3-{2-[2-Nitro- 4-(trifluoromethyl)phenoxy]ethyl}-1,3-oxazolidin-2-one as 1-fluoro-2- The title compound was obtained according to the method described in Reference Example 6 as the starting material of nitro-4-(trifluoromethyl)benzene and N,N-bis(2-hydroxymethyl)amine carboxylic acid t-butyl ester. Rate 5 3 %). (Reference Example 4 1 ) 3-{2-[2-Amino-4-(trifluoromethyl)phenoxy]ethyl}-1,3-oxazolidin-2-one-87- 201124398 to 3 - {2-[2-Nitro-4-(trifluoromethyl)phenoxy]ethyl}-1,3-oxazolidin-2-one as a starting material, according to the method described in Reference Example 7, The title compound was obtained (yield 91%). NMR spectrum (CDC13, 400 MHz), δ: 7.00-6.91 (m, 2H), 6.78 (d, 1H, J = 8.3 Hz), 4.3 7-4.3 3 (m, 2H), 4.23-4.18 (m, 2H) , 4_00 (s, 2H), 3.76 - 3.6 7 (m, 4H). (Reference Example 42) (2S)-2-{[5-Chloro-2-nitro-4-(trifluoromethyl)phenoxy]methyl}pyrrolidine-1-carboxylic acid t-butyl ester as 2 , 4-dichloro-5-nitrobenzotrifluoride and (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester were used as starting materials, and obtained according to the method described in Reference Example 6. The title compound (yield 76%). H NMR spectrum (CDC13, 400MHz), δ: 8.23 (s, 1H), 7.40 (s, 1H), 4.3 5-4.02 (m, 3H), 3.42-3.3 3 (m, 2H), 2.13-1.80 (m , 4H), 1.46 (s, 9H). Mass Spectrum (ESI+), m/z: 447 ( (M + Na)+). (Reference Example 4 3 ) (2S) -2- {[5-Methyl-2-nitro-4-(trifluoromethyl)phenoxy]methyl}pyrrolidine-1-carboxylic acid t-butyl ester Reference Example 42 obtained (2S)-2-{[5-chloro-2-nitro-4-(trifluoromethyl)phenoxy]methyl}pyrrolidine-1-carboxylic acid t-butyl ester 603 mg ( 1 · 4 2 mm ο 1 ) Dissolved in a mixed solvent of 1,4-dioxane/water (1 0 /1) (3.3 ml), added trimethyl boroxine 355 mg (2_84 mmol), 肆 (:r -88- 201124398 Phenylphosphine) 82.1 mg (0.07 mmol) fine and potassium carbonate 3 92 mg (2.8 4 mmol), heated to reflux overnight. After the reaction mixture was filtered over EtOAc (EtOAc)EtOAc. After filtration, the solvent was evaporated, and the residue was purified mjjjjjjlilililili (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-(trimethyl)phenoxy]methyl}pyrrolidin-1-carboxylic acid t-butyl ester as starting material, based on The title compound (yield 7 7 %) was obtained by the method of the procedure described in Example 7. 4 NMR spectrum (CDC13, 400 MHz), δ: 6.96 (br s, 1H), 6.73 - 6.60 (m, 1H), 4.30-4.07 (m, 2H), 4.01-3.69 (m, 3H), 3.52-3.3 2 (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 Recorded Compound: WO2009/32326A1 (2009/ 03/12) A mixture of 〇g (86.9 mmol), lithium aluminum hydride 3.58 g (86.9 mmol) and anhydrous tetrahydrofuran (i?ml) was stirred at 80 ° C for 24 hours. The reaction solution was ice-cooled, and a 15% aqueous sodium hydroxide solution (1 〇 m 1 ) was dropped. After the diatomaceous earth product was passed through a furnace, the solvent was evaporated, and the residue was evaporated to dryness (yield: 80°C / 50mmHg) to give the title compound (yield: 91%). -89- 201124398 】H NMR spectrum (CDC13, 400MHz), δ: 3.61-3, 54 (m, 1H)' 3.45 -3.3 8 (m, 1H), 3.3 8 -3.3 0 (m, 1H), 3.21- 3.12 (m, 1H), 2.8 6-2.7 7 (m, 1H), 2.29 (s, 3H), 2.22-2.11 (m, 1H), 1.94-1.83 (m, lH) helium mass spectrometry (EPCI+), m/ z : 102 ((M + H)+). (Reference Example 46) 2-{[(2S)-1-methylindole-st-yl]methoxy}-5-(trifluoromethyl)aniline as 1-fluoro-2-nitro-4 -(Trifluoromethyl)benzene and [(2S)-1-methylazetidin-2-yl]methanol obtained in Reference Example 45 were used as starting materials, and the title was obtained according to the methods described in Reference Example 6 and Reference Example 7. Compound (yield 4% NMR spectrum (CDC13, 400 ΜΗζ), δ: 6.9 5 (d, 1 Η, J = 8.3 Hz), 6.92 (s, 1 Η), 6.81 (d, 1 Η, J = 8.3 Ηζ) , 4.14-4.02 (m, 2H), 3.5 6- 3.4 5 (m, 2H), 2.9 8 -2.8 8 (m, 1H), 2.43 (s, 3H), 2. 