TW201121944A - 5-fluorouracil compound having dutpase-inhibiting activity or salt thereof - Google Patents

Abstract

A 5-fluorouracil compound represented by general formula (I) or a salt thereof, which has an excellent dUTPase-inhibiting activity and is useful as an efficacy potentiator for anti-tumor agents or the like. (In general formula (I), n represents a numeral value of 1 to 3; X represents a bond, an oxygen atom, a sulfur atom, an alkenylene having 2 to 6 carbon atoms, a bivalent aromatic hydrocarbon group which may have a substituent, or a bivalent saturated or unsaturated heterocyclic group which may have a substituent; Y represents a bond, or a linear or branched alkylene group having 1 to 8 carbon atoms; Z represents -SO2NR1R2, -NR3SO2-R4, or a group represented by formula (II) (a R5-substituted pyrrolidinylcarbonyl); R1 and R2 independently represent a hydrogen atom, or the like; R3 represents a hydrogen atom, or the like; R4 represents an aromatic hydrocarbon group which may have a substituent, or the like; and R5 represents a methyl group which may have a substituent.)

Description

[Technical Field] The present invention relates to a novel novel having excellent human dUTP enzyme inhibitory activity and useful as a disease-inducing agent for a dUTP enzyme, such as an anticancer drug. a fluorouracil compound or a salt thereof. [Prior Art] Deoxyuridine tri-acidase (hereinafter also referred to as doxylidine triphosphatase (EC 3.6.1.23)) is a prophylactic DNA (deoxyribonucleic acid) repair enzyme. It is considered that it only specifically recognizes deoxyuridine triphosphate (hereinafter referred to as dUTP (deoxyuridine triphosphate)) in natural nucleic acid triphosphate, and decomposes into deoxyuridine single wall acid (hereinafter referred to as dUMP (deoxyuridine monophosphate). An enzyme related to pyrophosphate (Non-Patent Document 1); the following two reactions are carried out: (1) by reducing the amount of dUTP in the cell, and avoiding urinary biting instead of thymine mis-mixing into the DNA; (2) A substrate dUMP for supplying thymidine synthase, which is an important de novo pathway for supplying thymine to DNA (Non-Patent Document 2). The dUTP enzyme is known to be essential for the survival of cells of both prokaryotes and eukaryotes. Therefore, it is suggested that the enzyme can be an anticancer drug (Non-Patent Document 3), an antimalarial drug (Patent Document 1 and Non-Patent Document 4), an antituberculosis drug (Non-Patent Document 5), and an anti-Helicobacter pylori drug (Patent Document 2) ), anti-parasitic drugs such as trypanosomes or Leishmania (Non-Patent Document 6), and cancer treatments such as human herpes simplex virus, cellular giant virus, Epstein-Barr (Eberstein-Barr) virus Antiviral drug 152528.doc 201121944 target such as virus (Non-Patent Document 7) or vaccinia virus (Non-Patent Document 8). As shown above, the dUTP enzyme has been attracting attention as a dry standard for therapeutic agents for various diseases, and extensive studies have been conducted on dUTP enzyme inhibitors. As the dUTP enzyme inhibitor, for example, a pseudotriphosphate type low molecular compound (for example, Patent Document 3, Non-Patent Document 9 and the like) and a 5'-0-substituted phenyl-deoxyuridine compound (Non-Patent Document 10) are known. [Prior Art Document] [Patent Document 1] [Patent Document 1] International Publication No. 2005/065689 Manual [Patent Document 2] International Publication No. 2003/089461 Handbook [Patent Document 3] International Publication No. 1995/15332 Manual [Non [Patent Document] [Non-Patent Document 1] Structure, 4, 1077-1092 (1996) [Non-Patent Document 2] Acta Biochim. Pol., 44, 159-171 (1997) [Non-Patent Document 3] Curr. Protein Pept. Sci., 2, 361-370 (2001) [Non-Patent Document 4] Structure, 13, 329-338 (2005) [Non-Patent Document 5] J. Mol. Biol., 341, 503-517 (2004) [Non Patent Document 6] Bioorg. Med. Chem. Lett., 16, 3809-3812 (2006) [Non-Patent Document 7] Curr. Protein Pept. Sci., 2, 371-379 (2001) [Non-Patent Document 8] Acta Crystallogr. D. Biol. Crystallogr, 63, 571-580 (2007) [Non-Patent Document 9] Mol. Pharmacol., 29, 288-292 (1986) [Non-Patent Document 1 N] Nucleosides Nucleotides & Nucleic Acids, £ 152528.doc 201121944 . 2〇, 1691-1704 (2001) [Summary of the Invention] [Problems to be Solved by the Invention] However, these inhibitory activities against human dUTP enzymes are insufficient, and are not used as pharmaceuticals. Compound. Therefore, an object of the present invention is to provide a compound or a salt thereof which is excellent in dUTp enzyme inhibitory activity and which is useful as an effect enhancer for an anticancer drug. [Means for Solving the Problem] The inventors of the present invention have repeatedly conducted an effort to solve the above problems, and as a result, have found that the N-1 position of the 5-fluorourine cough ring has a continuous amine structure or a slightly bite base group/carbonyl structure. The 5-fluorouracil compound or a salt thereof has excellent UTPase inhibitory activity and is useful as an effect enhancer for an anticancer drug, and the like. P The present invention provides a 5-fluorouridine compound or a salt thereof, which is represented by the following formula (I):

’ in the general formula (1) represents η! (I) X represents a bond, an oxygen enthalpy, a sulfur atom, a carbon number of 2 to 6, a divalent aromatic group having a substituent, or a substituent The valence of 2 is saturated or 152,528.doc 201121944 and the heterocyclic group; y represents a bond, or a linear or branched chain of carbon number 8; z represents -S〇2NRir2, _nr3s〇2_r4, or The following formula: [Chemical 2] Human y R and R are the same or different 'except hydrogen atom, carbon number 6 alkyl group or an aromatic group which may have a substituent, or may be formed with a neighboring nitrogen atom a group of a heterocyclic group having a substituent; R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and R represents an aromatic fluorenyl group which may have a substituent or an unsaturated heterocyclic group which may have a substituent; A thiol group which may have a substituent]. Further, the present invention provides a pharmaceutical composition comprising a 5-fluorouracil compound represented by formula (1) or a salt thereof. Further, the present invention provides a dUTP enzyme inhibitor comprising 5-fluorourine represented by the formula (1). A compound or a salt thereof. Further, the present invention provides a 5-fluorouracil compound of the formula (I) or a salt thereof for use in the prevention or treatment of a disease in which a dUTP enzyme is involved. Further, the present invention provides a use of a 5-fluorouracil compound of the formula (I) or a salt thereof for use as a prophylactic or therapeutic agent for a disease in which a dUTP enzyme is involved. Further, the present invention provides a disease prevention or treatment of dUTP enzyme involvement 152528.doc 201121944

The method of treatment is characterized in that an effective amount of the 5-fluorouracil compound or a salt thereof is not administered by the formula (I). [Effect of the Invention] Novel 5-fluorouracil compound of the present invention

The sputum or its salt has excellent dUTP enzyme inhibitory activity, and is useful as a disease of dUTP enzyme ginseng, and an effect agent such as an anticancer drug. [Embodiment] The novel 5-fluorouridine compound of the present invention is characterized in that it has a sulfonamide structure or a sulfonamide structure at the N-position of the 5-leuuracyclic ring from the above formula (1). Bilobidine-1-yl-carbonyl structure. A urethane (tetra) ring substituent is disclosed in Japanese Patent Laid-Open Publication No. 2005-65675 (Patent Document No.), which has a substituent such as a trityl* or a triphenyl residue (e(r6)(r7)(r8) group). The urinary (four) compound at the terminal is described as having an anti-malarial drug which exhibits dUTP-enzyme inhibitory activity. Iron does not disclose a hydrazine-containing bond having a compound of the present invention. Further, as the following test As shown in the examples, a compound having a trityl group as a terminal of the N 1 substituent of the urinary (tetra) ring hardly exhibits a human activity. It is disclosed in Japanese Patent Laid-Open Publication No. 2002-28 Na. The acid residue is a uracil compound having a sulfonamide bond as a urethane ring oxime substituent, that is, a hydroxyamino acid group or the like having a substituent on the alkyl chain bonded to the uracil ring oxime], The compound of the present invention is different. Further, it contains "the inhibition of MMP, but does not mention the activity of dUTp enzyme inhibition at all. I52528.doc 201121944 The present specification + the aromatic cigarette base of female, can be two;;: family: base", Preferably, the carbon number is 6 to 14, and the second aspect is better. a group, an inhibitory group of two or more saturated or heterocyclic groups, preferably an early or bicyclic group having one or two saturated or my hydrazine atoms, for example, For example, pyrrolidinyl, piperidinyl, \:"methyleneimido, morphinyl, thio- phenanthyl, gaoba. Dingsi = 'sityl, thienyl, furyl, pyrrolyl, Carbazolyl, iso-oxazole, salivation, iso-(tetra)yl, fluorene, trisyl, tetradyl, pyrene, pyrimidinyl, hydrazine, sulfhydryl, isodecyl , stilbene, fluorenyldioxyphenyl, ethylenedioxyphenyl, benzoated, succinyl, benzoxazolyl, benzoxazolyl, benzothiazole a group, a mercapto group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, a quinoxalinyl group, a tetrahydrofuranyl group, a hydropyranyl group, etc. Among them, it is preferred to have either a "oxygen atom or a nitrogen atom" The 5- to 7-membered saturated or unsaturated heterocyclic group is more preferably a tetrahydrofuranyl group, a quaternary group or a pyridyl group in terms of dUTP enzyme inhibitory activity, and is also referred to as a "saturated heterocyclic group". Examples of the monocyclic saturated heterocyclic group having one or two oxygen atoms, nitrogen atoms, and sulfur atoms include pyrrolidinyl, piperidinyl, piperidinyl, and hexamethyleneimine. And a morpholinyl group, a thiomorpholinyl group, a homopiperidinyl group, etc. The "alkyl group" is exemplified by the alkyl group substituted with an aromatic hydrocarbon group having 6 to 1 carbon atoms. An alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted by a naphthyl group, etc. 152528.doc 201121944 A substitutable group as the above aromatic (tetra)hydrocarbyl group, a saturated or residual heterocyclic group, and an aryl group. (Substituent), for example, a dentate atom via a group, an aryl group, a nitro group, an alkyl group, a dentate alkyl group, a cycloalkylcycloalkyl group, an aralkyl group, a aryl group, an alkoxy group, Tooth oxime oxime, block alkoxy group, ring oxime oxyl group & oxy group, aryl alkoxy group, thiol group, cycloalkyl group, thiol group, amine group, mono or dimorphyl amine a sulfhydryl group, a fluorenyl group, a fluorenyl group, a fluorenyl group, a aryloxy group, a pendant oxy group, a saturated or unsaturated heterocyclic group, an aromatic fluorenyl group, a saturated heterocyclic oxy group, etc., in the presence of the above substituent When it is shaped, its number is usually 1 to 3. In the above substituent, 'the halogen atom' may, for example, be a chlorine atom, a bromine atom, a fluorine atom or a moth atom. In the above substituent, the alkyl group or the halogenated alkyl group preferably represents a linear or branched alkyl group having 1 to 6 carbon atoms or a group in which the alkyl group is substituted with the above halogen atom, and examples thereof include methyl group and ethyl group. Base, n-propyl, isopropyl, trifluoromethyl, and the like. In the above substituent, 'as a cycloalkyl group' is preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. In the above substituent, the cycloalkyl-alkyl group is preferably an alkyl group having 1 to 6 carbon atoms which is substituted with a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropylmethyl group and a cyclopropyl group B. Base, cyclobutylmethyl, cyclopentylmethyl and the like. In the above substituent, 'as an aryl group, a linear or branched alkyl group having a carbon number substituted with an aromatic hydrocarbon group having 6 to 4 carbon atoms is preferable, and a benzyl group or a phenylethyl group is exemplified. , phenylpropyl, naphthylfluorenyl, naphthylethyl and the like. 152528.doc 201121944 In the above substituent, 'as an alkenyl group, a hydrocarbon group having a carbon-carbon double bond, preferably having a carbon number of 2 to 6, is exemplified by a vinyl group, an allyl group, a methylvinyl group, a propenyl group, and the like. Butenyl, pentenyl, hexenyl, and the like. In the above substituent, the alkoxy group, the halogenated alkoxy group, and the alkynyl alkoxy group are each preferably a linear or branched alkoxy group having a carbon number of 6, and the alkoxy group is bonded to the above halogen atom. The substituent group or the group in which the alkoxy group is substituted by the alkynyl group having 2 to 6 carbon atoms may, for example, be an anthracenyloxy group, an ethoxy-n-propoxy group, an isopropoxy group or a 1-mercaptopropoxy group. , n-butoxy, second butoxy, isobutoxy, 2-mercapto-butoxy, neopentyloxy, pent-2-yloxy 'fluorodecyloxy, difluoromethoxy, Trifluoromethoxy, 2-fluoroethoxy, 1,1-diethoxyethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2 ,2-tetrafluoroethoxy, perfluoroethoxy, 3fluoro-2-((methylmethylpropoxy), 1,3-difluoropropan-2-yloxy, 2,2,3,3,3 _ pentafluoropropoxyl, butyl-3-alkyn-2-yloxy, etc. Among the above substituents, a cycloalkyloxy group is preferably a cycloalkyloxy group having 3 to 7 carbon atoms. Decano group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group and the like. Among the above substituents, a cycloalkyl·alkoxy group is preferably substituted with a cycloalkyl group having 3 to 7 carbon atoms. Bu 6 carbon atoms, alkoxy of include: cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentyl methoxy, ⑴ methyl cyclopropyl) methoxy and the like. In the above substituent, the aryl group having the above-mentioned aryl group is preferably an oxy group, a phenylethoxy group, a phenylpropoxy group, a naphthylmethoxy group or a naphthyl group. Ethoxylate and the like.

In the above substituent, the alkylthio group is preferably a thio group having an alkyl group having 1 to 6 carbon atoms, and examples thereof include a thiol group, an ethylthio group, a n-propylthio group and the like. In the above substituent, 'as cyclohexyl-p-thio group' is preferably an alkylthio group having 1 to 6 carbon atoms substituted by a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropylmethylthio group and a ring. Propylethylthio, cyclobutylmethylthio, cyclopentylmethylthio and the like. In the above substituent, the mono- or dialkylamino group means an amine group which is mono- or di-substituted with the above-mentioned alkyl group, and examples thereof include a methylamino group, a dimethylamino group, an ethylamino group, and a diethyl group. Amine group, methyl ethyl amine group and the like. In the above substituent, the cycloalkyl-alkylamino group represents an alkylamino group substituted by the above cycloalkyl group, and examples thereof include a cyclopropylmethylamino group, a cyclobutylguanidino group, and a cyclopentyl group. Methylamino group and the like. In the above substituent, examples of the fluorenyl group include a methyl group, an ethyl fluorenyl group, a propyl aryl group, a n-butyl aryl group, an isobutyl aryl group, a pentyl group, an isoprene group, and a thiol group. The carbon number of the chain or branch is a sulfhydryl group, a benzamidine group or the like. Among the above substituents, as an emergency, the depressing group, μ β -

Benzoyloxy and the like. Among the above substituents, the saturated or unsaturated heterocyclic group preferably has one or two oxygen atoms and a nitrogen atom.

The hydrazinyl group is a succinyl group, a tetrahydrofuranyl group, and a saturated heterocyclic group which is preferably a nitrogen atom or a sulfur atom. Thio, tetrahydrogen 17 fluorenyl, imine D, I52528.doc •12· 201121944 thienyl 'furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazoline , triazolyl, tetrazolyl, pyridyl, pyridinyl, pyrimidinyl, hydrazine, decyl, isodecyl, carbazolyl, methylenedioxyphenyl, ethylidene Oxyphenyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, quinacridyl, isoquinolinyl, quinazoline, In the above substituent, the aromatic hydrocarbon group preferably has an aromatic hydrocarbon group of 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group. Among the above substituents, a saturated heterocyclic oxy group is used. And an oxy group having the above saturated heterocyclic group, which may be exemplified by tetrahydrofuranyloxy group, tetrahydroanthranyloxy group 0, and dUTP enzyme inhibitory activity. In the formula (I), n is a number of 1 to 3, preferably 1 or 3. In the formula (1), X represents a bond, an oxygen atom, a sulfur atom, an alkenyl group having 2 to 6 carbon atoms, a divalent aromatic hydrocarbon having a substituent; or a divalent saturated or unsaturated heterocyclic group which may have a substituent. In X, a bond is preferably a single bond. In X, as a carbon number The alkenyl group of 2 to 6 may, for example, be an alkenyl group, preferably an alkenyl group having 2 to 4 carbon atoms, more preferably a vinyl group. The soil is referred to as "a divalent aromatic hydrocarbon group which may have a substituent or a divalent saturated or unsaturated heterocyclic group which may have a substituent" in X. "Organic group of smoke groups: or "saturated or unsaturated heterocyclic group" The above-mentioned aromatic hydrocarbon group and the above-mentioned saturated or unsaturated heterocyclic group may be the same, and particularly preferably a stabilizing group. Than two bases. & 152528.doc £ 201121944 As a preferred example of X' in the dUTP enzyme inhibitory activity, a bond, an oxygen atom, a sulfur atom, a vinyl group, a phenylene group, a pyridyl group, and an oxygen atom are preferred. Or stretch the base. In the formula (I), Y represents a bond, or a linear or branched alkyl group having a carbon number of 丨8 or more having a ring alkylene structure having a carbon number of 3 to 6 on one carbon atom, preferably It is a linear or branched alkyl group which is a bond or a carbon number of 8. Here, 'as a linear or branched alkyl group having 1 to 8 carbon atoms, an alkylene group, an exoethyl group, a trimethylene group, a tetradecylene group, a penta-indenyl group, and a sixth group are mentioned. Methylene, propyl, butyl, dimethyltrimethylene, dimethyltetralinylene, ethyltrimethylene, diethyltetradecyl, and the like. Further, in the case where "wherein" represents a bond in the formula (I), (CH2)n_XY represents an alkylene group having 3 to 6 carbon atoms, preferably a triindenylene group or a pentamethylene group. As a preferable example of Y' in the dUTP enzyme inhibitory activity, a bond or a linear or branched carbon number of the alkyl group is preferred, and an ethyl group and a diterpene group are particularly preferred. (Where, when X represents a bond, (CH2)nXY represents a tri-indenyl group or a penta-indenyl group). In the formula (1), 'Z represents -SOzNRiR2 or _nR3S02-R4, or the following formula: [Chem. 3] R5 In the oxime, R1 and R2 are the same or different and each represents a hydrogen atom, a carbon number of 6 or an alkyl group. An aralkyl group, or a unit of a saturated heterocyclic group which may have a substituent, 152528.doc •14·201121944. In R1 and R2, the "alkyl group having 1 to 6 carbon atoms" and the linear or branched alkyl group having a carbon number of 丨6 are exemplified by methyl, ethyl, n-propyl and isopropyl. , n-butyl, t-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. In the case of R and R2, the "aralkyl group" which is a "aroyl group which may have a substituent" is preferably a carbon number of 1 to 6 which is substituted with an aromatic hydrocarbon group having a substituent of 6 to 14 carbon atoms. The chain or branched alkyl group may, for example, be a benzyl group, a phenylethyl group, a phenylpropyl group, a naphthylfluorenyl group or a naphthylethyl group, and is preferably a benzyl group. And a linear or branched alkyl group having 1 to 6 carbon atoms which is substituted with an aromatic aryl group which may have a substituent of 6 to 14 carbon atoms which constitutes the above-mentioned "aralkyl group", and has a linear or branched alkyl group having 1 to 6 carbon atoms; In the case of a substituent, examples of the substituent include a carbon number of a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a 2-methylpropyl group, a n-butyl group, a n-pentyl group, and the like. 6 alkyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and other cycloalkyl groups having a carbon number of 3 to 7; methylthio, ethylthio, n-propylthio, isopropylthio and the like An alkylthio group of 1 to 6; an aromatic hydrocarbon group which may have a substituent such as a halogen atom, a methoxy group, an ethoxy group, an isobutoxy group, a cyclobutoxy group, a cyclopentyloxy 'cyclopropylmethoxy group or The unsaturated heterocyclic group such as a thienyl group may have the same or different i~2 substituents. Further, in the case where two of the substituents are an alkyl group having 1 to 6 carbon atoms, the carbon atoms of the alkyl group may form a % sub-glossy "base structure". Further, in the linear or branched alkyl group having 1 to 6 carbon atoms substituted by the aromatic hydrocarbon group having a carbon number of 6 to 14 and having a substituent of the above-mentioned "aralkyl group", When the group of a hydrocarbon group has a substituent, the substituent may be used.