1 7-2.08 (m, 2H) Mass spectrometry (EPCI+), m/z: 261 ((M + H)+) (Test Example 1) Evaluation of inhibition of BRAF kinase activity (in vitro) Evaluation of inhibition of BRAF kinase activity of each of the Example compounds was carried out. The evaluation was performed using purified human recombinant V 6 0 E active variant BRAF kinase (Δ1-416, GST fusion) and BRAF matrix of rabbit recombinant inactive MEK1 (full length, GST and His fusion, MEK 1 unactive , Upstate, LakeP1 acid, NY), by ΗTRF method (homogeneous time resolved camping method (homogeneous time resolved f 1 uorescence )) To detect the degree of phosphorylation of inactive Μ EK 1. -90- 201124398 Specifically, variant BRAF2ng/well, ΑΤΡΙΟΟμΜ, ΜΕΚ UOOng/well, and test compound (from final concentration ο. ΟίηΜ to 30 μΜ), in a kinase reaction buffer (50 mM Tris-HCl, 10 mM MgCl 2 , 2 mM EGTA, lmMNa 3 V 〇 4, 0.1 mg/mL BSA, pH 7.4), the total reaction volume was 50 μί / hole, so that The reaction was carried out for 60 minutes at 30 ° C. Thereafter, the following PBS* solution was added at 25 pL/well, and the reaction was stopped overnight, and the phosphorylation reaction was stopped and the HTRF reaction was carried out. * PBS solution composition: 60 mM EDTA (final concentration 20 mM) , 1.2 M KF (final concentration 400 μΜ), 1 mg / m LBS Α (final concentration 333 pg/mL), 63 0 ng/mL anti-rabbit IgG-cryption (IgG-Cryptate) (Cisbiointernational, France, final concentration 210ng /mL), 3 μg / m L anti-GS TX L 6 6 5 (C isbiointernati ο na 1, France, final concentration lpg/mL), anti-phospho-MEKl/2 (final 1/1000 dilution) The PBS was dissolved in pH 7.0 as above. The average enthalpy of the wells to which only DMSO was added was taken as 100%, and T/C% (T/C = test compound addition group/only DMSO group added) of each test compound addition group was calculated, and T/C% was 50%. The concentration of IC5G値 is calculated from the approximation of the linear function of the two concentrations from this point. The IC 5Q of each test compound is shown in Table 1, and is considered to be a potent inhibitor of BRAF kinase activity. -9 1- 201124398 [Table i] Example No. IC50 値(μΜ) Example No. IC50 値(μΜ) 1 0.0039 16 0.0054 2 0.0049 17 0.0079 3 0.0090 18 0.0029 4 0.0033 19 0.0029 5 0.0034 20 0.0023 6 0.0071 21 0.0036 7 0.0064 22 0.0060 8 0.0071 23 0.0059 9 0.0033 24 0.0028 10 0.0096 25 0.0067 11 0.0035 26 0.0034 12 0.0028 27 0.0026 13 0.0030 28 0.008 2 14 0.0071 29 0.0043 15 0.0070 30 0.0032 (Test Example 2) Cell proliferation inhibition (in vitro) Evaluation of each Cell proliferation inhibition of the compounds of the examples. The cells were cultured in a 96-well plate at 50 μί / well to inoculate an appropriate amount of the BRAF variant human cancer cell line Α375 (Japan Pharmaceutical Co., Ltd.), and cultured at 37 ° C, 5%-C02 for one night. The test compound was dissolved in DMSO to prepare a dilution series. The test compound solution was diluted with a medium on the day of cell inoculation, and then added to the cells in a volume of 50 μυ. The final DMSO concentration was adjusted to 0.1%. After incubation for 72 hours at 37 ° C, 5% _C02, the Cell Titer-Glo solution (Promega, Madison, WI) was added at ΙΟΟμΙν/well, and after 1 minute, the luminescence was measured with a luminescence assay (Wallac ARVOTMSX). Hey, measure the number of viable cells. The average enthalpy of the wells to which only DMSO was added was taken as 100%, and T/C% (T/C = test compound addition group/DMSO only group) of each test compound addition group was calculated, and T/C% was 50%. The concentration of I c 5 値 is calculated from the