S 152528.doc -15- 201121944, a halogen atom such as a broken atom;

Any one of the substituents having i~2 such substituents may be a fluorine atom, a chlorine atom, a bromine atom having a p to a group, a halogen atom, an ethynyl group, or a bond-like carbon number of 1~ 6 oxy;; pentyloxy, cyclohexyloxy and the like in the general formula (I) having a carbon number of 3 to 7, as Ri and R2 may be formed together with an adjacent nitrogen atom, "may have a saturation of a substituent. The saturated heterocyclic group of the heterocyclic group "R saturated heterocyclic group" is exemplified. In the above formula (I), the "substituent" of the "saturated heterocyclic group which may have a substituent" which may be formed by a combination of a nitrogen atom and an adjacent nitrogen atom may be mentioned. In other words, R1 is a preferred example of the dUTP enzyme inhibitory activity, and a hydrogen atom is exemplified as R2. The dUTP enzyme inhibitory activity is preferably exemplified as a benzyl group which may have a substituent. When the sulfhydryl group has a substituent, 'as the substituent, it may have the same or different 2 hydroxyl groups, an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having a carbon number of 3 to 7 carbon number 1 An alkylthio group of 1-6, an aromatic hydrocarbon group which may have a substituent or an unsaturated heterocyclic group (in the case where two substituents are an alkyl group having 1 to 6 carbon atoms, the carbon atoms of the alkyl group may form each other a cycloalkylene structure), in the case of a phenyl group having a substituent in the case of a phenyl group, 152528.doc -16 - 201121944, as the substituent, may have two im atoms and a linear chain which may have a substituent Or a branched alkoxy group of 6 carbon atoms, a cycloalkoxy group having 3 to 7 carbon atoms, a cycloalkylalkoxy group having 3 to 7 carbon atoms, a cycloalkyl group of a carbon number of 3 to 7 Any one of a group and a saturated heterocyclic oxy group], in the case of 0 Z, R3 represents a hydrogen atom or an alkyl group having a carbon number of 6 and can be listed as an "alkyl group of carbon number The same base as the alkyl group in !^ and R2. Among them, in terms of dUTP enzyme inhibitory activity, a hydrogen atom is preferred. Wherein R represents an aromatic fluorenyl group which may have a substituent or an unsaturated heterocyclic group which may have a substituent. The "aromatic smoke base" which is the "aromatic group which can have a substituent" in R can be exemplified by the above aromatic smoked product, and is preferably used in the case of the duTPase inhibitory activity. Phenyl. The "substituent of the "aromatic group which may have a substituent" in R4 is preferably an alkoxy group having 1 to 6 carbon atoms which may be substituted by dentate, and has a carbon number of 3 to 7. The cyclooxy-alkoxy group of the oxy group having a carbon number of 3 to 7 is more preferably a cyclopropylmethoxy group, a 2,2-dioxyethoxy group or a group. The "unsaturated heterocyclic group" which is "unsaturated heterocyclic group which may have a substituent" in R may, for example, be the above-mentioned unsaturated heterocyclic group. The "substituent" as the "unsaturated heterocyclic group which may have a substituent" in R4 may, for example, be the above substituent. R5 is a "substituent" as a "substituent group", and a substituent "" is preferably an aromatic hydrocarbon group or a mercapto group, preferably benzene. 152528.doc -17· 201121944

Base, base. The aromatic hydrocarbon A group further has a substituent, and preferably a halogen atom ' is particularly preferably a fluorine atom. The pharmaceutically acceptable salt of the compound of the formula (I), which is a compound of the formula (I), may be exemplified by inorganic acids such as hydrochloric acid, hydrogen acid, hard acid, sulfuric acid, nitric acid, and wall acid, or

Formic acid, acetic acid, propionic acid, 苜T grass knock, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, frequency fruit acid, citric acid, tartaric acid, carbonic acid, picric acid, nail Ingredients, toluene rhyme, glutamic acid and other organic acid acid addition salts 'Na, unloading, town, each, Shao and other inorganic tests, or methylamine, ethylamine meglumine, ethanolamine and other organic tests, or with beets Test, arginine, ornithine and other salts of the test amine acid or recorded salt. X, the compound of the present invention also contains an optical isomer and also contains a hydrate. The 5-fluorourea compound of the present invention can be produced according to the following reaction step: [Chemical 4]

Step A

(1) Hyperthyroidism 9 (2) or Ra〇H (3> A-1

[wherein, Ra represents a linear or branched alkyl group having an alkyl number i to 6 which may have a substituent, a cycloalkyl group having 3 to 7 carbon atoms, or a cycloalkyl group having a carbon number of 3 to 7 And any of the saturated heterocyclic groups, Lg represents a dentate atom, a fluorenylsulfonyloxy group, a fluorenyloxy group, a trifluoromethyl fluorenyloxy group or the like. [A-1] (a) In this step, it can be easily obtained by the presence of a base. 3 Cyano i52528.doc • 18- 201121944 Benzene (1) and an alkyl halide of the formula 'Alkyl The compound represented by the above formula (4) is produced by reacting a mesylate, an alkyl toluene vinegar, or a hospital-based triflate.

The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include diethyl ether and tetrahydrofuran (hereinafter, THF (tetrahydr〇fUran)), dioxane, acetone, and dimethoxy B. Alkane, acetonitrile, N,N-dimercaptocarboxamide (hereinafter, DMF (N, N-dimethylformamide)), N,N-dimercaptoacetamide (hereinafter, DMA (N, N-dimethylacetamide)), Dimethyl sulfoxide (hereinafter DMSO (dimethyl sulfoxide)), etc., preferably! ;)]^. As the test to be used, an inorganic base such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, carbonic acid planer, sodium hydride or potassium hydride or trimethylamine, triethylamine, tripropylamine or diisopropyl can be exemplified. Ethylamine, N-methylmorpholine, pyridine, dimercapto. An organic amine such as a bite or a triterpene group, preferably a potassium carbonate. The number of equivalents is from 0.8 to 10 equivalents, preferably from 1 to 5 equivalents. The equivalent number of the formula (2) is 〇.8 to 1 〇 equivalent, preferably ι·〇 to 5.0 equivalent. The reaction temperature is 20 to 150 ° C, preferably 50 to 130 ° C. The reaction time is from 0.5 to 24 hours, preferably from 1.0 to 12 hours. (b) In this step, the compound represented by the formula (4) can also be produced by condensing the easily obtainable 3-cyanophenol (1) with the alcohol represented by the formula (3) by a light-diffusing reaction. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, 12-dioxaethane (hereinafter, DCE (1,2-dichloroethane)), benzene, and Toluene, methyl stupid, ethyl acetate 152528, doc 201121944 s, acetic acid propyl, acetic acid butyl vinegar, diethyl hydrazine, THF. Alkane, diketone, dimethoxyethane, acetonitrile, DMF, etc., preferably THF. The touch made by the light-reacting reaction towel is not particularly limited as long as it is a reagent which can be used in a usual light-span reaction, and is diethyl azodicarboxylate (hereinafter, DEAD (diethyl azodicarboxylate)), diisopropyl azodicarboxylate An ester (hereinafter, DIAD (diis〇propyl azodicarb〇xyiate)), a diazoalkyl azodicarboxylate, or an azodicarbonyl group such as 1,1·-(azodicarbonyl)dipiperidine A combination of an azo compound and a triarylphosphine such as triphenylphosphine or a tri-lower alkylphosphine such as tri-n-butylphosphine. A combination of DEAD and triphenylphosphine is preferred. The equivalent number of the general formula (3), the di-lower alkyl azodicarboxylate or the azo compound, the triarylphosphine or the tri-lower alkylphosphine is 〇 8 to 5 〇 equivalents, preferably 1.0 to 2.0 equivalents. The reaction temperature was _2 Torr. 〇~12 (TC, preferably 0 to 60 C. The reaction time is 0.1 to 24 hours' is preferably 〇·2 to 6.0 hours. [A-2] In this step, 'the general formula (4) can be made The cyano compound shown is reacted with a generally known reducing agent to produce a compound of the formula (5). The reaction solvent used 'is different depending on the kind of the reduction reaction to be used, and examples thereof include decyl alcohol, Ethanol, 1-propanol, 2-propanol, tert-butanol, dimethoxyethane, diethylene glycol dioxime ether, diisopropyl ether, diethyl ether, THF, dioxane, etc., preferably As the reducing agent to be used, lithium aluminum hydride (hereinafter referred to as LAH (lithium aluminium hydride)), hydrogenated diethoxy oxime, nitrided diethoxy chain, hydrogenated tri-tertiary butoxide can be exemplified.基铭Μ, Hydrazine, 152528.doc -20- 201121944 Aluminum hydride magnesium chloride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, or palladium/carbon, The contact reduction of a catalyst such as palladium hydroxide or platinum is preferably LAH, and the number of equivalents is 〇5 to 5.0 equivalents, preferably 0.8 to 2.0 equivalents. The reaction temperature is 〇〇c~1〇〇〇c, preferably 2〇~6 (RC. The reaction time is 0.1~24 hours' preferably 0.2~6.0 hours. [Formula 5]

Step B ”°°〇Η(7)

[In the formula, Ra and Lg have the same meanings as above, Rb represents a hydrogen atom or a dentate atom, and RC and Rd each independently represent a hydrogen atom or a linear or branched carbon number of 丨~6 which may have a substituent. Base, Hal represents a halogen atom]. [B-1] In this step, the carboxyl group of the easily obtainable compound (6) can be esterified by the alcohol compound (7) by a commonly known method, and then produced by the same method as the step [A i]. A compound of the formula (8). [B-2] In the present step, a compound of the formula (9) can be produced by reacting a compound of the formula (8) with a usual reducing agent. 152528.doc • 21-201121944 The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include diethyl ether, diisopropyl ether, THF, and dioxane. As the reducing agent to be used, LAH, hydrogenated diethoxy aluminum clock, hydrogenated lithium triethoxyaluminum, hydrogenated tri-t-butoxide aluminum lithium, hydrogenated magnesium, aluminum aluminum hydride, sodium aluminum hydride can be exemplified. , hydrogenated sodium triethoxyaluminate, hydrogenated bis(2-methoxyethoxy)aluminum sodium, hydrogenated diisobutylaluminum (hereinafter, DIBAL (diis〇butyl aluminum hydride)), hydrogen gelatinization clock, etc. Jia is hydrogen hydrogenated. The number of equivalents is from 0.8 to 10 equivalents, preferably from 1.0 to 5.0 equivalents. The reaction temperature is - the boiling point of the solvent, preferably the boiling point of the solvent. The reaction time is 〇1 to 24 hours, preferably 2 hours. [B-3] In this step, an aldehyde compound represented by the formula (?) can be produced by reacting a compound of the formula (9) with a generally known oxidizing agent. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction. Examples thereof include dichlorosilane, chloroform, tetra-carbonized carbon, DCE, gas benzene, toluene, and diphenylbenzene. It is dichloromethane. The oxidizing agent to be used may, for example, be a complex reagent such as chromic anhydride, pyridine or acetic acid, or a high valence such as a chromium-based oxidizing agent such as pyridine gas chromate or pyridine dichromate, and a Dess-Martin reagent. Iodine oxidizing agent, DMSO with acetic anhydride, oxalic acid chloride, dicyclohexylcarbodiimide (hereinafter DCC (diCycl〇heXyl carb〇diimide)), •ethyl_3 (3-didecylaminopropyl) Carbodiimide hydrochloride (hereinafter ΕοοΗεΚί-ΜΐιγΜ- Ο dimethyl aminopr〇pyl)carbodiimide.HCl)) 152528.doc -22· 201121944 DMSO oxidant, oxidized violent (Iv), 2, 2, 6,6_tetramethylhydrazine small oxygen radical; preferably manganese (IV) oxide. The number of equivalents is 〇 8 to 3 〇, equivalent, preferably ^ 2 〇 equivalent. The reaction temperature is -20 to 15 (TC, preferably 0 to 100 t. The reaction time is 0.1 to 24 hours, preferably 0 5 to 12 hours. Further, when R is a hydrogen atom, it can be easily obtained. 3-Phenylbenzene is used as a starting material, and the compound H of the formula (10) can be produced by the same method as [H], and it can also be known by the compound of the formula (4). A compound represented by the formula (10) can be produced by a reduction reaction, for example, a reduction method. [B-4] In this step, 'the compound represented by the above formula (10)) can be easily obtained by a 2·methyl group. 2. The reaction product of the above formula (11) is produced by reacting a propane and a brewing amine under acidic conditions. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include diethyl _ 'diisopropyl ether, thf, diterpene, gas, chloroform, carbon tetrachloride, and benzene. And diterpene benzene, etc., preferably benzene. The acid to be used may, for example, be hydrochloric acid, magnesium sulfate, p-toluenesulfonic acid, or a Lewis acid such as titanium tetraisopropoxide or titanium tetraethoxide, which is preferably titanium tetraisopropoxide. The equivalent number of 2-mercapto-2-propanesulfonamide and titanium tetraisopropoxide is 8 1 Torr, preferably 1. 〇 3 〇 equivalent. The reaction temperature is 2 Torr to 5 cc, preferably 50 to 120 C, and the reaction time is 0.1 to 24 hours, preferably 5% to 6.0 hours. [B-5] £ 152528.doc -23 201121944 In this step, the compound represented by the formula (11) can be reacted with the Grignard reagent (12) represented by RdMgHal or the organolithium reagent (13) represented by RdLi. The compound of the formula (14) is selectively produced instead of the enantiomer. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, THF, and dimethoxy B. Alkane, dioxane, methylene chloride, chloroform, carbon tetrachloride, toluene, xylene, and the like. The equivalent of the Grignard reagent or the organolithium reagent is from 0.8 to 20 equivalents, preferably from 1.0 to 10 equivalents. The reaction temperature is _100 ° c to 100 〇 c, preferably -78. 〇~50〇c. The reaction time is from 0.1 to 24 hours, preferably from 0.5 to 12 hours. [B-6] In this step, a compound of the formula (15) can be produced by subjecting a compound of the formula (14) to treatment with an acid. The solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol. The citron, ethyl acetate or the like is preferably decyl alcohol. The acid used may be exemplified by hydrochloric acid, sulfuric acid, acid, etc., preferably hydrochloric acid, and the equivalent number thereof is from 01 to 10 equivalents, preferably 1 〇~2·0 equivalent. The reaction temperature is -2 (TC~10〇t, preferably 〇~5〇. (: The reaction time is 〇.01~24 hours' is preferably 0.1~1.0 hours. In the case where Rd is a hydrogen atom, the compound represented by the formula (9) can be azide by a commonly known method, and then treated with a generally known reducing agent (for example, LAH) to produce a pass. The compound of the formula (15). Further, by the case of obtaining the 152528.doc •24·201121944 compound represented by the formula (15) as a racemate, the same method as in the step b. Conversion of a compound of the formula (10) to an alcohol compound, which is usually abbreviated by a commonly known method. The method of reduction, and producing the general formula (15) the compound is not: [Formula 6]

Step C

[wherein R and R have the same meanings as defined above, and Rf is the same or different and represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent]. [C-1] In this step, the compound (16) which can be easily obtained can be reacted with any of the amines represented by the general formulae (5) and (15) in the presence of a base to produce a general formula ( 7) The compound shown. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction. Examples thereof include acetone, THF, diethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, and tetra-gasification. Carbon, DMF, DMA, acetonitrile or the like is preferably dichlorodecane. As the base to be used, sodium hydrogencarbonate, sodium carbonate, and potassium carbonate can be exemplified.

S 152528.doc •25· 201121944 Inorganic base or dimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimercaptopyridine, three The organic amine such as methylpyridine is preferably diethylamine. The equivalent number of the base and the amine is 〇5 to 1 Torr, respectively, preferably 0.7 to 5.0 equivalent. The reaction temperature was _2 Torr.匸~1〇〇〇c, preferably 〇~50C. The reaction time is from 0.1 to 24 hours', preferably from 2 to 6 hours. [C-2] In this step, a chlorine compound represented by the formula (17) can be reacted with an ethyl ethoxylation reagent by a generally known method, and then a commonly known deacetylation method can be used to produce a pass. An alcohol compound represented by the formula (18). [C-3] In this step, 'the compound represented by the formula (18) can be subjected to oxime oximation by a method well known in the art, followed by Lewis acid After the treatment, a compound of the formula (19) is produced by reacting with commercially available 5-fluoro-2,4-bis(trimethyldecyloxy)pyrimidine in the presence of iodine. The solvent used in the Lewis acid treatment is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, carbon tetrachloride, DCE, toluene, xylene, etc., preferably dichloro. Methane. The Lewis acid may, for example, be boron trichloride (hereinafter referred to as Bcl3), boron trifluoride or boron tribromide, and is preferably BC13. The equivalent number is 〇 〜 1 〜 1 〇 equivalent is preferably 0.2 to 0.5 equivalent. The reaction temperature is _2〇~1〇〇<)(:, preferably 〇~5〇艽. The reaction time is 0.1 to 24 hours, preferably 〇5 to 5·〇 hours. As with 5-fluoro -2,4-bis(trimethyldecyloxy)pyrimidine 152528.doc -26· 201121944 The solvent used is not particularly limited if it does not affect the reaction, and it can be exemplified by: , chloroform, carbon tetrachloride, DCE, toluene, xylene, etc., preferably DCE or toluene. The equivalent number of 5-fluoro-2,4-bis(trimethyldecyloxy)pyrimidine is 〇.8~ 10 equivalents, preferably 0.9 to 5.0 equivalents, and the number of equivalents of iodine is 0.001 to 1.0 equivalents, preferably 0.05 to 0.5 equivalents, and the reaction temperature is 20 to 150 ° C, preferably 50 to 100 ° C. The reaction time is 0.1 to 120 hours, preferably 0.5 to 100 hours.

Step D

(27) [wherein, Ra, Rb, Re, and Rf have the same meanings as defined above, Pg represents a protecting group of a nitrogen atom on a sulfonamide group, and E represents a bond or a vinyl group (wherein, the case where E represents a bond) In the case of CH2-E-(CH2)m, it is a propyl group or a pentylene group, and m represents a number of 1 to 5, and Bz represents a benzyl group. S. 152528.doc -27- 201121944 [Dl] In this step, the nitrogen atom on the amine group of the compound represented by the formula (17) can be obtained by a commonly known method, for example, from methoxymethyl, After protecting the protecting group such as tributyloxycarbonyl, the compound of the formula (20) is produced by the same method as the step [C-2]. [D-2] In this step, 'the aldehyde compound can be obtained by the same method as the step [B-3], and then the non-alcohol compound of the formula (20) can be reacted with the H〇rner-Wadsworth-Emmons reagent. The compound of the formula (22) is produced. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include benzene, toluene, diethyl ether, diisopropyl ether 'THF, diethylene glycol dioxime ether, and dimethoxy B. Alkane, DMSO, etc. are preferably THF.

The Horner-Wadsworth-Emmons reagent is prepared, for example, by treating phosphinic acid triacetate (21) with a base such as sodium hydride, guanidine, lithium diisopropylamide or sodium decoxide. The number of equivalents of the base is 〇no equivalent, preferably 0.8 to 2_0 equivalent. The reaction temperature is _2〇»c~1〇〇〇c, preferably 〇~7〇〇c. The reaction time is from 0.05 to 12 hours, preferably from 0.1 to 2.0 hours. The number of equivalents of the Horner-Wadsworth-Emmons reagent is 0.1 to 1 Torr, and the amount ' is preferably 0.3 to 5.0 equivalents. The reaction temperature is from 0 ° C to 150 ° C, preferably from 1 ° C to 100 ° C. The reaction time is 0.0542 hours, preferably (Um o hour. [D-3] In this step, it can be reduced by the usual 152528.doc -28 - 201121944 of the compound of the formula (22). A method, preferably a DIBal reduction method, is used to produce a compound of the formula (23). [D-4] In the present step, a contact reduction method which is generally known by a compound represented by the formula (23) can be carried out. The compound of the formula (the compound of the two sentences is produced. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include methanol, ethanol, propanol, 2-propanol, and tert-butanol. , dimethoxyethane, diethylene glycol dioxime ether, diisopropyl ether, diethyl ether, THF, dioxane 'ethyl acetate, butyl acetate, etc., preferably decyl alcohol or ethyl acetate. The catalyst used may be exemplified by 5 to 丨〇% palladium/carbon, palladium hydroxide, indium, nickels, platinum oxide, rhodium-alumina, preferably 5 to 1% palladium/carbon. The number is 0.001 to 10 equivalents, preferably 〇〇1 to 5.0 equivalents, and the reaction temperature is 0 ° C to 100 ° C. Preferably, it is 20 to 6 (TC. The reaction time is , 1 to 24 hours, preferably 0.2 to 6.0 hours. Π > 5] In this step ' can be made according to the literature (Bi〇org. Med. Chem. Lett., 12, 1395-1397 (2002)) 3-Benzylmercapto-5-fluoropyrimidine-2,4(1H,3H)-dione (25) obtained by the method described, and any one of the formulas (20), (23), (24) The alcohol compound is subjected to the same retardation reaction as in the step [Al] (b) to produce a compound of the formula (26). [D-6] In the present step, the formula can be obtained by using a generally known deprotection method. (26) The compound shown is subjected to dephenylation and de-pgification to produce a compound represented by the formula (27): [Chem. 8]

Step E

If Ο

(29) (28) Ο

(30) Ε·2 [wherein, Hal, Ra, Rb, and RlRf have the same meanings as defined above, and Ar represents a divalent aromatic hydrocarbon group or a divalent unsaturated heterocyclic group]. [E-1] In this step, a compound represented by the formula (28) can be reacted with any of the amines represented by the formula (5) or hydrazine 5) by the same procedure as in the step [Cq]. The compound of the formula (29) is produced. [E-2] In this step, the compound represented by the formula (29) can be reacted with a commercially available 5-fluoro-2,4·bis(trimethyldecyloxy)pyrimidine by the presence of a cleavage. A compound of the formula (30) is produced. The solvent to be used is not limited as long as it does not affect the reaction. Illustrative: DCE, THF, dioxane, acetonitrile, preferably DCE or sputum. The equivalent number of 5-fluoro-2'4-bis(trimethyldecyloxy)pyrimidine is 〇545152.doc -30· 201121944 The equivalent number of iodine is O.Oly.O equivalent, preferably 1 0 to 1.5 equivalents, preferably 0.1 to 0.5 equivalents. The reaction time is a reaction temperature of 10 to 1 Torr (TC, preferably 7 Torr to 95 Torr, 0.1 to 120 hours, preferably 0.5 to 100 hours).

[Chem. 9] Step F

[wherein, Re, R/ and m have the same meanings as described above. Rg & Rh is the same or different, and represents a hydrogen atom, a dentate atom, a benzamethyleneoxy group, a linear or branched carbon group having a substituent of 丨~6, and a ring having a carbon number of 3 to 7. An alkyl group, a linear or branched carbon group having a carbon number of 丨6, a cycloalkyloxy group having 3 to 7 carbon atoms, a cycloalkyl group alkoxy group having 3 to 7 carbon atoms which may have a substituent. , Ar represents an aromatic hydrocarbon group or an unsaturated heterocyclic group, Cbz represents a benzyloxycarbonyl group, and Μ〇Μ represents a decyloxymethyl group]. [F-1] In the present step, the amine group of the amino alcohol compound represented by the formula (31) which can be easily obtained can be cbz-formed by a generally known method, and then MOM is carried out by a generally known method. And the production of the general formula (32)

S 152528.doc -31· 201121944 Compound. The amino alcohol compound represented by the formula (31), for example, in the case of m = 2, can be obtained by the method described in J. Med. Chem., 34, 633-642 (1991) by using LAH. 3_Amino_3_methylbutyric acid ethyl ester is reduced to produce; in addition, when Re and is a methyl group, it can be utilized; Am.

Manufactured by the method described in Chem. S〇c., 77, ι〇79·1〇83 (1955). [F-2] In this step, the compound represented by the formula (32) can be subjected to Cbz reaction by reacting with, for example, carbon in a hydrogen atmosphere by a generally known method, under alkaline conditions. And reacting with an easily obtainable arylsulfonyl sulfonium having a substituent (for example, which can be produced according to the method described in j. Pesticide chem, 13, 1 〇 7_ 5 (1988)) (33) All compounds. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include di-methane, DMF, ethyl acetate, THF, dioxane, diethyl ether, acetonitrile, etc., preferably dichloro Methane. The equivalent number of the arylsulfonyl chloride which may be substituted is from 0 to 9 to 5.0 equivalents, preferably from 1 to 1 to 1.5 equivalents. As the test to be used, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, hydrazine methylmorpholine, pyridine, rmethylhydrazine, dimethyl (tetra) can be exemplified. The organic amines such as 1,8·diazabicyclo[5 4 bucket 7 eleven (hereinafter, UdiazabiWoMoh^e·) are: triethylamine. The number of equivalents is 〇 9 to 1 〇 equivalent, preferably i 〇 〜3 〇 152528.doc • 32· 201121944 The reaction temperature is 0 to 60 ° C, preferably 〇 30 ° C. The reaction time is from 0.1 to 100 hours, preferably from 1.0 to 72 hours. Further, in the case where ... or ? is a benzoquinoneoxy group, it can be converted into various functional groups by a generally known method. [F-3] In this step, a compound of the formula (34) can be produced by reacting a compound of the formula (33) by the same method as [C-3]: [Chemical Formula 10]

Step G

[wherein, Ar1, Re, Rf, Rg, and Rh have the same meanings as described above]. [Gl] In the present step, for example, the formula (35) which can be easily obtained according to the method described in Tetrahedron Lett, 38, 1241-1244 (1997) can be obtained by the same method as [F-2]. The compound shown is reacted with an easily obtainable arylsulfonyl chloride which may have a substituent (for example, which can be produced according to the method described in J. Pesticide Chem., 13, 107-115 (198 8)). A compound of the formula (36). Furthermore, in the case where Rg or Rh is a benzoquinoneoxy group, it is possible to use the usual 152528.doc -33-

I 201121944 Converted into various functionalities by the method known in the art [G-2] This step towel can be obtained by using the same method as [E_2] to form a methyl group of a compound of the formula (10) with a generally known brominating agent, for example. The compound of the formula (37) is produced by reacting bromate with sodium hydrogen sulfite, or N-bromosyl iminoimide and azobisisobutyronitrile (AIBN (azobisisobutyr〇nhrile)). [G-3] In the present step, the hydroxyl group of 6-(hydroxymethyl)nicotinic acid nitrile (38) obtained by the method described in JP-A-2006-508054 can be used by a method which is generally known. Introducing a protecting group, preferably a tert-butyl-fluorenyl group (hereinafter, TBS (tert-butyldimethylsilyi) group), the obtained compound and a sensitizer which can be prepared from cerium chloride or methyl quinone After the reaction, the compound represented by the formula (39) is produced by the same method as [F_2], and reacted with an easily obtainable substituted arylsulfonyl chloride. The reaction used in the methylation is used. The solvent may, for example, be THF, di-oxygen, diethyl ether or the like, preferably THF or diethyl ether. The equivalent number of cerium chloride is 〜5.0 equivalents, preferably 2.0 to 4.0 equivalents, and the equivalent number of fluorenyl lithium is 1 〇~5.0 equivalents, preferably 2. 〇~4.0 equivalents. The reaction temperature for methylation is -100 to 40 ° C, preferably -78 to 30. (: The reaction time is 0.5 to 5_0 hours, compared It is preferably 2.0 to 3.0 hours. In addition, when Rg*Rh is a benzoquinone group, it can be used in general. The method is converted into a functional group. 152528.doc -34- 201121944 [G-4] In this step, 'the TBS group of the compound represented by the general formula (39) is removed, and the well-known one is used to 'by For example, after triphenylphosphine and carbon tetrabromide bromine the resulting hydroxyl group, the compound of the formula (40) is produced by the same method as [Ε·2]: [Chemical Step 11]

[wherein R, Rj and R are the same or different and each represents a hydrogen atom, a hydroxyl group, a halogen atom, an aromatic hydrocarbon group which may have a substituent or an unsaturated heterocyclic group which may have a substituent]. [H-1] This step can be obtained by using the method described in the literature (Med. Chem. Res., 10, 3 90-403 (2001)) 4 (5 gas 4 dioxo 3, The compound of the formula (42) is produced by condensing 4-i-hydropyrimidin-1(2H)-yl)butyric acid (41) with an easily obtainable pyrrolidine derivative. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include _, toluene, methylene chloride & hexane, THF, etc., and preferably dioxin & As a condensing agent to be used, as a DCC, EDC.HC, and a condensation auxiliary agent, it can be exemplified as: a light-based base and a three-supplement (a 152528.doc • 35-201121944 is a HOBt (l-hydroxy benzotriazole)), etc. Jia is a combination of EDC 'HCl ' HOBt. The equivalent number thereof is 〇 8 to 5 〇 equivalents, preferably 1.0 to 3.0 equivalents, respectively. The equivalent number of the amine compound is 〇8 to 5 当量 equivalent, preferably 1.0 to 3.0 equivalents. The reaction temperature is 〇~1〇 (rc, preferably 10 to 40 ° C. The reaction time is 0. U 4 hours, preferably 〇 5 to 4 〇 hours. Above, the compound of the present invention and the synthesis thereof are produced as above. The intermediate can be usually isolated and purified by well-known separation and purification methods such as recrystallization, crystallization, hydrazine distillation, column chromatography, etc. The compound of the present invention and the synthetic intermediate it can often be formed by the well-known method to form its pharmacology. The salt which is allowed in the above can be mutually converted. As shown in the following examples, the 5-fluorouracil compound of the present invention or a salt thereof has excellent dUTP enzyme inhibitory activity, and thus the effect of a disease in which the *dUTp enzyme is involved, such as an anticancer drug. The pharmaceutical agent represented by the enhancer is more useful. The medicinal carrier can be formulated with the pharmaceutical carrier according to the purpose of prevention or treatment for the purpose of preventing or treating the fluorochemical. In the case of the above-mentioned form, for example, an oral preparation, an injection, a suppository, an ointment, or the like can be used in various forms. For example, a patch or the like is preferably used. Oral agent. It is well known that the pharmaceutical preparation method can use various organic or inorganic carrier materials which are conventionally used as a material for preparation, and is used as a shape agent, a binder, a disintegrator, a lubricant and a colorant in a solid preparation; In liquid preparations, it can be formulated with a mixture of ingredients, dissolution aids, suspensions, isotonic agents, buffers, and analgesics. Also, preservatives, antioxidants, colorants, and sweetening can be used as needed. Flavor, stabilizer, etc. 152528.doc • 36· 201121944 Additives. In the case of preparing an oral solid preparation, an excipient, an optional binder, a disintegrating agent may be added to the compound of the present invention. After the lubricant, the coloring agent, the flavoring, the flavoring agent, etc., the tablet, the lozenge, the granules, the powder, the capsule, etc. are produced by a conventional method. As the excipient, it may be mentioned: lactose, white sugar, D_ Mannitol, glucose, starch, acid-breaking, kaolin, microcrystalline cellulose, anhydrous oxalic acid, etc. As a binding agent, water, ethanol, L-propanol, 2-propanol, monosaccharide, glucose solution CW Temple powder, gelatin solution, D•mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, thiol cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinyl吼 啶 啶 等 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Examples of the lubricant include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol. Examples of the coloring agent include titanium oxide and iron oxide. Examples of the odor agent include white sugar, scalp, tartaric acid, etc. In the case of preparing a liquid preparation for oral administration, it can be used in the present invention: force I: taste agent, buffer agent, stabilizer, bridge odor agent, etc. , conventional sputum liquid, syrup, granules and the like. In this case, the following items can be used as a buffering agent, and can be used as a buffering agent. As a stabilizer, only silicone rubber or gum arabic can be used. 152528.doc -37-201121944 Ming Sheng, etc. . The enteric coating may also be applied by a well-known method in order to carry out an enteric coating as needed or in order to maintain the effect. Examples of the above-mentioned coating agent include acetaminophen, ethylcellulose, methylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween8® (registered trademark), and the like. In the case of a preparation for injection, a hypoactive preparation, a buffer, an elixir, an isotonic agent, a local anesthetic or the like may be added to the compound of the present invention, and a subcutaneous, intramuscular, and intravenous injection may be produced by a conventional method. Examples of the pH adjusting agent and the buffering agent in the case of the case include sodium gluconate, sodium 2 =, sodium phosphate, and the like. Examples of the stabilizer include sodium metabisulfite, TA (ethylene diamine), acid glycol, ethylene glycolate, and lactic acid. As the local anesthetic, the more acidic procaine, lidocaine hydrochloride and the like can be mentioned. Examples of the isotonic agent include sodium, glucose, D-mannitol, and glycerin. In the case of L-supplement, a well-known carrier for preparation such as polyethylene glycol, lanolin, cocoa butter, and fatty acid diglycerin can be added to the compound of the present invention. Tween80 (registered as a surfactant or the like, and then manufactured by a conventional method. In the case of preparing an ointment, it can be formulated as needed in the compound of the present invention. , wetting agent, preservative, etc., and the method is mixed and formulated. As a base, the liquid L is used as the two forests, the white bee, the octyldodecanol, the stone butterfly B: The agent may be exemplified by decyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, p-propyl benzoate, etc. The information on the preparation of the patch is _ when using conventional methods in the usual support 152528. Doc •38- 201121944 Apply the above ointment, cream, gel, paste, etc. It is more suitable for fabrics containing cotton, staple fibers, chemical fibers, non-woven fabrics or soft ethylene, polyethylene. Thin, polyamino carboxylic acid, etc. The film or the foam sheet. The amount of the compound of the present invention which can be adjusted in each of the above-mentioned administration unit forms is not fixed depending on the symptoms of the patient to be used, or the dosage form thereof, and is usually 'per unit dosage form The oral preparation is about 〜5~1〇〇〇, the injection is about 〇·01~500 mg, and the suppository is about 1~1000 mg. Further, the administration of the above-mentioned administration form is administered every day. The amount varies according to the patient's symptoms, weight, age, sex, etc. It cannot be determined - usually adult (body weight 5 〇 kg) is about 〇.〇5~5〇〇〇mg& Preferably, it is 0.1 to 1000 mg, and it is preferred to administer the drug to the i-go group for about 2 to 3 times per day. As a disease which can be treated by administering a drug containing the compound of the present invention, it can be enumerated : malignant tumors, malaria, tuberculosis, etc., for example, in the case of malignant tumors' can be enumerated: head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder, cholangiocarcinoma, pancreatic cancer, lung cancer, breast cancer, ovarian cancer , cervical cancer, uterine body cancer, kidney cancer, bladder cancer Prostate cancer, pen tumor, bone soft tissue sarcoma, leukemia, malignant lymphoma, multiple bone tumor, skin cancer, brain tumor, etc. Also, it can also be used as anti-Helicobacter pylori, anti-parasitic, anti-viral drugs [Examples] Hereinafter, the present invention will be described in detail with reference to Examples, Examples, Test Examples, and Preparation Examples, but the present invention is not limited to the Examples. 152528.doc •39· 201121944 Reference Example 1 Synthesis of 3-(cyclopropylmethoxy)phenyl)methaneamine [Chemical 12]

3-cyanophenol (12.4 g) was dissolved in N,N-dimethylformamide (hereinafter DMF, 100 mL), potassium carbonate (30.5 g), potassium moth (1_74 g), (chlorine) was added. The fluorenyl)cyclopropane (10.2 mL) was stirred at 90 ° C for 4 hours. Water (13 mL) was added to the reaction mixture. The mixture was extracted with hydrazine (130 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The residue was dissolved in tetrahydrofurfuran D (hereinafter referred to as THF '60 mL), and slowly hydrotreated at 0 ° C under the THF solution (2·4 Μ '68 mL) of Ming (hereinafter referred to as lAH). The reaction solution was stirred at 45 ° C for 4 hours. Water (1 〇 mL), an aqueous sodium hydroxide solution (1_0 ’ '10 mL), and water (5 '0 mL) were slowly added to the reaction mixture at 0 °C. The resulting precipitate was removed by a transition and washed with 1% decyl alcohol/THF (400 mL), and the combined filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue and extracted with ethyl acetate (50 mL×3). The organic layer was washed with a saturated aqueous solution of sodium chloride (5 mL), and dried under reduced pressure, and concentrated under reduced pressure to give a crude compound (18.1 g). Reference Example 2 Synthesis of (R)-1-(3-(cyclopentyloxy)phenyl)ethaneamine hydrochloride [Chem. 13]

152528.doc • 40· 201121944 Dissolve 3-hydroxybenzaldehyde (12.2 g) in DMF (120 mL), add Cyclopentane (32.8 mL), Potassium Carbonate (27.6 g), Potassium Iodide (1.66 g), Stir at 120 ° C for 3.5 hours. After the reaction solution was allowed to stand for cooling, water (12 mL) was added and extracted with toluene (12 mL). The organic layer was washed with water (12 〇 mL), a sodium hydroxide aqueous solution (1 〇 M, 120 mL), and brine (1 〇〇 mL) and dried over anhydrous sodium sulfate. The residue was dissolved in toluene (250 mL), and (SH_)_2_mercapto-2-propanesulfonamide (13.3 g) and tetraisopropanol (44.4 mL) were added and the mixture was stirred at 70 °C. hour. After the reaction solution was left to cool, a saturated aqueous sodium hydrogencarbonate solution (13 mL) was added. The formed precipitate was removed by filtration, washed with ethyl acetate (2 mL mL 4), and the filtrate was concentrated under reduced pressure. Saturated brine (200 mL) was added to the residue and extracted with ethyl acetate (2 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. One part (1 47 g) of the residue (29.3 g) was dissolved in THF (75 mL), and a solution of bismuth bromide magnesium diethyl ether (3 〇M, 3 33 mL) was added dropwise to 〇 <>c gave a 4 hour drop. Saturated ammonium chloride water and glutamic acid (6. 〇 mL) were added to the reaction mixture at 0 ° C for 5 minutes, and extracted with ethyl acetate (1 mL). The organic layer was saturated with brine (6. 〇 mL) and dried over anhydrous sodium sulfate. Residue 1 was purified by Shixia gel chromatography (4% acetic acid ethyl acetate / hexane). The obtained compound G(10)3) was dissolved in methanol hydrazine, and a hydrochloric acid-two-burn solution (4.0 M, 1.1 mL) was added, and a mixture of 30 knives was placed under a chamber. The reaction liquid was concentrated under reduced pressure, and then azeotroped with toluene (5 〇.3) to obtain a labeled compound (845 mg). Reference Example 3 £ 152528.doc 201121944 Synthesis of (R)-l-(3-((R)-tetrahydrofuran-3-yloxy)phenyl)ethaneamine hydrochloride