approximation of the linear function of the two concentrations that sandwich this point. -92- 201124398 The IC5 of each test compound is shown in Table 2' to be considered to have potent cell proliferation inhibition. [Table 2] Example No. IC50 値(μΜ) Example No. IC50 値(μΜ) 1 0.12 16 0.53 2 0.38 17 0.49 3 0.77 18 0.28 4 0.65 19 0.42 5 0.57 20 0.97 6 0.076 21 0.24 7 0.72 22 0.26 8 0.76 23 0.60 9 0.67 24 0.37 10 0.68 25 0.53 11 0.18 26 0.38 12 0.28 27 0.092 13 0.64 28 0.29 14 0.11 29 0.26 15 0.30 30 0.22 (Test Example 3) Antitumor effect in vivo BRAF variant human cancer cell line A3 7 5 was transplanted subcutaneously into the right axilla of nude mice. In the transplantation method, a tumor piece of about 5 mm square is transplanted to the skin using a transplant needle, or a suitable number of tumor cells are suspended in physiological saline (Otsuka Pharmaceutical Co., Ltd.) and transplanted subcutaneously into a hypodermic syringe with a two-stage needle. After confirming that the transplanted tumor survived adhesion, the tumor volume was used for grouping, and each test compound (the compound of Examples 4, 6, 21, 24, 25, 26, 27) was undissolved and suspended in a 0.5% methylcellulose solution. Forced oral administration to mice. During the administration period, depending on the tumor, it is fixed for 2 weeks to 4 weeks, and the drug is stopped on Saturday and Sunday, and is administered continuously every day. The tumor long diameter (mm) and short diameter (mm) were measured with an electronic digital measuring device over time, and the tumor growth inhibition rate (GI %) was evaluated by the following formula (the principle is the final administration day). At the same time, the body weight measurement and the whole body state were observed over time, so that it was not considered to have a significant effect of -93-; ε; 201124398 weight loss or appearance abnormality. Any of the tested compounds showed good anti-tumor effects. GI ( % ) = ( 1-A/B ) X 1 00 A: average tumor volume on the day of the compound administration group * B: mean tumor volume on the day of the judgment of the untreated control group * * : tumor volume in l/ 2x [tumor long diameter] X [tumor short diameter] 2 was calculated. Industrial Applicability The compound of the present invention has potent BRAF inhibitory activity and has excellent antitumor activity, and is useful as a medicine, particularly as an antitumor agent. [Simple description of the diagram] None. [Main component symbol description] to . j\w -94-

Claims (1)

201124398 VII. Patent application scope: A compound represented by the following formula (1) or a pharmacologically acceptable salt thereof, (CHJ, , 3/ η (1) [wherein R and R2 are the same or different from a hydrogen atom, a halogen atom, a Ci4 alkyl group, or a halogen Cm alkyl group, and R is a trans group 'c2.4 alkynyl group (the c2_4 alkyne) The group may have 1 hydroxy or ethoxylated group as a substituent), -NR5aR5b, azetidinyl (the 吖TD group may have a Ci4 alkyl group as a substituent), oxazolidinyl group (the group may have one side) An oxy group as a substituent), a pyrrolidinyl group (which may have a Ci4 alkyl group as a substituent), a dioxanyl group or a pyrazolyl group, and R5a and R5b are the same or different in a hydrogen atom, (^.4) An alkyl group or a hydroxy Cm alkyl group, R4 is a hydrogen atom or a C, -4 alkyl group, η is 1 or 2, Υ is a C-R6 or a nitrogen atom, and R6 is a hydrogen atom or a halogen atom. -9 5- 201124398 2 The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein Y is CH or CF. 3. The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein Y is nitrogen A compound or a pharmacologically acceptable salt