CIH · H2N Dissolves 3-hydroxybenzaldehyde (1.3 g), triphenylphosphine (3.6 g), (S)-(+)-tetrahydro-3-0-drink methanol (1.2 mL) in In a THF (20 mL), a toluene solution of diethyl azodicarboxylate (hereinafter, DEAD) (2.2 Μ, 6.2 mL) was slowly added dropwise at 0 ° C, and then stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (20 mL) was evaporated. The organic layer was washed with aqueous sodium hydroxide (1 〇μ, 5.0 mL) and dried over anhydrous sodium sulfate. The residue was purified by Shih Tzu chromatography (50% acetic acid / hexane). The obtained compound was dissolved in toluene (6.5 mL), and (S)-(-)-2-mercapto-2-propanesulfonamide (33〇11^), titanium tetraisopropoxide (1.1111)^ was added. ), at 75. Stir for 6 hours under the crucible. After the reaction solution was cooled, a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added. The resulting precipitate was filtered off and washed with ethyl acetate (20 mL x 4). The combined filtrate was concentrated under reduced pressure. Saturated brine (30 mL) was added to the residue, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in THF (7.5 mL), and then diethyl ether (br. To the reaction mixture, a saturated aqueous solution of ammonium sulfate (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with saturated brine (1 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure. The residue was purified by silica gel chromatography (100% ethyl acetate) to give the obtained compound 152528.doc -42 · 201121944; glutamic acid in methanol (5.0 mL) _, hydrochloric acid _2 No. Hyun solution ('.ο %, 470 μί), stirred at room temperature for 3 minutes. The reaction solution was concentrated under reduced pressure, and then azeotroped with terpene (4_0 mL×3) to obtain a labeled compound (244 mgp. Example 4 Synthesis of (3-(cyclopropyl decyloxy)_4·fluorophenyl) guanidine amine [Chemical 15]

H2N 4-Fluoro-3-hydroxybenzoic acid (15 〇g) was dissolved in dmf (200 mL), (chloromethyl)cyclopropane (18.0 mL), potassium carbonate (29.2 g), and decomposed ( 1.6 g) 'Stirring at 90 ° C for 6 hours. After the reaction solution was allowed to stand for cooling, water (120 mL) was added and extracted with toluene (12 mL). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in toluene (65 mL), and a solution of hydrogenated diisobutylaluminum (hereinafter referred to as DIBAL) in hexane (1.0 M, 130 mL) was added under 〇t»c, and then at 0 ° C. The reaction solution was stirred for 2 hours. Water (10 mL) and an aqueous sodium hydroxide solution (丨〇 μ, 1 mL) were slowly added to the reaction mixture. The formed precipitate was removed by filtration, washed with ethyl acetate (1 mL mL 5), and then the filtrate was concentrated under reduced pressure. " Water (1 mL) was added to the residue. mL) for extraction. The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography (40% ethyl acetate /hexane). The obtained compound was dissolved in THF (75 mL), and diphenyl azido phosphate (12·9 mL) and 1,8-diazabicyclo[5 4.〇]_7 were added dropwise at room temperature. -H--ene (hereinafter DBU) 152528.doc -43- 201121944 (9.4 mL) 'Stirring at room temperature for 1 hour. Saturated salt water (100 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (1 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (2% hexyl acetate / hexane). The obtained compound was dissolved in THF (80 mL), and a THF solution (2·4 Μ, 40 mL) of LAH was slowly added dropwise at 〇 ° C, and stirred at 〇 ° C for 1 hour. Water (5. 〇 mL) and an aqueous sodium hydroxide solution (1.0 Μ, 5 · 0 mL) were slowly added dropwise to the reaction mixture at 0 °C. The precipitate was removed by filtration, washed with 10% decyl alcohol / THF (200 mL), and the mixture was concentrated under reduced pressure. Saturated brine (1 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL), and the organic layer was dried over anhydrous sodium sulfate. 〇5. Reference Example 5 Synthesis of (R)-1-(3-(cyclopropyldecyloxy)_4-fluorophenyl)ethaneamine hydrochloride [Chem. 16]

4-Fluoro-3-hydroxybenzoic acid (12.0 g) was dissolved in ethanol (2 mL), and sulfuric acid (3.5 mL) was added and heated under reflux at 4 ° C for 4 hours. After the reaction mixture was allowed to cool, the mixture was concentrated under reduced pressure. Water (100 mL) and sodium carbonate (18.0 g) were added to the residue, and the aqueous layer was extracted with ethyl acetate (loo mLx2). The mixed organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and then evaporated. The residue was azeotroped with hydrazine (丨 5 mL×2), dissolved in DMF (100 mL), and added at 90 ° C (gas sulfhydryl) 152528.doc • 44. 201121944 Cyclopropylamine (6·9 mL) Potassium carbonate (19.8 g) and potassium iodide (1.2 g) were stirred for 3.5 hours. After the reaction solution was left to cool, water (200 mL) was added and extracted with toluene (100 mL×2). The organic layer was washed with brine (1 mL), dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in THF (75 mL), and then a THF solution of lithium borohydride (2.0 ’ ' 54 mL) was dropped at room temperature and refluxed at 80 ° C for 35 hours. After the reaction solution was allowed to stand for cooling, water (200 mL) was added dropwise at 0 C, and extracted with ethyl acetate (1 mL mL). The organic layer was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in dichloromethane (250 mL), and then, then, then,,,,,,,,,,,,,,,,,, After the reaction solution was allowed to stand for cooling, the insoluble matter was removed by filtration. After washing with a gas-like (100 mL), the combined filtrate was concentrated. The residue was dissolved in toluene (150 mL), and (s)-(-)-2-mercapto-2-propanesulfonamide (8.5 g) and titanium tetraisopropoxide (28·4 mL) were added at 75 Stir at °c for 6 hours. After the reaction solution was allowed to stand for cooling, a saturated aqueous solution of sodium hydrogencarbonate (150 mL) was added. The formed precipitate was removed by filtration, washed with ethyl acetate (200 mL×6), and the filtrate was concentrated under reduced pressure. Saturated brine (150 mL) was added to the residue, and ethyl acetate (2 mL) was applied. After drying the organic layer with anhydrous sulfuric acid, it was concentrated under reduced pressure. The residue was dissolved in THF (85 mL). EtOAc (EtOAc m. Under a vacuum of 10 minutes, a saturated aqueous solution of chlorinated chloride (? mL) was added to the reaction mixture, and ethyl acetate (100 mL <<2> The organic layer was washed with saturated brine (1 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure 152528.doc -45 - 201121944. The residue was purified by silica gel chromatography (5 EtOAc/EtOAc). The obtained compound was dissolved in methanol (70 mL), and a hydrochloric acid-dioxane solution (4.0 ’ ' 13 mL) was added and stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was azeotroped with toluene (4 〇 mL x 3), whereby the title compound (9.09 g) was obtained. Reference Example 6 Synthesis of (R)-1-(3-(cyclopropyldecyloxy)-4-fluorophenyl)-2-methylpropan-1-amine hydrochloride [Chem. 17]

4-Fluoro-3-hydroxybenzoic acid (1.2 g) was dissolved in ethanol (2 mL), and sulfuric acid (350 μί) was added at 1〇5. (: heating under reflux for 4 hours. After allowing the reaction solution to cool, 'concentrate under reduced pressure. Add water (1 〇 mL) 'sodium carbonate (1.8 g) to the residue, using ethyl acetate (2 mL) << 2) The aqueous layer was extracted, and the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene (4.0 mL×2) and dissolved in DMF (50 mL) In the middle, (chloromethyl)cyclopropane (762, potassium carbonate (2.1 g), potassium iodide (133 mg) was added, and the mixture was stirred at 90 ° for 3.5 hours. After the reaction solution was allowed to stand for cooling, water (2 mL) was added. The organic layer was washed with a saturated aqueous solution of sodium chloride (2 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (8.0 mL). The THF solution of lithium hydroboride (2〇152528.doc -46·201121944 Μ '7.5 mL) was heated under reflux for 3.5 hours at 75 ° C. The reaction solution was allowed to cool and then dropped at 0 ° C. Water (20 mL) was added, and the aqueous layer was extracted with ethyl acetate (20 mL <2). The organic layer was washed with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in di-methane (25 mL), and then, then, and then, at room temperature, manganese dioxide (8.6 g) was added at 45. The mixture was heated and refluxed for 6 hours. After the reaction mixture was allowed to stand for cooling, the insoluble material was filtered and removed, and washed with chloroform (20 mL×4), and then the filtrate was concentrated. The residue was dissolved in toluene (17.5 mL) and added (R) )-(+)-2-mercapto-2_propanesulfonamide (985 mg), tetraisopropanol oxime (3.3 mL), stirred at 75 ° C for 6 hours. After standing to cool, 'add saturated sodium bicarbonate Aqueous solution (i 5 mL). The resulting precipitate was removed by filtration and washed with ethyl acetate (2 mL mL). The combined filtrate was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The residue was dissolved in EtOAc (EtOAc) (EtOAc) 78. (:: Add a saturated aqueous solution (10 mL) to the reaction solution, and extract the aqueous layer with ethyl acetate (20 mL×2). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated. A solution of hydrochloric acid-dioxane (4.0 Μ, 470 μί) was added to decyl alcohol (7.0 mL), and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was azeotroped with <RTI ID=0.0>> The amines shown in the following table were synthesized according to any of Reference Examples 2, 3, 5 and 6. 152528.doc •47· 201121944 [Table l] Reference Example Raw Material Amine Manufacturing Method 7 Η〇χαΓ \ CIH . 5 8 h\j°h CIH · H2N^^X^j^|^0^VV 2 9 Λχ CIH · 5 10 Λχη CIH 6 11 Λτ / CIH . H2N^^^j^〇, V 2 12 hVh CIH . H2N^^0^〇O 3 13 0 hA^^〇CF2CHF2 c old · h2n, |0^OCF2CHF2 2 14 Η^α°Η CIH · H2N^v|j^|^〇^CF3 2 48- 152528.doc 201121944 [Table 2] Reference Example Raw Material Amine Manufacturing Method 15 ηΛΊ〇Τ〇η CIH . Η2Ν,|^^0丫2 16 CIH · 2 17 η1〇Γ〇Η JL CIH · H2N^Y^j^ i 2 18 CIH · 3 19 ηΛ〇Γ〇η CIH . 2 20 Λχ CIH · H2N^|^j^〇^V% 3 21 H\yH CIH . H2N/'v'|^j^〇/V^ 3 22 ηΧ〇"η CIH · H2N^|^^0 3

S 152528.doc •49- 201121944 [Table 3] Reference Example Raw material Amine Manufacturing method 23 CIH - 3 24 Λχ f . Person / CIH ♦ H2N^|^^U 3 25 ηΧΧ70Η f 人八 CIH · 3 26 - * XA CIH · 3 27 C丨H · H2N^|^0八CF2CF3 2 28 aH,^Q^Q〇3 29 CIH · H2N, ^f^^〇>^) 3 30 η1〇γ〇η ! CIH · 3 Reference Example 3 1 N-(3-(Cyclopropylmethoxy)benzyl)-3-(decyloxy) Synthesis of decyloxy)propane-1-sulfonamide [Chem. 18] -50- 152528.doc 201121944

MOMO

(3-(cyclopropylmethoxy)phenyl)methaneamine (1〇.〇g) obtained in Reference Example 1 was dissolved in Digastric Institute (50 mL), and triethyl bethane was added at 〇 °c. The amine (11.9 g), 3-acesulfamesulfonate (10.6 g) was stirred at room temperature for 12 hours. Water (100 mL) was added to the reaction mixture, and extracted with chloroform (5 mL). The organic layer was washed with diluted hydrochloric acid (1.0 mL, 100 mL) and brine (1 mL) and dried over anhydrous sodium sulfate. The residue was dissolved in DMF (100 mL). 'Add sodium acetate (1 〇 2 g) 'Sodium hydride (18 6 g) and stir at 80 C for 8 hours. After the reaction solution was allowed to cool, add water (100 mL). ), extraction was carried out using ethyl acetate (8 〇 mL x 2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by hydrazine column chromatography (5% EtOAc/hexane). The obtained compound was dissolved in a 5 丨〇% hydrochloric acid/methanol solution (100 mL), and heated under reflux for 8 hours at 8 rc. The reaction solution was allowed to stand for cooling, and then concentrated under reduced pressure. The residue was purified by the method (66% ethyl acetate / hexane). The obtained compound was dissolved in dioxane (80 mL). N,N-diisopropylethylamine (141 mL) Methyl ether (4.1 mL), stirring at room temperature for 1 hour, adding saturated ammonium chloride water solution (50 mL) to the reaction mixture, and extracting with chloroform (5 mL). Using saturated brine (30 mL) The organic layer was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate /hexane) to give the title compound (115 g). The compound shown in the table was synthesized according to the method of Reference Example 31 using any of the amines obtained in Reference Examples 2 to 3'.

S 152528.doc •51· 201121944 [Table 4] Reference Example Amine Reference Example No. Target 32 2 33 3 MOMO "^^0^〇,, 0〇34 4 MOMO ~ 35 5 momo^^-^sn^OCq ^^ 36 6 37 7 MOMO^^SN^OC〇/^^ 38 8 mom〇-^^sn^〇L〇/^ 39 9 ΜΟΜΟ^'^^-ΒγΧΧο^Ο 40 10 momo^^|-R^ 〇C. ^^ 152528.doc 52- 201121944 [Table 5] Target amine reference example number target 41 11 42 12 λ/ιομο^^-H^OLo^^ 43 13 M〇M〇-^|-K^Xl〇CF2CHF2 44 14 M〇M〇~^|-i3y〇L〇ACF3 45 15 momo^^^sn^〇L〇J^f 46 16 MOMO^^^SN^XX〇^^ 47 17 momo-^^sn^JOLq /s^^ 48 18 momo^^^sn^〇L〇^^ 49 19 M〇M〇-^|-a^〇Lo^CHF2 50 20 MOM〇-^^|-Sy0L〇J^ £ 152528.doc 53- 201121944 [Table 6] Reference Example Amine Reference Example No. Target 51 21 MOM〇/^|-Sy0l〇A% 52 22 ΜΟΜ〇·"^^8-Ν^ΧΧ〇/^Ρ 53 23 momo"^ ^sn^J〇L〇A^ 54 24 55 25 56 26 mom〇-^^sn^〇L〇A^. 57 27 Pay. -^|-Ky〇L0ACF2CF3 58 28 M〇M〇^^sN^x〇L〇X^J 59 29 mom〇-^^sn^〇L〇>C/0 60 30 ΜΟΜ<Τ^^-ΗγΧΧ 〇/\^ Reference Example 61 (R)-N-(Bu(3-(cyclopropyldecyloxy)-4-fluorophenyl)ethyl)-3-hydroxy-N-(methoxymethyl) Synthesis of propane-1-sulfonamide [Chem. 19] 152528.doc •54· 201121944

(R)-l-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethaneamine hydrochloride (1.20 g) obtained in Reference Example 5 was dissolved in dioxane (7). In a solution of 5 mL), triethylamine (1.6 mL) and 3-air-propanesulfonium chloride (550 μM) were added at 〇 ° C, and stirred at room temperature for 2 hours. Water (1 〇 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL). The organic layer was washed with brine (15 mL) and dried over anhydrous sodium sulfate. The residue was purified by a silica gel column chromatography (40 ° / 〇 乙 乙 乙 / / / / / / The obtained compound was dissolved in dichloromethane (7.0 mL), and N,N-diisopropylethylamine (5.0 mL) and methylene ether (1.5 mL) were added and stirred at 40 ° C 6 hours. A saturated aqueous solution of chlorinated chloride (1 〇 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (20 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by a Shih-Hui-gel column chromatography (20% ethyl acetate / hexane). The obtained compound was dissolved in DMF (8.0 mL). sodium acetate (887 mg) and sodium iodide (1.62 g) were added, and the mixture was stirred at 80 ° C for 8 hours. After the reaction solution was allowed to stand for cooling, water (20 mL) was added and extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (5 〇% ethyl acetate / hex). The obtained compound was dissolved in a solution of mercaptoamine in decyl alcohol (40%, 7.0 mL) and stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (yield: 66% ethyl acetate) to afford the title compound (932 mg). S' 152528.doc -55- 201121944 Reference Example 62 (R,E)-N-(l-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-5-carbyl- Synthesis of N-(methoxymethyl)indole-3-dilute-1-anthracene amine [Chem. 20]

(R)-N-(l-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-3-hydroxy-N-(decyloxymethyl) obtained by Reference Example 61 Propane-1-sulfonamide (844 mg) was dissolved in dichloromethane (1 mL), and then was added with a Dess-Martin reagent (1.4 g) and stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium hydrogencarbonate (20 mL) and a saturated aqueous solution of sodium thiosulfate (20 mL) was added to the mixture, and the aqueous layer was extracted with ethyl acetate (30 mL×2). The organic layer was washed with brine (15 mL) and dried over anhydrous sodium sulfate. The residue was azeotroped with toluene (15 mL x 2) and dissolved in thF (2.5 mL). To a suspension of sodium hydride (55%, 150 mg) in THF (5.0 mL) was added <RTI ID=0.0>> To the reaction mixture, a THF solution of a toluene-to-boiling residue was added to the reaction mixture, and the mixture was stirred at 70 ° C for 1 hour. The reaction solution was cooled, and a saturated aqueous solution of ammonium sulfate (10 mL) was added and extracted with ethyl acetate (2 〇 mL x 2). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by hydrazine column chromatography (33 EtOAc/hexanes). The obtained compound was dissolved in THF (8.0 mL), and a DIBAL THF solution (1. 〇 152528.doc - 56 · 201121944 Μ, 4.0 mL) was added at -78 ° C, and stirred at -78 ° C. hour. Water (10 mL) was added to the reaction mixture, and extracted with ethyl acetate (2 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by hydrazine column chromatography (5% ethyl acetate / hexane) to thereby afford the title compound (33 mg). Reference Example 63 (R)-N-(l-(3-(cyclopropylmethoxy).4_fluorophenyl)ethyl)5•hydroxy_N_(decyloxyfluorenyl) oxime-1 Synthesis of continuous amines [Chem. 21]

(R,E)_N_(1_(3_(cyclopropyldecyloxy)-4)fluorophenyl)ethyl)-5-hydroxy(nonyloxyindenyl)penta-3-ene obtained in Reference Example 62 _丨_sulfonamide (296 mg) was dissolved in ethyl acetate (5. 〇mL) 'add 10 〇 / 〇 palladium - carbon (170 mg), and stir the reaction solution at room temperature under hydrogen atmosphere 2 hour. The insoluble matter was removed by filtration using diatomaceous earth, and the mixture was washed with ethyl acetate (1 mL), and the combined solution was reduced in pressure to obtain a labeled compound (208 mg) as a crude product. The compounds shown in the table were synthesized according to any of Reference Examples 61 to 63 using the amines of Reference Examples 1, 2, 8, 11, and 19. 152528.doc •57- 201121944 [Table 7] Reference Example Amine Reference Example Number Target Manufacturing Method 64 1 MOM [\\ 62 65 1 63 66 2 /V. MOM \]\ ΓΛ H〇-^^s-NvAJiv0Ay 61 67 2 MOM \ |1 ΓΛ HO^^^S-Ny^X〇Xy 62 68 2 63 69 8 MOM \ |1 Λ Η0^ΥΝγ^α^Δ 61 70 8 MOM| (I 62 71 8 /v. ^ N. MOMf |] H〇s-Ny^Ao^ 63 72 11 61 73 19 H〇rHY^〇^f 61 74 19 八^MOM广1 c H〇^^rr^〇JF 62 75 19 ho^^| _^〇l〇Jf 63 Reference Example 76 (R)-4-(Bromomethyl)-indole-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)benzenesulfonate Synthesis of guanamine [Chem. 22] 152528.doc • 58 - 201121944

(R)· 1-(3-(cyclopropyl decyloxy)·4_fluorophenyl) ethionine hydrochloride (393 mg) known in Reference Example 5 was dissolved in dichlorohydrazine (3〇). In the above, triethylamine (670 μΙ〇 and 4-(bromomethyl)benzenesulfonium chloride (45 〇mg) were added and dropped for 2 hours. Water (!_〇mL) was added to the reaction solution to utilize The mixture was extracted with a methylene chloride (3 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified to obtain a labeled compound (308 mg). The compound shown in the following table was synthesized according to the method of Reference Example 76 using the amines of Reference Examples 2, 8, 11, and 19. [Table 8] Example amine reference example number target 77 2 78 8 79 11 Br drink., 80 19 Reference example 81 152528.doc -59- 201121944 5-(methyllacylmethoxy)-2 -mercaptoin-2- Synthesis of alkaloid decanoic acid group g [Chem. 23]

It is used in the literature (J. Am. Chem. Soc., 77, 1079-1083 (1955)). The 4-amino-4-methylindole-1-ol (6·7 g) obtained by the method of the above method was dissolved in Dichlorohydrazine (100 mL), and N-benzyloxycarbonyloxylated was added. Diimine (18 g) was stirred at room temperature for 22 hours. The reaction mixture was evaporated. The organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (40% ethyl acetate / hexane). The obtained colorless oily substance (7.9 g) was dissolved in di-methane (1 mL), and N,N-diisopropylethylamine (19 mL) and chloromethylcarbazide (6.0 mL) were added. , and mix for 3 hours at room temperature. A saturated aqueous solution of ammonium sulfate (2 mL) was added to the reaction mixture, and ethyl acetate (300 mL) was applied. The organic layer was washed with a saturated aqueous solution of ammonium chloride (15 mL) and brine (1 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (yield: ethyl acetate/hexane) to give the title compound (7.8 g) as a colorless oil. Further, the oxycarbonyl group is labeled as Cbz. Reference Example 82 Synthesis of 3-(cyclopropylmethoxy)-N-(5-(decyloxymethoxy)_2-methylpentane-2-yl)benzenesulfonamide 152528.doc -60· 201121944 [Chem. 24]

o"s-=o

OMOM The benzyl 5-(decyloxymethoxy)-2-methylpentane-2-ylamino decanoate (242 mg) obtained in Reference Example 81 was dissolved in decyl alcohol (5.0 mL), and 10% was added. Palladium-carbon (250 mg) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration using diatomaceous earth, and after washing with methanol (2 〇 mL), the solution was concentrated. Dissolve the residue in the Erqi brothel (3. 〇 mL) Add triethylamine (170 μΙ〇, use literature (J_ Pesticide)

3-Benzene oxybenzenesulfonate (297 mg) obtained by the method described in Chem., 13, 107-115 (1988)), was stirred at room temperature for 2 hours. Water (7.0 mL) was added to the reaction mixture, and extracted with ethyl acetate (1 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by hydrazine column chromatography (3% EtOAc/hexane). The obtained colorless oily substance (165 mg) was dissolved in a solution of decylamine (40%, 3.0 mL) and stirred at room temperature for 30 minutes. After concentrating the reaction solution, the residue was dissolved in DMF (3.0 mL), and potassium sulphate (102 mg), moth (6.0 mg), (gas methyl) cyproterone (3 4 μι) was added to 90 Stir at ° C for 14 hours. After the reaction mixture was cooled, water (10 mL) was evaporated and evaporated. The organic layer was washed with water (1 mL) and brine (1 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (yield: 30%, EtOAc, EtOAc, EtOAc) Reference Example 83 Synthesis of 3-(2,2-difluoroethoxy)-indole_(5·(methoxymethoxy)_2methylpentane-2-yl)phthalic acid [Chem. 25] ΓΛ

The benzyl 5-(decyloxymethoxy)-2-methylpentane-2-ylamino decanoate (628 mg) obtained in Reference Example 81 was obtained as a pale yellow rubber according to the method of Reference Example 82. Labeled compound (367 mg). Reference Example 84 Synthesis of 3_(cyclopentyloxy)-N-(5-(methoxymethoxy)_2-decylpentane-2-yl) oxasulfonyl decylamine [Chem. 26]

The benzyl (5-methoxymethoxy)-2-methylpentylamino decanoate (628 mg) obtained in Reference Example 81 was obtained as a pale yellow rubbery material according to the method of Reference Example 82. Labeled compound (379 mg). Reference Example 85 152528.doc -62·201121944 Synthesis of N-(2-(4-(indiyl)phenyl)propan-2-yl)-3-(cyclopropylmethoxy)benzamine [化27]

2-P-tolylpropan-2-amine (298 mg) obtained by the method described in the literature (Tetrahedron Lett., 38, 1241-1244 (1997)) was dissolved in dioxane (5.0 mL). Addition of triethylamine (420 pL), 3-benzoyloxybenzene chlorohydrazine (445 mg) obtained by the method described in the literature (J. Pesticide Chem., 13, 107-115 (1988)), Stir at room temperature for 16 hours. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated aqueous sodium chloride (1 mL) and dried over anhydrous sodium sulfate. The residue was purified by hydrazine column chromatography (20% ethyl acetate /hexane). The obtained colorless rubbery substance (316 mg) was dissolved in a methanol solution of methylamine (4 〇〇 / 0, 4.0 mL) and stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was azeotroped with toluene (5.0 mL), dissolved in DMF (5.0 mL), potassium carbonate (213 mg), potassium iodide (13 mg), (78 μΙ〇, stirred at 90 ° C for 16 hours. After the reaction solution was allowed to cool, water (15 mL) was added and extracted with ethyl acetate (2 mL). Water (15 mL), brine The organic layer was washed with (1 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane). (233 mg) 152528.doc -63- 201121944 Dissolved in four gasified carbon (6.0 mL) with N-bromosuccinimide (125 mg), azobisisobutyronitrile (hereinafter AIBN, 3.0) (mg), heating under reflux for 2 hours at 9 (rc. removal of insolubles by filtration) After washing with a gas imitation (3 mL), the filtrate was concentrated. Saturated brine (1 mL) was added to the residue. The extract was extracted with 50% ethyl acetate / hexane (10 mL). This gave the labeled compound (255 mg) as a crude product. Reference Example 8 6 N-(2-(4-(Methyl)phenyl)propan-2-yl)·3·(2,2·difluoro Synthesis of ethoxy) phenyl hydrazine

2-P-Phenylphenylpropane-2-amine (414 mg) obtained by the method described in the literature (Tetrahedron Lett., 38, 1241-1244 (1997)) was obtained as a colorless method according to the method of Reference Example 85. Solid labeled compound (54 mg). Reference Example 87 Synthesis of N-(2-(4-(bromomethyl)phenyl)propan-2-yl)_3·(cyclopentyloxy)benzenesulfonamide [Chem. 29] 152528.doc 201121944

2-P-tolylpropan-2-amine (414 mg) obtained by the method described in the literature (Tetrahedron Lett., 38, 1241-1244 (1997)) was obtained as a colorless solid according to the method of Reference Example 85. Labeled compound (549 mg). Reference Example 8 8 N-(2-(6-(Methyl-methyl) oxime. _3_))propanze-2-yl)_3_(cyclopropyldecyloxy) Synthesis of oxasulfonamide ]

The 6(hydroxymethyl)nicotinic acid nitrile (1.59 g) obtained by the method described in JP-A-2006-508054 was dissolved in DMF (30 mL), and the mixture was added (2.丨g). Tributyl dimethyl decyl alkyl (2.33 g) was stirred at room temperature for 1.5 hours. Water (60 mL) was added to the reaction mixture, and then extracted with 50% ethyl acetate/hexane (60 mL). The organic layer was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane). The obtained colorless solid (199 g) was obtained by using toluene (10 mL×3); s. 0 S: 152528.doc 201121944 The ruthenium chloride (1.48 g) was suspended in THF (12 mL) and incubated at room temperature. Mix for 2 hours. After the ultrasonic wave was applied to the reaction solution for 5 minutes, it was cooled to -78 ° C, and a solution of methyllithium in diethyl ether q 〇 9 μ, 5.5 mL) was slowly added dropwise, and the reaction mixture was stirred at -78 ° C for 30 minutes. One part (497 mg) of a toluene-azeotropic colorless solid was dissolved in THF (2.0 mL), and slowly added to the reaction mixture at -78t, and stirred at room temperature for 2 hours. Saturated aqueous ammonia (5.0 mL) was added to the mixture and stirred at room temperature for 30 min. The insoluble matter was removed by filtration using celite, washed with THF (1 mL), and the filtrate was concentrated. Water (20 mL) was added to the residue and extracted with chloroform (30 mL). The organic layer was washed with brine (2 mL), dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in dichloromethane (6.0 mL), and triethylamine (420 μM, 3-benzene obtained by the method described in J. Pesticide Chem., 13, 107-115 (1988)) was added. Methoxy sulfonium sulfonate (593 mg) was stirred at room temperature for 3 days. Water (10 mL) was added to the mixture and extracted with ethyl acetate (15 mL). The organic layer was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate /hexane). 700 mg) dissolved in methanol solution of methylamine (40%, 3.0 mL), and stirred for 20 minutes at room temperature. The reaction solution was concentrated under reduced pressure and then chromatographed on silica gel column (60% acetic acid The residue was purified by ester (hexane / hexane). The obtained pale yellow oily material (522 mg) was dissolved in DMF (12 mL), hexane (332 mg), potassium iodide (20 mg), (chloromethyl) Cyclopropane (122 pL), stirred at 90 ° C for 18 hours. After the reaction solution was allowed to cool, add water (2〇152528.doc •66· 201121944 mL) The mixture was extracted with ethyl acetate (3 mL), and the organic layer was washed with water (25 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated and concentrated. Chromatography (5 % sterol. / chloroform) was carried out; the residue was purified to obtain a depilation base (254 mg). The decomposed phantom (249 mg) was dissolved in THF (3.0 mL), and three were added. Phenylphosphine (182 mg) and carbon tetrabromide (23 0 mg) were stirred at room temperature for hr. The reaction mixture was concentrated under reduced pressure and then purified by EtOAc EtOAc The residue was purified to obtain a labeled compound (226 mg) as a purple rubbery substance. Reference Example 89 2-·(2-(6-(bromoindolyl)acridin-3-yl)propane_2-yl )_3_(22 difluoroethoxy) benzene sulfonamide synthesis [31]

A 6-(hydroxymethyl)nicotinic acid nitrile (372 mg) obtained by the method described in JP-A-2006-508054 was used as a labeling compound as a purple oily substance according to the method of the reference example (丨43) Reference Example 90 Synthesis of N-(2-(6-(bromoindolyl)pyrene _3_yl)propane-2·yl)_3_(cyclopentyloxy)phenylidene amide ] S. 152528.doc -67- 201121944

The label of the purple blister substance was obtained by the method of Reference Example 88, which was obtained by the method described in JP-A-2006-508054, by the method described in JP-A-2006-508054. Compound (139 mg). Example 1 N-(3-(cyclopropyl decyloxy)benzyl)_3_((5-fluoro-2,4-dioxo-3,4·dihydro-bite-1(2H)-yl) Synthesis of decyloxy)propane-1-sulfonamide [Chem. 33] Ο

N-(3-(cyclopropyldecyloxy)benzyl)-3-(methoxymethoxy)propane-indolesulfonamide (588 mg) obtained in Reference Example 31 was dissolved in two In chlorodecane (5.0 mL), a solution of boron trichloride (hereinafter referred to as bC13) in dichloroindole (1.0 Μ, 561 μί) was added at 〇 ° C, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 1,2-dichloroethane (hereinafter DCE, 3.0 mL). Commercially available 5-fluoro-2,4·bis(tridecyldecyloxy)pyrimidine (657 mg) was dissolved in DCE (2.0 mL), DCE (3.0 mL) solution of residue was added, and iodine (60 mg) The mixture was heated to reflux at 95 ° C for 3.5 hours. After the reaction solution was left to cool, water (30 mL) and a saturated aqueous solution of sodium thiosulfate (2.0 mL) were added, and 152528.doc -68 - 201121944 was extracted with 10 ° / methanol / gas (20 mL x 3). The mixed organic layer was washed with brine (15 mL) and dried over anhydrous sodium sulfate. The residue was purified by hydrazine column chromatography (yield: 90% ethyl acetate/hexane) to thereby obtain a labeled compound (3 〇 5 mg, yield 41 ° / 〇) as a colorless blister. !H-NMR (CDC13) δ (ppm): 0.32-0.39 (2H, m), 0.61-0.68 (2H, m), 1.20-1.31 (1H, m), 2.00-2.17 (2H, m), 3.02 ( 2H, t, J—7.0 Hz), 3.65 (2H, t, J=6.2 Hz), 3.81 (2H, d, J=7.〇Hz), 4.26 (2H, d, J=5.7 Hz), 4.64 ( 1H, brs), 5.09 (2H, s), 6.83-6.89 (3H, m), 7.29-7.35 (2H, m) Example 2 to Example 30 The following compounds were obtained from each of Reference Examples 32 to 60. The compound was synthesized according to the method of Example 1. The results are shown in the table below. Example 2 (R)-N-(l-(3-(Cyclopentyloxy)phenyl)ethylfluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2Η)·yl Methoxy)propane-sulfonamide Example 3 3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(211)-yl)methoxy)- >^((R)-l-(3-((R)-tetrahydrofuran-3-yloxy)phenyl)ethyl)propane·丨_sulfonamide Example 4 N-(3-(cyclopropyl) Methoxy)_4_fluorobenzyl)_3_((5-fluoro-2,4·dioxo-3,4-dihydropyrimidine-i(2H)-yl)decyloxy)propane-sulfonate Amine Example 5

S 152528.doc 201121944 (R)-N-( 1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-3-((5-fluoro-2.4-dioxo- 3,4-Dihydropyrimidin-1(2H)-yl)decyloxy)propane-1-sulfonamide Example 6 (R)-N-(l-(3-(cyclopropyldecyloxy)- 4-fluorophenyl)-2-methylpropyl)-3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)decyloxy) Propane-1-sulfonamide Example 7 (R)-N-(l-(3-(cyclopropylmethoxy)-4-fluorophenyl)propyl)-3-((5-fluoro-2.4) - Dioxo-3,4-dihydropyrimidin-1(211)-yl)methoxy)propane_1_sulfonamide Example 8 (R)-N-(l-(3-(cyclopropyl) Methoxy)phenyl)ethyl)-3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)decyloxy)propane·ι· Sulfonamide Example 9 (R)-N-(1-(3-(cyclopentyloxy)-4-fluorophenyl)ethyl)-3-((5-fluoro-2,4-dioxo- 3,4-Dihydropyrimidin-1(2H)-yl)decyloxy)propane-1-sulfonamide Example 10 N-(1-(3-(cyclopropyldecyloxy)-4-fluorobenzene 2-mercaptopropyl)-3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(211)-yl)decyloxy)propane-1_sulfonate Indoleamine Example 11 (R)-N-(l-(3-(cyclopropylmethoxy) Phenyl)propyl)·3_((5-fluoro-24-dioxo-3,4-dihydropyrimidin-1(2Η)-yl)methoxy)propane_methanesulfonamide Example 12 (R)-N-indole-(3-(cyclopentylmethoxy)phenyl)ethyl)-3-((5-fluoro-2,4-di 152528.doc •70-201121944 oxo-3 4, 2 gas shouting Example 13 ° ^ _1 (2 Η) · yl) methoxy) propane burning _ continuation of amine (R) -3- ((5_ gas, 4 dioxo 3, 4 · Dihydropyrimidin-1(2H)-yl)methoxy_A',,2,2-tetrafluoroethoxy)phenyl)ethyl)propane-1-sulfonamide Example 14) Fluorine 2, 'two Oxo-3,4-dihydropyrimidin-1(211)-yl)decyloxy)-N-(l-(3-(2 2 ?--, ,difluoroethoxy)phenyl)ethyl Propane_ι_sulfonamide Example 15 () (丨(^(丨'3-difluoropropyl-2-yloxy)phenyl)ethyl)-3-((5-fluoro-2,4) -dioxo-3,4-dihydropyrimidin-1(2拗-yl)methoxy)propane_丨_sulfonamide Example 16 (R)-3-((5-fluoro-2,4- Dioxo_3,4_Dihydropyrazine _ι(2Η)_yl) decyloxy)-N-(l-(3-isobutoxyphenyl)ethyl)propane 丨 sulfonamide Example 17 3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidine·ι(2Η)-yl)methoxy)-N - ((R)-l-(3-((S)-2-methylbutoxy)phenyl)ethyl)propane sulfonamide Example 18 (R)-3-((5-Fluoro- 2,4·dioxo-3,4-dihydropyrimidine_ι(2Η)_yl)decyloxy)-N-(l-(3-((methylcyclopropyl)methoxy)phenyl)) Ethyl)propanesulfonate Example 19 (R)-N-(l-(3-(2,2-difluoroethoxy)phenyl)ethyl)_3_((5-fluoro-2,4 · Dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propane·sulphonamide £152528.doc •71 · 201121944 Example 20 N-((R)-l- (3-((S)·丁-3·acetyl-2-yloxy)phenyl)ethyl)_3_((5-fluoro-2.4-dioxo-3,4-dihydropyrimidine_1 (211 Guang曱)oxy)propane·丨_sulfonamide Example 21 N-((R)-l-(3-((R> Buty_3_yn-2-yloxy)phenyl)ethyl) _3_((5_Fluoro-2.4-dioxo-3,4-dihydropyrimidin-1(211)-yl)decyloxy)propane_丨_sulfonamide Example 22 (R)-3-(( 5-fluoro-2,4-dioxo-3,4-dihydropyrimidinyl)methoxy)-N-(1-(3-(2-fluoroethoxy)phenyl)ethyl)propane 丨Sulfonamide Example 23 ((1〇-1-(3-(11)-Seconbutoxyphenyl)ethyl)_3_((5-fluoro-2,4-dioxo) -3,4-dihydropyrimidin-1(2H)-yl)decyloxy)propane-1-sulfonamide Example 24 N-((R)-l-(3-(S)-Second-butoxy Phenyl)ethyl)ethyl 3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propane-1-sulfonamide Example 25 3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidine·ι(2Η)-yl)decyloxy)·Ν-((R)-l-(3 -((S)-pentan-2-yloxy)phenyl)ethyl)propane-1-sulfonamide Example 26 3-((5-Fluoro-2,4-dioxo-3,4 -dihydropyrimidine-i(2H)-yl)methoxy)-N-((R)-l-(3-((R)-pentan-2-yloxy)phenyl)ethyl)propane -1-sulfonamide Example 27 (R)-3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)-: ^-(1_(3-(2,2,3,3,3-pentafluoropropoxy)phenyl)ethyl)propane-1_sulfon 152528.doc •72· 201121944 Stearic amine example 28 (R) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine·1(2Η)-yl)methoxy)-N-(l-(3-(tetrahydro-2Η) -»biam-4-yloxy)phenyl)ethyl)propane-l_sulfonamide Example 29 3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidine) -1(2Η)-yl)methoxy)-indole-((R)-l-(3-((R)-tetrahydrofuran-3-yloxy) Phenyl)ethyl)propane-indolesulfonamide Example 30 (R)-N-(1-(3-(2-cyclopropylethoxy)phenyl)ethyl)_3_((5·Fluorine · 2,4-dioxo-3,4-dihydropyrimidin-1(2Η)-yl)methoxy)propanesulfonamide 152528.doc •73· 201121944 [Table 9] Example Reference Example No. Target Product Rate (%) ^-NMR δ (ppm) Shape 2 32 0 m\F ^t〇^^|-NyCX〇X) 44 (CDCls) 1.53 (3H, d, J = 7.0 Hz), 1.62-1.65 (2H , m), 1.72-1.97 (8H, m), 2.70-2.88 (2H, m), 3.50-3.56 (2H, m), 4.56 (1H, quin, J = 6.8Hz), 4.74-4.78 (1H, m ), 4.92 (1H, brs), 5.03 (2H, s), 6.78-6.88 (3H, m), 7.21-7.32 (2H, m), 9.08 (1H, brs) blister 3 33 35 (CDC1S) 1.53 (3H, d, J = 7.0Hz), 1.85-1.95 (2H, m), 2. 06-2. 24 (2H, m), 2.68-2.88 (2H, m), 3.51-3.57 (2H, m) , 3.89-4.06 (4H, m), 4.53-4.61 (1H, m), 4.70-4.74 (1H, m), 4.93-4.96 (1H, m), 5.03 (2H, s), 6.77 (1H, dd, J = 8. 1, 2.4 Hz), 6.82-6.84 (1H, m), 6.92 (1H, d, J = 7.3 Hz), 7.24-7.34 (2H, m), 8.76 (1H, brs) blister 4 34 26 (CDCI3) 0. 33-0.39 (2H, m), 0.62-0. 69 (2H, m), 1.22-1.29 (1H, m), 1.99-2.08 (2H, m), 2.99 (2H, t, J = 7.6Hz), 3.65 (2H, t, J = 6.2Hz), 3.88 (2H, d, J = 7.0Hz), 4.22 ( 2H, d, j = 5.4 Hz), 4.78 (1H, brs), 5.08 (2H, s), 6.82-6.87 (1H, m), 6. 94-6. 98 (2H, m), 7. 34 ( 1H, d, J = 5. 4 Hz), 8.62 (1H, brs) blister 74- 152528.doc 201121944 [Table ι] Example Reference Example Number Target Yield (.%) frNMR δ (ppm) Shape - 5 35 16 (CDCI3) 0.33-0.39 (2H, m), 0.63-0.70 (2H, m), 1.23-1.31 (1H, m), 1.52 (3H, d, J=7.0 Hz), 1.83-1.98 ( 2H, m), 2.63-2.83 (2H, m), 3.55 (2H, t, J = 6.2Hz), 3.89 (2H, d, J = 7.0 Hz), 4.58 (1H, quin, J = 5. 9 Hz ), 4. 78 (1H, d, J = 6. 2 Hz), 5.04 (2H, s), 6.84-6.96 (2H, m), 7.02-7.09 (1H, m), 7..33 (1H, d, J = 5.1 Hz), 8.76 (1H, brs) blister 6 36 47 (CDC13) 0.32-0.39 (2H, m), 0.61-0.69 (2H, m), 0.80 (3H, d, J = 6.5 Hz), 1.03 (3H, d, J = 6.8 Hz), 1.21-1.29 (1H, m), 1.70-2.00 (3H, m), 2.58-2.79 (2H, m), 3. 49 (2H, t, J = 5.9 Hz), 3. 89 (2H, d, J = 7.0 Hz), 4.05 (1H, t, J = 8.1 Hz), 4.91 (1H, d, J = 8.1Hz), 5.01 (2H, s) , 6.76-6.81 (1H, m), 6,83-6.87 (1H, m), 7. 02-7. 09 (1H, in), 7. 32 (1H, d, J = 5. 2 Hz), 8.67 (1H, brs) blister 7 37 40 (CDCI3) 0. 32-0. 38 (2H, m), 0.62-0. 69 (2H, m), 0.89 (3H, t, J = 7.0 Hz), 1.22-1.28 (1H, m), 1.72-1.94 (4H, m), 2.60-2.81 (2H, m), 3. 51 (2H, d, J = 5. 9 Hz), 3. 89 (2H, d , J = 7.3 Hz), 4.25 (1H, q, J = 7.6 Hz), 5.02 (2H, s), 5.10 (1H, d, J =7.0 Hz), 6.80-6.85 (1H, m), 6.88-6.92 (1H, m), 7.02-7.09 (1H, m), 7.34 (1H, d, J = 5.1 Hz), 9.20 (1H, brs) blister 152528.doc -75- s·. •S& 201121944 [ Table 11] Example Reference Example No. Target Yield (%) ^-NMR δ (ppm) Shape 8 38 〇hn\f 57 (CDCls) 0.32-0.38 (2H, m), 0.63-0.69 (2H, m), 1.23-1.31 (1H, m), 1.53 (3H, d, J = 6.8 Hz), 1.83-1.98 (2H, m), 2.70-2.90 (2H, m), 3.50-3.59 (2H, m), 3.81 ( 2H, d, J = 7. 0 Hz), 4. 55 (1H, quin, J = 5.1 Hz), 4.95 (1H, d, J = 7.0 Hz), 5.03 (2H, s), 6.80-6.84 (1H , m), 6.88-6.92 (2H, m), 7.22-7.33 (2H, m), 9.10 (1H, brs) blister 9 39 61 (CDC13) 1.53 (3H, d, J = 6 .8Hz), 1.61-1.70 (2H, m), 1.76-2.00 (8H, m), 2.68-2.83 (2H, m), 3.55 (2H, t, J = 5.9 Hz), 4.53-4.60 (2H, m ), 4.81-4.85 (1H, m), 5.03 (2H, s), 6.81-6.87 (1H, m), 6.92-6.96 (1H, m), 7.00-7.08 (1H, m), 7.31 (1H, d , J = 5.1 Hz), 8.51 (1H, brs) blister 10 40 52 (CDCI3) 0.32-0.39 (2H, m), 0.61-0.69 (2H, m), 0.80 (3H.d, J = 6. 5 Hz), 1.03 (3H, d, J = 6.5 Hz), 1.21-1.29 (1H, m), 1.70-2.00 (3H, m), 2.58-2.79 (2H, m), 3. 49 (2H, t , J = 5.9 Hz), 3. 89 (2H, d, J = 7.0Hz), 4.04(1H, t, J = 8.1Hz), 5.01 (2H, s), 5.16 (1H, brs), 6.76-6.81 (1H, m), 6,84-6.88 (1H, m), 7. 02-7. 09 (1H, m), 7. 33 (1H, d, J = 5. 4 Hz), 9.08 (1H, Brs) blister substance · 76· 152528.doc 201121944 [Table 12] Implementation iH Reference example No. Target yield (%) Ή-NMR δ (ppm) Shape 11 41 〇41 (CDC13) 0.34-0.38 (2H, m) , 0.62-0.69 (2H, m), 0.90 (3H, t, J = 7.6 Hz), 1.22-1.28 (1H, m), 1.72-1.94 (4H, m), 2.60-2.83 (2H, m), 3.48 -3.52 (2H, m), 3.81 (2H, d, J = 6.8 Hz), 4. 27 (1H, q, J = 7. 0 Hz), 4.74 (1H, brs), 5.01 (2H, s),6.81-6.87 (3H, m), 7.22-7.31 (2H, m), 8.60 (1H, brs) blister 12 42 43 (CDC13) 1.29-1.39 (2H, m), 1.53 (3H, d, J = 7.0 Hz), 1.54-1.78 (6H, m), 1.81-1.94 (2H, m), 2.32-2.38 (1H, m), 2.72-2.93 (2H, m), 3.50-3.55 (2H, m), 3.83 (2H, d, J = 7. 0 Hz), 4. 53-4. 61 (2H, m), 5. 03 (2H, s), 6.82-6.90 (3H, m), 7.26-7.30 (2H, m), 8.34 (1H, brs) blister 13 43 48 (CDC13) 1.55 (3H, d, J = 6,8 Hz), 1.88-1.96 (2H, m), 2.69-2.88 (2H, m), 3.54 (2H, t, J = 6.2Hz), 4.62-4.70 (1H, m), 4.78 (1H, brs), 5.03 (2H, s), 5.94 (1H, tt, J = 52. 9, 2. 7 Hz,), 7.13-7. 29 (4H, m), 7.40 (1H, d, J = 8.1 Hz), 8.60 (1H, brs) blister substance 152528.doc 77- £ 201121944 [Table 13] Example Reference Example No. Target Yield (%) ^-NMR δ (ppm) Shape 14 44 46 (DMSO-i/^ 1.37 (3H, d, J = 7.0 Hz), 1.68-1.84 (2H, m), 2.60-2.71 ( 1H, n〇, 2.80-2.91 (1H, m), 3.36-3.47 (2H, m), 4.37-4.47 (1H, m), 4.68-4.80 (2H, m), 4.96 (2H, s), 6.89- 6.95 (1H, m), 7.03-7.07 (2H, m), 7. 29 (1H, t, J = 8.1 Hz), 7. 74 (1H, d, J = 8.6 Hz ), 8.07 (1H, d, J = 6. 8 Hz), 11.83 (1H, brs) blister 15 45 0 36 (CDCI3) 1.53 (3H, d, J = 6.8 Hz), 1.87-1.94 (2H, m), 2.72-2.87 (2H, m), 3.49-3.57 (2H, m), 4. 59-4. 77 (7H, m), 5.03 (2H, s), 6.90-6.99 (3H, m), 7.27-7.34 (2H, m), 8.44 (1H, brs) blister 16 46 47 (CDClj) 1.02 (6H, d, J = 6. 8 Hz), 1.53 (3H, d, J = 7.0 Hz), 1.82-1.96 (2H, m), 2.00-2.09 (1H, m), 2.65-2.90 (2H, m), 3. 50-3. 59 (2H, m), 3. 72 (2H, d, J = 6. 5 Hz), 4. 57 (1H, quin, J = 6. 8 Hz), 4.99 (1H, brs), 5.03 (2H, s), 6.80-6.91 (3H, m), 7.23-7.32 (2H , m), 9.20 (1H, brs) blister substance -78-152528.doc 201121944 [Table 14] Example Reference Example No. Target Yield (%) 3H-NMR δ (ppm) Shape 17 47 55 (CDClj) 0.95 (3H,t, J = 7.3 Hz), 1.02 (3H, d, J = 6.8Hz), 1.20-1.34 (1H, m), 1.53 (3H, d, J = 6.8Hz), 1.54-1.60 (1H, m), 1.80-1.95 (3H, m), 2.70-2.92 (2H, m), 3.50-3.56 (2H, m), 3.70-3.84 (2H, m), 4.56 (1H, quin, J = 6.8Hz) , 4.76 (1H, brs), 5.03 (2H, s), 6.80-6.90 (3H, m), 7.23-7.31 (2H, m), 8.71 (lH, brs) Bubbly substance 18 48 hn\f °ν〇^1-Μ^Χλ0^ 35 (CDC13) 0. 41-0.46 (2H, a), 0.50-0.54 (2H, m), 1. 23 (3H, s) , 1.53 (3H, d, J = 6.8 Hz), 1.80-1.98 (2H, m), 2.68-2.93 (2H, m), 3.51-3.56 (2H, m), 3.73 (2H, s), 4.54-4.62 (1H, m), 4.88-4.96 (1H, m), 5.03 (2H, s), 6.80-6.91 (3H, m), 7.22-7.32 (2H, m), 9.06 (1H, brs) blister 19 49 18 (CDC13) 1.53 (3H, d, J = 7.0 Hz), 1.88-1.96 (2H, m), 2.71-2.84 (2H, m), 3.54 (2H, t, J=5.9Hz), 4.21 (2H , td, J = 13. 2, 4.1 Hz), 4. 60(1H, quin, J = 6.8 Hz), 5.03 (1H, brs), 5.04 (2H, s), 6.10 (1H, tt, J=54 8, 3.8 Hz), 6.85 (1H, dd, J = 8.1, 1.6 Hz), 6.93 (1H, s), 6.93-7.00 (1H, m), 7.27-7.33 (2H, m), 9.05 (1H, Brs) blister substance 152528.doc 79- s: 201121944 [Table 15] Example Reference Example No. Target Yield (3⁄4) iH-NMR δ (ppm) Shape 20 50 12 (CDCl) 1. 53 (3H, d, J = 6. 8 Hz), 1. 67 (3H, d, J = 6.8 Hz), 1.84-1.96 (2H, m), 2.53-2.54 (1H, m), 2.75-2.92 (2H, m), 3.46 -3.53 (2H, t, J = 5.9 Hz), 4.56-4.62 (1H, m), 4.80-4.92 (2H, m), 5.34 (2H, s), 6. 92-6.97 (3H, m), 7.21-7.32 (2H, m), 8.55 (1H, brs) Foaming substance 21 51 〇21 (CDC13) 1. 53 (3H, d, J = 6.8 Hz), 1. 67 (3H, d, J = 6.8 Hz), 1.84-1.96 (2H, n〇, 2.53-2.54 (1H, m), 2.69-2.91 (2H, m), 3.48-3.53 (2H, m), 4.56- 4. 62 (2H, m), 4.80-4.92 (1H, ra), 5.34 (2H, s), 6.93-6.97 (3H, m), 7.26-7.32 (2H, m), 8.53 (1H, brs) Shaped substance 22 52 〇人ΐΌν^·\^Ι』Υ〇·^\^ 32 (CDClj) 1.53 (3H, d, J = 6.8 Hz), 1.87-1.98 (2H, m), 2.71-2.86 (2H, m), 3.52 (2H, t, J = 5. 1 Hz), 4. 24 (2H, dt, J = 28. 6, 3.8 Hz), 4.56-4.67 (2H, m), 4.77 (2H, dt, J=47.0, 4.3 Hz), 5.03 (2H, s), 6.85-6.96 (3H, m), 7.26-7.33 (2H, m) Foaming substance 80-152528.doc 201121944 [Table 16] Example Reference Example No. Target yield (3⁄4) δ (ppm) Shape 23 S3 35 (CDC13) 0.98 (3H, t, J = 7.3 Hz), 1.29 (3H, d J = 6. 2 Hz), 1. 54 (3H, d, J = 6. 8 Hz) 1.58-1.78 (2H, n〇, 1.86-1.95 (2H, m) 2.74-2.90 (2H, ra), 3.52-3.58 <2H, m) 4.28-4.36 (1H, m) , 4.53-4.62 (1H, m) 4.69-4.72 (1H, m), 5.03 (2H, s) 6.81-6.89 (3H, m), 7. 22-7.31 (2H, m) 8.63 (1H, brs) blister 24 54 hn-Vf 23 (CDCls) 0.98 (3H, t, J=7.3Hz), 1.29 (3H, d J = 6. 2 Hz) , 1. 54 (3H, d, J = 7. 0 Hz) 1.58-1.78 (2H, m), 1.86-1.95 (2H, m) 2.74-2.90 {2H, m), 3.52-3.58 (2H, m) 4.29-4.37 {1H, m), 4.53-4,62 (1H, m) 4.69-4,72 (IK, m), 5.03 (2H, s) 6.81-6.89 (3H, m), 7.22-7/31 (2H, m) 8.62 (1H, brs) blister 25 55

34 (CDC13) 0.94 (3H, t, J = 7.3Hz), 1.29 (3H, d, J = 6.2 Hz), 1.38-1.64 (5H, m), 1.66-1.74 (2H, m), 1.84-1.99 ( 2H, m), 2.73-2.90 (2H, m), 3.50-3.58 (2H, m), 4.36-4.42 (1H, m), 4.52-4.62 (1H, m), 4.98 (1H. brs), 5.03 ( 2H, s), 6.80-6.89 (3H, m), 7.22-7.31 (2H, m), 8.60 (1H, brs) blister substance S- 152528.doc '81 · 201121944 Table example reference example number target yield (%) 1H-NMR 8 (ppm) Shape 26 56

35 (CDClj) 0. 94 (3H, t, J = 7. 0 Hz), 1. 29 (3H, d J = 6.2 Hz). 1.39-1.62 (5H, m) 1. 66-1. 73 (2H (m), 1. 4.73 (1H, brs), 5.03 (2H, s) 6.80-6.89 (3H, m), 7.22-7.31 (2H, m) 8.69 (1H, brs) blister 27 57 47 (CDC13) 1.55 (3H, d , J = 6.8 Hz), 1.86-1.99 (2H, m), 2.70-2.90 (2H, m), 3.51-3.59 (2H, m), 4.45 (2H, t, J = 12.4 Hz), 4.61 <1H , quin, J = 6.8Hz), 4.93 (1H, brs), 5.04 (2H, s), 6.87 (1H, dd, J = 8.4, 2. 2 Hz), 6.95 (1H. s), 7.02 (1H, d, J = 7.6Hz), 7.29-7.35 (2H, m), 9.10 (1H, brs) blister 58

35 (CDC13) 1.53 (3H, d, J = 6.8 Hz), 1.73-2.10 (6H, m), 2.70-2.91 (2H, m), 3.51-3.66 (4H, in), 3.95-4.05 (2H, m ), 4.48-4.62 (2H, m), 4.81 (1H, brs), 5.04 (2H, s), 6.83-6.93 (3H, m), 7.24-7.32 (2H, m), 8.83 (1H, brs) Shape 152528.doc 82- 201121944 [Table 18] Example Reference Example No. Target Yield (%) 'H-NMR 5 (ppm) Shape 〇41 (cdci3) 1.53 (3H, d, J = 6.8 Hz), 1.85 -1.95 (2H, m), 2.09-2.24 (2H, m), 2.68-2.88 (2H, m), 3. 51-3. 57 (2H, m), 3.90-4.06 (4H, m), 4.53- 4.61 (1H, m), 4.70-4.74 (1H, m), 5.03 (2H, s), 5.06 (1H, brs), 6.77 (1H, dd, J = 7.8, 2.2 Hz), 6.82-6.84 (1H, m), 6.92 (1H, d, J = 7.6 Hz), 7. 24-7. 34 (2H, m), 8. 76 (1H, brs) blister substance Λ

49 (CDClj) 0. 11-0. 16 (2H, m), 0.45-0. 53 (2H, m), 0. 81-0. 89 (1H, m), 1. 53 (3H, d, J = 7. 0 Hz), 1.63-1.72 (2H, ra), 1.85-1.96 (2H, m), 2.69-2.90 (2H, m), 3.50-3.58 (2H, m), 4.04 (2H, t, J = 6. 8 Hz), 4.58 (1H, quin, J = 6.8Hz), 4.89 (1H, d, J = 6.8Hz), δ.03 (2H, s), 6.81-6.91 (3H, in), 7.23 -7.31 (2H, m), 8.97 (1H, brs) vesicular material Example 3 1 (R)-N-( 1-(3-(cyclopropyldecyloxy)-4-fluorophenyl)ethyl Synthesis of 3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propane-1-sulfonamide [Chem. 34] Ο

152528.doc -83- S, 201121944 (R)-N-(l-(3-(cyclopropyldecyloxy)-4-fluorophenyl)ethyl)-3 obtained by reference Example 61 -Hydroxy-N-(decyloxymercapto)propane-1_sulfonamide (230 mg) was dissolved in THF (4.5 mL), triphenylphosphine (189 mg) was added, according to the literature (Bioorg· Med. Chem_) 3-Benzenyl-5-fluoropyrimidine-2,4(1h,3H)-dione (162 mg) obtained by the method described in Lett., 12, 1395-1397 (2002)), at room temperature Stir for 5 minutes. A solution of DEAD in benzene (2.2 ’ '330 μί) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified using silica gel column chromatography (7% ethyl acetate / hexane). The obtained compound was dissolved in a methanol solution of methylamine (40%, 4.0 mL), and stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure and then purified by <RTI ID=0.0>> The obtained compound was dissolved in dioxane (丨5 mL), and a hydrochloric acid-dioxane solution (4.0 Μ, 500 μΙ〇) was added and stirred at room temperature for 3 hours at 0. (: in the lower reaction solution After adding a saturated aqueous solution of sodium hydrogencarbonate (4.0 mL) and neutralizing, extraction was carried out with ethyl acetate (15 mL×2), 1% methanol/methanol (15 mL >< 2). The organic layer was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (1 7 mg, yield 6 %). H-NMR (CDCI3) δ (ppm): 0.32-0.38 (2H, m), 0.60-0.67 (2H, m), 1.22-1.30 (1H, m)s 1.51 (3H5 d, J=6.8 Hz), 1.97-2.05 (2H, m), 2.63-2.75 (2H, m), 3.63-3.80 (2H, m), 3.88 (2H, d, J=7.0 Hz), 4.51-4.58 (1H, m) , 5.54 (1H, brs), 6.86-7.09 (3H, m), 7.32 (1H, d, J=5.4 Hz) 152528.doc • 84 · 201121944 Example 32 to Example 45 The following compounds are used in the respective reference examples. The compound obtained in 62 to 75 was synthesized according to the method of Example 31. The results are shown in the following table. Example 32 (R,E)-N-(l-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)·5-(5-fluoro-2.4-dioxo-3 4-Dihydropyrimidine-1(211).yl)penta-3-ene-1-sulfonamide Example 33 (R)-N-(l-(3-(cyclopropyldecyloxy)_4_ Fluorophenyl)ethyl)-5-(5-fluoro-2.4-dioxo-3,4-dihydropyrimidin-1(211)-yl)pentan-1-sulfonamide Example 34 (E) -N-(3-(cyclopropylmethoxy)-yl)_5_(5_gas_2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pent-3-ene -1-sulfonamide Example 35 N-(3-(cyclopropylmethoxy)benzyl)-5-(5-fluoro-2,4-dioxo-3;4-dihydropyrimidin-1 (2H )-yl)pentane sulfonamide Example 36 (R)-N-(l-(3-(cyclopentyloxy)phenyl)ethyl)·3_(5-fluoro-2,4-dioxo代 _ 3.4- 二风鸣淀-1 (2 Η)-based) propyl- 1 - aryl amine Example 37 (R, E)-N-(l-(3-(cyclopentyloxy)phenyl Ethyl)·5_(5·fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2Η)-yl)pent-3-ene-1-sulfonamide Example 38 (R -N-(l-(3-(cyclopentyloxy)phenyl)ethyl)_5·(5·fluoro-2,4-dioxo- 3.4--hydrogen lanceolate-1(2Η)-yl ) pentane-1-continued amine

S 152528.doc -85- 201121944 Example 39 (R)-N-(l-(3-(cyclopropylmethoxy)phenyl)ethyl)_3-(5-fluoro-2,4-dioxo Generation-3,4-dihydropyrimidin-1(2H)-yl)propane-1·sulfonamide Example 40 (R,E)-N-(l-(3-(cyclopropyldecyloxy)benzene Ethyl)ethyl)_5_(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pent-3-ene-1-sulfonamide Example 41 (R )-N-(l-(3.(cyclopropylmethoxy)phenyl)ethyl)-5-(5-fluoro-24-dioxo-3,4-dihydropyrimidin-1 (211)- Pentyl-1-sulfonamide Example 42 (R)-N-(l-(3-(cyclopropylmethoxy)phenyl)propyl)_3_(5-fluoro-2,4_2 Oxo-3,4-dihydropyrimidin-l(2H)-yl)propane-1-sulfonamide Example 43 (R>N-(l-(3-(2,2-difluoroethoxy)) Phenyl)ethyl)_3_(5•fluoro-2,4-dioxo-3,4-dihydro-nose _1(211)-yl) propyl sulphate <-1-branched amine Example 44 ( R,E)-N-(l-(3-(2,2-difluoroethoxy)phenyl)ethyl)_5·(5_fluoro·24_dioxo-3,4-dihydrosulfanyl) __3_稀丨丨_sulfonamide Example 45 (r)_N-(1-(3-(2,2-difluoroethoxy)phenyl)ethyl)-5-(5-fluoro-24 Dioxo-3,4-dihydropyridyl)pentane-1-sulfonamide 152528.doc * 86 - 201121944 [Table 19] Example Reference Example No. Target Yield (%) δ (ppm) Shape 32

33 63

12 (CDC13) 0.33-0.39 (2H, m), 0.62-0.70 (2H, ra), 1.25-1.32 (1H, m), 1.53 (3H, d, J = 6.8 Hz), 2.39-2.44 (2H, m ), 2. 64-2. 84 (2H, m), 3. 89 (2H, d, J = 6.8 Hz), 4.23 (2H, d, J=6.2Hz), 4.58 (1H, quin, J = 6.8 Hz), 4.81 (1H, brs), 5.44-5.52 (1H, m), 5.59-5.67 (1H. m), 6. 85-7. 10 (3H, m), 7.25 (1H, d, J = 5.1 Hz), 8.75 (1H, brs) Foam (CDC1S) 0.33-0.39 (2H, m), 0.62-0.69 (2H, m), 1.22-1.38 (3H, m), 1.53 (3H, d. J = 6.8 Hz), 1.54-1.73 (4H, m), 2. 62-2. 74 (1H, m), 3. 65 (2H, t, J = 6. 5 Hz), 3. 89 (2H, d, J = 7.0 Hz), 4. 57 (1H, quin, J = 6.8 Hz), 4.68 (1H, brs), 4.79 (1H, brs), 6.82-7.11 (3H, m), 7.20 (1H, d, J = 5.7 Hz), 8.60 (1H, brs) 34 64

Foam (CDClj) 0.32-0. 37 (2H, m), 0.61-0.69 (2H, m), 1.23-1.29 (1H, m), 2.51-2.59 (2H, m), 3.00 (2H, t, J = 7.3 Hz), 3.80 (2H, d, J = 7. 0 Hz), 4.23-4.29 (4H, a), 4.69-4.72 (1H, brs), 5.52-5.60 (1H, m), 5.67-5.75 (1H, m), 6.82-6.91 (3H, m), 7.23-7.29 (2H, m) blister substance 152528.doc 87-201121944 [Table 20] Reference example target yield 1H~NMR 6 (ppm) - Example No. (%) Shape 35 65 2 (CDClj) 0.33-0.37 (2H, a), 0.60-0.66 (2H, π), 1.22-1.30 (13⁄4 m), 1-39-1.44 (2H, m), 1.64 -1.88 (4H, nO, 2.92 (2H, t, J = 7. 6 Hz), 3.67 (2H, t, J = 7. 0 Hz), 3.80 (2H, d, J = 7.0 Hz), 4.25 (2H , d, J = 6.2 Hz), 5.12 (1H, t, J = 6.2 Hz), 6.80-6.85 (1H, m), 6.89-6.92 (2H, m), 7.21-7.27 {2H, m), 9.38 ( 1H, brs) blistering material 36 66 . ^卿14 (CDC13) 1.53 (3H, d, J = 6.8 Hz), 1.54- 2.10 (10H, m), 2.56-2.74 (2H, m), 3.54- 3,82 (2H, m), 4.54-4.59 (1H, m), 4.74-4.78 (1H, m), 5.22 (1H, brs), ' 6.79-6.89 (3H, m), 7.22-7.28 (2H, m) blister 37 67 13 (CDClj) 1.54 (3H, d, J = 6.8 Hz), 1.62-1.93 (8R m), 2.36-2.46 (2H, m), 2.64-2.84 (2H, m), 4.21-4.30 (2H, m), 4.54-4.59 ( (1H, m) m), 7.21-7.34 (2H, m), 9.21 (1H, brs) blister 38 68 10 (CDClj) 1.26-1.38 (4H, m), 1.53 (3H, d, J = 7.0 Hz), 1.54- 1.96 (10H, m), 2.59-2.80 (2H, m), 3.60-3.65 (2H, m), 4.52-4.58 (1H, m), 4.74-4.78 (1H, m), 5.20 (1H, d, J = 7.3 Hz), 6.77-6.90 (3H.m), 7.21-7.27 (2H, m), 9.51 (1H, brs) Foaming material 88-152528.doc 201121944 [Table 21] Example Reference Example No. Target Yield (3⁄4) 'HHNMR 8 (ppm) Shape 39

(CDC13) 0.33-0.39 (2H, m), 0.62-0.70 (2H, b). 1.22-1.30 (1H, η), 1.53 (3H, d, J = 7.0 Hz), 1.95-2.05 (2H, m) , 2.61-2.72 (2H, m), 3.61-3.70 (1H, m), 3.79-3.82 (3H, ta), 4.53-4.61 (1H, m), 5.01 (1H, brs), 6.81-5.90 (3H, m), 7.24-7.30 (2H, m), 8.91 (1H, brs) blister

(CDC1,) 0.32-0.38 (2H, m), 0.62-0.69 (2H, m), 1.22-1.30 (1H, m), 1.54 (3H, d, J = 7.0 Hz), 2.37-2.43 (2H, m ), 2.66-2.89 (2H, m), 3.80 (2H, d, J = 6. 8 Hz), 4. 22 (2H, d, J = 6. 2 Hz), 4.58 (1H, quin, J = 7 . 0 Hz), 4.85 (1H, brs), 5,41-5.48 (lH, m), 5.56-5.66 (1H, m), 6.80-6.84 (1H, in), 6.88-6.92 (2H, m), 7.22-7.29 (2H, m), 8.89 (1H, brs) blister 41 71

11 (CDC1S) 0.32-0.37 (2H, m), 0.62-0.68 (2H, m), 1.22-1.36 (3H. m), 1.53 (3H, d, J = 7.0 Hz), 1.54-1.78 (4H, m ), 2.61-2.82 (2H, m), 3.60-3.66 (2H, m), 3.80 (2H, d, J = 7.0 Hz), 4.57 {1H, quin, J = 7.3Hz), 4.93 (1H, brs) , 6.80-6.84 (1H, m>, 6.89-6.92 (2H, m), 7.19-7.28 (2H, m), 8.95 (1H, brs) blister substance s. 152528.doc 89. 201121944 [Table 22] 152528 .doc Example 42 72 Target Yield (%) δ (ppm) Shape

(CDC13) 0.32-0.39 (2H, m), 0.62-0.70 (2H, m), 0.90 (3H, t, J = 7.6 Hz), 1.22-1.32 (1H, m), 1.75-2.01 (2H, m) , 2.57-2.68 (2H, m), 3.52-3.64 (1H, m), 3.70-3.79 (2H, m), 3.80 (2H, d, J = 7.0 Hz), 4.26-4.32 (2H, m), 5.08 (1H, brs), 6.80--6.88 (3H, m), 7.21-7.29 (2H, m), 8.98 <1H, brs) blister 43 73

(CDC13) 1.53 (3H, d, J = 7.0 Hz), 2.01-2.09 (2H, π), 2.67 {2H, t. J = 7. 3 Hz), 3.63-3.91 (2H, m), 4.21 (2H , td, J = 13.0 Hz, 4.1 Hz), 4.57-4.67 (1H, in), 5.08 (1H, brs), 6.10 (1H, tt, J = 55.1, 4.1 Hz), 6.83-6.99 (3H, m) , 7.22-7. 33 (2H, m) blister 44 74 17 (CDC13) 1.54 (3H, d, J = 7.0 Hz), 2.39-2.48 (2H, m). 2. 64-2. 88 (2H , m), 4.14-4. 26 (4H, m), 4.62 (1H, quin, J = 7.0 Hz), 4.78 (1H, brs), 5.42-5.50 (1H, m), 5.57-5.66 (13⁄4 m) , 6.10 (1H, tt, J = 55.1, 3. 8 Hz), 6.85 (1H, dd, J = 8. 4, 2.4 Hz), 6.92-6.94 (1H, m), 6.98-7.01 (1H, m) , 7.21-7.34 (2H, m), 8.63 (1H, brs) blister substance 90-201121944 [Table 23] Example

45 75

j-BsiXX^F 13 (CDC1S) 1. 39-1. 44 (2H, m), 1. 54 (3H, d, J = 7. 〇Hz), 1.55-1.78 (4H, m), 2.66-2.78 (2H, n〇, 3.61-3.67 (2H, m), 4.20 (2H, td, J= 13· 2,4.1 Hz), 4.61 (1H, quin, j =7.0 Hz), 4.81 (1H, d, J = 6.5 Hz), 6.10 (1H, tt, J = 55.4, 4.1 Hz), 6.83-6.87 (1H, m), 6.93-6.95 (1H, m), 6.99 (1H, d, J = 7.6 Hz), 7.17 -7.34 (2H, m), 8.62 (1H, brs) vesicular material Example 46 (R)-N-(1_(3_(cyclopropylmethoxy)_4_fluorophenyl)ethyl)_4_(( 5_Fluoro-2,4_dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzenesulfonamide [Chem. 35] 〇

((R)-4-(Bromomethyl)-fluorene-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)) sulfonate obtained by Reference Example 76 Indoleamine (12 mg) and commercially available 5_fluoro-2,4-bis(trimethyldecyloxy)pyrimidine (112 mg) were dissolved in dCE (1.5 mL). Add iodine (13 mg at room temperature) The mixture was heated to reflux for 4 hours at 95 ° C. After the reaction solution was allowed to stand for cooling, 'addition of water (1 () mL), saturated thiosulfuric sulphur sulphur sulphur sulphur sulphur sulphate (1.0 mL), using ι 〇% methanol/chloroform (i〇mLx3) was extracted, and the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate/hexane) The residue was purified, whereby a labeled compound (44.2 mg, yield 33 ° / 〇) was obtained as a blister material.] H-NMR (DMSO-d6) δ (ppm): 0.32-0.36 ( 2H,m),0.59-0.62 (2H,m),1.14-1.38 (4H,m), 3.76 (2H,d,J=7.0 Hz), 4.33 (1H, quin, J=7.6 Hz), 4.86 (2H , s), 6.65 (1H, brs), 6.89. 6.96 (2H, m), 7.38 (2H, d, J = 8.3 Hz), 7.62 (2H, d, J = 8.3

Hz), 8.14-8.20 (2H, m), 11.88 (1H, brs) The compounds of the following Examples 47 to 5 are the compounds obtained in each of Reference Examples 77 to 8, according to the method of Example 46. synthesis. The results are shown in the table below. Example 47 (R)-N-(l-(3-(Cyclopentyloxy)phenyl)ethyl)_4_((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (211)-yl) mercapto) benzenesulfonamide Example 48 (R)_N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-4-((5-fluoro- 2,4-dioxo-3,4-dihydropyrimidine-U2H)-yl)methyl) oxasulfonamide Example 49 (R)-N_(1_(3·(cyclopropylmethoxy)benzene) Phenylfluoro-2,4·dioxo-3,4-dihydropyrimidin-1(211)-yl)methyl)benzenesulfonamide Example 5 0 (R) N (1 (3-( 2,2-difluoroethoxy)phenyl)ethyl)_4_((5_气·2木152528.doc •92- 201121944 dioxo-3,4-dihydropyrimidin-1(2H)-yl曱 )) oxasulfonamide [Table 24] Example Reference Example No. Target Yield (%) Ή-NMR δ (ppm) Shape 47 77

ΐ^〇Ύ) (CDC1S) 1.45 (3H, d, J = 6.8 Hz), 1.53-1.64 (2H, m), 1.71-1.90 (6H, m), 4.49 (1H, quin, J = 6.9 Hz), 4.62-4.68 (1H, m), 4.75 (1H, d, J = 7.1Hz), 4.88 (2H, s), 6.57-6.66 (3H, m), 7.03 (1H, t, J = 8.1 Hz), 7.15 (1H, d, J = 5.4 Hz), 7. 25-7. 29 (2H, m), 7. 72 (2H, d, J = 8. 4 Hz). 8.29 (1H, brs) blister 48 78 12

(CDC13) 0.31-0.34 (2H, m), 0.60-0.67 (2H, m), 1.22-1.30 (1H, m), 1.43 (3H, d, J = 6.8 Hz), 3.69 (2H, d, J = 7.0Hz), 4.47 (1H, quin, J = 7. 0 Hz), 4. 89 (2H, s), 5.10 (1H, d, J = 7.3Hz), 6.51-6.59 (3H, m), 6.99- 7.07 (1H, a), 7.16-7.27 (3H, in), 7. 69 (2H, d, J = 8. 4 Hz), 9. 05 (1H, brs) blister 49 79 (CDC13) 0.29- 0.34 (2H, m), 0.60-0.67 (2H, m), 0.82 (3H, t, J = 7.3 Hz), 1.18-1.28 (1H, m), 1.68-1.83 (2H, m), 3.66 (2H, d, J = 6.8 Hz), 4.20 (1H, q, J = 7. 3 Hz), 4.86 (2H, s), 5.07 (1H, d, J = 7.6 Hz), 6.50-6.65 (3H, m), 6.99 (1H, t, J = 7.8 Hz), 7.15-7.24 (3H.m), 7.63 (2H, d, J = 8.4Hz), 8.90 (1H, brs) blister substance 152528.doc -93- 201121944 [Table 25] Example Reference Example No. Target Yield g * H-NMR δ (ppm)

(CDCl,) 1.45 (3H, d, J = 6.9Hz), 4.05 (2H, td, 13.2, 4.5 Hz), 4.53 (iH, quin> J = 6·9ΗΖ), 4.80 (1H,brs>, 4 ribs (2h 80 ^ίχΎ

S), 6 05 (1H. U, J = SS.2, 4.lHz) 6·δ6 (1H, s), 6.67-6.77 (2H, lA (1H, t, J = 8.1 HZ), 7.17 (ih } d&gt; j 6.4 HZ), 7.25-7.28 (2H, m)&gt;7[&amp;g {m 8-23JIH. brs) Foaming substance Examples 51 to 53 The following compounds are each of the reference examples 82. The compound obtained in ~84 was synthesized according to the method of Example 1. The results are shown in the following table. Example 5 1 3-(cyclopropylmethoxy)-indole-(5-((5-fluoro·2,4-dioxo-3,4-dihydropyrimidine-1(2Η)-yl)) Oxy)-2-decylpentan-2-yl)benzenesulfonamide Example 52 3-(2,2-Fluoroethoxy)_n-(5-((5-fluorodioxo-3) , 4-dihydro 0f ace-1 (2H)-yl) methoxy)-2-mercaptobutyl-2-yl) stilbene amine Example 53 3-(cyclopentyloxy)-N-( 5-((5-Fluoro-2,4-dioxo-3,4-dihydromouthbit-1(2H)-yl)methoxy)-2-decylpentan-2-yl)benzene continued Amine amine 152528.doc •94·201121944 [Table 26] Example Reference Example No. Target Yield (%) Ή-NMR δ (pfMn) Shape 51 82 .丄WU°v^V^|~NS—^ f! 49 (DMSO-dg) 0.30-0. 36 (2H, m), 0.53-0.60 (2H, η) 1.02 (6Η, s), 1.19-1.25 <1Η, m) 1.32-1.45 (4H, m), 3.27-3.33 (2H, m) 3.85 (2H, d, J = 6.9Hz), 4.97 (2H, s) 7.09-7.13 (1H, m), 7.30 -7.45 (4H, m) 8.08 {1H, d, J = 6.4 Hz), 11.83 (1H brs) blister 52 83 (DMS0-d6) 1.03 (BH, s). 1.33-1.51 (4H, m), 3.28-3.33 (2H, m), 4.39 (2H, td, J = 14.7, 3.5 Hz), 4.99 &lt;2H, s), 6.41 (1H, tt, J=54.4, 3.5 Hz), 7.21-7.25 (1H , m), 7.40-7.54 (4H, m), 8.09 (1H, d, J = 6.6 Hz), 11.82 (1H, brs) colorless rubbery substance 53 84

49 (DMSO-de) 1.03 (6H, s), 1.31-1.49 (4H, ro), 1,50-1.76 (6H, m), 1.83-2.02 (2H, m), 3.28-3.32 (2H, m) , 4.82-4.86 (1H, m), 4.98 (2H, s), 7.07-7.11 (1H, m), 7. 29-7. 45 (4H, m), 8. 09 (1H, d. J = 6 4 Hz), 11.84 (1H, brs) Foaming substance £152528.doc 95 · 201121944 Examples 54 to 56 The following compounds are the compounds obtained in each of Reference Examples 8 5 s &gt; Examples 85 to 87. And synthesized according to the method of Example 46. The results are shown in the table below. Example 54 3-(cyclopropylmethoxy)H(2.(4.(5.Fluoro-2,4-dioxo-3,4·2 gas-bite-1(2Η)-yl)methyl) Phenyl)propan-2-yl)benzene-based amine example 55 3-(2,2·difluoroethoxy)-fluorene-(2-(4-((5-fluoro-2,4-) Oxo-3,4_dihydrobine bite-1(2Η)-yl)decyl)phenyl)propan-2-yl) stupid amine Example 5 6 -(cyclopentyloxybu:^ -^-^^^-Fluoro-mono-dioxo^'heart dihydro squirt-1(2Η)-yl)decyl)phenyl)propan-2-yl) oxasulfonamide 152528.doc 96 - 201121944 [Table 27] Example Reference Example No. Target Yield JH-NMR δ (ppra) (3⁄4) Shape 54 85 40 (DMSO-de) 0.30-0.36 (2H, m), 0.54-0.61 (2H, m) , 1.16-1.27 (1H, m), 1.45 (6H, s), 3.78 (2H, d, J = 7. 1 Hz), 4.72 (2H, s), 6.96-7.00 (1H, m), 7.06-7.10 (4H, m), 7.21-7.28 (3H, m), 8.02 (1H, brs), 8.15 (1H, d( J = 6.8 Hz), 11.85 (1H, brs) blister substance. 55 86 乂rF h9_y= ^T 10 (DMS〇-d6) 1.47 (6H, s), 4.32 (2H, td, J = 14.7, 3.5 Hz), 4.73 (2H, s), 6.40 (1H, tt, J = 54.2, 3,5 Hz), 7.07-7.18 (5H, ra), 7.24-7.34 (3H, m), 8.06 (1H, br s), 8. 16 (1H, d, J = 6.8 Hz), 11.81 (1H, brs) blistering material 56 87. 永hid ο 1~' 31 (DMSO-de) 1.45 (6H, s), 1.51- 1.72 (6H, n〇, 1.83-1.97 (2H, m), 4.72 (2H, s), 4.74-4.78 (1H, m), 6.92-6.96 (1H. m), 7.02-7.10 (4H, m), 7.19-7.28 (3H, m), 8.04 (1H, brs), 8. 15 (1H, d, J = 6.8 Hz), 11.85 (1H, brs) Foaming material Example 57 to Example 59 The following compounds are The compound obtained in each of Reference Examples 88 to 90 was synthesized according to the method of Example 46. The results are shown in the table below. Example 57 3-(cyclopropylmethoxy)-&gt;^-(2-(6-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-97- 152528. Doc 201121944 pyridine-1(2H)-yl)methyl)acridin-3-yl)propan-2-yl)benzenesulfonamide Example 58 3-(2,2-difluoroethoxy)-yi 2-(6-((5-fluoro_2,4·dioxo-34-dioxapyrimidin-1(2Η)-yl)indolyl)acridin-3-yl)propan-2-yl)benzenesulfonate Amine Example 59 3-(Cyclopentyloxy)-indole-(2-(6.(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2Η)-yl) Methyl) "Compound-3-yl)propan-2-yl) Stupid amine 152528.doc 98 - 201121944 8 2 Table Examples Reference Example No. Target Yield (%) HFNMR δ (ppra) Shape 57 88

12 (CD3OD) 0.23-0.33 (2H, m), 0.50-0.57 (2H, m), 1.10- 1.21 (1H, m), 1.51 (6H, s), 3.71 (2H, d, J = 6.9 Hz), 4.88 (2H, s), 6.87-6.91 (1H, m)s 6.97-7.05 (3H, m), 7.11- 7.16 (1H, m), 7.60 (1H, dd, J = 2.5, 8. 2 Hz), 7.76 (lH, d, J=6.1Hz), 8.33 (1H, d, J = 2.3 Hz) Yellow rubbery material 58 89 4.4

(cd3〇d) 1.62 (6H, s), 4.23 (2H, td, J = 13.9, 3.9 Hz), 4.90 (2H, s), 6.33 (1H, tt, J = 54, 3.9 Hz), 7.05 -7.08 (1H, m), 7. 10-7.13 (2H, m), 7.15-7.18 (1H, m), 7. 28 (1H, t, J = 8.1 Hz), 7. 69 (1H, dd, J = 2. 4, 8.1 Hz), 7. 84 (1H, d, J = 6. 3 Hz), 8.42 (1H, d, J = 2.0 Hz) Yellow rubbery substance 59 12 (CD, OD) 1.60 ( 6H, s), 1.63-1.67 (2H, m), 1.72-1.83 (4H, m), L 87-1. 99 (2H, m), 4.76-4.79 (1H, m), 4.90 (2H, s) , 6.94-6.97 (1H, m), 7.04-7.15 (3H, m), 7.21 (1H, t, J = 8.1Hz), 7.71 (1H, dd, J = 2.4, 8.1 Hz), 7.84 (1H, d , J = 6.1 Hz), 8.44 (1H, d, J = 2.0 Hz) Yellow rubbery material Example 60(S)-5-fluoro-1-(4-(2-(hydroxybutyl)pyrimidine-2, 4(lH,3H)-[Chemical 36]phenylphenylpyrrolidin-1-yl)-4_sideoxy ketone 152528.doc -99- 201121944 ο

4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-obtained by the method described in the literature (Med. Chem. Res., 10, 390-403 (2001)) 1(2H)-yl)butyric acid (25 mg) was dissolved in dioxane (2.5 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide salt was added. Acid salt (hereinafter EDC.HC1, 34 mg), 1-hydroxybenzotriazole (hereinafter referred to as HOBt, 23 mg), and readily available (S)-diphenyl ("pyrrolidin-2-yl) Methanol (56 mg) ' was stirred at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (yield: 90% ethyl acetate/hexane) to afford the title compound (23 mg, yield 46%). 'H-NMR (CDC13) δ (ppm): 0.83-0.90 (1H, m), 1.55-1.70 (3H, m), 1.96-2.11 (2H, m), 2.44-2.48 (2H, m), 3.06- 3.12 (1H, m), 3.33-3.42 (1H, m), 4.32-4.44 (2H, m), 5.21-5.25 (1H, m), 6.73 (1H, brs), 7.26-7.33 (9H, m), 7.40-7.43 (2H, m), 7.62 (1H, brs) The following compounds were synthesized according to the method of Example 60. The results are shown in the following table. Example 61 (S)· 1-(4-(2-(bis(4-fluorophenyl)(hydroxy)decylpyrrolidin-1-yl)-4-sideoxy 152528.doc •100- 201121944 Butyl)-5-fluoropyrimidine-2,4(1Η,3Η)-:_ [Table 29] Yield of target product ^-NMR δ (pfHn) Example (%) Shape 61 〇λϊ^λνο 38 (CDC13) 0.85 -0.90 (1H, m), 1.55-1.70 (3H, m), 1.87-1.95 (1H, m), 2.02-2.11 (1H, m), 2.44-2.48 (2H, m), 3.12-3.18 (1H, m), 3.42-3.45 (1H, m), 4.32-4.44 (2H, m), 5.13-5.18 (1H, m), 6.85 (1H, brs), 6.94-7.04 (4H, m), 7.27-7.40 ( 5H, ra), 7.64 (1H, brs) Foaming material Comparative Example 1 ((2-(triphenylphosphonium)ethoxy)indolyl)pyrimidine-2,4-(1H,3H)-dione [化37] 〇

It is synthesized by the method described in International Publication WO2005-065689 (Patent Document 1). Comparative Example 2 4-(2,4-dioxo-3,4-dihydropyrimidin-1(211)-yl)-:^-hydroxy-2-(!^-mercapto-4-phenoxybenzene Sulfolamine) butanamine [Chem. 38] 152528.doc - 101 - 201121944

It is synthesized by the method described in Japanese Laid-Open Patent Publication No. 2002-284686. Test Example 1 Human dUTP enzyme inhibition [5-3H] deoxyuridine monophosphate derived from [5-3H]deoxyuridine triphosphate (hereinafter referred to as [5-3H]dUTP) by the following method (hereinafter referred to as The inhibitory activity of the compound of the present invention on the human dUTP enzyme was determined by the formation of [5_3H]dUMP). That is, 1 μΜ dUTP ([5-3H]dUTP containing 588 Bq/mL) 0.02 mL, 0,2 Μ trishydroxymethylamino decane buffer (pH 7.4) 0.05 mL, 16 mM magnesium chloride 0.05 mL, 20 mM 2-mercaptoethanol 0.02 mL, 1% fetal bovine serum albumin solution 0.02 mL, various concentrations of test compound solution or 0.02 mL of pure water as a control, and human dUTP expressed and purified using Escherichia coli The enzyme solution 0.02 mL total 0.2 mL was reacted at 37 ° C for 15 minutes. Immediately after the reaction, the mixture was heated at 100 ° C for 1 minute to stop the reaction, and centrifuged at 15,000 rpm for 2 minutes. After centrifugation, an Atlantis dC 1 8 column (manufactured by Waters, 4.6 x 250 mm) was used, and high-performance liquid chromatography (manufactured by Shimadzu Corporation, Prominence) was used to obtain a fraction of the supernatant (15 0 μ! 〇Analysis was carried out at a flow rate of 0.8 mL/min from mobile phase A (10 mM acid dihydrogen (pH 6.7), 10 mM tetrabutylammonium, 0.25% methanol) and mobile phase B (50 mM potassium dihydrogen phosphate). (pH 152528.doc -102 - 201121944 6.7), 5·6 mM tetrabutylammonium, 30% methanol) The 4:6 mixture was flowed to the mobile phase B for 30 minutes to form a concentration gradient, thereby performing elution. The scintillant (Ultima-Flo AP, manufactured by Parkin Elmar) was mixed in a ratio of 1:2 in the eluent, and the [5-3H] was produced by the Radiomatic Flow Scintillation Analyzed, 525TR). Radioactivity of dUMP (RT 10.2 min). The inhibitory activity of the test compound is determined by the following formula, and the concentration of the test liquid which inhibits 50% of the amount of [5-3H]dUMP produced by the human dUTP enzyme is Ι(:5()(μΜ) The form is shown in Table 30: [Number 1] Inhibition rate (%) = 1 [5-3H]dUMP amount (dpm) in the presence of test liquid 1 -------- X100 Control [5-3H ]dUMP amount (dpm) The following table shows human dUTP enzyme inhibitory activity data. 152528.doc 103-201121944 [Table 30] Example No. Ι〇5〇 (μΜ) Example No. ICS0 UM) 1 2.71 32 0.12 2 0 50 33 0.18 3 4.14 34 1.30 4 1.96 35 2. 51 5 0. 28 36 5. 73 6 0.19 37 0. 36 7 0.16 38 0.46 8 0.57 40 0. 29 9 0.19 41 1. 15 10 0. 39 42 3 90 11 0.31 43 8.99 12 7.83 44 0. 23 13 8.61 45 0.44 14 1.82 46 2.19 15 2.67 47 4. 52 16 1.70 48 6. 85 17 2.47 49 5.34 18 3. 56 50 6.10 19 1.08 51 0. 78 20 3.06 52 1.48 21 3· 98 53 0.90 22 2.08 54 0. 89 23 2,05 55 1.07 24 2.23 56 0.41 25 3. 93 57 0. 50 26 3.83 58 0. 78 27 6.11 59 0. 25 28 1.73 60 7.26 29 7 62 61 8.39 30 2.61 Comparative Example 1 185 31 2.71 Comparative Example 2 97.2 15252 8.doc 104-

Claims (1)

201121944 VII. Patent application scope: It is represented by the general formula (I): 1. A 5-fluorouracil compound or a salt thereof [Chemical Formula 1] 〇 (In the formula (I), n represents the number of U; X represents a bond, an oxygen atom, a sulfur atom, an alkenyl group having 2 to 6 carbon atoms, a 2{beta aromatic hydrocarbon group which may have a substituent, or a divalent saturated or unsaturated heterocyclic group having a substituent; Y represents a bond or a linear or branched alkyl group having a carbon number of 丨8; Z represents -S02NR1R2, _NR3s〇2_R4, or the following Formula [Chemical Formula 2] 0 ^n^r5 R and R2 are the same or different and each represents a hydrogen atom, an alkyl group having a carbon number of 6 or an aralkyl group which may have a substituent, or may be formed together with an adjacent nitrogen atom. a group of a saturated heterocyclic group having a substituent; R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R4 represents an aromatic hydrocarbon group which may have a substituent or an unsaturated heterocyclic group which may have a substituent; a methyl group having a substituent). 2. The 5-fluorouracil compound of claim 1 or a salt thereof, wherein X represents a bond 152528.doc 201121944 a knot, an oxygen atom, a sulfur atom, a vinylidene group, a phenylene group or a beta group, and a bond represents a bond. Or a linear or branched carbon group having a carbon number of 丨8. 3. The 5-fluorouracil compound of claim 1 or a salt thereof, wherein ζ represents -S〇2NR R2 ' R1 is a hydrogen atom, and R 2 is a benzyl group which may have a substituent (the methylene group of the benzyl group has a substituent) In the case of the substituent, the substituent may have the same or different 1 to 2 alkyl groups having 1 to 6 carbon atoms (in the case where two of the substituents are a group of 1 to 6 gorges), the base is used. The carbon atoms may form a cycloalkylene structure with each other. When the phenyl group of the benzyl group has a substituent, the substituent may have a halogen atom of 2 to 2 halogen atoms, a linear group which may have a substituent or Any one of a branched carbon number of 66, a cycloalkyloxy group having 3 to 7 carbon atoms, a cycloalkyl-alkoxy group having 3 to 7 carbon atoms, and a saturated heterocyclic oxy group. The 5-fluorouracil compound of claim 1 or a salt thereof, wherein n represents i or 3 'X represents a bond, an oxygen atom or a vinyl group; γ represents a bond, an ethyl group, or a dimethylene group (wherein When χ represents a bond, (CH2)n· XY represents a dimethylene or penta-indenyl group, and Z is -s〇2nr丨R2 'r1 is a hydrogen atom' R is a benzyl group which may have a substituent ( When the methylene group of the benzyl group has a substituent, the substituent may have the same or different 1 to 2 alkyl groups having 1 to 6 carbon atoms (in the case of 2 substituents, the carbon number is 1 to 6). In the case of an alkyl group of 6 , the carbon atoms of the alkyl group may form a cycloalkylene structure with each other, and when the phenyl group of the nodal group has a substituent, as the substituent, it may have 1 to 2 halogens. Atom, a linear or branched alkoxy group having 1 to 6 carbon atoms, a cycloalkyloxy group having 3 to 7 carbon atoms, a nucleus group-alkoxy group having 3 to 7 carbon atoms; Any of saturated heterocyclic oxy groups). 152528.doc • 2 201121944 5. The 5-fluorouracil compound or a salt thereof according to Item 1, which is selected from the group consisting of: (R)-N-(1_(3_(cyclopentyloxy)phenyl) Ethyl)_3_((5•Fluoro-24 dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propanesulfonamide (R)-N-( 1-(3) -(cyclopropylmethoxy)·4_fluorophenyl)ethyl)_3_((5 gas_2.4-dioxo-3,4-dihydropyrimidin-1(2Η)-yl)decyloxy) Propane-indole-sulfonamide (R)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)-2-mercaptopropyl)-3_ ((5-fluoro-) 2,4-dioxo-3,4-dihydropyrimidine_ι(2Η)·yl)methoxy)propane _ 1-continuous guanamine (R)-N-( 1-(3-(cyclopropyl) Methoxy)-4-fluorophenyl)propyl)-3-((5-fluoro-2.4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)decyloxy)propane- ^sulfonamide (R)-N-indole (3-(cyclopentyloxy)-4-fluorophenyl)ethyl)-3-((5-fluoro-2,4-dioxo-3,4 _ dihydropyrimidine β-denyl) decyloxy) propyl ketone - 1 N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)-2-mercaptopropyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propane-i_sulfonamide (R)-N-〇 -( 3-(cyclopropylmethoxy)phenyl)propyl)-3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy Propane-sulfonamide (R,E)-N-(l-(3-(cyclopropyldecyloxy).4.fluorophenyl)ethyl)_5-(5·fluoro-2,4- Dioxo-3,4-dihydropyrimidin-1(2H)-yl)pent-3-ene-1-sulfonamide (R)-N-( 1-(3-(cyclopropylmethoxy)) 4-fluorophenyl)ethyl)-5-(5-fluoro-2.4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pentan-1-sulfonamide S 152528. Doc 201121944 (R,E)-N-(1 -(3-(cyclopentyloxy)phenyl)ethyl)_5_(5·fluoro-2,4-dioxo-3,4-di &amp;pyrimidine -1(2H)-yl)pent-3-ene-1-sulfonamide (11)-1^-(1-(3-(cyclopentyloxy)phenyl)ethyl)_5_(5_fluoro- 2,4-dioxo-3,4-dihydropyrimidine-i(2H)-yl)pentan-1-sulfonamide (R,E)_N_(Bu(3-(cyclopropylmethoxy)) Phenyl)ethyl)-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(211)-yl)penta-3-ene-2-indolesulfonamide ,E)-N-(1-(3-(2,2-difluoroethoxy)phenyl)ethyl)-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidine _1(211)-yl)penta-3-ene_丨_sulfonamide (R)-N-(l-(3-(2,2-difluoroethoxy)phenyl) ) _5_ (5_ _2,4- fluoro-3,4-dihydro-pyrimidin-dioxo _1 (Ao-2-yl) pentane sulfonamide Amides small. 6. A pharmaceutical composition, which comprises a 5-fluorouracil compound or a salt thereof according to any one of claims 1 to 5, which is a compound of any one of claims 1 to 5. A cleavage inhibitor of the present invention, which comprises the 5-fluorouracil compound or a salt thereof according to any one of claims 1 to 5. 152528.doc -4- 201121944 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If the case has a chemical formula, please reveal the best display. Chemical formula of the invention features: 0 S: 152528.doc