thereof, wherein R3 is a hydroxyl group, an ethynyl group, or a propyne group, according to any one of claims 1 to 3. , hydroxypropynyl, ethoxypropynyl, amine, methylamino, ethylamino, isopropylamino, dimethylamino, (2-hydroxyethyl) (methyl) Amino, azetidinyl, methyl azetidinyl, ethyl azetidinyl, pyrrolidinyl, methylpyrrolidinyl, oxazolidinyl, oxooxazolidinyl, dialkyl or pyrazolyl. The compound of any one of claims 1 to 4, or a pharmacologically acceptable salt thereof, wherein the substituent represented by the formula -(CH2)n_R3 is 2-hydroxyethyl, prop-2-yne- 1-yl, 4-hydroxybut-2-yn-1-yl, 4-ethenylbut-2-yn-1-yl, 2-(methylamino)ethyl, 2-(ethylamine Ethyl, 2-(isopropylamino)ethyl, 2-(dimethylamino)ethyl, 2-(2-hydroxyethyl)(methyl)aminoethyl, (1- Methyl azetidin-2-yl)methyl, (1-ethylazetidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl, pyrrolidin-2-ylmethyl , (1-methylpyrrolidin-2-yl)methyl, 1,4-dioxan-2-ylmethyl, 2-(2-o-oxy-1,3-Boxazolidine-3- Ethyl or 2-(1Η-pyrazole-1 A compound or a pharmacologically acceptable salt thereof, wherein R1 is a hydrogen atom, a chlorine atom or a trifluoromethyl group. -96- 201124398. The compound of any one of claims 1 to 5, wherein R1 is a hydrogen atom, a chlorine atom or a trifluoromethyl group. 7. A salt permissible as a compound of any one of items 1 to 6 wherein R2 is a hydrogen atom or a methyl group. 8. As claimed in any one of claims 1 to 7. A permissible salt on a compound wherein R4 is methyl. 9. 1-{2-[2-(Dimethylamino)ethoxy]-5-(tripyridin-3-yl}-3-(33-[(3-methyl-4-)-side oxygen Benzyl-3,4-di-6-yl)oxy]phenyl}urea. 1 0 ·-species { 3 - [( 3 -methyl-4 -trioxy-3,4-dihydroquinazolyl)丨oxy]phenyl} ·3-[2-{ [( 2S) -1-methylpyrrolidin-2-yl-5-(trifluoromethyl)phenyl]urea 11. A kind of 1_(4 - Gas - 2- { [(2S) -1-methyl U than slightly U 疋-2-ylphenyl)-3 - { 3 - [( 3 -methyl-4 - pendantoxy-3,4 - two Hydrogen sulphonyloxy]phenyl}urea 12.--1-[2- { [( 2S) -1-methylazetidin-2-yl]methyl (trifluoromethyl)pyridine-3 -yl]-3 - { 3-[(3-methyl-4- side dihydroquinazolin-6-yl)oxy]phenyl}urea. 13_- species l-[2-{[(2S) -l-ethylazetidin-2-yl]methyl(trifluoromethyl)pyridin-3-yl]-3-{ 3-[(3-methyl-4-trihydroquinazoline-6 -yl)oxy]phenyl}urea 14--- 1-{ 3-[(3-Methyl-4-oxo-3,4-dihydroquinazolyloxy)phenyl}-3- [2-{[(2R)-1-methylpyrrolidin-2-yl-5-(trifluoromethyl)phenyl]urea] or its pharmacology or its pharmacological fluoromethyl) Hydroquinazoline Lin-6 -base)]methoxy }]Methoxy} phenyl-6-yl) benzyl quinone-5-oxy-3,4-oxy}-5-oxy-3,4-oxalin-6-yl)]methoxy} 97- 201124398 15. 1-(4-Chloro-2-{[(23)小methyl]]azetidine-2-yl]methoxy}phenyl)·3 - { 3-[ ( 3 -Methyl-4-isoxyl_3,4-hydroquinazoline-6-yl)oxy]phenyl}urea. 1-6. A pharmacologically acceptable salt of a compound as claimed in any of claims 9 to 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient. An antitumor agent comprising a compound according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient. A B R A F inhibitor comprising the compound of any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient. 2 0. The anti-tumor agent of claim 18, wherein the tumor is leukemia, lymphoma, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendix cancer, colon cancer, anal cancer, gallbladder Cancer, cholangiocarcinoma, pancreatic cancer, digestive tract stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, renal pelvic cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer, endometrial cancer, child Cervical cancer, ovarian cancer, osteosarcoma, soft sarcoma, Kaposi's sarcoma, muscle tumor, renal pelvic cancer, bladder cancer' and/or 睪9 cancer. -98- 201124398 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None 0. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: