TW201141839A - Substituted 5-hydroxypyrimidine-4-carboxamide compounds - Google Patents

Abstract

The present invention provides a compound which promots production of erythropoietin. The present invention provides a compound represented by formula (1). [wherein R1: an alkyl group that may have a substituent, R2: alkyl group, -X-Q1, -X-Q1-Y-Q2, Q1: cyclohydrocarbon that may have a substituent, heterocycle that may have a substituent; Q2: cyclohydrocarbon that may have a substituent, heterocycle that may have a substituent; X: single bond, -(CH2)n-, -O(CH2)n-, -(CH2)nO- and the like; Y: single bond, -CH2-, -(CH2)2-, -(CH2)3- and the like; n: integer of 1 to 6; R3: H, methyl.].

Description

201141839 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to low molecular compounds which induce the production of erythropoietin. [Prior Art] Erythropoietin (hereinafter referred to as EPO) is a glycoprotein hormone which is indispensable for red blood cell hematopoiesis, and is usually secreted by the renal pelvis, and promotes red blood cell production by acting on the red blood cell stem cells of the bone marrow. With the intrinsic EPO producing a low-grade disease (e.g., chronic renal failure) and the like, since the red blood cells are low and exhibit anemia symptoms, the recombinant human EPO is used for the supplementary therapy. However, since recombinant human EPO is a biological preparation, it has a high medical cost, and it is accused of being inconvenient for injection and having antigenicity. On the other hand, a low molecular weight EPO production inducer is known as a pyrimidine derivative, a porphyrin derivative, a quinoline derivative or an isoquinoline derivative (refer to Patent Documents 1 to 6, or 8), 6-hydroxy- 2,4 di-oxy-tetrahydropyrimidine derivatives (refer to Patent Document 7), 5-hydroxypyrimidine derivatives (see Patent Document 9 or 10), and the like. [Prior Art Document] [Patent Document 1] [Patent Document 1] International Publication No. 2003/049686 Booklet [Patent Document 2] International Publication No. 2003/053 997 Booklet [Patent Document 3] International Publication No. 2004/1 08 68 No. 1 booklet [Patent Document 4] International Publication No. 2 006 / 1 3 3 3 9 Booklet 201141839 [Patent Document 5] International Publication No. 2007/038571 Booklet [Patent Document 6] International Publication No. 2007/ Booklet No. 1 3 6990 [Patent Document 7] International Publication No. 2007/1 500 1 1 Booklet [Patent Document 8] International Publication No. 2008/002576 Booklet [Patent Document 9] International Publication No. 2 0 0 9 / 1 3 1 1 2 Booklet 7 [Patent Document 10] International Publication No. 2009/ 1 3 1 1 29 Booklet [Invention]

[Problems to be Solved by the Invention] The inventors of the present invention have provided a low-molecular novel compound which is excellent in EPO-producing ability and is useful for treating a disease caused by a low EPO, and provides a medicine containing the same. research. [Method for Solving the Problem] The inventors of the present invention found that the novel compound having a 5-hydroxypyrimidine-4-carboxycarboxamide structure has excellent EPO-producing ability and is effective for treating a disease caused by a decrease in erythropoietin. this invention. The present invention provides a novel 5-quinolidine-4-carboxamide compound represented by the following formula (1) or a pharmacologically acceptable salt thereof. That is, the present invention provides the following [丨] to [丨9] ^

[1] A compound represented by the formula (1) or a pharmacologically acceptable salt thereof ΟΗ Ο R3 D

(1) [In the formula (1), 'R represents C丨-C6 alkyl group, halogenated C丨_c3 alkyl group, or cyclopropyl group, 201141839 R2 represents C, -C8 alkyl group, or ---Q1 or -X- Q'Y-Q2 represents a group, and Q1 represents a monocyclic or bicyclic hydrocarbon ring group which may also have 1 to 3 substituents independently selected from the substituent group A (the hydrocarbon ring group contains 3 to 10 members of aroma) a hydrocarbon ring and a non-aromatic hydrocarbon ring), or a monocyclic or bicyclic heterocyclic group having 1 to 3 substituents independently selected from the substituent group A (the heterocyclic group includes 4 to 10) Aromatic heterocyclic ring and non-aromatic heterocyclic ring containing 1 or 2 atoms in a group consisting of a free nitrogen atom, a sulfur atom and an oxygen atom, and Q2 may also be selected independently from the substituent group A. a monocyclic or bicyclic hydrocarbon ring group of 1 to 3 substituents (the hydrocarbon ring group contains 3 to 1 member)

An aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring), or a monocyclic or bicyclic heterocyclic group which may have 1 to 3 substituents independently selected from the substituent group A (the heterocyclic group includes 4 to 10) Aromatic heterocyclic ring and non-aromatic heterocyclic ring containing 1 or 2 atoms in a group consisting of a free nitrogen atom, a sulfur atom and an oxygen atom, X represents a single bond, -(CH2)n-, -0 (CH2)n-, -(CH2;)n〇_, , -S -, _ Ν Η -, or -N (C Η 3)-, n represents an integer from 6 to 6, Y represents a single bond, -CH2 -, -(CH2)2-, -(CH2)3-, -CH2〇_, -〇CH2-, or -〇, r3 represents a hydrogen atom or a methyl group, and the substituent group A represents a halogen atom, a hydroxyl group, Amine, nitro, cyanide 201141839, Cl-C6 alkyl, halogenated c, -C3 alkyl, cyclopropyl, Ci_C6 alkyl fluorenyl, halogenated Ci-C: 3 alkoxy, and c2_c7 alkyl fluorenyl Group]. [2] A compound represented by [1] or a pharmacologically acceptable salt thereof, wherein R1 is a Ci-C4 or a cyclopropyl group, and R is a Ci-Cs alkyl group, or Or _;^_(^1,¥!1-(^23 袠

Base, N

Qla represents a phenyl group which may also be substituted, and a naphthyl group which may also be substituted (the substituent of the phenyl φ group or the naphthyl group is 1 窆 3 groups independently selected from the substituent group Aa), a thienyl group, or a benzene group. And a thienyl group, Q2a represents a phenyl group which may also be substituted (the substituent of the phenyl group is 1 to 3 groups independently selected from the substituent group Aa),

Xa represents a single bond, -(CH2)n-, _0(CH2)n-, -(CH2)nO-, s-, Y represents a single bond, -CH20·, or ·〇(^Η2-, a substituent group Aa represents a group consisting of a fluorine group, a chlorine group, a bromo group, a Cl_c4 alkyl '-difluoromethyl group, a cyclopropyl group, a C1-C3 alkoxy group, and a trifluoromethoxy group. [3] A compound represented by the formula or a pharmacologically acceptable salt thereof, wherein the compound is selected from the group consisting of U[6-(3,5-dichlorophenyl)-5-hydroxy-2-methylpyrimidine -4_yl]carbonyl]amino)acetic acid, [({6-[2.(4-fluorophenyl)ethyl) 5-hydroxy-2-methylpyrimidin-4-ylcarbonyl)amino]acetic acid , 201141839 [({6-[2-(2,5-Dimethylphenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, [({5 -hydroxy-6-[2-(2-isopropylphenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, ({[5-hydroxy-2-methyl-) 6-(5-Methylhexyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[6-(3,4-dichlorobenzyl)-5-hydroxy-2-methylpyrimidine-4- Alkyl]carbonyl}amino)acetic acid, [({5-hydroxy-2-methyl-6-[4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl) φ amine] Acid, ({[5-hydroxy-2-methyl-6-(2-naphthylmethyl)pyrimidin-4-yl)carbonyl}amino)acetic acid, ({[6-(biphenyl-4-yl)) (5-hydroxy-2-methylpyrimidin-4-yl)carbonyl}amino)acetic acid, ({[6-(3,4-dimethylbenzyl)-5-hydroxy-2-methylpyrimidine) 4-yl]carbonyl}amino)acetic acid, ({[6-(3-chloro-4-methylbenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amine β) Acetic acid, [({6-[(6-fluoro-2-naphthyl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid' [({6-[3 -Chloro-4-(trifluoromethyl)benzyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, ({[6-(4-chloro-3-methyl) Benzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, 201141839 [({6-[(2-chlorobiphenyl-4-yl)methyl]-5-hydroxyl -2-methylpyrimidinium)amino]acetic acid, [({6-[(5-fluoro-2-naphthyl)methyl]-5-hydroxy-2-methylpyrimidinyl]amino]acetic acid, [({ 6-[(6-Chloro-2-naphthalenyl)methyl]-5-hydroxy-2-methylpyrimidinylamino]acetic acid, [({2-ethyl-6-[(6-fluoro-2-) Naphthyl)methyl]-5- via base dense-

[({6-[3-Fluoro-4-(trifluoromethyl)benzyl]-5-hydroxy-2-methylpyranyl)amino]acetic acid, [({6-[(3'-fluoride) Phen-4-yl)methyl]-5-hydroxy-2-methylpyrimidinyl]acetic acid], [({5-hydroxy-6-[(6-methoxy-2-naphthyl)methyl) ]-2-methylglycosyl)amino]acetic acid, and, {[(5-hydroxy-2-methyl-6-{[6-(trifluoromethyl)-2-naphthyl]methyl) Carbonyl]amino}acetic acid. [4] A pharmaceutical composition containing any of pharmaceutically acceptable salts such as guanidine] to [3] or a pharmacologically acceptable salt thereof. [5] The pharmaceutical composition of [4] is used for the treatment of anemia or 5 [6] such as [5] pharmaceutical composition, wherein anemia is renal anemia, anemia associated with chronic diseases, and cancer chemotherapy Cancerous anemia. [7] The pharmaceutical composition of [4], which is used to produce red blood cell έ-4-yl} oryl 4-methyl}carbonyl) 4-yl} oryl) 4-yl} fluorenyl) D--4 -Based on pyridine-4-yl}carbonyl-3-yl}carbonyl}pyrimidine-4 - a compound of ί. , premature babies are poor anemia, or three. The use of a compound according to any one of [1] to [3] or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition. [9] For the purposes of [8], where the pharmaceutical composition is used for the treatment or prevention of anemia. [10] The use of [9], in which anemia is renal anemia, anemia in premature infants, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, or cancerous anemia.

[11] The compound of any one of [3] or its pharmacologically acceptable salt is used in a method of treating or preventing a disease. [12] The compound according to any one of [1] to [3] or a pharmacologically acceptable salt thereof, wherein the disease is anemia. [13] A compound according to [12] or a pharmacologically acceptable salt thereof, wherein the anemia is renal anemia, anemia of premature infants, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, or cancerous anemia. [14] A method for treating or preventing a disease, which is a pharmacologically effective amount of a compound according to any one of [1] to [3] or a pharmacologically acceptable salt thereof to a mammal or a bird Cast. [15] The method of [I4] wherein the disease is anemia. [16] The method of [15], wherein anemia is renal anemia, anemia in premature infants, anemia in chronic diseases, anemia associated with cancer chemotherapy, or cancer anemia. The method of any one of [1 4] to [1, 6], wherein the mammal is a human, a horse, a cow or a pig. The bird is a chicken. -10-

The method of any one of [1 4 ] to [1 6 ], wherein the mammal is a human being. [1 9 ] A method for producing erythropoietin, which is a compound according to any one of [1] to [3] or pharmacologically acceptable for mammals or birds. In the compound represented by the formula (1) of the present invention [hereinafter also referred to as (1)", each group has the following meaning. "Ci-C6 thiol" represents a carbon number of up to 6 straight chains or minutes, for example: methyl, ethyl, n-propyl 'isopropyl, n-butyl, first butyl, tert-butyl, pentane Base, isoamyl, 2-methylpentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylmethylpentyl, 1-methylpentyl, 3,3-di Methyl butyl, 2 2. yl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, anthracene, 3-dimethyl 2,3-dimethylbutyl, or 2-B Butyl butyl. The "halogenated κ3" group represents a group in which one of the upper hydrogen atoms of the Cl_C3 alkyl group is substituted with the following halogen atom, for example, a chloromethyl group or a bromomethyl group. Difluoromethyl, dichloromethyl, dibromomethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, ethyl, 2-bromoethyl, 2'-chloro Ethyl, 2-fluoroethyl, 2-iodo-2-propyl, or 3-chloropropyl. "Ci-C8 yard base" represents a carbon number of up to 8 straight chains or eves. For example, the above-mentioned C "C6 alkyl group represents a group, a heptyl group, or a bird or a bird: an effective amount of a salt permitted" "compound < Alkyl, isobutylphosphonium butyl, neopentyl, 2-dimethylbutanylbutyl, or two: fluoromethyl, I-based, trifluoro 2,2,2-trichloro: '3-Fluoro> branched alkyl 1-octyl. -11- 201141839 "monocyclic or bicyclic hydrocarbon ring" represents a saturated or unsaturated carbon number of 3 to 10 monocyclic or bicyclic A hydrocarbon ring group containing an aromatic or non-aromatic hydrocarbon ring group. Monocyclic or bicyclic hydrocarbon ring group 'for example: monocyclic aromatic hydrocarbon ring group such as phenyl: such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl single ring a saturated hydrocarbon ring group; or a bicyclic hydrocarbon ring group such as a naphthyl group, a tetrahydronaphthyl group, a decahydronaphthyl group, a dihydroindenyl group, a fluorenyl group or a norbornyl group.

"monocyclic or bicyclic heterocyclic group", which represents a saturated or unsaturated 4 to 1 member of a monocyclic or divalent group containing one or two atoms in a group consisting of a free nitrogen atom, a sulfur atom and an oxygen atom. Cyclic heterocyclic group. Monocyclic or bicyclic heterocyclic groups such as, for example, tetrahydrofuranyl, tetrahydropyranyl, dioxolane (di ο X 〇rany 1), di ο X any 1 , monooxa Dio 院院_ (dioxepanyl), azetidinyl (azetidinyl), pyrrolidinyl, piperidinyl' azepanyl (azepanyl), dihydrolagido, dihydropyranosyl, tetrahydropyridyl, piperidine a monocyclic non-aromatic heterocyclic group having a well group, a morpholinyl group, a dihydrocarbazolyl group or a dihydrothiazolyl group; for example, a pyrrolyl group, a pyridyl group, a thienyl group, a furyl group, a pyrimidinyl group, a hydrazine group, and a pyridyl group. , pyrazolyl, imidazolyl 'thiazolyl, isothiazolyl, oxazolyl, isoxazolyl monocyclic aromatic heterocyclic group; fluorenyl, isodecyl 'dihydrobenzofuranyl, dihydrobenzo a bicyclic non-aromatic heterocyclic group of a thienyl-tetrazoloquinolyl group, a tetrahydroisoquinolyl group, a dihydrofuropyridylpyridyl group, a dihydrothienopyridyl group or a benzodioxanyl group; or a benzene group And furyl, benzothienyl, fluorenyl, isodecyl, fluorenyl, benzoxazolyl, benzothiazolyl, furopyridinyl, repubblylpyridyl, quin Group, a bicyclic aromatic isoquinolinyl, quinolinyl fathoms quinolinyl, quinazolinyl of -12-201141839 heterocyclyl group. The heterocyclic group having a cross-linking bond such as a tropyl group represented by the following formula is also contained in a bicyclic heterocyclic group. The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

"Ci-Ce alkoxy" represents a group in which one of the above CrQ alkyl groups is bonded to an oxygen atom, for example, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, Isobutoxy, second butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, n-hexyloxy, 4-methylpentyloxy , 3-methylpentyloxy, 2-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, or 2,3-dimethylbutoxy. "Halogenated C1-C3 oxime" represents a group in which one of the above-mentioned sulfonyl groups is bonded to an oxygen atom, for example, fluoromethoxy, chloromethoxy, difluoromethoxy, or Chloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, 2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy, 2-bromo Ethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2,2-dibromoethoxy, 3-fluoropropoxy, or 3-chloropropoxy. The "C2-C7 alkyl fluorenyl group" represents an alkylene group having 2 to 7 carbon atoms, for example, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentamidine group, a trimethylethyl group, a amyl group, Isoamyl, hexyl, or heptyl. -13- 201141839 R2 represents a group represented by -X-Q^Y-Q2, and Q1 is a divalent substituent. However, in the present specification, the symbol is the same as the monovalent substituent. For example, when r2 represents a group represented by -XC^-Y-Q2, and Q1 has a heterocycloalkyl structure, Q1 is a divalent substituent having a bond for bonding with X and Y. The alkyl group (or heterocycloalkanediyl group) is described as "heterocycloalkyl group". (^ represents the same as other ring structures, and Q1 may have a more substituent. When R2 represents a group represented by -X-Qi-Y-Q2, the substitution position of the base-YV in Q1 is preferably as follows. Q1 is In the case of a 5-member ring, when the position where X is bonded to X is set to 1 position, the substitution position of the base-Y-Q2 is preferably 3 or 4. When Q1 is a 6-member ring, when Q1 is bonded to X When the position is set to 1 position: the substitution position of the base-Y-Q2 is preferably 3 or 4. When Q1 is a phenyl group, when the position where X is bonded to X is set to 1 position, the base-Y-Q2 is compared. The preferred replacement position should be 3 or 4 (refer to the figure below).

In the present invention, R1 is preferably a Ci-Cfi alkyl group or a cyclopropyl group, more preferably a Cl_C4 alkyl group or a cyclopropyl group. Q1 is preferably a phenyl group which may be substituted, a naphthyl group which may be substituted, or a monocyclic or bicyclic aromatic heterocyclic group which may also be substituted (the phenyl group, naphthyl group or aromatic heterocyclic group) The substituent is one to three groups independently selected from the substituent group A), more preferably a phenyl group which may be substituted, or a naphthyl group which may be substituted (the substituent of the phenyl or naphthyl group) One to three bases selected from the substituent group A) are a thienyl group or a benzothienyl group. -14- 201141839 X is preferably a single bond, -(CH2)n-, -〇(CH2)n-, -(cH2)n〇_, or _S-. The bonding hands of the left and right sides of each group in X are bonded to the pyrimidine ring and Q 1 in the formula (I), respectively. Q2 is preferably a phenyl group which may be substituted or a monocyclic aromatic heterocyclic group which may be substituted (the substituent of the phenyl group or the aromatic heterocyclic group is selected independently from the substituent group A) Up to 3 groups), more preferably a phenyl group which may be substituted (the substituent of the phenyl group is 1 to 3 groups independently selected from the substituent group A).

Y is preferably a single bond, -CH20-, or -OCH2-. In Y, the bonding hands shown on the left and right sides of each base are respectively bonded to Q 1 and Q2. The substituent group A' is composed of a halogen atom, a C^-C^alkyl group, a halogenated Cl-C3 alkyl group, a cyclopropyl group, a C^-C:6 alkoxy group, and a halogenated Ci-C:»alkoxy group. The group formed is more preferably a group consisting of a fluorine group, a chlorine group, a bromine group, a Cl-C4 alkyl group, a trifluoromethyl 'cyclopropyl group, a Ci-Cs alkoxy group, and a trifluoromethoxy group. . Preferably, R 2 is C, -C 8 alkyl, or a group represented by -Xa-Qla or -乂, () 13-Ya-Q2a,

Qla represents a phenyl group which may also be substituted, a naphthyl group which may also be substituted (the substituent of the phenyl or naphthyl group is independently selected from the substituent group Aa, 1 to 3 groups), a thienyl group, or a benzo group. a thienyl group, Q2a represents a phenyl group which may also be substituted (the substituent of the phenyl group is one to three groups independently selected from the substituent group Aa), and X3 represents a single bond, -(CH2)n-, -0 (CH2)n-, -(CH2)nO-, or -S-, -15- 201141839

Ya represents a single bond, -ch2o-, or - och2-, and the substituent group Aa represents a fluorine group, a chloro group, a bromo group, a Ci-C* alkyl group, a trifluoromethyl group, a cyclopropyl group, a Cl-C3 alkoxy group. a group consisting of a base and a trifluoromethoxy group.

In the compound (1) of the present invention, an isomer such as a geometric isomer, a tautomer or an optical isomer may be present depending on the kind of the substituent. The present invention encompasses such isomers and mixtures thereof (including racemates) in any ratio. Further, a calibration substance, that is, a compound in which one or more atoms of the compound of the present invention are substituted with a radioisotope or a non-radioactive isotope is also included in the present invention. When the compound of the present invention has a basic group such as an amine group, an acid addition salt can be formed. Such salts are, for example, hydrofluoride, hydrochloride, hydrobromide, hydrogen iodine

a hydrogen halide such as a salt; a mineral acid salt such as a nitrate, a perchlorate, a sulfate or a phosphate; a lower alkanesulfonate such as a methanesulfonate, a trifluoromethanesulfonate or an ethanesulfonate; Aryl sulfonates such as besylate or p-toluenesulfonate: organic acid salts such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate Or an amino acid salt such as ornidamine, glutamate or aspartate. When the compound of the present invention has an acidic group such as a carboxyl group, a base addition salt can be formed. Such salts include, for example, alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; or dibenzylamine salts, porphyrin salts, and phenylglycine. Acid alkyl ester salt, ethylene diamine salt, N-methyl reduced glucosamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzyl B Diamine salt, diethanolamine salt, N-benzyl-N-(2-phenylethyl-16 - 201141839 oxy)amine salt, phosphonium salt, tetramethylammonium salt, ginseng (hydroxymethyl) amino methane Organic amine salts such as salts The compounds of the invention may exist in the form of free bodies or solvates

In the case of a nitrogen atom, N- may be formed, but water N-oxidation is preferred. Further, the presence of the N-oxide body in the compound (1) of the present invention, such as a solvate and an N-oxide, are also included in the present invention.

The compound (1) of the present invention or a pharmacologically acceptable salt thereof exhibits excellent Ep〇 production ability in an analysis system using Hep 3B cells or the like. That is, the compound of the present invention (or its pharmacologically acceptable salt can be produced by administration to a mammal (for example, human, cow, horse, or pig) or a bird (for example, chicken, etc.). EPO. Therefore, the compound (1) of the present invention or a pharmacologically acceptable salt thereof can be used for the prevention or treatment of a disease caused by Ep〇 low, or self-storage for a patient undergoing a predetermined operation, etc. E p 〇β is low. The disease caused by 'for example, anemia, anemia should be renal anemia (dialysis period and shelf life), anemia of premature infants, anemia accompanied by chronic diseases, anemia associated with cancer chemotherapy, or cancerous anemia. 1) or a pharmacologically acceptable salt thereof can also be used as a pharmaceutical for the treatment or prevention of a disease or pathology such as ischemic brain disease. [Embodiment] [Best Embodiment of the Invention] The present invention The compound can be produced by various known synthetic methods depending on the type of the basic skeleton or the substituent -17-201141839. In this case, the type of the functional group sometimes has the functional group. The stage of the raw material to the intermediate is protected with a suitable protecting group, or the functional group is first substituted with an easily switchable group, which is effective in the manufacturing technique. Functional groups which can be protected by a protecting group, for example, an amine group, a hydroxyl group , carboxyl groups, etc., such protecting groups, for example: Greene and Wuts, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, 1999 [TWGreene, PGM Wuts,

The protective group or the like described in Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons Inc., 1 999 is appropriately selected depending on the reaction conditions. According to such a method, after the protective group is introduced and reacted, the protective group can be removed or converted into a desired base as needed.

Get the compound you want. The obtained compound of the present invention is identified by standard analytical techniques such as elemental analysis, NMR, mass spectrometry (mass spectr0SC0py), analysis, and the like, and its composition or purity can be analyzed. The starting materials and reagents used in the manufacture of the compounds of the present invention can be purchased from commercial suppliers or can be synthesized according to the methods described in the literature. Representative production methods of the compounds of the present invention are exemplified below. Further, the production method of the present invention is not limited to the following examples. (First step) The first step is a step of producing a compound of the formula (1) from a compound of the formula (2) which will be described later. -18- 201141839 Step 1

R1 (6) l]d3 steps

Md3

R1 (6) l-ld4 step 1-1d3

Pr〇2 (7)

Pro3 (4) (6)

In the above, R 1 to R_3 ran "the same meaning, R4 or unsubstituted aryl or heteroaryl, r5 # $ K represents h-Ce alkyl or represents C丨-C6 alkyl, or substituted or deuterated I, -Non-substituted aryl or heteroaryl The above R2 or may be converted to a group of R2, RZb represents a group represented by the following i ld2 step, pr〇1 to pr〇 a known method (for example: TW Greene, pGMWuts,

Groups in Organic Synthesis, Third Edition, Johi Sons Inc., 1 999) The selected protecting group for each functional group, the reaction is present and does not hinder the reaction, that is, it is not particularly limited, but: represents a substituted benzyl group, R6, R2a generation Idl and ι_ are represented by 'rotective i Wiley & As long as I: Pro1 -19- 201141839 represents benzyl, Pro2 represents a third butyl group, and Pro3 represents a methyl group, an ethyl group, a tert-butyl group or a benzyl group. The group in which X1 is obtained as a leaving group is not particularly limited, but is preferably a trifluoromethanesulfonyloxy group. Each step is detailed below. (Step 1-1) The step 1-1 is a step of producing a compound of the formula (3) from a compound of the formula (2) which will be described later. The necessary reaction is, for example: (Ι-la step): deprotection reaction of the protecting group Pro2; (Ι-lb step): condensation reaction with an amino acid or an amine acid salt having the general formula H2NCH(R3)C02Pro3; -lc step): a reaction for converting a 6-position hydroxyl group to a leaving group (-X1); and (Ι-ld step): a reaction for converting a leaving group (-X1) into a substituent 1123. The order of the steps 1 - 1 a to 1 - 1 d is not limited, and the order of the person having ordinary knowledge in the field can be easily and appropriately selected. (1-1 a step) This step is a step of deprotecting the protecting group Pro2, depending on the pro2 used, for example, TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons A known method described in Inc., 1 999, etc. is carried out in accordance with this. Here, a preferred Pro2 system selects a third butyl group, a base is used in a passive solvent to convert Pro2 into a hydrogen atom (i_lai step), or an acid is used to convert Pro2 into hydrogen in a passive solvent. Atomic method (1 _ a2 step), but this step is not limited to this -20- 201141839 (1 -1 a 1 step) This step is to convert Pro2 into a hydrogen atom using a suitable base in a passive solvent. method.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; Chloroforms are hydrocarbons; such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane ethers; alcohols such as methanol, ethanol, and butanol; An ester of ethyl acetate or propyl acetate; a nitrile such as acetonitrile; a guanamine such as formamide or N,N-dimethylformamide; an anthracene such as dimethyl hydrazine; or a majority A mixed solvent of an arbitrary ratio of an organic solvent, a mixed solvent of an arbitrary ratio with water, or the like. The base to be used is not particularly limited as long as it is a base user in a usual reaction, for example, an organic base such as triethylamine; an alkali metal carbonate such as sodium carbonate or potassium carbonate; and an alkali metal carbonate such as carbonic acid An alkali metal hydrogencarbonate such as potassium hydrogencarbonate; an alkaline earth metal hydrogencarbonate such as calcium hydrogencarbonate; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; Metal-like hydroxides; or alkali metal phosphates such as tripotassium phosphate. The reaction temperature varies depending on the starting compound 'reagent' and the like, and is usually -10 ° C to 150 ° C, preferably 10 ° C to 90 °. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 1 minute to 24 hours, preferably from 1 minute to 6 hours. -21- 201141839 After completion of the reaction, the objective compound can be obtained as a solid by distilling off an organic solvent, adding water, and then adding an acid. On the other hand, even if a solid cannot be obtained by adding an acid, 'the organic substance can be extracted with an organic solvent such as ethyl acetate, 'the organic layer is dried by a usual procedure, and then concentrated, or concentrated under reduced pressure. The target compound is obtained. (Step l-la2) This step is a method in which Pro2 is converted into a hydrogen atom using a suitable acid in a passive solvent. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can be dissolved to some extent as a starting material, and is preferably, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; an ester such as ethyl acetate or propyl acetate; an ether such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; such as methanol or ethanol Alcohols; nitriles such as acetonitrile; decylamines such as formamide, hydrazine, dimethyl dimethyl carbamide; hydrazines such as dimethyl hydrazine; or mixtures of solvents in any ratio of most organic solvents , plus a mixture of solvents and any ratio of water.

The acid to be used is not particularly limited as long as it is an acid user in a usual reaction, for example, a mineral acid such as hydrochloric acid or sulfuric acid; for example, boron trifluoride, boron trichloride, boron tribromide or trimethyl decane iodide. Lewis acid; or an organic acid such as trifluoroacetic acid. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -1 〇 0 ° C to 150 ° C, preferably -7 8 ° C to 1 0 0 ° C » reaction time depending on the starting compound 'reagent The difference is usually from 5 minutes to 24 hours, preferably from 1 minute to 6 hours. -twenty two-

After the completion of the reaction, the compound of the present invention can be obtained by, for example, concentrating the mixture, and adding an organic solvent such as ethyl acetate, washing the organic layer containing the objective compound, and drying the solvent with anhydrous sodium sulfate or the like. The obtained compound can be further purified by a usual method such as crystal, re-sinking, sand column chromatography or the like as needed. (1 -1 b step) This step is a step of condensing a carboxylic acid obtained in the step ι-la with an amino acid or an amine acid salt having H2NCH(R3)C02Pr〇3, in the presence of a base in a passive solvent The solvent to be used in the presence or absence of the condensing agent is not particularly limited as long as it does not hinder the reaction and can be used in a certain solution, but is preferably, for example, an aromatic hydrocarbon such as benzene or xylene. Such as methylene chloride, chloroform halogen such as ethyl acetate, propyl acetate ester; such as diethyl ether, tetrahydrofuran dioxane ' 1,2-dimethoxyethane ether; such as methyl alcohol , ethanol, alcohols of the φ alcohol; nitriles such as acetonitrile; such as formamide, N,N-dimethylformamide; such as dimethyl hydrazine; or most organic solvents The base used in the mixed solvent of any ratio, and the mixed solvent with any ratio of water, etc., is not limited as long as it is an alkali user in a usual reaction, and is preferably, for example, triethylamine, N, N. _Diisopropylethylamine methyl sulphate, lutidine, pyrimidine organic bases; such as sodium carbonate, potassium alkali metal carbon Salts; plane as the carbonate of the alkaline earth metal carbonate, potassium bicarbonate, alkali metal bicarbonate salts; alkaline earth such as calcium bicarbonate: After the reaction will be,: based on the Formula recrystallization row. : degree soluble toluene hydrocarbons; * 1,4-: tributylamine is more than bismuth, N-carbonic acid; such as metal-23- 201141839 carbonic acid salt; such as alkali metal hydroxide of sodium hydroxide Such as alkaline earth metal hydroxides of hydroxide; or alkali metal phosphates such as tripotassium phosphate. The condensing agent used is only used as a condensing agent for the formation of a guanamine bond (for example: Nanben Zheng~ et al., Experimental Science Lecture IV; Japanese Chemical Society; Jiushan, 1 990 ' or Izumi Yufu, etc., peptide synthesis The basis and experiment; the method described in Jiushan '1985 et al.' is not particularly limited, and is preferably: 〇_benzoxazole-N, N, N', N'-tetramethyl hexafluorophosphate urea (HBTU) , 2-(1H_benzobisazol-1-yl)-l,l,3,3-tetramethyltetrafluoroborate urea (TBTU), 1-(3-dimethylaminopropyl)-3 -Ethylcarbonyldiamine imide hydrochloride (Edci), 丨-cyclohexyl-3-(2-N-tyrosolinylethyl)carbonyldiimide imine p-toluenesulfonate (CMC), two Cyclohexylcarbonyldiamine (DCC), 1,1'-carbonyl bis(1H-imidazole) (CDI), (1H-benzotriazol-1·yloxy) (tripyrrolidinium-yl) Iron fluorophosphate (PyBOP), bromine (tripyrrolidin-1-yl) ruthenium hexafluorophosphate (PyBr〇P), 4_(4,6-dimethoxy-1,3,5-trian-2-yl -4 -Methyl porphyrin chloride (DMT-MM) or 2-chloro-4,6-dimethoxy-purine 5 - triple trap (DMT). Further, 1-hydroxybenzotriazole (H0BT) or N,N-dimethylaminopyrimidine may be added as an additive. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 150 ° C, preferably 0 ° C to 100 ° C. The reaction time varies depending on the starting compound, test, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 24 hours. -24- 201141839 After the reaction, the objective compound of the reaction can be obtained by, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the objective compound, and drying with anhydrous sodium sulfate or the like. It was obtained by distilling off a solvent. The obtained compound can be further purified by a usual method such as recrystallization, reprecipitation, or ruthenium column chromatography, if necessary. (1 - 1 c steps)

This step is a step of converting the 6-position hydroxyl group into a leaving group (-X1), which is carried out in a passive solvent or in the presence or absence of a base by reacting an acid chloride or an acid anhydride. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; an ester such as ethyl acetate or propyl acetate; an ether such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; a nitrile such as acetonitrile For example; guanamines such as formamide φ, N,N-dimethylformamide; hydrazines such as dimethyl hydrazine; or mixed solvents of any ratio of most organic solvents. The acid chloride or acid anhydride to be used is not particularly limited as long as the -X1 group is an acid chloride or an acid anhydride having X 1 which can be a known leaving group, and is preferably substituted or unsubstituted such as trifluoromethanesulfonic anhydride. An alkylsulfonic anhydride or an arylsulfonic anhydride; a substituted or unsubstituted alkylsulfonyl chloride or an arylsulfonyl chloride such as methanesulfonyl chloride or p-toluenesulfonyl chloride; or a substituted or unsubstituted alkane Phosphate chloride or aryl phosphate chloride. -25- 201141839 The base to be used is not particularly limited as long as it is used as a base user in a usual reaction, and is preferably, for example, diethylamine, N,N-diisopropylethylamine or N-methyl An organic base of a porphyrin, a lutidine or a pyrimidine; an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkali metal carbonate such as an alkali metal carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; a test-type metal hydrogencarbonate of calcium bicarbonate; a metal hydroxide such as sodium hydroxide; an alkaline earth metal hydroxide such as a hydroxide; or an alkali metal phosphate such as tripotassium phosphate; . The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually from _ 1 〇 至 to 150 ° C, preferably from - 80 ° C to 40 ° C. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 24 hours, preferably from 〇 minute to 6 hours.

After the completion of the reaction, the objective compound of the present reaction can be obtained, for example, by concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the objective compound, and drying with anhydrous sodium sulfate or the like, and then saturating the solvent. Further, the obtained compound can be further purified by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like as needed. (1 - 1 d step) In this step, the step of converting the leaving group (-X1) into R2a is performed, and the method of synthesizing Rh is different, so the following details will be described in detail. (1-1 dl step): Rh is an arylsulfanyl group, a heteroarylsulfanyl group, an aryloxy group, a heteroaryloxy 'arylamino group' an arylamino group, N-methyl-N- Aromatic amine group, -26-201141839 or N-methyl-N-heteroarylamino group (wherein the aryl or heteroaryl group may also be substituted); (l-ld2 step): Min 23 (: 丨-C8 alkyl 'aryl, heteroaryl, aryl C丨·C6 alkyl' or heteroaryl C^-C: 6 alkyl (the 'aryl or heteroaryl group in each of the above groups may also be (Substituted): (i-id3 step): R2a is an arylmethyl or heteroarylmethyl group (in the above-mentioned groups, an 'aryl or heteroaryl group may also be substituted); or '

(Step l-ld4): The case where R2a is a substituted or unsubstituted ethynyl group. In the above or below, the aryl group represents an aromatic hydrocarbon ring group, and the heteroaryl group represents an aromatic heterocyclic group. (1 -1 d 1 step) This step is carried out in a passive solvent in the presence or absence of a base to 'make a metal salt of a corresponding thiol' thiol containing a group represented by R2a, a metal salt of phenol 'phenol The amine, or methylamine is reacted with a compound of the formula (4) or (6). The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; such as ethyl acetate 'propyl acetate; such as diethyl ether, tetrahydrofuran, 1,4-dioxane, I, 2-dimethoxyethane ether; such as methanol, ethanol, An alcohol of a third butanol; a nitrile such as acetonitrile; a guanamine such as formamide or N,N-dimethylformamide; an anthracene such as dimethyl hydrazine; or a majority of organic solvents A mixed solvent of any ratio, a mixed solvent with an arbitrary ratio of water, and the like. -27- 201141839 The base to be used is not particularly limited as long as it is used as a base in a usual reaction, and is preferably, for example, triethylamine, N,N-diisopropylethylamine or N-methylmorpholine. An organic base such as lutidine or pyrimidine; an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkali metal carbonate such as an alkali metal carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; Alkaline earth metal hydrogencarbonate of hydrogen hydride; alkali metal hydroxides such as sodium hydroxide; alkali metal hydroxides such as oxyhydroxide; alkali metal phosphates such as tripotassium phosphate; Sodium tributoxide, metal alkoxides of potassium butoxide, and the like. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -1 〇 t to 150 ° C, preferably 0 ° C to 100 ° C. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 12 hours. After the completion of the reaction, the target compound of the present reaction can be obtained, for example, by concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the objective compound, and drying with anhydrous sodium sulfate or the like, and then distilling off the solvent. And get. The obtained compound can be further purified by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like as needed. (1 -1 d 2 step) This step is carried out in a passive solvent, in the presence or absence of a base, in the presence or absence of an additive, in the presence of a metal catalyst, to give a corresponding boron compound having a group represented by 1123 It is carried out by reacting with a compound having the formula (4) or (6). The reaction conditions can be appropriately selected, for example: Tsuji, J. Palladium -28- 201141839

Reagents and Catalysts; John Wiley & Sons, Inc.: England, 2004., or Meta 1 - Cata 1 yzed Cross-Coupling Reactions; de Meijere, A.; Diederich, F.; Wiley-VCH: Weinheim' 2004 A well-known method such as the one described is carried out. Here, the following preferable conditions are described, but are not limited thereto.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; a halogenated hydrocarbon of chloroform; an ester such as ethyl acetate or propyl acetate; an ether such as diethyl ether, tetrahydrofuran 'oxime, 4-dioxane, 1,2-dimethoxyethane; a nitrile such as acetonitrile For example, a decylamine such as formamide or N,N-dimethylformamide; or a mixed solvent of any ratio of a plurality of organic solvents, a mixed solvent with any ratio of water, and the like. The base to be used is not particularly limited as long as it is used as a base in the usual reaction, and is preferably, for example, triethylamine, hydrazine, hydrazine-diisopropylethylamine, N-methyl morpholine, or dimethyl. An organic base such as sodium pyridine or pyrimidine; for example, sodium carbonate, potassium carbonate, and alkali metal carbonate; such as alkali metal carbonates of carbonic acid; such as alkali metal hydrogencarbonates of potassium hydrogencarbonate; Alkaline earth metal hydrogencarbonates; such as alkali metal hydroxides of sodium hydroxide; such as alkali metal hydroxides of hydroxide; such as alkali metal phosphates of tripotassium phosphate; or Sodium butoxide, metal alkoxides of potassium butoxide, and the like. The additive to be used is not particularly limited as long as it is a user in a known method, and is preferably, for example, a metal oxide such as silver oxide or aluminum oxide; triphenylphosphine, tri-tert-butylphosphine, or tricyclohexylphosphine. , tris(o-tolylmethyl) -29- 201141839 phosphine 'diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy _ 1,1'-linked Benzene (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl (X-PHOS), 2,2'-bis (two a phosphine of phenylphosphino)-l, quinone-binaphthyl (BINAP); a phosphine oxide such as triphenylphosphine oxide; a metal salt such as lithium chloride, potassium fluoride or fluorinated; or An ammonium salt of an ammonium bromide or the like. These can also be used in combination in any ratio.

The metal catalyst used is not particularly limited as long as it is a user in a known method, and is preferably, for example, palladium (triphenylphosphine) palladium, bis(tri-tert-butylphosphine)palladium or palladium acetate. 2 palladium chloride diphenylphosphinoferrocene complex, 2 n-benzonitrile chloride complex, 2 chlorinated acetonitrile complex, bis(diphenyl; ketone) palladium, ginseng (two Benzyleneacetone) dipalladium, bis[I,2-bis(diphenyl) ethane]palladium, 3-chloropyrimidine [1,3-bis(2,6-diisopropylphenyl) Palladium, palladium-activated carbon palladium catalyst.

The boron compound used is not particularly limited as long as it is a known reactant user, but when 1^2!1 is an alkyl group, for example, an alkylboronic acid, a decyl phthalate, an alkenylboronic acid or an alkenyl boron When R2a is a substituted or unsubstituted aryl or heteroaryl group, an arylalkyl group or a heteroarylalkyl group, for example, a corresponding boric acid or a boric acid ester or the like. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually 丨〇. 〇 to 200 ° C, preferably 〇 ° C to 150 ° C. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from s minute to 48 hours, preferably from 10 minutes to 12 hours. -30-

201141839 After the completion of the reaction, the objective compound of the reaction can be obtained, for example, by concentrating the mixture, adding an organic solvent such as ethyl acetate, washing with water, and containing an organic layer of the objective compound, followed by drying with anhydrous sodium sulfate and the like. The obtained compound can be further purified by a usual method such as re-precipitation, reprecipitation, gel column chromatography or the like as needed. Further, when the ruler 23 is an alkenyl group, it can be derivatized into a corresponding alkyl group by performing a decomposition reaction in the l_2al step described later. This step is in a passive solvent, in the presence of a base, in the presence of an additive, in the presence of an additive, the corresponding arylacetic acid alkyl benzyl acetate, alkyl aryl aryl acetate, or heteroaryl group containing a group represented by R 2a The benzyl acetate is reacted with a compound of the formula (4) or (6). The solvent to be used is not particularly limited as long as it does not interfere with the reaction, and is preferably a certain amount of a solvent, and is preferably, for example, an aromatic hydrocarbon such as benzene, toluene or φ benzene; a halogen system such as dichloromethane or chloroform. Hydrocarbons; such as ether 'tetrahydrofuran, 1,4-dioxane, ether of 1,2-dimethoxyethane, such as formamide, amide of N,N-dimethylformamide, and the like. The additive to be used is not particularly limited as long as it is a user in a known method, and is preferably hexamethylphosphoniumamine (ΗΜPA). The base to be used is not limited as long as it is used as a base in the usual reaction, and is preferably, for example, such as lithium diisopropylamide, lithium hexamethyldichloride, lithium cyclohexylisopropylamide, hydrazine. Lithium amine, hexamethyldiamine can be reverse-separated to dissolve crystals under hydrogenation or esters, and with metal decyl amine; or especially non-deuterated sodium-31-201141839; An organic base such as ethylamine, hydrazine, hydrazine diisopropylethylamine, N-methyl saccharoline, lutidine or pyrimidine; an alkali metal carbonate such as sodium carbonate or potassium carbonate; Metal-like carbonates; such as alkali metal hydrogencarbonates of potassium hydrogencarbonate; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide; a metal hydroxide; for example, an alkali metal phosphate such as tripotassium phosphate; or a metal alkoxide such as sodium t-butoxide or potassium t-butoxide.

The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -100 ° C to 50 ° C, preferably -78 ° C to 〇 ° C. The reaction time varies depending on the starting compound 'reagent' and the like, and is usually from 5 minutes to 48 hours, preferably from 1 minute to 12 hours. When R5 is a benzyl group, the hydrodecomposition reaction of the l-2al step described later is carried out after the step, and when the R5 is an alkyl group, the hydrolysis reaction of the step 1-1 a is carried out after the step. The group represented by the formula -co2r5 in the compound (7) or (8) is removed.

(1 - 1 d 4 steps) This step also gives the corresponding ethynyl group containing a group represented by R2a in the presence of a base, in the presence or absence of a base, in the presence or absence of an additive, in the presence of a metal catalyst. The compound is reacted with a compound having the formula (4) or (6). The reaction conditions are appropriately selected, for example: Sonogashira, K.; Tohda, Y.; Hagiwara, N. Tetrahedron Lett. 1975, 50, 4467., or Sonogashira, KJ Organomet Chem. 2 0 0 2, 6 5 3, 4 The well-known method described in 6, etc. is carried out according to it. Here, the following appropriate conditions are described but are not limited thereto. The solvent of -32-201141839 is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen-based hydrocarbon of chloroform; such as an acetate of ethyl acetate or propyl acetate; an ether such as diethyl ether, tetrahydrofuran, anthracene, 4-dioxane' 1,2-dimethoxyethane; such as acetonitrile Nitriles; such as formazan, amides of N,N-dimethylformamide; or any ratio of most organic solvents? The solvent is added, and a mixed solvent of any ratio with water is added.

It is not particularly limited as long as it is a usual reaction as a base user. For example, it is preferably, for example, triethylamine, hydrazine, hydrazine-diisopropylethylamine, hydrazine-methyl sulphate dimethylpyridine, An organic base of pyrimidine; for example, a metal carbonate of sodium carbonate or potassium carbonate; an alkali metal carbonate such as an alkali metal carbonate; an alkali metal hydrogencarbonate such as potassium hydrogencarbonate; an alkaline earth metal such as calcium hydrogencarbonate; a hydrogencarbonate; an alkali metal hydroxide such as sodium hydroxide; an alkaline earth metal hydroxide such as a hydroxide; an alkali metal phosphate such as tripotassium phosphate; or a sodium butoxide, Metal alkoxides of potassium tributoxide, and the like. The additive to be used is not particularly limited as long as it is a known method, and is preferably, for example, copper (I) bromide or copper (I) bromide (I). The metal catalyst used is not particularly limited as long as it is a user in a known method, and is preferably, for example, palladium (triphenylphosphine) palladium, bis(tri-tert-butylphosphine)palladium or palladium acetate. 2 palladium chloride diphenylphosphinoferrocene complex, 2 palladium chloride benzonitrile complex, 2 palladium chloride acetonitrile complex, bis(dibenzylideneacetone) palladium, ginseng (two sub Benzylacetone) dipalladium, bis[1,2-bis(diphenylphosphino-33- 201141839)ethane]palladium, 3-chloropyrimidine [1,3-bis(2,6-diisopropylbenzene) Palladium, palladium-activated carbon palladium catalyst. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually _10. (: to 200 ° C, preferably 0 ° C to 150 ° C. The reaction time varies depending on the starting compound, the reagent, etc., and is usually from 5 minutes to 48 hours, preferably from 1 minute to 12 hours. After the completion of the reaction, the objective compound can be obtained by, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the objective compound, and drying with anhydrous sodium sulfate and then distilling off the φ solvent. The obtained compound can be further purified by a usual method, for example, recrystallization, reprecipitation, gel column chromatography, etc. after the step, followed by hydrogenation reaction according to the reaction conditions of the 1 - 2 a 1 step described later. The group represented by the formula R6-C = C- in the compound (9) or (1〇) can be converted into a group represented by the formula R6-(CH2)2-.

The step 1-2 is a step of producing a compound of the formula (1) from a compound of the formula (3). The necessary reactions are: (step l-2a): deprotection reaction of protecting group Pro1; and (1-2b step): deprotection reaction of protecting group Pro3, and adding (l-2c step) as needed: R2a Transform to the reaction of R2. The order of the steps 1-2 a to 2 c is not limited, and the person who has the usual knowledge in the field can easily select the order thereof appropriately. -34- 201141839 (Step l-2a) This step is a step of deprotecting the protective group Pro 1, depending on the Pro1 used, for example, T.W. Greene, P.G.M. Wuts,

A well-known method described in Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons Inc., 1999, etc., is carried out. Herein, a preferred method for selecting a benzyl group in Pro1, in a hydrogen atmosphere, in a passive solvent, in the presence or absence of an additive, and using a catalyst to convert Pro1 into a hydrogen atom (1_2al), a hydrogen atom is described. Instead of using a catalyst to convert Pro1 into a hydrogen atom in the presence of an organic compound capable of becoming a hydrogen source in a nitrogen or argon atmosphere, in a passive solvent, in the presence or absence of an additive, and using a catalyst (1_2a2) Or, in a passive solvent, a method of converting Pro1 into a hydrogen atom using a suitable acid (1_2a3), but this step is not limited thereto. (l-2al step) This step is a step of converting Pro1 into a hydrogen atom using a catalyst under a hydrogen atmosphere in a passive solvent in the presence of φ or in the absence of an additive. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; for example, dichloromethane or chloroform. a halogen-based hydrocarbon; an ester such as ethyl acetate or propyl acetate; an ether such as diethyl ether, tetrahydrofuran, hydrazine, 4-dioxane or 1,2-dimethoxyethane; such as methanol or ethanol An alcohol; a nitrile such as acetonitrile; a guanamine such as formamide or N,N-dimethylformamide; a hydrazine such as dimethyl sulfoxide; or a mixed solvent of any organic solvent in any ratio. 'Add a mixed solvent with any ratio of water, etc. -35- 201141839 The additive used is not particularly limited as long as it is a user of a known method, and hydrochloric acid is preferred. The metal catalyst used is not particularly limited as long as it is a user in a known method, and is preferably palladium-activated carbon, ginseng (triphenylphosphine) ruthenium chloride or palladium hydroxide. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually from 1 to 10 ° C, preferably from 0 ° C to 1,100 ° C. -

The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 1 minute to 24 hours, preferably from 5 minutes to several hours. After the completion of the reaction, the objective compound of the present reaction can be obtained by, for example, filtering the insoluble matter to concentrate the filtrate under reduced pressure. The obtained compound can be further purified by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like as needed. Further, when 1123 is an alkenyl group, it can be converted into a corresponding alkyl group in this step. (1 - 2 a 2 step) This step is a substitute for a hydrogen atom and is used in the presence or absence of an additive in an inert solvent in the presence of an organic compound capable of becoming a hydrogen source under a nitrogen or argon atmosphere. The step of converting the Pro | into a hydrogen atom. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is preferably, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; or a halogen such as dichloromethane or chloroform. Hydrocarbons; such as ethyl acetate, propyl acetate esters; such as diethyl ether, tetrahydrofuran, 1,4-dioxane ' 1,2-dimethoxyethane ether; such as methanol, ethanol alcohol a nitrile such as acetonitrile-36-201141839; a guanamine such as formamide or N,N-dimethylformamide; an anthracene such as dimethyl hydrazine; or any ratio of most organic solvents A mixed solvent, a mixed solvent with an arbitrary ratio of water, and the like. The organic compound to be used as the hydrogen source is not particularly limited as long as it is a known method, and formic acid is preferred. The additive to be used is not particularly limited as long as it is a user in a known method, and hydrochloric acid is preferred.

The metal catalyst to be used is not particularly limited as long as it is a user of a known method, and is preferably palladium-activated carbon, ginseng (triphenylphosphine) ruthenium chloride or palladium hydroxide. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually - loo °c to 150 ° C, preferably -78 ° C to 100 ° C. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours. After the end of the reaction, the target compound of the reaction can be obtained by, for example, concentrating the anti-Φ mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the objective compound, and drying it with anhydrous sodium sulfate or the like. Obtained by removing the solvent. The obtained compound can be further purified by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like as needed. (1 - 2 a 3 step) This step is carried out in a passive solvent and a method of converting Pr 〇 1 to a hydrogen atom using an appropriate acid, in accordance with the step 1-la2. -37- 201141839 (1 - 2 b steps) This step is a step of deprotecting the protective group Pro3 in accordance with the id a step. When Pro3 is a benzyl group, it can also be carried out according to the procedure of l-2al. (Step l-2c) This step is a step of converting R2a to R2, and when R2a is an alkenyl group, it can be converted into a corresponding alkyl group according to the above 1-2 aal step. (Second Step) The second step is a step of producing the aforementioned compound (2).

Step 2? In the above, Pro1 and Pro2 represent a protecting group of the aforementioned functional group. Pro4 represents a protecting group of various functional groups selected from known methods (for example, TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons Inc., 1989, etc.), and only in the reaction The medium is stable and does not hinder the reaction, that is, it is not particularly limited, and preferably represents a methyl group. The compound of the formula (2) can be obtained by a known method ((i) a substituted ethaneimine decylamine (1 1) and a 2-alkyloxy-3-oxo succinic acid prepared according to a known method. Method for the condensation of ester (12) in the presence of a base: Dreher, SD; -38- 201141839

Ikemoto, N.; Gresham, V.; Liu, J.; Dormer, PG; Balsells, J.; Mathre, D.; Novak. T.; Armstrong III, JD Tetrahedron Lett. 2004, 45, 6023, or (ii A method of condensing an N-trans group-substituted ethaneimine amide amine (13) with an acetylene dicarboxylic acid diester (14): Culbertson, TPJ Heterocycl. C hem. 1 9 7 9, 1 6, 1 423) ' Or synthesize a method modified by a known method.

The reaction product obtained by the above various production methods can be isolated and purified in the form of various solvates such as a free compound, a salt thereof or a hydrate. The salt can be produced according to the usual method. The separation and purification can be carried out by usual chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, or various chromatography. The various isomers can be separated according to the usual methods by utilizing the difference in physicochemical properties between the isomers. For example, an optical isomer can be separated by a general optical division method such as crystallization or chromatography. Further, the optical isomer can also be produced from a suitable optically active starting material compound. The preparation of the compound (1) of the present invention as an active ingredient can be prepared by using an additive such as a carrier or an excipient which is usually used for formulation. The dosage form can be administered orally as a lozenge, a nine-dose, a capsule, a granule, a powder, or a liquid, or an injection (including intravenous and intramuscular injection), a suppository, a transdermal agent, a nasal spray, and an inhalation. Any form such as a dose that is not administered orally. The dose can be appropriately determined depending on the symptoms, the age of the subject, the sex, etc., depending on the occasion, 'usually for oral administration', the adult is about 1 mg/kg to 100 mg/kg each time. One dose is administered, or divided into 1 to 6 doses. Further, -39- 201141839, depending on the symptoms, when administered intravenously, the adult usually takes one to several times per day in the range of 0.0001 mg/kg to 10 mg/kg.

The solid composition of the present invention for oral administration can be used as a tablet, a powder, a granule or the like. In such a solid composition, one or more active ingredients are mixed with at least one blunt excipient (e.g., lactose, mannitol, or glucose, etc.). The solid composition may further contain a blunt additive (for example, a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, or a dissolution aid). The lozenge or the nine doses may also be coated with a sugar-coated or stomach-soluble or enteric coating agent to form a film. The liquid composition for oral administration contains a pharmaceutically acceptable emulsion, a liquid, a suspending agent, a syrup, an elixir, and the like, and contains a blunt solvent (e.g., pure water or ethanol) which is generally used. The liquid composition may further contain a solubilizing agent, a wetting agent, an adjuvant (e.g., a suspending agent), a sweetener, a flavoring agent, a flavoring agent, or a preservative.

An injection for parenteral administration comprising a sterile aqueous or nonaqueous liquid, suspension, or emulsion. The aqueous solvent includes, for example, distilled water for injection and physiological saline. The nonaqueous solvent includes, for example, a vegetable oil such as propylene glycol, polyethylene glycol, olive oil, an alcohol such as ethanol, such as polysorbate 80 (Japanese Pharmacopoeia). Such an injection composition may further contain an isotonic agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, or a dissolution aid. The composition for injection can be sterilized by, for example, filtering through a filter which the bacteria cannot pass, or blending or irradiating the sterilizing agent. Further, the composition for injection, when a sterile solid composition is produced, can be used by dissolving or suspending it in sterile water or a sterile injectable solvent before use. [Examples] The examples and the test examples are described below, and the present invention will be described in more detail, but the scope of the present invention is not limited thereto. (Example 1) [({6-[(3,4-Chlorophenyl)thioindolyl]-5-transyl-2-methylpicky-4-yl} ore)

(1) 5-(benzyloxy)-6-hydroxy-2-methylpyrimust-4-residual acid tert-butyl ester

Diisopropylamine (15 mL) was dissolved in tetrahydrofuran (55 mL), and then n-hexane solution (2.6 M, 41 mL). (: Stirring for 30 minutes. After the reaction solution was added dropwise at -78 °C for 30 minutes to a solution of t-butyl oxalate (17 g) and methyl (benzyloxy)acetate (18 g) in tetrahydrofuran (200 mL) 'The mixture was stirred at the same temperature for 1 hour. The reaction solution was slowly warmed up to -40 ° C. After adding hydrochloric acid (1 Μ, 150 mL), the organics were extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give 4-(benzyloxy)-3-oxo-succinic acid 4-t-butyl 1-methyl ester as a yellow oil. This was dissolved in methanol (1 20 mL) with ethaneimine decylamine hydrochloride (6.1 g), and added to a solution of sodium methoxide in methanol (28%, 42 mL) at 0 ° C. One night. After adding hydrochloric acid (1 Μ, 250 mM) and water to the reaction solution, the precipitated solid was collected by filtration to give the title compound (16 g, yield 76%) as white solid. 'H-NMR (400 MHz, CDC13) δ: 7.46 (2Η, d, J = 7 Hz), 7.39-7.33 (3H, m), 5.25 (2H, s), 2.49 (3H, s), 1.53 ( 9H, s). (2)({[5-(Benzyloxy)-6-hydroxy-2-methyl) 4-yl] carbonyl} amino) ethyl acetate

Adding 3-(benzyloxy)-6-hydroxy-2-methylpyrimidine-4-carboxylic acid tert-butyl ester (35 g) to a mixed solvent of tetrahydrofuran (240 mL) and methanol (240 mL), and adding hydrogen After an aqueous sodium hydroxide solution (8 M, 80 mL), the mixture was stirred at 60 ° C for 6 hours. The reaction solution was concentrated under reduced pressure, and water and hydrochloric acid (1 M) was added, and the precipitated solid was collected by filtration to obtain white of 5-(benzyloxy)-6-hydroxy-2-methylpyrimidine-4-carboxylic acid. solid. This was dissolved in hydrazine, hydrazine-dimethylformamide (330 mL), and 1,1'-carbonylbis(1H-imidazole) (18 g) was added at room temperature and stirred for 30 minutes, then glycine acid B was added. The ester hydrochloride (20 g) and hydrazine, hydrazine diisopropylethylamine (50 mL) were stirred for 4 hr. The reaction mixture was concentrated under reduced pressure and ethyl acetate (·········· The solvent was evaporated under reduced pressure. EtOAc was evaporated. 'H-NMR ( 5 00 MHz, CDC13) δ: 8.13 (1Η, t, J = 5 Hz), 7.53 (2H, d, J = 7 Hz), 7.3 6-7.3 0 (3 H, m), 5.36 (2H, s), 4.25 (2H, q, J = 7 Hz), 4.16 (2H, d, J = 5 Hz), 2.47 (3H, s), 1.3 1 (3H, t, J = 7 Hz). 201141839 (3)({[5_(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)ethyl acetate

N octa C02Et Η ({[5-(Benzyloxy)-6-hydroxy-2-methylpyrimidin-4-yl)carbonyl}amino)acetate (7.2 g) in dichloromethane (75 mL) Adding a solution of trifluoromethanesulfonic anhydride (7·〇mL) in dichloromethane (3〇mL) and pyrimidine (5.1 mL) at 0 °C

After that, it was stirred at the same temperature for 1.5 hours. After water was added to the reaction mixture, the mixture was extracted with methylene chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography. The eluent solvent was distilled off under reduced pressure and the mixture was evaporated to dryness. ) White solid. H-NMR (5 00 MHz, CDC13) δ: 8.14 (1Η, t, J = 5 Hz), 7.50 (2H, d, J = 8 Hz), 7.3 9- 7.3 5 (3 H, m), 5.33 ( 2H, s), 4.28 Lu (2H, q, J = 7 Hz), 4.24 (2H, d, J = 5 Hz), 2.71 (3H, s), 1.32 (3H, t, J = 7 Hz). ( 4) [({5-(Benzyloxy)-6-[(3,4-dichlorophenyl)sulfanyl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate OBn 0 , C02Et

Xrs妒({[5-(benzyloxy)-2-methyl-6·{[(trifluoromethyl)sulfonyl)]oxy}pyrimidyl]carbonyl}amino}) ethyl acetate ( 0.24 g) and 3,4-dichlorobenzenethiol (0.18 g) were dissolved in N,N-dimethylformamide (1 mL), and after adding -43-201141839 potassium (0.14 g) at room temperature Stir for 2.5 hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate was evaporated and evaporated. After the solvent was evaporated under reduced pressure, crystals crystals crystals crystals crystals 'H-NMR (5 00 MHz, CDC13) δ: 8.35 (1H, t, J = 5 Hz), 7.63-7.61 (2H, m), 7.50 (1H, d, J = 8 Hz), 7.44-7.43 ( 5H, m), 5.24 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 5 Hz), 2.50 (3H, s), 1.32 (3H, t, J = 7 Hz). (5) [({6-[(3,4-Dichlorophenyl)sulfanyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid ester

[({5-(Benzyloxy)-6-[(3,4-dichlorophenyl)sulfanyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.21 g) Dissolved in ethanol (25 mL), concentrated hydrochloric acid (0.75 mL) was added at room temperature, and then stirred at 45 ° C for 2 hours. After the reaction mixture was concentrated under reduced pressure, water was evaporated and evaporated. The solvent was evaporated under reduced pressure. W-NMR (500 MHz, CDC13) δ: 11.73 (1H, s), 8.41 (1H, t, J = 5 Hz), 7.69 (1H, s), 7.50 (1H, d, J = 8 Hz), 7.40 (1H, d, J = 8 Hz), 4.28 (2H, q, J = 8 Hz), 4.21 (2H, d, J = 5 Hz), 2.44 (3H, s), 1.33 (3H, t, J = 8 Hz). 201141839 (6) [({6-[(3,4-Dichlorophenyl)sulfanyl) 5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid] ({6-[(3,4-Dichlorophenyl)sulfanyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.16 g) was dissolved in tetrahydrofuran ( A mixed solvent of 5 mL) and methanol (5 mL) was added to a sodium hydroxide aqueous solution (1 M, 5.0 mL) at room temperature, followed by stirring for 30 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc m. MS m/z: 3 8 8 (M + H) + ; 'H-NMR (400 MHz, CD3〇D) δ: 7.75 (1H, d, J - 4 Hz), 7.61 (1H, d, J = 8 Hz), 7.48 (1H, dd, J = 8 Hz, 4 Hz), 4.09 (2H, s), 2.42 (3H, s). (Example 2) ({[5-hydroxy-2-methyl- 6 -(2-naphthylsulfanyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

({[5-(Benzyloxy)-2-) obtained according to Example 1-(4) to 1-(6), and using 2-naphthylthiol (0.16 g) and Example 1-(3) Methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead of 3,4-dichlorobenzenethiol The title compound (0.10 g, yield 55%) Mp: 205-208 °C; *H-NMR (400 MHz, CD3〇D) δ: 8.12 (1H, s), 7.94-7.89 (3H, m), 7.60-7.5 2 (3 H, m), 4.13 (2H, s), 2.34 (3H, s). -45- 201141839 (Example 3) ({[2-butyl-6-(4-fluorophenyl)-5-hydroxypyrimidin-4-yl]carbonyl) Amine)acetic acid

(1) 5,6-bis(benzimidyloxy)-2-butylpyrimidine-4-carboxylic acid methyl ester

The valeronitrile (16 mL) was dissolved in ethanol (75 mL), and aqueous hydroxylamine (50%, 15 mL). After the reaction mixture was concentrated under reduced pressure, toluene was added to the obtained residue, and the solvent was evaporated under reduced pressure. The residue obtained was dissolved in chloroform (60 mL), and dimethyl acetylenedicarboxylate (21 mL) was added dropwise at 0 ° C for 15 min. After the reaction mixture was concentrated under reduced pressure, toluene was added to the obtained residue, and the mixture was refluxed for 2 days. After the reaction solution was cooled to room temperature, the resulting precipitate was separated from the solvent by decantation. Dichloromethane was added to the obtained precipitate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give methyl 2-butyl-5,6-dihydroxypyrimidine-4-carboxylate (21 g). This was dissolved in dichloromethane (200 mL), and pyrimidine (22 mL) and benzamidine chloride (21 mL) were sequentially added at 0 ° C, and then stirred at room temperature overnight. Hydrochloric acid (1 M) was added to the reaction mixture, and the mixture was extracted with dichloromethane. After distilling off the solvent under reduced pressure, the residue obtained was purified by silica gel column chromatography to give the title compound (6.5 g, yield: 1%). -46 - 201141839 !H-NMR (400 MHz, CDC13) δ: 8.12-8.03 (4H, m), 7.63-7.55 (2H, m), 7.4 6-7.3 8 (4H, m), 3.89 (3H, s ), 3.08 (2H, t, J = 8 Hz), 1.9 0-1.8 3 (2H, m), 1.50-1.41 (2H, m), 0.96 (3H, t, J = 7 Hz). (2)5 -(benzylideneoxy)-2-butyl-6-chloropyrimidine-4-carboxylic acid methyl ester OBz 0

Methyl 5,6-bis(benzylideneoxy)-2-butylpyrimidine-4-carboxylate (6.5 g) was dissolved in hydroxyphosphonium chloride (20 mL) and heated to reflux for 6 hours. After the reaction mixture was poured into ice, ethyl acetate was evaporated, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by chromatography on silica gel column to afford the title compound (5.1 g, yield 98%). iH-NMR (400 MHz, CDC13) δ: 8.23 (2H, d, J = 8 Hz), 7.72 (1H, t, J = 8 Hz), 7.57 (2H, t, J = 8 Hz), 3.89 (3H , s), 3.05 (2H, t, J = 8 Hz), 1.8 9-1.8 2 (2H, m), 1.49- 1.42 (2H, m), 0.98 (3H, t, J = 7 Hz). (3 Methyl 5-(benzimidyloxy)-2-butyl-6-(4-fluorophenyl)pyrimidine-4-carboxylate

Methyl 5-(benzimidyloxy)-2-butyl-6-chloropyrimidine-4-carboxylate (〇·3 5 g) and (4-fluorophenyl)boronic acid (0.28 g) were dissolved in toluene A mixed solvent of (15 mL) and water (0.18 mL) was added to a solution of palladium (triphenylphosphine) palladium--47-201141839 (0.17 g) and sodium carbonate (0.2 1 g) under a nitrogen atmosphere, followed by heating and refluxing. 12 hours. Hydrochloric acid (1 M) was added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to give the title compound (0.38 g, yield 94%). 'H-NMR (400 MHz, CDC13) δ: 8.13 (2Η, d, J = 8 Hz), 7.96-7.93 (2H, m), 7.5 6-7.4 8 (3 H, m), 7.14-7.09 (2H , m), 3.88 (3H, s), 3.12 (2H, t, J = 8 Hz), 1.93 - 1.8 8 (2H, m), 1.51-1.44 (2H, m), 0.99 (3H, t, J = 7 Hz). (4)({[2-butyl-6-(4-fluorophenyl)-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid 5-(benzhydryloxy) Methyl -2-butyl-6-(4-fluorophenyl)pyrimidine-4-carboxylate (0.38 g) was dissolved in 1,4-dioxane (20 mL). (1 M, 4.0 mL) was stirred at 60 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and water (30 mL) and hydrochloric acid (1 M, 4.0 mL) were sequentially added, and the precipitated solid was collected by filtration, whereby 2-butyl-6-(4-fluorophenyl group was obtained. -5-hydroxypyrimidine- 4-carboxylic acid (0.18 g, yield 65%). This was dissolved in N,N-dimethylformamide (30 mL), and ethyl glycinate (0.17 g), 1-cyclohexyl-3-(2-N-morpholinylethyl) After carbonyl dioxime imine p-toluenesulfonate (CMC) (0.52 g), 1-hydroxybenzotriazole (HOBt) (0.19 g) and N-methyl morpholine (0.2 7 mL), Stir for 2 days. After the hydrochloric acid (1 M) was added to the mixture, the mixture was extracted with ethyl acetate. The residue obtained was purified by silica gel column chromatography to obtain ({[2_丁-48- 201141839 -6-(4-fluorophenyl)-5-hydroxypyrimidin-4-yl 1 pinpin) fluorenyl} Amino)ethyl acetate (0.17 g, yield 75%). This was dissolved in hydrazine, 4_2b (6 mL), and then aqueous sodium hydroxide (1 M, 1.5 mL) was added at room temperature, and m was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. Water and hydrochloric acid (yield M) was obtained, and the precipitated solid was filtered, and dried under reduced pressure to give the title compound (1,5 g, yield 94%) as a white solid. Mp: 15 8 ° C ; H-NMR (400 MHz, DMSO-d6) δ: 12.89 (lH, s), 12.78 (1 Η, s), 9.56 (1 Η, t, J = 6 Hz), 8.29 (2 Η, Dd, j = 9 Ηζ> 6 Hz), 7.38 (2Η' t, J = 9 Ηζ), 4·04 (2Η, dj = 6 Ηζ), 2 9ι (2η, t, J = 8 Hz), 1.8 5 - 1.79 (2Η, m), 1.43-1.35 (2H, m), 0.94 (3H, t, J = 7 Hz). (Example 4) ({[2-cyclopropyl-6-(4-fluorobenzene) Base-5-yl-pyrimidin-4-yl]p-amino)amino)acetic acid

n^co2h ΝγΝ Η

A (l) 5-(benzylideneoxy)-6-chloro-2-cyclopropylpyrimidine-4-carboxylic acid methyl ester OBz 0

The title compound (3.0 g, yield 16%) was obtained as a pale yellow oil. 'H-NMR (400 MHz, CDCh) δ: 8 2 2 - 7.4 6 (5 Η, m), 3 · 8 6 (3H, s), 2.40-2.34 ( 1 H, m), 1.26-1.15 (4H , m). -49- 201141839 (2) ({[2-cyclopropyl-6-(4-fluorophenyl)-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 3- (3) and 3-(4), and use 5-(benzylideneoxy)-6-chloro-2-cyclopropylpyrimidine-4-carboxylic acid methyl ester (0.23 g) instead of 5" (benzamide) Methyl oxy)-2-butyl-6-chloropyrimidine-4-carboxylate gave the title compound (0.091 g, yield 39%) as a white solid. MS m/z: 332 (M + H) + ; H-NMR (400 MHz, DMSO-d6) 6: 12.69 (1H, s), 9.57 (1H, t, J = 6 Hz), 8.22 (2H, t, J = 8 Hz), 7.60 (2H, t, J = 8 Hz), 4.02 (2H, d, J = 6 Hz), 2.27-2.23 ( 1 H, m), 1.11-1.03 (4H, m). (Example 5) ({[6-(4 - Fluorophenyl)-5-hydroxy-2-propylpyrimidin-4-yl]carbonyl}amino)acetic acid

F ΟΒζ Ο Cl

(1) methyl 5-(benzimidyloxy)-6-chloro-2-propylpyrimidine-4-carboxylate according to Examples 3-(1) and 3-(2), and using butyronitrile (10 g) Instead of valeronitrile, the title compound (3.8 g, yield 8%) was obtained. 'H-NMR (400 MHz, CDC13) δ: 8.22 (2Η, d, J = 7 Hz), 7.71 (1H, t, J = 7 Hz), 7.56 (2H, t, J = 7 Hz), 3.88 ( 3H, s), 3.02 (2H, t, J = 8 Hz), 1.8 6- 1.84 (2H, m), 1.03 (3H, t, J = 7 Hz). -50- 201141839 (2)({[6 -(4-fluorophenyl)-5-hydroxy-2-propylpyrimidin-4-yl]carbonyl}amino)acetic acid according to Examples 3-(3) and 3-(4), and using 5-(benzene Methyl formazanoxy)-6-chloro-2-propylpyrimidine-4-carboxylate (0.21 g) instead of 5-(benzhydryloxy)-2-butyl-6-chloropyrimidine-4-carboxylate The title compound (0.057 g, yield 27%) MS m/z: 334 (M + H) + ;

'H-NMR (400 MHz, CD3〇D) δ: 8.3 5 -8.3 2 (2H, m), 7.24- 7.20 (2H, m), 4.16 (2H, s), 2.92 (2H, t, J = 7 Hz), 1.90 (2H, qt, J = 7 Hz), 1.01 (3H, t, J = 7 Hz). (Example 6) ({[6-(4-chlorophenyl)-5-hydroxy-2) -propylpyrimidin-4-yl]carbonyl}amino)acetic acid

In accordance with Examples 3-(3) and 3-(4), and using 5-(benzylideneoxy)-6-chloro-2-propylpyrimidine-4-carboxylic acid methyl ester (0.21 g) instead of 5- Methyl (benzimidyloxy)-2-butyl-6-chloropyrimidine- 4-carboxylate, and (4-chlorophenyl)boronic acid (0.19 g) was used instead of (4-fluorophenyl)boronic acid, The title compound (0.03 8 g, yield 17%) MS m/z: 3 5 0 (M + H) + ; 'H-NMR (400 MHz, CD3 〇D) δ: 8.28 (2H, d, J = 8 Hz), 7.50 (2H, d, J = 8 Hz), 4.17 (2H, s), 2.93 (2H, t, J = 7 Hz), 1.90 (2H, qt, J = 7 Hz), 1.01 (3H, t, J = 7 Hz). -51 - 201141839 (Example 7) [({5-Hydroxy-2-methyl-6-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}nonyl)amino]acetic acid

F3cXXIi^rA^c〇2H ΝγΝ (1)[({5-(Benzyloxy)-2-methyl-6-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}carbonyl)amine Ethyl acetate Γ^ίΐ ?Βη ° F3C^^PY^N^C02Et

ΝγΝ Η ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl)oxy}pyrimidin-4-yl) obtained in Example 1-(3) Ethyl acetate (0.15 g) and [3-(trifluoromethyl)phenyl]boronic acid (0.12 g) are dissolved in a mixed solvent of toluene (5H1L) and water (0.06 mL). After adding ruthenium (triphenylphosphine) palladium complex (0.03 6 g) and potassium carbonate (0.08 7 g) at room temperature under nitrogen atmosphere, stir at ·7 〇π

Mix 2 • 5 hours. After adding water to the reaction mixture and extracting with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain a yellow oily substance of the title compound (〇15 g, quantitative yield). 'H-NMR (400 MHz, CDC13) δ: 8.3 1 (1H, t, J = 6 Hz), 8.23 (1Η, s) , 8.15 (1 H, d, J = 8 Hz), 7.71 (1H , d, J = 8 Hz), 7.53 (1 Η, dd, J = 8 Hz, 8 Hz), 7.24-7.11 (5H, m), 4.88 (2Η, s) , 4 • 28 (2H, q, J = 7 Hz), 4.27 (2H, d, J = 6 Hz), 2.79 (3 Η, s), 1 _ 3 3 (3H, t, J = 7 Hz). -52- 201141839 (2)[({ 5-hydroxy-2-methyl-6-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}carbonyl)amino]ethyl acetate

[({5-(卞oxy)_2_methyl-6-[3-(trimethyl)phenyl]& dimethylidene-4-yl}amino)amino]acetic acid ethyl acetate ( 0.15 g) dissolved in ethyl acetate (6 mL), 5% palladium-activated carbon (20 mg), then stirred under a hydrogen atmosphere at room temperature

1 hour. After the reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give the title compound (0.10 g, yield 86%) as white solid. 'H-NMR (400 MHz, CDC13) δ: 12.15 (1Η, s), 8.60 (1H, t, J = 6 Hz), 8.55 (1H, s), 8.48 (1H, d, J = 8 Hz), 7.73 (1H, d, J = 8 Hz), 7.61 (1H, dd, J = 8 Hz, 8 Hz), 4.30 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 6 Hz) , 2.73 (3H, s), 1.34 (3H, t, J = 7 Hz). φ (3) [({5-hydroxy-2-methyl-6-[3-(trifluoromethyl)phenyl] Pyrimidine-4-yl}carbonyl)amino]acetic acid according to Example 1 - (6), and using [({ 5 -hydroxy-2-methyl-6-[3-(trifluoromethyl)phenyl) Acetylpyrimidin-4-yl}carbonyl)amino]acetate (〇.1〇g) in place of [({6-[(3,4-dichlorophenyl)sulfanyl]-5-hydroxy-2) Ethyl-methylpyrimidin-4-yl}carbonyl)amino]acetate gave the title compound (0.086 g, yield: MS m/z: 3 5 6 (M + H) + ;

'H-NMR (400 MHz, CD3OD) δ: 8.56 (1H, s), 8.53 (1H, d, J -53- 201141839 =8 Hz), 7.79 (1H, d, J = 8 Hz), 7.69 (1H , t, J = 8 Hz), 4.16 (2H, s), 2.72 (3H, s). (Example 8) ({[6-(3-chlorophenyl)-5-hydroxy-2-methylpyrimidine) -4-yl]carbonyl}amino)acetic acid

(1) ({[5-(Benzyloxy)-6-(3-chlorophenyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetate and ({[6-(3) -Chlorophenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

({[5-(Benzyloxy)-2-methyl-6) according to Example 7-(1), using (3-chlorophenyl)boronic acid (0.68 g) and Example 1-(3) -{[(Trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (1.0 g) in place of [3-(trifluoromethyl)phenyl]boronic acid, Obtaining ({[5-(benzyloxy)-6-(3-chlorophenyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.35 g, yield 38%) ({[6-(3-Chlorophenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.40 g, yield 59%). ({[5-(Benzyloxy)-6-(3-chlorophenyl)-2-methylpyrimidin-4-yl]carbonyl}amino) Ethyl acetate: 'H-NMR (400 MHz, CDC13) δ: 8.27 (1Η, t, J = 6 Hz), 7.98 (1 H, s), 7.89 ( 1 H, d, J = 8 Hz), 7.45 (1 H, d, J = 8 Hz), 7.46- 7.19 (6H, m), 4.86 (2H, s), 4.28 (2H, q, J = 8 Hz), 4.26 (2H, d, J = 6 Hz), 2.78 (3H, s), 1.33 (3H, t , J = 8

Hz). 201141839 ({[6-(β-chlorophenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetate: 'H-NMR (400 MHz, CDC13) δ: 12.12 (1Η, s), 8.61 (1H, t, J = 6 Hz), 8.2 7- 8.26 ( 1 H, m), 8.19-8.16 (1H, m), 7.45-7.40 (2H, m), 4.30 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 6 Hz), 2.72 (3H, s), 1.34 (3H, t, J = 7 Hz).

(2) ({[6-(3-Chlorophenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 1-(6), and used ({[ Ethyl 6-(3-chlorophenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.62 g) in place of [({6-[(3,4_2) Chlorophenyl)sulfanyl]-5-hydroxy-2-methylpyrimidin-4-ylhydrazinylamino)acetic acid ethyl acetate afforded the title compound (0·59 g, yield quantitative) as a white solid.

Mp: 1 78 - 1 8 0 °C ; 'H-NMR (400 MHz, CDC13) 8.21-8.16 (2H, m), 7.63-7.56 Hz), 2.69 (3H, s). δ: 9·63 (1H , t, J = 6 Hz), (2H, m), 4 〇3 (2H, d, J = 6 (Example 9) -Methylpyrimidin-4-yl]carbonyl}amine ({[6-(3) -ethyl-4-fluorophenyl)-5-hydroxy-2-yl)acetic acid

Octaco2h (1)({[5-(Benzyloxy)-6-(4-fluoro-3-vinylphenyl)_2-methylpyrimidin-4-yl]carbonyl oxime) ethyl acetate-55- 201141839 ΟΒη Ο

N^COzEt

A solution of n-butyllithium (1.6 M, 1, 8 mL) was diluted in a mixture of Zhengjiyuan (1.3 mL) and tetrahydrofuran (3 mL) under a nitrogen atmosphere at -78. (: Add 4 - bromo-bufluoro-2-vinylbenzene (〇·51 g) to a mixture of Zhengjiyuan (1.5 m L) and tetrahydrofuran (1.5 m L) after '-5 h ° C After stirring for 1 hour, trimethyl borate (0.40 mL) was added to the reaction mixture at -78 ° C, then the temperature was slowly raised to room temperature and stirred overnight. Hydrochloric acid (1 M) was added to the reaction mixture and extracted with diethyl ether. Thereafter, the solvent was distilled off under reduced pressure to obtain (4-fluoro-3-vinylphenyl)boronic acid (0.43 g, yield quantitative). According to Example 7 - (1), and using (4-fluoro -3 -vinylphenyl)boronic acid (0.25 g) and ({[5-(benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl) obtained in Example 1-(3) Ethyl acetate of methoxy}pyrimidin-4-yl]carbonyl}amino) (0.24 g) was obtained in the title compound (0·15 g). Rate 6 5 %).

'H-NMR (400 MHz, CDC13) δ: 8.29 (1Η, t, J = 6 Hz), 8.21 (1H, dd, J = 7 Hz, 2 Hz), 7.9 3 - 7.90 ( 1 H, m), 7.26-7.21 (5 H,m),7 · 1 1 (1 H,t,J = 9 H z),6 · 8 7 (1 H,dd,J = 1 8 H z, 11 Hz), 5.77 ( 1H, d, J = 18 Hz), 5.38 (1H, d, J = 11 Hz), 4.85 (2H, s), 4.28 (2H, q, J = 7 Hz), 4.27 (2H, d, J = 6 Hz), 2.78 (3H, s), 1.33 (3H, t, J = 7 Hz). (2)({[6-(3-ethyl-4-fluorophenyl)_5_hydroxy-2-methyl) Butridin-4-yl]carbonyl}amino)acetic acid-56- 201141839 According to Examples 7-(2) and 1-(6), and using ({[5-(benzyloxy)-6-(4- Ethyl fluoro-3-vinylphenyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.15 g) in place of [({5-(benzyloxy)-2.methyl-) Ethyl 6-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}carbonyl)amino]acetate gave the title compound (0.064 g,yiel. Mp : 1 3 6- 1 3 7 °C ;

'H-NMR (5 00 MHz, DMSO-d6) δ: 12.90 (1Η, s), 9.60 (1H, t, J = 6 Hz), 8.15 (1H, dd, J = 8 Hz, 2 Hz), 8.12 -8.09 (1H, m), 7.30 (1H, t, J = 8 Hz), 4.03 (2H, d, J - 6 Hz), 2.72 (2H, q, J = 7 Hz), 2.67 (3H, s) , 1.22 (3H, t, J = 7 Hz). (Example 10) ({[6-(3,4 - monochlorophenyl)-5-yl-yl-2-methyl-II) -yl]hydrazino}amino)acetic acid

八 co2h (1) ({[5-(Benzyloxy)-6-(3,4-dichlorophenyl)-2-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

ClΟΒη Ο

According to Example 7-(1), and using (3,4-dichlorophenyl)boronic acid (0.12 g) and Example 1-(3), ({[5-(benzyloxy)-2-methyl) Ethyl 6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.15 g) in place of [3-(trifluoromethyl)phenyl To a solution of the title compound (0.092 g, yield 62%). 201141839 'H-NMR (400 MHz, CDC13) δ: 8.28 (1H, t, J = 6 Hz), 8.11 (1H, d, J = 2 Hz), 7.86 (1H, dd, J = 9 Hz, 2 Hz ), 7.47 (1H, d, J = 9 Hz), 7.2 8 - 7.2 4 (3 H, m), 7.21-7.18 (2H, m), 4.90 (2H, s), 4.28 (2H, q, J = 7 Hz), 4.26 (2H, d, J = 6 Hz), 2.77 (3H, s), 1.31 (3H, t, J = 7 Hz). (2)({[6-(3,4-Dichloro) Phenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl)amino)acetic acid according to Examples 1 - (5) and - (6) ' and used ({ [ 5 - (oxyl) -6-(3,4-dichlorophenyl)-2-methylpyrimidin-4-yl]fluorenyl}amino)acetic acid ethyl acetate (0.092 g) instead of [({5-(benzyloxy) Ethyl acetate-6-[(3,4-dichlorophenyl)sulfanyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate afforded the title compound (0.043 g, yield 62 %) White solid. MS m/z: 3 5 6 (M + H) + ; 'H-NMR (400 MHz, CD3 〇D) δ: 8.45 (1H, d, J = 2 Hz 8.24 (1H, dd, J - 9 Hz, 2 Hz), 7.64 (1H, d, J = 9 Hz 4.15 (2H, s), 2.70 (3H, s). (Example 11) ({[6-(3,4--fluoro-based)-5 -transmethyl-2-methylpyrimidin-4-yl]carbonyl guanamine)

N C02H was obtained according to Examples 7-(1), 7-(2) and 1-W, using (3,4-difluorophenyl)boronic acid (0.099 g) and Example (3) ({[ 5_(Hydroxyl)_2_methyl-6-{[(difluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)ethyl-58- 201141839 acid vinegar (〇· 2 g) In place of [3_(trifluoromethyl)phenyl]boronic acid, the title compound (?? MS m/z: 3 24 (M + H) + ; 'H-NMR (400 MHz, CD3〇D) δ: 8.26-8.19 (2H, m), 7.41-7.35 (1H, m), 4.16 (2H, s), 2.69 (3H, s). (Example 12)

({[6-(3-chlorophenyl)-5-hydroxy-2.propylpyrimidin-4-yl]carbonyl}amino)acetic acid (1) ({[5-(benzyloxy)-2-propane) Ethyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)ethyl acetate

In accordance with the examples - (1) to 1-(3), and using butaneimine decylamine hydrochloride (3.9 g) in place of ethaneimine decylamine hydrochloride, the title compound (9.0 g, yield 81%) White solids *H-NMR (400 MHz, CDC13) δ: 8 · 17 (1 Η, t, J = 5 Hz), 7.51-7.49 (2H, m), 7.40- 7.3 4 ( 3 H, m), 5.23 (2H, s), 4.27 (2H, q, J - 7 Hz), 4.23 (2H, t, J = 5 Hz), 2.92 (2H, t, J = 7 Hz), 1.84 (2H, Tq, J = 7 Hz, 7 Hz), 1.33 (3H, t, J = 7 Hz), 0.99 (3H, t, J = 7 Hz). (2)({[6-(3-chlorophenyl)) -5-hydroxy-2-propylpyrimidin-4-yl]carbonyl}amino)ethyl acetate-59- 201141839

, C02Et according to Example 7_(1), and use ({[5-(benzyl trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl (〇·3〇g) instead {[5_(Benzyloxy)_2-methyl-6-indole[(yl)oxypyrimidin-4-yl]carbonyl}amino)acetic acid, 綦)-2-propyl-6-{[ ( } 歧 base) ethyl acetate S fluoromethyl) sulfonate and (3-chlorophenyl)boronic acid (0.19 g) in place of [3_(trifluoromethyl)phenyl compound (0.17 g, yield 77 %) White solid. Boric acid, obtained the standard 'H-NMR (4〇〇MHz, CDC13) δ: 12.13 (ιΗ s) 5 8.6 4 ( 1 Η, t J = 6 Hz), 8.29-8.28 ( 1 H, m), 8.21- 8.]q 19 (1H, m), 7.46- 7.40 (2H,m), 4.30 (2H,q,J = 7 Hz), 4 ' 2 5 (2H , d, J = e

Hz), 2.93 (2H, t, J = 7 Hz), 1.88 (2H, qt H s J - 7 Hz, 7 Hz)

Hz) 'yl}carbonyl}amino)ethyl 1.34 (3H, t, J = 7 Hz), 1.02 (3H, t, J = 7 (3)({[6-(3-chlorophenyl)-5-) Hydroxy-2-propylpyrimidin-4 acid according to Example 1-(6), and used ({[6-(3·chlorobenzene) r-glucosyl)-5-hydroxy-2-propylpyrimidine Ethyl -4-yl]carbonyl}amino)acetate (〇_17 g) in place of [({6 [(3 4 -dichlorophenyl)sulfanyl]-5-hydroxy-2-methylpyrimidine_4 Ethyl acetate of carbonyl)amino]acetic acid afforded the title compound (0.12 g,yield: 75%) as a white solid. MS m/z: 3 5 0 (M + H) + ; 'H-NMR (400 MHz, CD3OD) δ: 8.3 2- 8.25 ( 1 H, m), 8.25- 8_15 (1H, m), 7.55-7.38 (2H, m), 4.14 (2H, s), 2.94 (2H, t, J = 7 Hz ), 1.91 (2H, qt, J = 7 Hz, 7 Hz), 102 (3H, t, J = 7 Hz). -60- 201141839 (Example 1 3 ) [({5 -hydroxy-2-methyl) - 6- [3-(Trifluoromethoxy)phenyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [(5-Hydroxy-2-methyl-6-[3-(trifluoromethoxy)phenyl]pyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 7-(1), and using [3-(trifluoromethoxy)phenyl]boronic acid (0.17 g) and Example 1-(3) ({[5-(benzyloxy)-) 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.20 g) in place of [3-(trifluoromethyl) Phenyl]boronic acid gave the title compound (0.16 g, yield:

*H-NMR (400 MHz, CDC13) δ: 12.16 (1Η, s), 8.62 (1H, t, J = 6 Hz), 8.3 2-8.22 ( 1 H, m), 8.22-8.17 (1H, m) , 7.57-7.43 (1H, m), 7.41-7.28 (1H, m), 4.30 (2H, q, J = 7 Hz), 4.25 (2H, d, J = 6 Hz), 2.72 (3H, s), 1.34 (3H, t, J = 7 Hz). (2) [({5-Hydroxy-2-methyl-6-[3-(trifluoromethoxy)phenyl]pyrimidin-4-yl}carbonyl) Amino]acetic acid according to Example 1-(6), and using [({5-hydroxy-2-methyl-6-[3-(trifluoromethoxy)phenyl]pyrimidin-4-yl}carbonyl) Ethyl acetate ethyl acetate (0.16 g) in place of [({6-[(3,4-dichlorophenyl)sulfanyl]-5-hydroxy-2-methylpyrimidine-4--61 - 201141839) Ethyl acetate of carbonyl]amino]] gave the title compound (0.13 g, yield Mp : ^ ί 2 4 - 1 2 6 °C ; 'H-NMR (400 MHz, CD3〇D) δ: 8.29 ( 1 H, d, J = 8 Hz), 8.18 (1H, s), 7.59 (1H , dd, J = 8 Hz, 8 Hz), 7.41 (1H, d, J = 8 Hz), 4.16 (2H, s), 2.71 (3H, s). (Example 14) ({[6-(3 -chloro-4-fluorophenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1) ({[5-(Benzyloxy)-6-(3-chloro-4-fluorophenyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetate

According to Example 7-(1), and using 〇-chloro-4-fluorophenyl)boronic acid (015 g) and Example 1-(3), ({[5-(benzyloxy)_2-methyl) -6-{[(Trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.2 〇g) in place of [3-(trifluoromethyl)phenyl ]Boronic acid, the title compound (〇1 6 g> yield 81%) was obtained. 'H-NMR (400 MHz, CDCI3) δ: 8 · 2 9 (1Η, t, J = 6 Η ζ) 8.11-8.08 (1Η, m), 7.95-7.91 (1Η, m), 7.2 8 - 7.24 ( 5 Η, m) 7.21-7.14 (1H, m), 4.89 (2H, s), 4.28 (2H, q, J = 7 Hz) 4.26 (2H, d, J = 6 Hz), 2.77 (3H, s) , 1.33 (3H, t, J = 7 Hz). -62- 201141839 (2)({[6-(3-Chloro-4-fluorophenyl)-5-hydroxy-2-methylpyrimidin-4-yl) ]carbonyl]amino)acetic acid according to Examples 1-(5) and 1-(6), and using ({[5-(benzyloxy)-6-(3-chloro-4-fluorophenyl)-2) -methylpyrimidin-4-yl]carbonyl}amino)acetate (0.16 g) in place of [({5-(benzyloxy)-6-[(3,4-dichlorophenyl)sulfanyl) Ethyl acetate of -2·methylpyrimidin-4-yl}carbonyl)amino]] gave the title compound (0.095 g, yield: MS m/z: 340 (M + H) + ; lH-NMR (400 MHz, DMSO-d6) δ: 9.63 (1H, t, J = 6 Hz), 8.40- 8.3 8 ( 1 H, m), 8.2 8 - 8.27 ( 1 H, m), 7.62-7.5 8 ( 1 H, m), 4.02 (2H, d, J = 6 Hz), 2.69 (3H, s). (Example 1 5 ) ({[5 -hydroxy-2-methyl-6-(3,4,5-trifluorophenyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

(1) ({[5-(Benzyloxy)-2-methyl-6-(3,4,5-trifluorophenyl)pyrimidin-4-yl]carbonyl}amino)acetate

({[5-(Benzyloxy)-2) obtained according to Example 7-(1), using (3,4,5-trifluorophenyl)boronic acid (0.15 g) and Example 1-(3) -methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.20 g) -63- 201141839 instead of [3-(three Fluoromethyl)phenyl]boronic acid, titled g, yield 47%). 'H-NMR (400 MHz, CDC13) δ: 8.28 (1Η, t, J = (1H, d, J = 7 Hz), 7.72 (1H, d, J = 7 Hz), 7.3 m), 4.95 (2H , s), 4.28 (2H, q, J = 7 Hz), 4.26 5 Hz), 2.77 (3H, s), 1.33 (3H, t, J = 7 Hz). (2)({[5-hydroxy- 2-methyl-6-(3,4,5-trifluorophenyl)pyrimidine-. Amino)acetic acid according to Examples 7-(2) and 1-(6), and using ({[5-(benzyl) Substituted [6-(3,4,5-trifluorophenyl)pyrimidin-4-yl]carbonyl}amine (0.091 g) in place of [({5-(benzyloxy)-2-methyl-6-[ Ethyl 3-(trifluoropyrimidin-4-yl}carbonyl)amino]acetic acid afforded the title compound mjjjjjjj NMR (400 MHz, DMSO-d6) δ: 12.93 (1H, s) t, J = 6 Hz), 8.15-8.11 (2H, m), 4.03 (2H, d, 2.69 (3H, s). 16) [({6-[4-(Benzyloxy)-3-fluorophenyl]-5-hydroxy-2-methylpyrimidinyl)amino]acetate (0.0 9 1 5 Hz), 7.73 1- 7.25 (5H, (2H, d, J = 4-yl)carbonyl}

Ethoxy)-2-methyl)ethyl acetate methyl)phenyl] complex (0.049, 9.67 (1H, φ J = 6 Hz), -4 -yl} fluorenyl)

N丫N -64- 201141839 According to Examples 7-(1), 7-(2) and 1-(6), and using [4-(benzyloxy)-3-fluorophenyl]boronic acid (0.31 g) And ({[5-(benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl)oxy}pyrimidin-4-yl]carbonyl) obtained in Example 1-(3) The title compound (0.12 g, yield 45%) was obtained as a white solid.

'H-NMR (400 MHz, DMSO-d6) δ: 9.58 (1H, t, J = 6 Hz), 8.12-8.09 (2H, m), 7.51-7.49 (2H, m), 7.44-7.3 7 (4H , m), 5.29 (2H, s), 4.02 (2H, d, J = 6 Hz), 2.66 (3H, s). (Example 17) ({[6-(3,5-dichlorophenyl)) -5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

CI

Eight co2h according to Examples 7-(1), 7-(2) and 1-(6), and using (3,5-dichlorophenyl)boronic acid (0.24 g) and Example 1-(3) ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) In place of [3-(trifluoromethyl)phenyl]boronic acid, the title compound (j. MS m/z: 356 (M + H) + ; 'H-NMR (400 MHz, DMSO-d6) 5: 9.66 (1H, t, J = 6 Hz), 8.20 (2H, d, J = 2 Hz) , 7.82 (1H, t, J = 2 Hz), 4.03 (2H, d, J - 6 Hz), 2.69 (3H, s). -65- 201141839 (Embodiment 18) ({[6-(3,4) -difluorophenyl)-2-ethyl-5-hydroxypyrimidin-4-yl]carbonyl}amino)

(1) 5-(Benzamethyleneoxy)-6-chloro-2-ethylpyrimidine-4-carboxylic acid methyl ester ΟΒζ Ο

The title compound (1 4 g, yield 13%) was obtained according to the procedure of 3-(1) and 3-(2), using acetonitrile (25 mL). 'H-NMR (400 MHz, CDC13) δ: 8.23 (2Η, d, J = 8 Hz), 7.71 (1H, t, J = 8 Hz), 7.56 (2H, t, J = 8 Hz), 3.88 ( 3H, s), 3.09 (2H, q, J = 8 Hz), 1.42 (3H, t, J = 8 Hz). (2) 5-(benzhydryloxy)-6-(3,4 -difluorophenyl)-2.ethylpyrimidine-4-carboxylic acid

In accordance with Example 3-(3), and using 5-(benzylideneoxy)-6-chloro-2-ethylpyrimidine-4-carboxylic acid methyl ester (0.64 g) instead of 5-(benzhydryloxy) )-2-butyl-6-chloropyrimidine-4-carboxylic acid methyl ester, and (3,4-difluorophenyl)boronic acid (0.63 g) was used instead of (4-fluorophenyl)boronic acid to obtain the title compound (0.81 g, quantitative basis). -66- 201141839 Ή-NMR (400 MHz, CDC13) δ: 8.15-8.12 (1H, m), 7.88- 7.83 (1H, m), 7.75-7.71 (1H, m), 7.71-7.67 (1H, m) , 7.56-7.52 (2H, m), 7.31-7.16 (2H, m), 3.88 (3H, s), 3.15 (2H, q, J = 8 Hz), 1.46 (3H, t, J = 8 Hz). (3) ({[6-(3,4-Difluorophenyl)-2-ethyl-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid

According to Example 3 - (4), and using 5-(benzylideneoxy)-6-(3,4-difluorophenyl)-2-ethylpyrimidine-4-carboxylic acid methyl ester (0.81 g) Instead of methyl 5-(benzimidyloxy)-2-butyl-6-(4-fluorophenyl)pyrimidine-4-carboxylate, the title compound (0.29 g, yield 43%) MS m/z: 3 3 8 (M + H) + ; 'H-NMR (400 MHz, DMSO-d6) δ: 12.91 (1H, s), 9.63 (1H, t, J = 4 Hz), 8.26- 8.2 3 ( 1 H, m), 8.19-8.13 (1H, m), 7.66-7.59 (1H, m), 4.03 (2H, d, J = 4 Hz), 2.95 (2H, q, J = 8 Hz) , 1.37 (3H, t, J - 8 Hz). Φ (Example 19) ({[6-(4-chloro-3-methylphenyl)-5-hydroxy-2-methylpyrimidine-4- Amine

(1) ({[5-(Benzyloxy)-6-(4-chloro-3-methylphenyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetate

Cl丫^ OBn 0

-67- 201141839 According to Example 7-(1), and using (4-chloro-3-methylphenyl)boronic acid (0.22 g) and Example 1-(3) ({[5-(benzyloxy) Ethyl 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) instead of [3-(three Fluoromethyl)phenyl]boronic acid gave the title compound (yield: 2 1 g, yield 7.4%). 'H-NMR (400 MHz, CDC13) δ: 8.26 (1Η, t, J = 5 Hz), 7.88 (1 H, d, J = 2 Hz), 7.80 (1 H, dd, J = 9 Hz, 2 Hz), 7.40 (1H, d, J = 9 Hz), 7.2 8 - 7.2 0 (5 H, m), 4.83 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.25 (2H, d, J = 5 Hz), 2.77 (3H, s), 2.38 (3H, s), 1.33 (3H, t, J = 7 Hz). (2)({[6-(4-chloro-3-) Phenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid according to Examples 7-(2) and 1-(6), and using ({[5-(benzyloxy) Ethyl 6-(4-chloro-3-methylphenyl)-2-mercaptopyrimidin-4-yl]carbonyl}amino)acetate (0.21 g) in place of [({5-(benzyloxy) Ethyl acetate, 2-methyl-6-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}carbonyl)amino], the title compound (0.14 g, yield: . Mp : 2 0 8 -2 1 1 ° C ; 'H-NMR (400 MHz, DMSO-d6) δ: 9.60 (1H, t, J = 6 Hz), 8.17 (2H, d, J - 2 Hz), 8.06 (1 H, dd, J = 9 Hz, 2 Hz), 4.03 (2H, d, J = 6 Hz), 2.68 (3H, s), 2.42 (3H, s). (Example 20) ({[ 6-(4-Fluoro-3-methylphenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amine-68- 201141839

(1) ({[5-(Benzyloxy)-6-(4-fluoro-3-methylphenyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetate and ({ [6-(4-Fluoro-3-methylphenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetate ΟΒη Ο

K c〇2E, OH Ο

(〇 according to Example 7-(1), using (4-fluoro-3-methylphenyl)boronic acid. 19 g) and Example 1-(3) ({[5-(benzyloxy)) Ethyl -2-methyl-6-{[(fluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) in place of [3-(trifluoromethyl) Phenyl]boronic acid to obtain ({[5-(benzyloxy)-6-(4-fluoro-3-methylphenyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid B Ester (0.14 g, yield 51%) and ({[6-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid B Ester (0.0 8 0 g, yield

3 7%) ° ({[5-(Benzyloxy)-6-(4-fluoro-3-methylphenyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetate: H-NMR (400 MHz, CDC13) δ: 8.26 (1 H, t, J = 6 Hz), 7.8 7 -7.8 4 (2H, m), 7.2 8 -7.22 ( 5H, m), 7.0 8-7.04 ( 1 H, m), 4.82 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.25 (2H, d, J = 6 Hz), 2.77 (3H, s), 2.28 (3H, s) , 1.33 (3H, t, J = 7 Hz). ({[6-(4-Fluoro-3-methylphenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino) Ethyl acetate: -69- 201141839 'H-NMR (400 MHz, CDC13) δ: 12.07 (1H, s), 8.61 (1H, t, J = 6 Hz), 8.12-8.09 (2H, m), 7.12- 7.08 (1H, m), 4.30 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 6 Hz), 2.70 (3H, s), 2.36 (3H, s), 1.34 (3H, t , J = 7 Hz). (2)({[6-(4-Fluoro-3-methylphenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to Example 1-(6), and using ({[6-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid B Ethyl ester (0.14 g) in place of [({6-[(3,4-dichlorophenyl)sulfanyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetate The title compound (0.11 g, yield 90%) was obtained as white solid. Mp: 18 7-191 °C; 'H-NMR (400 MHz, DMSO-d6) δ: 9.57 (1H, t, J = 6 Hz), 8.14-8.08 (2H, m), 7.3 2 -7.2 7 ( 1 H, m), 4.03 (2H, d, J = 6

Hz), 2.68 (3H, s), 2.32 (3H, s).

(Example 21) ({[6-(3-ethylphenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1) ({[5-(Benzyloxy)-2-methyl-6-(3-vinylphenyl)pyrimidin-4-yl]carbonyl}amino)ethyl acetate

-70-201141839 According to Example 7 (1), and using (3-vinylphenyl)boronic acid (〇3〇g) and Example 1-(3) ({[5-(benzyloxy))) -2 -Methyl-6-{[(trimethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (〇24 g) instead of [3_(trifluoromethyl) The title compound (0.14 Ο, yield 64%). 'H-NMR (400 MHz, CDC13) δ: 8.27 (1Η, t, J = 6 Hz), 8.05 (1H, s), 7.89 (1H, d, J = 8 Hz), 7.53 (1H, d, J = 8 Hz)j

7 · 4 2 ( 1 H,t,J = 8 H z),7 · 2 8 - 7 , 1 9 ( 5 H,m),6.7 3 (1 H,dd,J =20 Hz, 12 Hz), 5.76 (1H, d, J = 20 Hz), 5.29 (1H, d, J = 12 Hz), 4.81 (2H, s), 4.28 (2H, q, J = 8 Hz), 4.26 (2H, d, J = 6 Hz), 2.79 (3H, s), 1.33 (3H, t, J = 8 Hz). (2)({[6-(3-ethylphenyl)-5-hydroxy-2-methylpyrimidine) 4-yl]carbonyl}amino)acetic acid according to Examples 7-(2) and 1-(6), and using ({[5-(benzyloxy)-2-methyl-6-(3-ethylene) Ethyl phenyl)pyrimidin-4-yl]carbonyl}amino)acetate (〇.14 g) in place of [({5-(benzyloxy)-2-methyl-6-[3-(trifluoro)) Ethyl acetate of methyl)phenyl]pyrimidin-4-yl}carbonyl)amino]] gave the title compound (j. Mp: 1 42- 1 43 ° C ; 'H-NMR (500 MHz, DMSO-d6) δ: 12.74 (1H, s), 9.58 (1H, t, J = 6 Hz), 8.00 (1H, s), 8.00 (1H, d, J = 8 Hz), 7.44 (1H, t, J = 8 Hz), 7.39 (1H, d, J = 8 Hz), 4.02 (2H, d, J = 6 Hz), 2.70 ( 2H, q, J = 8 Hz), 2.68 (3H, s), 1.23 (3H, t, J = 8 Hz). -71- 201141839 (Example 2 2 ) ({[6-(3-chloro-4) -methylphenyl)_ 5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid.

(1) ({[5-(Benzyloxy)-6-(3-chloro-4-methylphenyl)-2-methylpyrimidin-4-yl)carbonyl}amino)acetate

({[5-(Benzyloxy)-2) according to Example 7-(1), using (3-chloro-4-methylphenyl)boronic acid (0.26 g) and Example 1-(3) -methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid ethyl acetate (0.24 g) in place of [3-(trifluoromethyl) Phenyl]boronic acid gave the title compound (0.22 g, yield: 5%). 'H-NMR (400 MHz, CDC13) δ: 8.25 (1Η, t, J = 6 Hz), 8.06 (1H, d, J = 2 Hz), 7.87 (1H, dd, J = 8 Hz, 2 Hz) , 7.30-7.25 (6H, m), 4.86 (2H, s), 4.28 (2H, q, J = 8 Hz), 4.26 (2H, d, J = 6 Hz), 2.78 (3H, s), 2.45 ( 3H, s), 1.33 (3H, t, J = 8 Hz). (2)({[6-(3-chloro-4-methylphenyl)-5-hydroxy-2-methylpyrimidine-4 - ]]carbonyl]amino)acetic acid according to Examples 7-(2) and 1-(6), and using ({[5-(benzyloxy)-6-(3-chloro-4-methylphenyl)) Ethyl 2-(methylpyrimidin-4-yl)carbonyl}amino)acetate (0.22 g) in place of [({5_(benzyloxy)_2_methyl-6_[3_(trifluoromethyl)phenyl) 201141839 Ethyl pyrimidine-4-yl}carbonyl)amino]acetate gave the title compound (0.12 g,iel. Mp : 1 73 - 1 74 °C ; 'H-NMR (400 MHz, DMS Ο - d 6) δ: 12.81 (lH, s), 9.59 (1H, t, J = 6 Hz), 8.25 (1H, s ), 8.12 (1H, d, J = 8 Hz), 7.52 (1H, d, J = 8 Hz), 4.03 (2H, d, J = 6 Hz), 2.66 (3H, s), 2.4 1 (3H, s)_

(Example 23) ({[5-Hydroxy-6-(3-isobutylphenyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

In accordance with Examples 9-(1), 7-(2) and 1-(6), and using 1-bromo-3-(2-methylprop-1-en-1-yl)benzene instead of 4-bromo- 1-Fluoro-2-vinylbenzene afforded the title compound (0.026 g,iel. Mp : 7 0-7 5 ° C ; 'H-NMR (5 00 MHz, DMS Ο - d 6) δ: 9.52 (1Η, s), 8.01 (1H, d, J = 8 Hz), 7.96 (1H, s), 7.43 (lH, t, J = 8 Hz), 7.32 (1H, d, J = 8 Hz), 3.95 (2H, s), 2.67 (3H, s), 2.54 (2H, d, J = 7 Hz), 1.87 (1H, m), 0.90 (6H, d, J = 6 Hz). (Example 24) [({6-[3-chloro-4-(trifluoromethyl)phenyl]-5 -hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid. -73- 201141839

According to Example 7, (1) and 1-(6), and using [3-chloro-4-(trifluoromethyl)phenyl]boronic acid (0.23 g) and Example 1-(3) obtained ({ [5-(Benzyloxy)-2-methyl-6({(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) In place of [3-(trifluoromethyl)phenyl]boronic acid, the title compound (0.089 g, yield 38%) Mp : 19 8 ° C ; *H-NMR (400 MHz, CD3〇D) δ: 8.49 (1H, s), 8.39 (1H, d, J Φ =8 Hz), 7.90 (1H, d, J - 8 Hz), 4.14 (2H, s), 2.72 (3H, s). (Example 25) ({[6-(3-cyclopropyl-4-fluorophenyl)-5-hydroxy-2-methylpyrimidine) -4 -yl]carbonyl]amino)acetic acid

(1) 4-Moly-2-cyclopropyl-1-benzene

The methyl (triphenyl) brominated scale (3.6 g) was dissolved in tetrahydrofuran (1 〇〇m L), and a solution of sodium hexamethyldiamine in tetrahydrofuran was added dropwise at 〇 ° C (1. 〇Μ, 1 After 2 mL), the mixture was stirred at the same temperature for 1 hour. After adding 5-bromo-2-fluorobenzaldehyde (1.4 g) to the reaction mixture for 4 hours at room temperature, water was added, and ethyl acetate was evaporated. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to give 4-bromo-1-fluoro-2-vinylbenzene (1.32 g, yield 95%) as a yellow amorphous solid. . -74- 201141839 Add trifluoroacetic acid (0.51 mL) to diethyl hexane solution (1.0 Μ, 6.6 mL) at 〇 ° C under a nitrogen atmosphere, stir at the same temperature for 20 minutes, then add dropwise Diiodomethane (0.54 mL) was stirred for 20 minutes. 4-Bromo-1-fluoro-2-vinylbenzene (1.3 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure.

'H-NMR (400 MHz, CDC13) δ: 7.72-7.18 (1Η, m), 6.99 (1H, dd, J = 7 Hz, 2 Hz), 6.87 (1H, t, J = 7 Hz), 2.08- 2.01 (1H, m), 1.03 -0.98 (2H, m), 0.72 (2H, dt, J = 7 Hz, 5 Hz). (2)({[6-(3-cyclopropyl-4-fluorobenzene) 5-)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid according to Examples 9 - (1) and 1 - (6)' and using 4-bromo-2-cyclopropyl- 1-Fluorobenzene (0.70 g) was used instead of 4-bromo-1-fluoro-2-vinylbenzene to give the title compound (0.15 g, yield 31%) as a white solid. Mp : 16 0-161 ° C ; 'H-NMR (400 MHz, CDC13) δ: 11.93 (1Η, s), 8.58 (1H, t, J = 5 Hz), 8.04 (1H, brs), 7.85 (1H , d, J = 8 Hz), 7.10 (1H, t, J = 8 Hz), 4.33 (2H, d, J = 5 Hz), 2.69 (3H, s), 2.13 (1H, m), 1.04-0.99 (2H, m), 0.8 3 -0.8 0 (2H, m). (Example 2 6 ) [({6-[2-(4-Fluorophenyl)ethyl]-5-hydroxy-2-methyl Pyrimidin-4-yl}carbonyl)amino]acetic acid-75- 201141839 OH Ο

(l) [({5-(Hydroxy)-6-[(4-fluorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

({[ 5 _ (Benzyloxy) 2 -methyl-6 - {[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl) obtained in Example 1 - (3) Ethyl acetate ethyl acetate (8.0 g) and 1-ethynyl-4-fluorobenzene (4.0 g) were dissolved in triethylamine (400 mL), and a solution of ruthenium (dibasic scale) was added at room temperature. (2.0 g), copper (1.3 g) and triphenylphosphine (1.8 g) were stirred at 60 ° C for 90 minutes. The reaction mixture was concentrated under reduced pressure. The solvent was evaporated under reduced pressure. 'H-NMR (400 MHz, CDC13) δ: 8.23 (1Η, brs), 7.58-7.56 (2H, m), 7.48 -7.44 (2H, m), 7.3 7-7.3 4 (3 H, m), 7.07 -7.02 (2H, m), 5.39 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 6 Hz), 2.76 (3H, s), 1.32 (3H, t, J = 7 Hz). (2) [({6-[2-(4-Fluorophenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid Ethyl ester 201141839

Dissolve [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (6.2 g) A mixed solvent of ethyl acetate (120 mL) and methanol (80 mL) was added to 5% palladium-activated carbon (3.0 g), and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. 'H-NMR (400 MHz, CDC13) δ: 11.36 (1Η, s), 8.50 (1H, t, J = 6 Hz), 7.23-7.19 (2H, m), 6.9 8-6.94 (2H, m), 4.28 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 6 Hz), 3.15-3.11 (2H, m), 3.04- 3.00 (2H, m), 2.63 (3H, s), 1.33 (3H, t, J = 7

Hz). (3) [({6-[2-(4-Phenylphenyl)ethyl]-5-yl-2-methylindole- 4·-ylindolecarbonyl)amino]acetic acid) Example 1-(6)' and using [({6-[2-(4-fluorophenyl)ethyl]_5_^hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetate ( 4.2 g) in place of [({6-[(3,4-dichlorophenyl)sulfanyl]-5-hydroxy-2-methylpyrimidin-4-yl})-yl)amino]acetate, The title compound was obtained (3.9 g, yield quantitative, white solid. mp: 19 1-193 °C; H-NMR (400 MHz, CD3OD) δ: 7.24-7.22 (2 Η, m), 6.99- 6 · 9 5 (2 Η,m ),4 · 1 2 (2 Η,s),3 . 1 4 - 3 . 1 〇(2 Η,m), 3 . 〇4 - 3 〇2 (2Η, m), 2.60 (3Η, s). -77- 201141839 (Example 27) ({[5-hydroxy-2-methyl-6-(2-phenylethyl)pyrimidin-4-yl]carbonyl}amino)acetic acid)

According to Example 2 6 - (1 ), 2 6 - (2 ) and 1 - (6) ' and using ethynylbenzene (〇. 13 g) and Example 1 - (3) obtained ({[ 5 - (Benzyloxy)-2 -methyl-6 - {[(trifluoromethyl)sulfonyl]oxy}pyrimidinyl]carbonyl}amino)acetate (0.30 g) in place of 1-ethynyl- 4-Fluorobenzene, the title compound (0.12 g,yiel. MS m/z: 3 1 6 (M + H) + ; 'H-NMR (400 MHz, CD3OD) δ: 7.27-7.16 (5H, m), 4.13 (2H, s), 3.15-3.11 (2H, m ), 3.04-3.00 (2H, m), 2.60 (3H, s). (Example 28) [({5-Hydroxy-2-methyl-6-[2-(4-methylphenyl)ethyl) Pyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-(Benzyloxy)-2-methyl-6-[(E)-2-(4-methylphenyl)vinyl]pyrimidin-4-yl}carbonyl)amino] Ethyl acetate

According to Example 7-(1), and using [(E)-2-(4-methylphenyl)vinyl]boronic acid (0.17 g) and Example 1-(3), ({[5-(( Benzyloxy)-2-methyl--78- 201141839 6-{[(Trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.25 g) In place of [3-(trifluoromethyl)phenyl]boronic acid, the title compound (0.12 g, yield 52%) was obtained. 1 H-NMR (400 MHz , CDC13) δ : 8 _ 3 5 (1H, t, J : =6 Hz), 7.98- 7.94 (1H, m), 7.53- 7.51 (2H,1 n), 7.39 -7.34 (6H, m), 7.19- 7.17 (2H, m), 5.13 (2H, s), 4. .27 (2H, q, J =7 Hz), 4.25 (2H, d, J =6 Hz), 2.74 (3H, s), 2.38 (3H, s), 1.32 (3H, t, J =7 Η z)·

(2) [({5-Hydroxy-2-methyl-6-[2-(4-methylphenyl)ethyl]pyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 7-(2) And 1-(6), and using [({5-(benzyloxy)-2-methyl-6-[(E)-2-(4-methylphenyl)vinyl]pyrimidine-4_) Ethyl acetate (0.092 g) in place of [({5-(benzyloxy)-2-methyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-4-) Ethyl acetate, carbonyl)amino]acetic acid afforded the title compound (0.090 g,j. Mp: 170-174. . ; W-NMR (400 MHz, DMSO-d6) δ: 12_85 (1H, s), 11.95' (1H, s), 9.42 (1H, t, J = 6 Hz), 7.14-7.07 (4H, m), 3.99 (2H, d, J = 6 Hz), 3.07-2.94 (4H, m), 2.59 (3H, s), 2.25 (3H, s). (Example 29) [({6-[2-(3 -fluorophenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

-79- 201141839 (1) [({5-(Benzyloxy)-6-[(3-fluorophenyl)ethynyl]-2-methylpyrimidin-4-yl) carbonyl)amino]ethyl acetate

According to Example 26-(1), and using 1-ethynyl-3-fluorobenzene (〇_23 g) and Example 1-(3), ({[5-(benzyloxy)-2-methyl) Ethyl 6-{[((trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) in place of 1-ethynyl-4-fluorobenzene, title Compound (ο υ g, yield 89%). 'H-NMR (400 MHz, CDC13) δ: 8 · 3 5 (1 Η, t, J = 5 Η ζ), 7.58-7.56 (2H, m), 7.3 8 -7.26 (5 H, m), 7.15 -7.11 (2H, m), 5.30 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 5 Hz), 2.76 (3H, s), 1.32 (3H, t, J = 7 Hz). (2) [U6-[2-(3-Fluorophenyl)ethyl]_5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid according to the examples 26-(2) and ^(6), and using [({5_(benzyloxy[(3-fluorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl), ethyl acetate (0.25 g) in place of [({5_(benzyloxy)_6[(4fluorophenyl)ethynyl]2methylpyrimidinyl)-carbonyl}amino]acetate ethyl acetate to give the title compound (0.081 g) , yield 44%) white solid. mp: 1 93 - 1 9 5 ; m), 7.34-7.29 (1H,, ———— 'H-NMR (400 MHz, DMSO-d6) δ: 11.97 (1Η, s), 9 42 〇H m), 3.9 9-3.98 ( 2H,

OH, (3H, s). -80- 201141839 (Example 30) {[(5-Hydroxy-2-methyl-6-{2-[2-(trifluoromethyl)phenyl)ethyl}pyrimidine _4_yl)carbonyl]amino}acetic acid

According to Examples 2 6 - ( 1 ), 2 6 - ( 2 ) and 1 - (6 ), and using 丨-ethynyl-2-(trifluoromethyl)benzene (〇_37 g) and Example 1 (3) Acetate ({[5_(benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.25 g) </ RTI> </ RTI> DMSO-d6) δ: 11.97 (1H, s), 9.44 (1H, t, J = 6 Hz), 7.70 (1H, d, J = 7 Hz), 7.62 (1H, t, J = 7 Hz), 7.51 (1H, d, J = 7 Hz), 7.43 (1H, t, J = 7 Hz), 3.99 (2H, d, J = 6 Hz), 3.22-3.16 (2H, m), 3.11-3.07 (2H, m), • 2.60 (3H, s). (Example 31) {[(5-Hydroxy-2-methyl-6-{2-[3-(trifluoromethyl)phenyl]ethyl}pyrimidine- 4-yl)carbonyl]amino}acetic acid

In accordance with Examples 26-(1), 26-(2) and 1-(6), and using 1-ethylidyl-3-(trifluoromethyl)benzene (0.37 g) and Example 1-(3) ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl)oxy}pyrimidin-4-yl]carbonyl-81- 201141839}Amino) The title compound (0.086 g, yield 43%) was obtained. Mp : 1 74- 1 76 ° C ; 'H-NMR (400 MHz, DMSO-d6) δ: 11.96 (1H, s), 9.42 (1H, t, J = 6 Hz), 7.60-7.49 (4H, m ), 3.99 (2H, d, J = 6 Hz), 3.13 (4H, s), 2.60 (3H, s). (Example 32) [({6-[2-(4-chlorophenyl)ethyl) ]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-(Benzyloxy)-6-[(4-chlorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

({[5-(Benzyloxy)-2-methyl) according to Example 26-(1), using 1-chloro-4-ethynylbenzene (0.29 g) φ and Example 1-(3) -6-{[(Trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.50 g) in place of 1-ethynyl-4-fluorobenzene to give the title compound (0.39 g, yield 81%). 'H-NMR (400 MHz, CDC13) δ: 8.23 ( 1 H, t, J = 6 Hz), 7.5 7 - 7.5 5 (2H, m), 7.40-7.3 2 (7H, m), 5.29 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 6 Hz), 2.76 (3H, s), 1.32 (3H, t, J = 7 Hz). -82- 201141839 (2) [({6-[2-(4.Chlorophenyl)ethyl]-5.hydroxy-2-methylpyrimidin-4)yl)-based)amino]acetic acid according to Example 26-(2) And 1-(6), and using [({5-(benzyloxy)_6_[(4-chlorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate) Ester (0.20 g) in place of [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate, The title compound (0.25 g, yield 88%) was obtained as white solid. MS m/z: 3 5 0 (M + H) + ; *H-NMR (400 MHz, DMSO-d6) δ: 9.42 (1H, t, J = 6 Hz), 7.28 (2H, d, J = 9 Hz), 7.09 (2H, d, J = 9 Hz), 3.99 (2H, d, J = 6 Hz), 3.09-2.9 8 (4H, m), 2.59 (3H, s). (Example 33) ( {[5-Hydroxy-2-methyl-6-(5-phenylpentyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

(1) ({[5-(Hydroxy)-2-methyl-6-(5-phenylpent-1-yn-1-yl) tl·Mindidine-4-yl]carbonyl}amino group Ethyl acetate

({[5-(Benzyloxy)-) obtained according to Example 2 6 · (1), and using penta-4 -yne-1 -ylbenzene (〇. 8 7 g) and Example 1_(3) 2-methyl-6-{[((trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (〇24 g) instead of 1-ethynyl_4·fluoro The title compound (〇.丨2 g, yield 49%) was obtained from benzene. -83- 201141839 'H-NMR (400 MHz, CDC13) δ: 8.19 (1 H, t, J = 4 Hz), 7.5 4-7.5 2 (2H, m), 7.3 4-7.2 5 ( 5H, m) , 7.21-7.13 (3H, m), 5.23 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 4

Hz), 2.72 (3H, s), 2.72 (2H, t, J - 8 Hz), 2.48 (2H, t, J = 8 Hz), 1.88 (2H, tt, J = 8 Hz, 8 Hz), 1.31 (3H, t, J = 7

Hz). (2)({[5-Hydroxy-2-methyl-6-(5-phenylpentyl)pyrimidin-4-yl]carbonyl}amino)

Acetic acid according to Examples 26-(2) and 1-(6), and using ({[5-(benzyloxy)-2-methyl-6-(5-phenylpent-1-yn-1-yl) Ethylpyrimidin-4-yl]carbonyl}amino)acetate (0.12 g) in place of [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl]-2-methyl) Ethylpyrimidin-4-yl}carbonyl)amino]acetate gave the title compound (0.049 g, m. MS m/z: 3 5 8 (M + H) + ;

'H-NMR (400 MHz, CD3OD) δ: 7.24-7.21 (2H, m), 7.16-7.10 (3H, m), 4.12 (2H, s), 2.86 (2H, t, J = 8 Hz), 2.65 (2H, t, J = 8 Hz), 2.59 (3H, s), 1.77- 1.66 (6H, m). (Example 34) [({6-[2-(3-chlorophenyl)ethyl]] -5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amine

Acetate

Octaco2h (1)[({5-(Benzyloxy)-6-[(3-chlorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate-84 - 201141839

According to Example 26-(1), and using 1-chloro-3-ethynylbenzene (0-18 g) and Example 1-(3) ({[5-(benzyloxy)-2-methyl-) 6-{[(Trifluoromethyl)sulfonyl]oxy}pyrimidinyl]carbonyl}amino)acetate (0.30 g) in place of 1-ethynyl-fluorobenzene' gave the title compound (〇.2〇g , yield 67%). 'H-NMR (400 MHz, CDC13) δ: 8.24 (1Η, t, J = 6 Hz),

7.5 8 - 7.5 6 (2 H,m), 7.42 -7.29 ( 7H,m), 5.29 (2H,s), 4.27 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 6 Hz ), 2.76 (3H, s), 1.33 (3H, t, J = 7 Hz). (2) [({6-[2-(3-Chlorophenyl)ethyl]-5-hydroxy-2) _Methylpyrimidin-4-yl) forging)amino]acetic acid according to Examples 26-(2) and 1-(6)' and using [((5-(oxy)6)[(3-chlorophenyl) Ethyl 2-methylpyrimidin-4-yl}carbonyl); 棊 棊 ethyl acetate (0.20 g) instead of [({5_(benzyloxy)·6_[(4-fluorophenyl)ethynyl) Ethyl acetate of 2 φ-pyrimidinyl-4-ylpyridinylcarbonyl)amino], gave the title compound (0.068 g, yield 46%) as a white solid. mp : 1 8 6 - 1 8 9 ° C ; = 6 Hz ), '3 0 1 (4H, j-NMR (400 MHz, DMSO-d6) δ: 9.43 (1H 7.3 3 - 7.20 (4H, m), 3.99 (2H, d, J = 6 Hz), m), 2.59 (3H, s). (Example 35) [U5. hydroxy-2-methyl·6-[2-(3-methylphenyl)ethyl]pyrimidinyl)-ylamino)acetic acid-85- 201141839

(1) [({5·(卞-oxy)-2-methyl-6-[(3-methylphenyl)ethynyl]pyridin-4-yl}carbonyl)amino]ethyl acetate

According to Example 26-(1), and using 1-ethynyl-3-methylbenzene (〇15 g) and Example 1-(3), ({[5-(hydroxy))-2 Methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid ethyl acetate (0.30 g) instead of 1-ethynyl-4-fluorobenzene The title compound (〇 18 g, yield 54%). 'H-NMR (400 MHz, CDC13) δ: 8.23 (1Η, t, j = 6 Η ζ), 7.61-7.59 (2Η, m), 7.3 8 -7.2 3 (7Η, m), 5.31 (2Η, s ), 4.27 (2Η, q, J = 7 Ηζ), 4·23 (2Η, d, J = 6 ΗΖ), 2.76 (3Η, S), 2.32 (3Η, s), 1.32 (3Η, t, J = 7 Hz). (2) [({5-Hydroxy-2-methyl-6-[2-(3-methylphenyl)ethyl]pyrimidin-4-yl}carbonyl)amino]acetic acid according to the examples 26-(2) and 1-(6), and using [({5-()oxy)-2-methyl-6-[(3-methylphenyl)ethynyl]pyrimidine-4-yl} Ethyl acetoxy]acetate (0.18 g) in place of [({5·(benzyloxy)_6_[(4-fluorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amine The title compound (0.10 g, yield 97%) Mp : 1 8 6- 1 8 9 ° C ; 'H-NMR (400 MHz, DMSO-d6) δ: 11.96 (1H, s)5 9.4 3 ( 1 H, 201141839 t, J = 6 Hz), 7.16 ( 1H, t, J = 7 Hz), 7.07 (1H, s), 7.03 (1H, d, J = 7 Hz), 7.00 (1H, d, J = 7 Hz), 3.99 (2H, d, J = 6 Hz), 3.08 -3.02 (2H, m), 2.98-2.93 (2H, m), 2.60 (3H, s), 2.2 7. (3 H, s). (Example 36) [({5 - Hydroxy- 2-methyl-6-[2-(2-methylphenyl)ethyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

N^CO2H 依照 obtained according to Examples 26-(1), 26-(2) and 1-(6), and using 1-ethynyl-2-methylbenzene (0.15 g) and Example 1-(3) ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) In place of 1-ethynyl-4·fluorobenzene, the title compound (0.15 g, yield:

'H-NMR (400 MHz, DMSO-d6) δ: 12.87 (1H, s), 11.97 (1H, s), 9.44 (1Η, t, J = 6 Hz), 7.17-7.09 (4H, m), 3.99 (2H, d, J = 6 Hz), 3.04-2.9 3 (4H, m), 2.60 (3H, s), 2.32 (3H, s). (Example 37) [({6-[2-(2 -fluorophenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

87- 201141839 According to Example 2 6 - (1), 2 6 - (2) and 1 _ (6), and using hydrazine-ethynyl-2-fluorobenzene (0.19 g) and Example 1-(3) ({[5-(Benzyloxy)-2-methyl-6- {[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino) ethyl acetate (0.30 g) In place of 1-ethynyl-4-fluorobenzene, the title compound (0.13 g, yield 60%) Mp : 1 77- 1 80 ° C ; 'H-NMR (400 MHz, DMSO-de) δ: 11.94 (1H, s), 9.43 (1H, t, J = 6 Hz), 7.3 2-7.09 (4H, m), 3.99 (2H, d, J = 6 Hz), Lu 3.09-3.02 (4H, m), 2.58 (3H, s). (Example 38) [({6-[5·(4-Fluorobenzene) Pentyl]-5-hydroxy-2-methylpyrimidine-4-yl}carbonyl)amino]acetic acid

(1) 4-(4-Fluorophenyl)but-3-yn-1-ol

1-Fluoro-4-iodobenzene (6.7 g) and but-3-yn-1-ol (2.5 mL) were dissolved in N,N-diisopropylamine (1 mL), and hydrazine was added at room temperature. Phenylphosphine) ruthenium complex (〇·3 5 g) and copper iodide (〇1 1 g) were stirred at the same temperature for 2 hours. After the reaction mixture was passed through celite, the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography on silica gel column chromatography to afford the title compound (4.9 g, yield yield). -88- 201141839 H-NMR (400 MHz, CDC13) δ: 7.40-7.3 7 (2H, m), 7.01- 6.96 (2H, m), 3.81 (2H, dt, J = 8 Hz, 4 Hz), 2.68 (2H, t, J = 8 Hz), 1,81 (1H, t, J = 4 Hz). (2) 4-(4-Fluorophenyl)butan-1-ol

4-(4-Fluorophenyl)but-3-yn-1-ol (4.9 g) was dissolved in ethyl acetate (200 m L) after adding 1 〇% palladium-activated carbon (0.50 g) In a hydrogen atmosphere in the room

Stir for 4 hours. After the reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give the title compound (5.0 g, yield 99%). 'H-NMR (400 MHz, CDC13) δ: 7.15-7.11 (2Η, m), 6.98-6.94 (2H, m), 3.67 (2H, t, J = 8 Hz), 2.62 (2H, t, J = 8 Hz), 1,72- 1.5 8 (4H, m). (3) 1 -Fluoro-4 -pent-4 -yne-1-ylbenzene

Dissolve 4-(4-fluorophenyl)butan-ol (4.8 g) in dichloromethane (100 mL) at ot: add 1,3,5-trichloro-1,3,5-triple 2,4,6-trione (1,3,5-trich1〇rο -1,3,5-1riazinane-2,4,6 -1riοne) (7.0 g) and 2,2,6,6-tetra After the base-1-piperidinyloxy(oxime) (0·045 g), the mixture was stirred at the same temperature for 5 minutes and then at room temperature for 1 minute. After the reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 4-(4-fluorophenyl)butanal (3.7 g, yield 77%). -89- 201141839 Dissolve carbon tetrabromide (15 g) and triphenylphosphine (23 g) in dichloromethane (70 mL) and add 4-(4-fluorophenyl)butanal (3.7) at 0 °C. After g) a dichloromethane solution (70 mL), stir at room temperature for 40 min. The resulting brown solid was separated by filtration, and then the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 1-(5,5-dibromopent-4-en-1-yl)-4-fluorobenzene (3.1 g, yield 43%). 1-(5,5-Dibromopent-4-en-1-yl)-4-fluorobenzene (3.1 g) was dissolved in tetrahydrofuran (50 mL), and n-butyllithium was added dropwise at -78 °C. After the alkane solution (1.6 M, 15 mL), the mixture was stirred at the same temperature for 30 minutes. After a saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, the organic layer was extracted with diethyl ether. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to give the title compound (2.3 g, yield 75%) in 50% n-hexane. 'H-NMR (400 MHz, CDClj) δ: 7.16-7.13 (2Η, m), 6.99- 6-95 (2Η, m), 2.71 (2H, t, J = 8 Hz), 2.19 (2H, tt, J = 8 Hz, 8 Hz), 2.00 (1H, s), 1.82 (2H, t, J = 8 Hz). (4)[({5-(Benzyloxy)-6-[5-(4- Fluorophenyl)pent-1-yn-1-yl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 26-(1), and using a solution of 1-fluoro-4-pent-4-yn-1-ylbenzene in 50% n-hexane (0.37 g) and Example 1-(3) ({[ 5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxypyrimidin-4-yl]carbonyl}amino)acetate (0.36 g) instead of 1 - ethynyl-4-fluorobenzene gave the title compound (0.33 g, yield 94%). -90- 201141839 'H-NMR (400 MHz, CDC13) δ: 8.19 (1 H, t, J = 4 Hz), 7.5 4-7.5 2 (2H, m), 7.3 3 - 7.3 0 (2H, m) , 7.0 9- 7.0 5 (3 H, m), 6.95-6.91 (2H, m), 5.23 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 4 Hz), 2.72 (3H, s), 2.68 (2H, t, J = 8

Hz), 2.47 (2H, t, J = 8 Hz), 1.88 (2H, tt, J = 8 Hz, 8 Hz), 1.3 1 (3H, t, J = 7 Hz). (5)[({6 -[5-(4-fluorophenyl)pentyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl φ)amino]acetic acid according to Examples 26-(2) and 1-(6) And using [({5-(benzyloxy)-6-[5-(4-fluorophenyl)pent-1-yn-1-yl]-2-methylpyrimidin-4-yl}carbonyl)amine Ethyl acetate (〇_33 g) in place of [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino) Ethyl acetate gave the title compound (0.12 g, yield 38% Mp: 1 40- 1 42 °C;

^Η-ΝΜΙΙ ΗΟΟΜΗζ,ΟΟβΟΗΐ.ΙΤ-Τ.ΜρΗ,ηΟ,ό.Ρδ-6.93 (2Η, m), 4.12 (2H, s), 2.83 (2H, t, J = 8 Hz), 2.59 (2H, t, J = 8 Hz), 2.59 (3H, s), 1.79-1.71 (2H, m), 1.69-1.61 (2H, m), 1.4 3 - 1.3 5 (2H, m). (Example 39) [ ({6-[2-(2,4-difluorophenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

F N 丫卜

iTc〇2H -91 - 201141839

(0.35 g) and ({[5-(benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl)oxy}pyrimidine-4 obtained in Example 1-(3) Ethyl-carbonyl]amino)acetic acid ethyl ester (0.30 g) was used to give the title compound (0.26 g, yield 89%). 'H-NMR (400 MHz, CDC13) δ: 8.18 (1Η, t, J = 5 Hz), 7.5 7 -7.2 9 (6H, m), 6.91-6.88 (2H, m), 5.32 (2H, s) , 4.27 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 5 Hz), 2.76 (3H, s), 1.32 (3H, t, J = 7 Hz). (2)[({ 6-[2-(2,4-Difluorophenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 26-(2) and 1- (6) and using [({5-(benzyloxy)-6·[(2,4-difluorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid) Ethyl ester (0.26 g) in place of ethyl [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]] The title compound (0.13 g, yield 66%) Mp: 184-188 °C; 'H-NMR (400 MHz, DMSO-d6) 6: 11.93 (1H, s), 9.42 (1H, t, J = 6 Hz), 7.37-7.3 1 (1H, m) , 7.19-7.13 (1H, m), 7.01- -92- 201141839 6.97 (1H, m), 3.99 (2H, d, J = 6 Hz), 3.08-2.99 (4H, m), 2.57 (3H, s) (Example 40) [({5-Hydroxy-2-methyl-6-[2-(1-naphthyl)ethyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

(1) ({[5-(Benzyloxy)-2-methyl-6-(1-naphthylethynyl)pyrimidin-4-yl]carbonyl)

Ethyl acetate

According to Example 26-(1), and using 1-ethynylnaphthalene (0.38 g) and Example 1-(3), ({[5-(benzyloxy)-2-methyl-6-{[ (Trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) in place of 1-ethynyl-4-fluorobenzene afforded the title compound (0.25 g. Rate 83%). 'H-NMR (400 MHz, CDC13) δ: 8.3 8 - 8.3 6 ( 1 Η, m), 8.27 (1H, t, J = 6 Hz), 7.94-7.7 9 (3 H, m), 7.5 7- 7.44 (4H, m), 7.3 5 -7.2 5 (4H, m), 5.32 (2H, s), 4.28 (2H, q, J = 7 Hz), 4.25 (2H, d, J = 6 Hz), 2.79 (3H, s), 1.33 (3H, t, J = 7 Hz). (2) [({5-Hydroxy-2-methyl-6-[2-(l-naphthyl)ethyl]pyrimidine-4 -yl}carbonyl)amino]acetic acid according to Examples 26-(2) and 1-(6), and using ({[5-(benzyloxy)-2-methyl-6-U-naphthylethynyl) Pyrimidine-4-yl]carbonyl}amino)ethyl acetate-93- 201141839 (0.25 g) in place of [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl]-) Ethyl 2-methylpyrimidin-4-yl}carbonyl)amino]acetate gave the title compound (0.11 g,yiel. Mp: 188-192 °C; 'H-NMR (400 MHz, DMSO-d6) δ: 12.87 (1H, s), 12.02 (1H, s), 9.45 (1H, t, J = 6 Hz), 8.20 ( 1H, d, J = 8 Hz), 7.94 (1H, d, J = 8 Hz), 7.80 (1H, d, J = 8 Hz), 7.61-7.51 (2H, m), 7.4 5 - 7.3 9 ( 2H , m), 4.00 (2H, d, J = 6 Hz), 3.48-3.44 (2H, m), 3.20-3.16 (2H, m), 2.61 (3H, s). (Example 41) [({6 -[5-(4-chlorophenyl)pentyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({ 5 -(Benzyloxy)-6 - [ 5 - ( 4 - chlorophenyl) pent-1 -yne-1-yl]-2-methylpyrimidin-4-yl}carbonyl)amine Ethyl acetate

According to Example 26-(1), and using 1-chloro-4-pent-4-yn-1-ylbenzene (0.54 g) and Example 1-(3) ({[5-(benzyloxy) )-2-methyl-6·{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.96 g) in place of 1-ethynyl-4- Fluorobenzene gave the title compound (0.61 g, yield 60%). 201141839 'H-NMR (400 MHz, CDC13) δ: 8.20 (1H, t, J = 4 Hz), 7.5 4-7.5 2 (2H, m), 7.3 5 -7.3 2 (3 H, m), 7.22 ( 2H, d, J = 8

Hz), 7.05 (2H, d, J = 8 Hz), 5.23 (2H, s), 4.26 (2H, q, J =

7 Hz), 4.22 (2H, d, J = 4 Hz), 2.72 (3H, s), 2.68 (2H, t, J = 8 Hz), 2.47 (2H, t, J = 8 Hz), 1.88 (2H , tt, J = 8 Hz, 8

Hz), 1.3 1 (3H, t, J = 7 Hz). (2) [({6-[5-(4-Chlorophenyl)pentyl]-5-hydroxy-2-methylpyrimidine-4- Base carbonyl φ)amino]acetic acid according to Examples 26-(2) and 1-(6), and using [({5-(benzyloxy)-6-[5-(4-chlorophenyl)pentyl) 1--1-yn-1-yl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.25 g) in place of [({5-(benzyloxy)-6-[(4·) Ethyl fluorophenyl)ethynyl]2-methylpyrimidin-4-yl}carbonyl)amino]acetate gave the title compound (0.41 g, yield: m p : 1 5 4- 1 5 7 ° C ;

'H-NMR (400 MHz, CD3OD) δ: 7.22 (2Η, d, J = 8 Hz), 7.14 (2H, d, J - 8 Hz), 4.13 (2H, s), 2.82 (2H, t, J = 8 Hz), 2.59 (2H, t, J = 8 Hz), 2.59 (3H, s), 1.79-1.71 (2H, m), 1.69-1.61 (2H, m), 1.43-1.37 (2H, m) (Example 42) [({6-[5-(3-Chlorophenyl)pentyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

-95- 201141839 (1) 1-Chloro-3-pent-4-yn-1-ylbenzene

According to Examples 38-(1) to 38-(3), and using 1-chloro-3-iodobenzene (7.2 g) instead of 1-fluoro-4-iodobenzene or corresponding to Example 38-(2) In the step, and using platinum oxide instead of palladium-activated carbon, a title compound (3.8 g, yield 47%) in a 65 % n-hexane solution was obtained. 'H-NMR (400 MHz, CDC13) δ: 7.24-7.07 (4Η, τη), 2.72 (2Η, t, J = 8 Hz), 2.20 (2H, tt, J = 8 Hz, 8 Hz), 2.00 ( 1H, s), 1.84 (2H, t, J = 8 Hz). (2) [({5-(Benzyloxy)-6-[5-(3-chlorophenyl)pent-1-yne-丨Ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 26-(1), and using a solution of 1-chloro-3-but-4-yn-1-ylbenzene in 65% n-hexane (0.31 g) and Example 1-(3) ({[ 5-(Benzyloxy)-2-methyl-6-{[(dimethylmethyl)anthracene]oxy}glycol-4-yl]whenyl}amino)acetate (0.36 g In place of 1-ethynyl-4-fluorobenzene, the title compound (0.26 g, yield 65%) was obtained. • H-NMR (400 MHz, CDCI3) δ: 8.20 (1Η, t, J = 4 Hz), 7.54-7.52 (2H, m), 7.3 3 -7.3 0 (3 H, m), 7.19-7.13 (2H , m), 7.02-6.99 (2H, m), 5.23 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 4 Hz), 2.72 (3H, s) , 2.69 (2H, t, J = 8

Hz), 2.48 (2H, t, J = 8 Hz), 1.89 (2H, tt, J = 8 Hz, 8 Hz), 1.3 1 (3H, t, J = 7 Hz). -96- 201141839 (3) [({6-[5-(3-Phenylphenyl)pentyl]·5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 26-(2) and 1- (6) and using [({5-(benzyloxy)-6-[5-(3-chlorophenyl)pent-1-yn-1-yl]-2-methylpyrimidin-4-yl} Carbonyl)amino]acetate (0.26 g) in place of [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl) The title compound (0.071 g, yield 36%) of white solid.

H-NMR (400 MHz, CD3〇D) δ: 7.24-7.08 (4Η, m), 4.12 (2H, s), 2.83 (2H, t, J = 8 Hz), 2.60 (2H, t, J = 8 Hz), 2.60 (3H, s), 1.80- 1.72 (2H, m), 1.68-1.62 (2H, m), 1.44-1.36 (2H, m). (Example 43) ({[5-hydroxy-2) -methyl-6-(3-phenylpropyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

(^({[5-(benzyloxy)-2-methyl-6-vinylpyrimidin-4-yl]carbonyl}amino)acetate ΟΒη Ο

({ [5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl) obtained in Example 1-(3) Ethyl ethyl acetate (0.48 g) and 4,4,5,5-tetramethyl-2-vinyl-dioxaborane (0.19 g) dissolved-97- 201141839 in 1,2-dimethyl a mixed solvent of oxyethane (4 mL) and water (2 mL), and dichlorobis(triphenylphosphine)palladium complex (0.070 g) and sodium carbonate (〇·32) were added at room temperature under nitrogen. After g), it was stirred at 70 ° C for 1.5 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the organic layer was extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to give the title compound (0.16 g, yield 45%). 'H-NMR (400 MHz, CDC13) δ: 8.30 (1Η, t, J = 4 Hz), 7.51-7.49 (2H, m), 7.40-7.3 4 (3H, m), 7.16-7.08 (1H, m ), 6.68-6.63 ( 1 H, m), 5.67-5.64 ( 1 H, m), 5.08 (2H, s), 4.27 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 4 Hz), 2.73 (3H, s), 1.32 (3H, t, J = 8 Hz). (2)( {[5-Hydroxy-2-methyl- 6-(3-phenylpropyl)pyrimidine-4 -yl]carbonyl}amino) ethyl acetate

Ethyl ({[5-(benzyloxy)-2-methyl-6-vinylpyrimidin-4-yl)carbonyl}amino)acetate (0.05 3 g) and allylbenzene (0.11 mL) Dichloromethane, [1,3-bis(2,4,6-trimethylphenyl)-2.imidazolidinium]dichloro(phenylmethylene) (tricyclic) was added at room temperature under nitrogen atmosphere. After hexylphosphine) ruthenium (Grubbs catalyst (second generation)) (0.013 g), it was heated under reflux for 18 hours. After concentrating the reaction mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography to afford [({5-(benzyloxy)-2-methyl- 6-[(1Ε)-3-phenyl) Ethyl-1-en-1-yl]pyrimidin-4-yl}carbonyl)amino]acetate. This was dissolved in ethanol (7 mL), and 10% palladium-activated carbon (0.010 g) was added thereto, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction solution of -98-201141839 with diatomaceous earth, the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give the title compound (d.

!H-NMR (400 MHz, CD3〇D) δ: 11.33 (1Η, s), 8.49 (1H, t, J - 4 Hz), 7.31-7.15 (5H, m), 4.28 (2H, q, J = 8 Hz), 4.21 (2H, d, J = 4 Hz), 2.90 (2H, t, J = 8 Hz), 2.72 (2H, t, J = 8 Hz), 2.62 (3H, s), 2.07 (2H , tt, J = 8 Hz, 8 Hz), 1.32 (3 H, t, J = 8 Hz). (3)({[5-Hydroxy-2-methyl-6-(3-phenylpropyl)) Pyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 1-(6), and using ({[5-hydroxy-2-methyl-6-(3-phenylpropyl)pyrimidin-4-yl] Ethyl carbonyl}amino)acetate (0.012 g) in place of [({6-[(3,4·dichlorophenyl) thiomethyl]-5-yl-2-methylpyran-4-yl} Ethyl acetate of carbonyl)amino) gave the title compound (0.0040 g, yield 40%) as a white solid. MS m/z: 3 3 0 (M + H) + ; iH-NMR (400 MHz, CD3OD) δ: 7.24-7.12 (5H, m), 4.13 (2H, s), 2.86 (2H, t, J = 8 Hz), 2.70 (2H, t, J = 8 Hz), 2.60 (3H, s), 2.04 (2H, tt, J = 8 Hz, 8 Hz). (Example 44) [({6-[2 -(2,5-dimethylphenyl)ethyl]-5-hydroxy-2.methylpyrimidin-4-yl}carbonyl)amino]acetic acid

-99- 201141839 According to Examples 26-(1), 26-(2) and 1-(6), and using 2-ethynyl-1,4-dimethylbenzene (0.30 g) and Example 1-( 3) ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl)oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid B The title compound (0.13 g, yield 59%) was obtained as white solid. MS m/z: 344 (M + H) + ; *H-NMR (400 MHz, DMSO-d6) δ: 12.86 (1H, s), 11.98 (1H, s), 9.44 (1H, t, J = 6 Hz), 7.04-7.00 (2H, m), 6.91-6.90 (1H, m), 4.00 (2H, d, J = 6 Hz), 3.04-2.9 0 (4H, m), 2.60 (3H, s), 2.26 (3H, s), 2.23 (3H, s). (Example 4 5 ) [({5-Hydroxy-6-[2-(2-methoxyphenyl)ethyl]-2-methylpyrimidine -4-yl}carbonyl)amino]acetic acid

(1) [({5-(Benzyloxy)-6-[(2-methoxyphenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 26-(1), and using 1-ethynylmethoxybenzene (0.33 g) and Example 1-(3), ({[5-(benzyloxy)_2-methyl-6_{) [(Trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid ethyl acetate (0.30 g) instead of ethynyl-4-fluorobenzene' gave the title compound (0.18 g, yield The rate is 62%). -100- 201141839 Ή-NMR (400 MHz, CDC13) δ: 8.17 ( 1 H, t, J = 5 Hz), 7.61-7.59 (2H, m), 7.51-7.49 (1H, m), 7.41-7.30 ( 4H, m), 6.96 - 6.8 9 (2H, m), 5.38 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.25 (2H, d, J = 5 Hz), 3.74 (3H, s), 2.75 (3H, s), 1.31 (3H, t, J = 7 Hz). (2) [({5-Hydroxy-6-[2-(2-methoxyphenyl)ethyl]- 2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Examples 26-(2) and 1-(6), and using [({5-(benzyloxy)-6-[(2-methoxyphenyl)ethynyl]-2-methylpyrimidine- 4-(yl}carbonyl)amino]acetate (0.18 g) in place of [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl]-2-methylpyrimidine-4- Ethyl acetate was added to the title compound (0.070 g, yield 51%) as a white solid. m p : 150-160. . ; 'H-NMR (400 MHz, DMSO-d6) δ: 12.86 (1Η, s), 11.92 (1H, s), 9.42 (1H, t, J = 6 Hz), 7.2 0-6.8 3 (4H, m ), 3.99 (2H, d, • J = 6 Hz), 3.75 (3H, s), 3.0 5 - 2.94 (4H, m), 2.58 (3H, s). (Example 46) [({6-[ 3-(4-Fluorophenoxy)propyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid oh ο

Eight c〇2H

ΝγΝ H (l)[({5-(Benzyloxy)-6-[3-(4-fluorophenoxy)prop-1-yn-1-yl]-2-methylpyrimidin-4-yl} Carbonyl)amino]ethyl acetate-101 - 201141839

According to Example 2 6 - (1), and using 1-fluoro-4-(-propan-2-yl-1-yloxy)benzene (0.11 g) and Example 1-(3) ({[5- (Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid ethyl acetate (0.24 g) instead of 1-acetylene The title compound (〇〇97 Ο, yield 41%) was obtained. 'H-NMR (400 MHz, CDC13) δ: 8 · 1 7 (1 Η, t, J = 4 Η Η Ζ ), 7.48 -7.45 (2Η, m), 7.3 6-7.3 2 (3 Η, m) , 6.97-6.89 (4Η m) 5.16 (2Η, s), 4.90 (2Η, s), 4.26 (2Η, q, J = 7 Hz), 4 2l (2H, d, J = 4 Hz), 2.72 (3H , s), 1_31 (3H, t, J = 7 Hz). (2) [({6-[3-(4-fluorophenoxy)propyl]-5-hydroxy-2-methylpyrimidine-4 _yl} fluorenyl)amino]acetic acid according to Examples 26-(2) and 1-(6)' and using [({5-(benzyloxybu 6_[3-(4-fluorophenoxy)propane) Ethyl acetate (0.097 g) of 1--1-yn-1-yl]-2-methylpyrimidin-4-yl}carbonyl)amino]in place of [({5-(benzyloxy)-6-[(4- Fluorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid ethyl acetate </RTI> <RTI ID=0.0> ; 'H-NMR (400 MHz, CD3〇D) δ: 6.98-6.94 (2H, m), 6.83· 6.80 (2H, m), 4.12 (2H, s), 4.03 (2H, t, J = 8 Hz ), 3.02 (2H, t, J = 8 Hz), 2.59 (3H, s), 2.20 (2H, tt, J = 8 Hz, 8

Hz). -102- 201141839 (Example 47) [({6-[2-(4-Fluorophenyl)ethyl]-5-hydroxy-2-propylpyrimidin-4-yl}carbonyl)amino] Acetic acid

(1) 5-(Benzylmercaptooxy)-6-[(4-fluorophenyl)ethynyl]-2-propylpyrimidinecarboxylic acid methyl ester

Methyl 5-(benzimidyloxy)-6-chloro-2-propylpyrimidin-4-carboxylate (0.60 §) obtained according to Example 26-(1) and using Example 5-(1) Ethyl 4-fluorobenzene (0.43 g) instead of ({[5_(benzyloxy)_2-methyltrimethylmethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amine) Ethyl acetate gave the title compound (j. 'H-NMR (400 MHz, CDC13) δ: 8.29-8.27 (2Η, m) ( 7.72-7.70 (1H, m), 7.59-7.52 (2H, m), 7.27-7.26 (2H, m), 6.97. 6.92 (2H,m), 3.91 (3h,s), 3.06 (2H, t, J = 8 Hz), 1.92 (2H, qt, J = 8 Hz, 7 Hz), 1.04 (3H, t, J = 7 Hz). (2) [({6-[2-(4-Fluorophenyl)ethyl]_5-hydroxy-2-propylpyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 26-( 2) and 3-(4), and using methyl 5-(benzhydryloxy)-6-[(4-fluorophenyl)ethynyl]-2-propylpyrimidine-4-carboxylic acid (〇μg Substituting -103- 201141839 for methyl 5-(benzimidyloxy)-2-butyl-6(4-fluorophenyl)pyrimidine-4-carboxylate to give the title compound (0.068 g, yield 28 %) White solid. MS m/z: 3 62 (M + H) + ; 'H-NMR (400 MHz, DMSO-d6) δ: 11.95 (1H, s), 9.39 (1H, t, J = 6 Hz ), 7.27-7.05 (4H, m), 3.99 (2H, d, J = 6 Hz), 3.10-3.07 (4H, m), 2.79 (2H, t, J = 7 Hz), 1.77 (2H, qt, J = 7 Hz, 7 Hz), 0.90 (3H, t, J = 7 Hz). (Example 48) {[(6-{2-[4·Fluoro-2-(trifluoromethyl)phenyl)] Ethyl 5-hydroxy-2-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

(1) ethynyl-4_fluoro-2-(trifluoromethyl)benzene

1-Bromo-4-fluoro-2-trifluoromethylbenzene (2. 〇g) and ethynyl (trimethyl) decane (0.97 g) were dissolved in acetonitrile (40 mL) at room temperature under nitrogen After adding dichlorobis(triphenylphosphine)palladium complex (029 g), copper iodide (0.080 g) and triethylamine (2.3 mL), the mixture was heated under reflux for 7 hours. Water was added to the reaction mixture, and the organic layer was extracted with hexanes. The organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give [4-fluoro-3-(difluoromethyl)phenyl](trimethyl)decane (〇67 g, yield 31 %) Colorless oily substance. This was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride in tetrahydrofuran (1 M, 39 mL) was added at room temperature, and then stirred at the same temperature -104 - 201141839 for 3 hours. The reaction mixture was concentrated under reduced pressure. 'H-NMR (400 MHz, CDC13) δ: 7.6 5 -7.62 ( 1 Η, m), 7.39-7.36 (1H, m), 7.23-7.18 (1H, m), 3.33 (1H, s). (2 ({[5·(Benzyloxy)-6-{[4-fluoro-2-(trifluoromethyl)phenyl]ethynyl}-2-methylpyrimidin-4-yl]carbonyl}amino) Ethyl acetate

According to Example 26-(1), and using 1-ethynyl-4-fluoro-2-(trifluoromethyl)benzene (0.16 g) and Example 1-(3) ({[5-(benzyl) Ethyloxy-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.27 g) in place of 1-ethynyl- 4-Fluorobenzene, the title compound was obtained (0.22 g,yield 7 7 %). 'H-NMR (400 MHz, CDC13) δ: 8.15 (1Η, t, J = 5 Hz), 7.61-7.58 (1H, m), 7.50-7.41 (3H, m), 7.30-7.21 (4H, m) , 5.30 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 5 Hz), 2.75 (3H, s), 1.32 (3H, t, J = 7 Hz) 0){[(6-{2-[4-Fluoro-2-(trifluoromethyl)phenyl]ethyl) 5-hydroxy-2-methylpyrimidin-4-yl)carbonyl]amino} Acetic acid according to Examples 26-(2) and 1-(6), and using ({[5-(benzyloxy)-6-{[4-fluoro-2-(trifluoromethyl)phenyl]ethynyl) Ethyl acetate (0.22 g) of 2-methylpyrimidin-4-yl]carbonyl}amino) was substituted for [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl]-) Ethyl 2-methylpyrimidin-4-yl}carbonyl)amino]acetate gave the title compound (0.15 g,iel. -105- 201141839 mp: 166-169 °C; 'H-NMR (400 MHz, DMSO-d6) δ: 12.86 (1H, s), 11.95 (1H, s), 9.44 (1H, t, J = 6 Hz ), 7.5 8 -7.46 (3 H, m), 3.99 (2H, d, J - 6 Hz), 3.18-3.06 (4H, m), 2.59 (3H, s). (Example 49) {[(6 -{2-[4-Chloro-2-(trifluoromethyl)phenyl]ethyl}-5-hydroxy-methylpyridin-4-yl)carbonyl]amino}acetic acid

(1) ({[5-(Benzyloxy)-6-{[4-chloro-2-(trifluoromethyl)phenyl]ethynyl) 2-methylpyrimidin-4-yl]carbonyl}amino Ethyl acetate

According to Example 26-(1), and using 4-chloro-ethynyl-2-(trifluoromethyl)benzene (0.26 g) and Example 1-(3) ({[5-(( Benzyloxy)_2·methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) in place of 1-ethynyl- 4-Fluorobenzene gave the title compound (0.28 g, yield: 85%). 'H-NMR (400 MHz, CDC13) δ: 8.15 (1Η, t, J = 5 Hz), 7.70 (1H, s), 7.52-7.48 (4H, m), 7.31-7.29 (3H, m), 5.30 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 5 Hz), 2.75 (3H, s), 1.32 (3H5 t, J = 7 Hz). (2 ){[(6-{2-[4-chloro-2-(trifluoromethyl)phenyl]ethyl}-5-hydroxy-2-methylpyrimidin-4-yl)carbonyl]amino}acetic acid- 106- 201141839 According to Examples 26-(2) and 1-(6), and using ({[5-(benzyloxy)-6-{[4-chloro-2-(trifluoromethyl)phenyl)] Ethylyl}-2-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.28 g) in place of [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl) [Methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate' gave the title compound (0.11 g,yiel. MS m/z: 418 (M + H) + ;

'H-NMR (400 MHz, DMSO-de) δ: 12.86 (1H, s), 11.96 (1H, s), 9.44 (1H, t, J = 6 Hz), 7.74 (1H, d, J = 2 Hz ), 7.70 (1H, d, J = 8 Hz), 7.55 (1H, dd, J = 8 Hz, 2 Hz), 4.00 (2H, d, J = 6 Hz), 3.19-3.06 (4H, m), 2.59 (3H, s). (Example 5 0 ) [({6-[3-(4-Fluorophenyl)propyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino Acetic acid

1-Fluoro-4-prop-2-yn-1-ylbenzene (0.37 g) was dissolved in tetrahydrofuran (10 mL). After the addition of pinacol borane (0.64 g) under a nitrogen atmosphere, the mixture was heated to reflux for 12 hours. . The reaction mixture was cooled to room temperature. The solvent was distilled off under reduced pressure, whereby [3-(4-fluorophenyl)prop-1-en-1-yl]boronic acid was obtained. According to Examples 7-(1), 7-(2) and 1-(6), and using [3-(4-fluorophenyl)prop-1-en-1-yl]boronic acid and Example 1-(3) ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino-107- 201141839 The title compound (0.12 g, yield 16%) was obtained as a white solid. MS m/z: 3 4 8 (M + H) +; 'H-NMR (400 MHz, DMSO-d6) δ: 12.85 (1H, s), 11.92 (1H, s), 9.41 (1H, t, J = 6 Hz), 7.2 7- 7.2 3 (2 H, m), 7.11-7.06 (2H, m), 3.99 (2H, d, J = 6 Hz), 2.77 (2H, t, J = 7 Hz), 2.65 (2H, t, J = 7 Hz), 2.57 (3H, s), 1.97 (2H, tt, J = 7 Hz, 7 Hz). (Example 51) [({6-[2-(3- Ethoxyphenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Examples 26-(1), 26-(2) and 1-(6), and using 1-ethoxy-3-ethynylbenzene (0.37 g) and Example 1-(3) ({ [5-(Benzyloxy) 2 -methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) instead of 1 - ethynyl-4-fluorobenzene, the title compound (0.090 g,iel. MS m/z: 3 60 (M + H) + ; 'H-NMR (400 MHz, DMSO-d6) δ: 12.85 (1H, s), 11.96 (1H, s), 9.43 (1H, t, J = 6 Hz), 7.17 (1H, t, J = 8 Hz), 6.80-6.79 (2H, m), 6.74-6.72 ( 1 H, m), 3.99 (2H, q, J = 7 Hz), 3.99 (2H , d, J = 6 Hz), 3.09-2.95 (4H, m), 2.59 (3H, s), 1.30 (3H, t, J = 7 Hz). 201141839 (Example 52) [({6-[2 -(2-ethylphenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Example 2 6 - ( 1 ), 2 6 · (2 ) and 1 - ( 6 ) ' and using 1-ethyl-2-ethynylbenzene (〇_35 g) and Example 1-(3) ({[5-(Benzyloxy)-2-methyl·6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)^ ethyl acetate ( The title compound (0.11 g,yield: 51%) MS m/z: 3 44 (M + H) + ; 'H-NMR (400 MHz, DMSO-de) δ: 12.87 (1H, s), 12.00 (1H, s), 9.44 (1H, t, J = 6 Hz), 7.19-7.09 (4H, m), 3.99 (2H, d, J = 6 Hz), 3.02 -2.9 7 (4H, m), 2.68 (2H, q, J = 8 Hz), 2.60 (3H , s), 1.18 (3H, t, J = 8 Hz).

(Example 53) [({6-[2-(2-Chlorophenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amine]acetic acid

Cl N^N H τ

N octa C02H according to Example 2 6 - (1 ), 2 6 - ( 2 ) and 1 (6), and obtained using 1-chloro-2-ethynylbenzene (0.17 g) and Example 1-(3) ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl)oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) In place of 1-ethynyl-4-fluorobenzene, the title compound (0.08 g, yield 36%) -109- 201141839 MS m/z: 3 5 0 (M + H) + ; *H-NMR (400 MHz, DMSO-d6) δ: 9.42 (1H, t, J = 6 Hz), 7.43 -7.24 (4H , m), 3.98 (2H, d, J = 6 Hz), 3.15-3.05 (4H, m), 2.59 (3H, s). (Example 54) [({5-hydroxy-6-[2-( 2-isopropylphenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Examples 26-(1), 26-(2) and 1-(6), and using 1-ethynyl-2-isopropylbenzene (0.27 g) and Example 1-(3) ({ [5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) 1-Ethynyl-4-fluorobenzene gave the title compound (5 g, yield 67%) as a white solid. MS m/z: 3 5 8 (M + H) + ;

'H-NMR (400 MHz, DMSO-d6) δ: 12.86 (1H, s), 11.97 (1H, s), 9.44 (1H, t, J = 6 Hz), 7.29-7.07 (4H, m), 4.00 (2H, d, J = 6 Hz), 3.28-3.21 (1H, m), 3.01 (4H, s), 2.60 (3H, s), 1.19 (6H, d, J = 7 Hz). (Example 5 5) [({6-[2-(2,3-Dimethylphenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

Fc〇2h -110- 201141839 According to Example 26-(1), 26_(2) and ho), and using ethynyl-2,3-methylbenzene (0-33 g) and Example ^(3) ({[5_(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g The title compound (0.089 g, yield 42%) was obtained as a white solid. MS m/z: 344 (M + H) + ; 'H-NMR (400 MHz, DMS 〇-d6) δ: 12.86 (lH&gt; s), 11.98 (1H, φ s), 9.44 (1H, t, J ^ 6 HZ)} 7.〇〇(3H, s), 4.〇〇(2H, d, J = 6

Hz), 2.97 (4H, s), 2.60 (3H, s), 2.24 (3H, s)s 2.22 (3H, s). (Example 5 6 ) [({6-[2-(4_Fluor_) 2-methylphenyl)ethyl b-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid I ΝγΝ 依照 according to Example 48-(1) 'and using 1-bromo-4 Fluoro-2-methylbenzene (1.9 • g) and ethynyl (trimethyl)decane (2.1 mL) were substituted for κ bromo-4-fluoro-2-trifluoromethylbenzene to obtain 1-ethynyl-4-fluoro -2-methylbenzene (〇.4〇g, yield 3〇%). According to Examples 26-(1), 26-(2) and 1-(6), and using ethynyl-4-fluoro-2-methylbenzene (0.40 g) and Example 丨_(3) ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) In place of 1-ethynyl-4-fluorobenzene, the title compound (0.089 g, yield 40%) Mp: 172-175 ° C;, Η-NMR (400 MHz, DMSO-d6) δ: 12.86 (1H, s), u.97 (1H, -111 - 201141839 s), 9.43 (1H, t, J = 6 Hz), 7.17 (1H, dd, J = 8 Hz, 6 Hz), 7.01 (1H, dd, J = 10 Hz, 3 Hz), 6.92 (1H, dt, J = 8 Hz, 3 Hz), 3.99 (2H, d, J = 6 Hz), 3.02-2.92 (4H, m), 2.59 (3H, s), 2.32 (3H, s). (Example 57) [({5-hydroxy-6-[2 -(2-isopropoxyphenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Examples 26-(1), 26-(2) and 1-(6), and using 1-ethynyl-2-isopropoxybenzene (0.40 g) and Example 1-(3) ( {[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g) In place of 1-ethynyl-4-fluorobenzene, the title compound (0.049 g, yield 21%) Mp : 1 4 3 - 1 4 8 °C ;

'H-NMR (400 MHz, DMSO-d6) δ: 9.39 (1Η, t, J = 6 Hz), 7.16-7.12 (2H, m), 6.95-6.93 (1H, m), 6.83-6.79 (1H, m), 4.62-4.5 6 ( 1 H, m), 3.97 (2H, d, J = 6 Hz), 3.0 5 -2.90 (4H, m), 2.57 (3H, s), 1.24 (6H, d, J = 6 Hz). (Example 58) [({6-[2-(3,5-Dimethylphenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amine Acetate

!TC〇2H -112- 201141839 According to Examples 26-(1), 26-(2) and 1-(6), and using ethynyl-3,5-dimethylbenzene (〇.4〇£) And the obtained ({[5-(hydroxy))-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy-4-phenyl]carbonyl] The title compound (0.16 g, yield 74%) was obtained as a white solid. Mp : 209-2 1 1 °C ;

'H-NMR (400 MHz, DMSO-d6) δ: 12.85 (1H, s), 11.95 (1H, s), 9.43 (1Η, t, J = 6 Ηζ), 6.85 (2Η, s), 6.81 (1Η , s), 3.99 (2H, d, J = 6 Hz), 3.05-3.02 (2H, m), 2.91-2.88 (2H, m), 2.60 (3H, s), 2.33 (6H, s). Example 59) [({6-[2-(2,6-Dimethylphenyl)ethyl]-5-hydroxy-2-methylpyridin-4-yl}carbonyl)amino]acetic acid

According to Examples 26-(1), 26-(2) and 1-(6), and using 2-ethynyl-1,3-dimethylbenzene (0.40 g) and Example 1-(3) ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy} um _4_yl]carbonyl}amino)ethyl acetate (0.30 g) In place of 1-ethynyl-4-fluorobenzene, the title compound (0.04 8 g, yield 22%) Mp: 209-2 1 1 °C; 'H-NMR (400 MHz, DMSO-d6) δ: 9.45 (1H, t, J = 6 Hz), 7.01 (3H, s), 3.99 (2H, d, J = 6 Hz), 2.94-2.87 (4H, m), 2.62 (3H, s), 2.34 (6H, s). -113- 201141839 (Embodiment 6 0) [({6-[2-(2,4) - monomethylphenyl)ethyl]-5-transmethyl-2-methyl-chrysyl-4-yl}carbonyl)amino]acetic acid

(1) [({5-(Hydroxy)-6-[(2,4-dimethylphenyl)ethynyl]2methyl)pyridin-4-yl}carbonyl)amino]ethyl acetate

According to Example 26-(1), and using 1-ethynyl-24-, one-ply basic; (0-20 g) and Example 1-(3) ({[5-(benzyloxy)_2) Methyl-6([(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid ethyl acetate (0.27 g) was obtained in place of 1-ethyl fluoro-4-fluorobenzene. The title compound (〇43 g, yield 94%). 'H-NMR (400 MHz, CDC13) δ: 8.23 (1Η, t, j = 4 Hz) 7.64-7.60 (2H, m), 7.37-7.34 (2H, m), 7.29-7.26 (3H m) 7, 12 (1H,d, J = 8 Hz), 5.30 (2H, s), 4.27 (2H, q, j = 8

Hz), 4.23 (2H, d, J = 4 Hz), 2.75 (3H, s), 2 29 (3H, s) 2.23 (3H, s), 1.32 (3H, t, J = 8 Hz). (2 [({6-[2-(2,4-Dimethylphenyl)ethyl]-5-transyl-2-methyl-methyl)-amino]acetic acid]acetic acid according to the examples 26-(2) and 1-(6), and use benzyloxy)_6_[(2,4-dimethylphenyl)ethynyl]2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid Ethyl ester (0.43 g) in place of benzyloxy)-6-[(4-fluorophenyl)ethynyl-114-201141839]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate, The title compound (0.25 g, yield 77%) was obtained as a white solid. Mp : 1 74- 1 7 6 ° C ; !H, NMR (400 MHz, CDjOD) δ: 7.00 (1H, d, J = 8 Hz), 6.95 (1H, s), 6.89 (1H, d, J = 8 Hz), 4.13 (2H, d, J = 4 Hz), 3.0 5 -2.9 3 (4H, m), 2.61 (3H, s), 2.33 (3H, s), 2.24 (3H, s). φ ( Example 61) [({5-Hydroxy-2-methyl-6-[2-(2-propylphenyl)ethyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

(1) 1-ethynyl-2-((1Ε)-prop-1-en-1-yl]benzene and 1-ethynyl-2- [(1Ζ)-prop-1-en-1-yl]benzene

Ethyltriphenylphosphonium bromide (4.5 g) was dissolved in tetrahydrofuran (20 mL), and a solution of sodium hexamethyldiamine in tetrahydrofuran (1.0 mL, 13 mL) was added dropwise at 〇 ° C. Stir at the same temperature for 2 hours. After 2-bromobenzaldehyde (1·9 g) was added dropwise to the reaction mixture, the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The mixture was washed with brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography to give 1-bromo-2-[(1Ε)-prop-1-ene-indole-yl]benzene and bromo- 2·[( Ϊ́ζ) -propan-1-one-1-yl]benzene mixture (2.0 g, quantitative yield) -115- 201141839

Yellow oily substance. It was dissolved in ethynyl (trimethyl) decane (2.1 mL) in N,N-diisopropylamine (20 mL). Under a nitrogen atmosphere, hydrazine (triphenylphosphine) palladium complex (〇) was added at room temperature. · 58 g) and Yaohua copper (0.095 g), and stirred at 80 ° C for 8 hours. The reaction solution was cooled to room temperature, filtered over Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain trimethyl ({2-[(1Ε)_·prop-1-en-1-yl]phenyl}ethynyl)decane and trimethyl ({2) a mixture of -[(1Ζ)-prop-1-en-1-yl]phenyl}ethynyl)decane (0.81 g, yield 37%). This was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 7.8 mL) was added at room temperature and then stirred at room temperature for 1 hour. After the organic layer was extracted with n-hexane, the organic layer was dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified mjjjjlili E body (content rate 40%)

'H-NMR (400 MHz, CDC13) δ: 7.53-7.12 (4Η, m), 6.90 (1H, d, J = 16 Hz), 6.33 (1H, dq, J = 16 Hz, 7 Hz), 3.31 ( 1H, s), 1.93 (3H, d, J = 7 Hz). Z body (content ratio 60%) 'H-NMR (400 MHz, CDClj) δ: 7.53-7.12 (4H, m), 6.69 ( 1H, d, J = 12 Hz), 6.93 (1H, dq, J = 12 Hz, 7 Hz), 3.28 (1H, s), 1.85 (3H, d, J = 7 Hz). (2)[({ 5-hydroxy-2-methyl-6-[2-(2-propylphenyl)ethyl]pyrimidin-4-yl}carbonyl)amino]acetic acid-116- 201141839

According to Example 26-(1), 26-(2彳% I (iZ K } δ (2) and ^(6), and using 1-ethynyl-2·[(1Ε)-propanyl small base] a mixture of benzene and oxime-ethynyl group 2_[(ιζ) propyl acetophenone] benzene (0.27 g) and obtained in Example W3) ("Η 氧基 oxy)-2-methyl-6-{[( Trifluoromethyl)sulfonyl]oxy}pyrimidine _4_yl]carbonyl} Month-Ethyl Acetate Ethyl Acetate (0.30 g) instead of 丨_7 Burning / Bu / g _ White i acetylene _4 - The title compound (0.068 g, yield 30%) was obtained as a white solid. mp: 1 3 6 - 1 3 9 ° C; H-NMR (400 MHz, DMSO-d6) δ: 12.84 (iH, s) , 11.98 (1H, s), 9.44 (1H, t, J = 6 Hz), 7.19-7.09 (4H, m), 3.99 (2H, d, J - 6 Hz), 3.02-2.97 (4H, m), 2.62 (2H, t, J = 8 Hz), 2.60 (3H, s), 1.56 (2H, qt, J = 8 Hz, 7 Hz), 0.94 (3H, t, J = 7 Hz). (Example 6 2) [({6-[2-(2-cyclopropylphenyl)ethyl]-5-hydroxy-2-methylpyrano D--4-yl}carbonyl)amino]acetic acid

* OH Ο &quot;n^co2h 丫 u (1)1-cyclopropyl-2-ethynylbenzene

Dissolve 1-bromo-2-cyclopropylbenzene (1.3 g) and ethynyl (trimethyl)decane (1.4 mL) in hydrazine, hydrazine-diisopropylamine (20 mL) in a nitrogen atmosphere After the addition of bis(t-butylphosphine)palladium complex (0.067 g) and copper iodide (0.05 0 g), the mixture was heated under reflux for 8 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure of -117-201141839, and then the residue was purified by silica gel column chromatography to obtain [(2-cyclopropylphenyl)ethynyl] (three) Methyl) sand yard (0.32 g, yield 34%). This was dissolved in tetrahydrofuran (15 ml), and tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 7.8 mL) was added at 0 ° C and then stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the organic layer was extracted with n-hexane. The solvent was evaporated under reduced pressure. 'H-NMR (400 MHz, CDC13) δ: 7.46 (1Η, d, J = 8 Hz), 7.25 (1H, dd, J = 8 Hz, 8 Hz), 7.10 (1H, dd, J = 8 Hz, 8 Hz), 6.81 (1H, d, J = 8 Hz), 3.29 (1H, s), 2.42-2.3 7 ( 1 H, m), 1.06-1.01 (2H, m), 0.75-0.71 (2H, m (2) [({6-[2-(2-cyclopropylphenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 26 -(1), 26-(2) and 1-(6), and using 1-cyclopropyl-2-ethynylbenzene (0.07 0 g) and Example 1-(3) ({[5_(( Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.23 g) in place of 1-ethynyl 4-Fluorobenzene, the title compound (0.043 g, m. Mp: 136-139 °C; 'H-NMR (400 MHz, DMSO-d6) δ: 12.87 (1H, s), 11.96 (1H, s), 9.43 (1H, t, J = 6 Hz), 7.18- 6.92 (4H, m), 3.99 (2H, d, J = 6 Hz), 3.17-3.07 (4H, m), 2.60 (3H, s), 2.0 8 -2.02 ( 1 H, m), 0.95-0.91 ( 2H, m), 0.64-0.61 (2H, m). -118- 201141839 (Example 63) [({6-[2-(2,5-dichlorophenyl)ethyl]-5-hydroxy-2 -methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-(Benzyloxy)-6-[(2,5-dichlorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 2 6 - (1 ), and using 1,4-dichloro-2-ethynylbenzene (0.26 g) and Example 1-(3) ({[5-(benzyloxy)-2) -methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.48 g) in place of 1-ethynyl-4-fluorobenzene, The title compound (0.37 g, yield 73%) was obtained. 'H-NMR (400 MHz, CDC13) δ: 8.20 (1Η, t, J = 4 Hz), Lu 7.5 5 - 7.5 3 (2 H, m), 7.46- 7.3 0 (6H, m), 5.33 (2H , s), 4.29 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 4 Hz), 2.76 (3H, s), 1.32 (3H, t, J = 8 Hz). (2) [({6-[2-(2,5-Dichlorophenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 26-(2) And 1-(6), and using [({5-(benzyloxy)-6-[(2,5-dichlorophenyl)ethynyl]-2-methylpyrimidin-4-yl}carbonyl)amine Ethyl acetate (0.37 g) in place of [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl]--119- 201141839 2 -methylpyrimidin-4-yl} The title compound (〇_12 g, yield 41%) was obtained as a white solid. Mp: 204-21 1 °C ; 'H-NMR (400 MHz, CD3〇D) δ: 7.35-7.19 (3H, m), 4.12 (2H s), 3.4 8 -3.47 (2 H, m), 3.17 -3.12 (2H, m), 2.61 (3H, s). (Example 64) [({5 -Pyridyl-2-methyl-6(2-(4-methylbiphenyl)-3-yl) Ethyl]pyridyl_4_yl)carbonyl)amino]acetate φ

(1) 4-methylbiphenyl-3-carboxaldehyde

Copper (11) (0.80 g) and butyl nitrite (15 g) were dissolved in acetonitrile (50 mL), and 4-methylbiphenyl-3-amine (1.8 g) was added at 0 °C. After acetonitrile solution (25 mL), it was stirred at room temperature for 1 hour. The organic layer was extracted with EtOAc (2M). After the solvent was sufficiently evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain 3-bromo-4-methylbiphenyl (1.7 g, yield: 72%) of brown oil. This was dissolved in tetrahydrofuran (30 mL), and a n-hexane solution of n-butyllithium (2.7 M, 3.1 mL) was added dropwise at -78 °C under nitrogen atmosphere, and stirred at the same temperature for 1 hr. N,N-dimethylformamide (1·0 m L) was added to the reaction mixture at 7.8 ° C and stirred for 1 hour, and then warmed to room temperature at -120 - 201141839. After a saturated aqueous solution of ammonium chloride was added to the mixture, the organic layer was washed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After the solvent was evaporated to dryness crystals crystals crystals crystals crystals crystals • H-NMR (400 MHz, CDC13) δ: 9.91 (1Η, s), 7.87 (1H, s), 7.66 (1H, s), 7.49-7.43 (4H, m), 7.3 7 -7.3 3 (2H, m), 2.54 φ (3H, s). (2) 3-ethynyl-4-methylbiphenyl

4-Methylbiphenyl-3-carboxaldehyde (0.49 g) and carbon tetrabromide (1.7 g) were dissolved in dichloromethane (15 mL), and triphenylphosphine (2.6 g) was added at 0 ° C. Stir at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then filtered and evaporated. The filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 3 - (2,2-dibromo-vinyl)-4-methylbiphenyl (0.50 g, yield 56%) colorless oily substance. This was dissolved in tetrahydrofuran (20 mL), and n-butyllithium n-hexane solution (2.7 M, 1 - 6 mL) was added dropwise at -78 °C, and then stirred at the same temperature for 30 minutes. The organic layer was extracted with ethyl acetate. After the solvent was evaporated under reduced pressure, the residue was purified mjjjjjjd -121 - 201141839 Ή-NMR (400 MHz, CDC13) δ: 7.71-7.26 (8H, m), 3.3〇(1 H, s), 2.49 (3H, s). (3 )[( {5-hydroxy- 2-methyl-6-[2-(4-methylbiphenyl-3-yl)ethyl]pyranyl}carbonyl)amino]acetic acid

According to Example 26-(1) '26-(2) and 1-(6), and using 3_ethylidene-4-methylbiphenyl (0·27 g) and Example 1-(3) (丨[5_(Hydroxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]methyl}amino)acetic acid ethyl acetate (0.57 g) The title compound (0.26 g, yield 53%) Mp : 1 3 6 - 1 3 9 ° C ; 'H-NMR (400 MHz, DMSO-d6) δ: 12.86 (1H, s), 12.01 (1H s), 9.45 (1H, t, J = 6 Hz) , 7.61-7.23 (8H, m), 4.00 (2H, d J = 6 Hz), 3.12-3.02 (4H, m), 2.60 (3H, s), 2.36 (3H, s). (Example 65) [ ({6-[2-(2-Ethyl-1-naphthyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

iTc〇2H (1) 1-bromo-2-vinylnaphthalene

1-Bromo-2-naphthaldehyde (2.4 g) was dissolved in tetrahydrofuran (20 mL), and a solution of sodium hexamethyldiamine in tetrahydrofuran (1.0 Μ, 13 mL) was added dropwise to 〇t, and stirred at the same temperature. 45 minutes. A solution of methyltriphenyl iodide-122-201141839 scale (4.8 g) in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. *H-NMR (400 MHz, CDC13) δ: 8.36 (1Η, d, J = 8 Hz), η 80 (1H, d, J = 8 Hz), 7.77 (1H, d, J = 8 Hz), 7.67 (1H, d, J =

8 Hz), 7.60-7.5 7 ( 1 H,m), 7.5 2-7.49 ( 1 H,m), 7.40 (1H, dd, J = 20 Hz, 12 Hz), 5.84 (1H,d,J = 20 Hz), 5.50 (ih, d, J = 12 Hz). (2) 2-vinyl-1-naphthaldehyde. 1-Diethyl-2-ethylidene naphthalene (1.8 g) was dissolved in tetrahydrofuran (4 mL) After adding a n-hexane solution of n-butyllithium (1.6 m, 5.7 m L) at -78 °C under a nitrogen atmosphere, the mixture was stirred at the same temperature for 10 minutes. N,N-dimethylformamide (0·87 mL) was added to the mixture, and the mixture was stirred at room temperature for 15 min. After the solvent was evaporated under reduced pressure. H-NMR (400 MHz, CDC13) δ: 10.87 (1 Η, s), 8.98 (1H, d, J = 8 Hz), 8.02 (1H, d, J = 8 Hz), 7.86 (1H, d, J = 8 Hz), 7.65 -7.5 5 (3 H, m), 7.45 (1H, dd, J = 16 Hz, 12 Hz), 5.74 (1H, d, J = 16 Hz), 5.70 (1H, d, J = 12 Hz). (3) 1-ethynyl-2-vinylnaphthalene-123- 201141839

Following title 64-(2), and using 2-vinyl-1-naphthaldehyde (〇 46 g) instead of 4-methylbiphenyl-3-carbaldehyde, the title compound (0·15 g, yield 3 2%). 'H-NMR (400 MHz, CDC13) 6: 8.39 (1H, d, J = 8 Hz), 7.8 2- 7.72 (3 H, m), 7.5 9- 7.4 8 ( 3 H, m), 5.94 (1H , d, J = 20 Hz), 5.49 (1H, d, J = 8 Hz), 3.78 (1H, s). (4) [({5-(Benzyloxy)-2-methyl- 6-[ (2-vinyl-1-naphthyl)ethynyl]pyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 26-(1), and using 1-ethynyl-2-vinylnaphthalene (0.15 g) and Example 1-(3) ({[5-(benzyloxy)-2-methyl) -6-{[((Trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0 · 3 5 g) in place of 1-ethynyl-4-fluorobenzene, The title compound (〇. 14 g, yield 38%) was obtained. 'H-NMR (400 MHz, CDCI3) δ: 8.44 (1Η, d, J = 8 Hz), 8.29 (1H, t, J = 4 Hz), 7.87 (1H, d, J = 8 Hz), 7.82 ( 1H, d, J = 8 Hz), 7.76 (1H, d, J = 8 Hz), 7.60-7.46 (3 H, m), 7.36- 7.21 (5H, m), 5.94 (1H, d, J = 20 Hz), 5.36 (1H, d, J = 16

Hz), 5.34 (2H, s), 4.28 (2H, q, J = 8 Hz), 4.23 (2H, d, J = 4 Hz), 2.80 (3H, s), 1.33 (3H, t, J = 8 Hz). (5) [({6-[2-(2-ethyl-naphthyl)ethyl]_5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid-124- 201141839 Examples 26-(2) and 1-(6), and using [({5·(benzyloxy)_2_methyl-6-[(2-ethyl-naphthyl)ethynyl]pyrimidin-4-yl) }carbonyl]amino]ethyl acetate (0.14 g) in place of [({5_(benzyloxy)_6·[(4-fluorophenyl)ethynyl]-2.methylpyran-4-yl}carbonyl) The title compound (0. 〇 57 g, yield 5%) was obtained as white solid. Mp: 1 70- 1 74 °C;

'H-NMR (400 MHz, CD3〇D) δ: 8.30 (1H, d, J = i2 Hz) 7.80 (1H, d, J = 12 Hz), 7.69 (1H, d, J = 8 Hz), 7.54 -7.5〇(1H,m), 7.43 - 7.40 ( 1 H,m),7.36 (1H,d,J = 12 HZ),4 16

(2H, s), 3.49-3.4 5 (2H, m), 3.16-3.12 (2H, m), 2.93 (2H q, J = 8 Hz), 2.66 (3H, s), 1.31 (3H, t, J = 8 Hz). (Example 6 6) [({6-[2-(5-Chloro-2-ethylphenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amine Acetate

(1) 2-Bromo-4-chloro-1-ethylbenzene jQ〇 Copper dichloride (0-80 g) and butyl nitrite (0.77 g) were dissolved in acetonitrile (13 mL). A solution of -4-ethylaniline (1.0 g) in acetonitrile (2 mL) was stirred at room temperature for 1 hour. Hydrochloric acid (2 M) was added to the reaction mixture, and the organic layer was extracted with ethyl acetate. After the solvent was evaporated under reduced pressure, the residue was purified mjjjjjjjjjjjj -125- 201141839 'H-NMR (400 MHz, CDC13) δ: 7.54 (1H, d, J = 2 Hz), 7.23 (1H, dd, J = 8 Hz, 2Hz), 7.15 (1H, d, J = 8 Hz), 2.72 (2H, q, J = 7 Hz), 1.2 1 (3H, t, J = 7 Hz). (2) 4-Chloro-1-ethyl-2-ethynylbenzene

In accordance with Example 48-(1), 2-bromo-4-chloro-1-ethylbenzene (0.83 g) and ethynyl (trimethyl)decane (0.78 mL) were used instead of 1-bromo-4-fluoro- 2-Trifluoromethylbenzene gave the title compound (0.28 g, yield 36%). 'H-NMR (400 MHz, CDCI3) δ: 7.44 (1Η, d, J = 2 Hz), 7.25 (1 H, dd, J = 8 Hz, 2 Hz), 7.14 ( 1 H, d, J = 8 Hz), 3.28 (1H, s), 2.79 (2H, q, J = 7 Hz), 1.23 (3H, t, J = 7 Hz). (3)[({6-[2-(5-chloro- 2-ethylphenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Examples 26-(1), 26-(2) and 1-(6), and using 4-chloro-1-ethyl-2-ethynylbenzene (0.28 g) and Example 1-(3) ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.50 g) In place of 1-ethynyl-4-fluorobenzene, the title compound (0.18 g,iel. Mp : 1 3 6- 1 3 9 ° C ; 'H-NMR (400 MHz, DMSO-d6) δ: 12.87 (1H, s), 11.99 (1H, s), 9.44 (1H, t, J = 6 Hz ), 7.25 (1H, m), 7.20 (2H, m), 3.99 (2H, d, J = 6 Hz), 3.06 -2.9 7 (4H, m), 2.65 (2H, q, J =7 Hz), 2.60 (3H, s), 1.15 (3H, t, J = 7 Hz). -126- 201141839 (Embodiment 67)

{[(6-Hexyl-5-hydroxy-2-methylpyrimidin-4-yl)carbonyl]amino}acetic acid OH 0 (1) {[(6-hexyl-5-hydroxy-2-methylpyrimidine-4 -yl)carbonyl]amino}ethyl acetate

The stomach was obtained according to Examples 7 - (1) and 7 - (2), and (1 E )-hex-1 -en-1-ylboronic acid (0.15 g) and Example 1-(3) were obtained ({[ 5-(Benzyloxy)-; 2-methyl-indole-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.48 g) In place of [3-(trifluoromethyl)phenyl]boronic acid, the title compound (0·20 g, yield 62%) was obtained. 'H-NMR (400 MHz, CDC13) δ: 11.32 (1Η, s), 8.50 (1H, t5 J = 4 Hz), 4.28 (2H, q, J = 8 Hz), 4.21 (2H, d, J = 4 Hz), • 2.84 (2H, t, J = 8 Hz), 2.62 (3H, s), 1.74- 1.6 7 (2H, m), 1.41-1.31 (6H, m), 1.33 (3H, t, J = 8 Hz), 0.88 (3H, t, J = 8 Hz). (2) {[(6-Hexyl-5-hydroxy-2-methylpyrimidin-4-yl)carbonyl]amino}acetic acid according to the examples 1 - (6), and using {[(6-hexyl-5-hydroxy-2-methylpyrimidin-4-yl)carbonyl]amino}ethyl acetate (〇.20 g) instead of [({6- Ethyl [(3,4-dichlorophenyl)sulfanyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetate gave the title compound (0.17 g, ) White solid. -127- 201141839 mp: 1 20- 1 23 °C ; 'H-NMR (400 MHz, CD3〇D) δ: 4.13 (2H, s), 2.83 (2H, t, J =8 Hz), 2.60 (3H , s), 1.75-1.67 (2H, m), 1.43-1.2 9 (6H, m), 0.90 (3H, t, J = 8 Hz). (Example 68) {[(5-Hydroxy-2-A) Keto-6-pentylpyrimidin-4-yl)carbonyl]amino}acetic acid

(1) ({[5-(Benzyloxy)-2-methyl-6-pent-1-yn-1-ylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

N^C02Et ( ({[5-(Benzyloxy)-2-methyl) according to Example 26-(1), and using pent-1-yne (〇.15m L) and Example 1-(3) Ethyl -6-{[((trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.48 g). , yield 93%). 'H-NMR (400 MHz, CDC13) δ: 8.18 (1Η, t, J = 4 Hz), 7.56-7.5 5 (2H, m), 7.39-7.31 (3H, m), 5.23 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 4 Hz), 2.71 (3H, s), 2.46 (2H, t, J = 8 Hz), 1.67-1.61 (2H, m ), 1.31 (3H, t, J = 7 Hz), 1.01 (3H, t, J = 8 Hz). (2) {[(5-Hydroxy-2-methyl-6-pentylpyrimidine_4_yl) Carbonyl]amino}acetic acid according to Examples 2 6 - ( 2 ) and 1 - (6 ), and using ({[ 5 _ (benzyloxy) _ 2 _ methyl-6-pent-1-yne-1 -Pyrylpyrimidin-4-yl]carbonyl}amino)acetate (〇37-128-201141839 g) in place of [({5-(benzyloxy)-6-[(4-fluorophenyl)ethynyl) Ethyl acetate -2 -methylpyrimidin-4-yl}carbonyl)amino]] gave the title compound (0.21 g,yield: 81%) as a white solid. Mp : 13 1-13 3 °C ; *H-NMR (400 MHz, CD3〇D) δ: 4.12 (2H, s), 2.83 (2H, t, J =8 Hz), 2.60 (3H, s), 1.3 9- 1.3 5 (6H, m), 0.92 (3H, t, J = 8 Hz).

(Example 69) ({[5-Hydroxy-2-methyl-6-(5-methylhexyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

(1) ({[5-(Benzyloxy)-2-methyl-6-(5-methylhex-1-yn-1-yl)pyrimidin-4-yl]carbonyl}amino)acetate

({[5-(Benzyloxy)-) obtained according to Example 2 6 - (1), using 5-methylhex-1 -yne (0 · 20 m L) and Example 1-(3) Ethyl 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.48 g) in place of 1-ethynyl-4-fluorobenzene The title compound (0.42 g, quantitative yield) was obtained.

(2H, q, J Ή-NMR (400 MHz, CDC13) δ: 8.19 (1 Η, t, J = 4 Η ζ), 7.5 7 -7.5 5 (2Η, m), 7.40 - 7.3 2 ( 3 Η, m), 5.23 (2H, s), 4.26 =7 Hz), 4.21 (2H, d, J = 4 Hz), 2.71 (3H, s), -129- 201141839 2.4 8 ( 2 Η,t,J = 8 Η z),1 · 7 3 - 1 . 6 9 (m),1 · 6 0 -1 · 4 7 (2 Η, m), 1.31 (3H,t,J = 7 Hz), 0.89 (6H,d , J = 8 Hz). (2) ({[5-Hydroxy-2-methyl-6-(5-methylhexyl)pyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 26-(2) And 1-(6), and using ({[5_(benzyloxy)_2_methyl-6-(5-methylhex-1-yn-1-yl)pyrimidinyl]carbonyl]amino) Ethyl acetate (0.42 g) in place of [({5-(benzyloxy)_6_[(4-fluorophenyl)ethynyl]_2_

Ethyl acetate of methylpyrimidin-4-yl}carbonyl)amino] gave the title compound (0.24 g, yield 87%) as a white solid. MS m/z: 3 1 0 (M + H) + ; 'H-NMR (400 MHz, CD3OD) δ: 4.13 (2H, s), 2.83 (2H, t, J =8 Hz), 2.60 (3H, s), 1.74- 1.66 (2H, m), 1.57-1.51 (1H, m), 1.41-1.36 (2H, m), 1.26-1.21 (2H, m) 0.89 (6H, d, J = 6 Hz). (Embodiment 70)

({[6-(4-Fluorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid OH 0

fC〇2H (1)({[5-(Benzyloxy)-6-(4-fluoro)]-2-methylpyrimidin-4-yl]carbonyl}amino)acetate OBn 0

The oxy-p-methyltrifluoromethyl group obtained in Example 1-(3) is awake-based]oxy}pyrimust_4-yl]fluorenyl}moon-female)acetate (0·24 130 201141839) g) Dissolve in tetrahydrofuran (5 mL), add 4-fluorobenzyl zinc chloride in tetrahydrofuran (〇_5 M, 2.0 mL) and dichlorobis(triphenylphosphine)palladium complex (0.03 5) at room temperature. After g), it was stirred under light-shielding for 20 hours. Water and an aqueous solution of ammonium chloride were added to the reaction mixture, and the resulting white solid was separated, and the organic layer of the filtrate was extracted with dichloromethane. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (0.061 g, yield 28%).

*H-NMR (400 MHz, CDC13) δ: 8.34 (1Η, t, J = 4 Hz), 7.45-7.32 (5H, m), 7.17-7.14 (2H, m), 6.92-6.87 (2H, m) , 5.00 (2H, s), 4.25 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 4 Hz), 4.03 (2H, s), 2.70 (3H, s), 1.30 (3H, t, J = 8 Hz). (2) ({[6-(4-fluorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino))

According to Examples 7-(2) and 1-(6), and using ({[5-(benzyloxy)-6-(4-fluorobenzyl)-2-methylpyrimidin-4-yl]carbonyl} Ethyl ethyl acetate (0.061 φ g) in place of [({5-(benzyloxy)-2-methyl-6-[3-(trifluoromethyl)phenyl]pyrimidin-4-yl}carbonyl) The title compound (0.03 3 g, yield 73%) was obtained as white solid. MS m/z: 320 (M + H) + ; 4^1^11 (400 1^1^, 00300) 3:7.3 7-7.3 2 (211,111), 7.02-6.95 (2H, m), 4.14 (2H , s), 4.10 (2H, s), 2.61 (3H, s). (Example 71) ({[6-(3-chlorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl] Carbonyl}amino)acetic acid-131 - 201141839

(l) ({[6-(3-chlorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetate ethyl acetate

According to Examples 70-(1) and 7-(2), and using a solution of 3-chlorobenzylzinc chloride in tetrahydrofuran (0.5 M, 2.0 mL) and Example 1-(3) ({[5-(( Benzyloxy)_2·methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.71 g) in place of 4-fluorobenzyl The title compound (〇. 〇1 4 g, yield 2.7 %) was obtained from the title compound. 'H-NMR (400 MHz, CDC13) δ: 11.39 (1Η, s), 8.46 (1H, t, J = 4 Hz), 7.35 (1H, s), 7.27-7.17 (3H, m), 4.27 (2H , q, J =8 Hz), 4.19 (2H, d, J = 4 Hz), 4.14 (2H, S), 2.63 (3H, s), 1.32 (3H, t, J = 8 Hz). (2) ({[6-(3-chlorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]yl}amino)acetic acid according to Example 1-(6)' and used ({[6- (3-Chlorobenzyl)_5_ benzyl 2-methylpyrimidin-4-yl]carbonyl}amino)acetate (0·0Μ g) instead of [({6_[(3,4-dichlorobenzene) Ethylsulfonyl]-5-hydroxy-2-methylpyrimidin-4-yl}p-amino)amino]acetic acid' gave the title compound (0.008 g, yield 64%) as a white solid. MS m/z: 3 3 6 (M + H)+; 'H-NMR (400 MHz, CD3OD) δ· 7 34 ΠΗ s), 7.26-7.18 (3 H, m), 4 · 1 5 ( 2 H , s), 4 _ 1 2 (2 H, s), 2 · 6 2 (3 H, -132- 201141839 (Example 7 2) ({[5-hydroxy-2-methyl-6-(3, 4,5-trifluorobenzyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

(1) [({5-(Benzyloxy)-6-[2-ethoxy-2-yloxy-1-(3,4,5-trifluorophenyl)ethyl]-2-yl) Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

Dilute a solution of lithium hexamethyldiamine in tetrahydrofuran (1.0 Μ, 1.3 mL) in tetrahydrofuran (2 mL) under nitrogen atmosphere, and add it to (3,4,5- at -78 °C for 10 minutes. After a solution of trifluorophenyl)acetate (0.22 g) in THF (1 mL), ({[5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl)oxy}pyrimidine-4 obtained in Example 1-(3) was added to the reaction mixture. Ethyl-carbonyl]amino)acetic acid ethyl acetate (0.24 g), mp. The solvent was evaporated under reduced pressure. *H-NMR (400 MHz, CDC13) δ: 8.36 (1 Η, d, J = 5 Hz), 7.45 -7.3 6 (5 Η, m), 6.88 (2H, dd, J = 8 Hz, 7 Hz) , 5.30 (1H, s), 5.15 (1H, d, J - 11 Hz), 5.01 (1H, d, J = 11 Hz), 4.28-4.22 (4H, m), 4.18-4.08 (2H, m), 2.71 (3H, s), 1.30 (3H, t, J = 7 Hz), 1.17 (3H, t, J = 7 Hz). -133- 201141839 (2)({[5-hydroxy-2-methyl- 6-(3,4,5-trifluorobenzyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

[({5-(Benzyloxy)-6-[2-ethoxy-2-oxo-l-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidine) Ethyl acetate (0.27 g) was dissolved in ethyl acetate (5 mL). 5% palladium-activated carbon (0.010 g) was added and stirred at room temperature under a hydrogen atmosphere. 5 hours. After the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by chromatography on silica gel column to afford [({6-[2-ethoxy-2-oxoxy-1 -(3,4,5-trifluorophenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.21 g, yield 92%) It was dissolved in methanol (3 mL), and aqueous potassium hydroxide (2 M, 3 mL) was added at room temperature and stirred for 2 hr. Hydrochloric acid (1 M) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. ) yellow solid. m p : 18 3 °C ;

Ή-NMR (400 MHz, CDC13) 6: 11.36 (1Η, s), 8.44 (1H, t, J = 6 Hz), 7.00 (2H, t, J = 7 Hz), 4.30 (2H, d, J = 6 Hz), 4.09 (2H, s), 2.64 (3H, s). (Example 73) ({[6-(3,4-dichlorobenzyl)-5-hydroxy-2-methylpyrimidine-4 -yl]carbonyl}amino)acetic acid OH Ο

-134- 201141839 (1) [({5-(Benzyloxy)-6-[l-(3,4-dichlorophenyl)-2-ethoxy-2-oxoethyl]-2 -methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), using (3,4-dichlorophenyl)acetate (0.23 g) and Example 1-(3) ({[5-(benzyloxy)-2) -methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate I (0.22 g) instead of (3,4, Ethyl 5-(trifluorophenyl)acetate gave the title compound (0.28 g,yield). 'H-NMR (400 MHz, CDC13) δ: 8.35 (1 H, t, J = 6 Hz),

7.44- 7.3 5 (5 H, m), 7.35 (1H, d, J = 2 Hz), 7.32 (1H, d, J = 8 Hz), 7.11 (1H, dd, J = 8 Hz, 2 Hz), 5.36 (1H, s), 5.13

(1 H, d, J = 1 1 Hz), 4.95 (1 H, d, J = 1 1 Hz), 4.25 (2H, q, J =7 Hz), 4.22 (2H, d, J = 6 Hz) , 4.18-4.09 (2H, m), 2.71 (3H, s), 1.30 (3H, t, J = 7 Hz), 1.17 (3H, t, J = 7 Hz). ^ (2)({[6- (3,4-Dichlorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 72-(2), and using [({5-(benzyloxy) 6-[1-(3,4-Dichlorophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid Ethyl ester (〇_28 g) in place of [({5-(benzyloxy)-6-[2-ethoxy-2-yloxy-1-(3,4,5-trifluorophenyl)) Ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound (0.14 g,yiel. -135- 201141839 mp : 2 2 3 °C ; *H-NMR (400 MHz, CDC13) δ: 11.33 (1H, s), 8.44 (1H, t, J = 6 Hz), 7.46 (1H, d, J = 2 Hz), 7.34 (1H, d, J = 8 Hz), 7.21 (1H, dd, J = 8 Hz, 2 Hz), 4.29 (2H, d, J = 6 Hz), 4.12 (2H, s) , 2.63 (3H, s). (Example 74) ({[5-Hydroxy-2-methyl-6-(4-methylbenzyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

(1) [({5-(Benzyloxy)-6-[2-methoxy-1-(4-methylphenyl)-2-yloxyethyl]-2-methylpyrimidine-4 -yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), and using (4-methylphenyl)acetic acid methyl ester (0.095 mL) and Example 1-(3) ({[5-(benzyloxy)-2-methyl) Ethyl 6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonylindole)acetate (0.24 g) in place of (3,4,5-trifluorophenyl) Ethyl acetate' gave the title compound (0.16 g, yield 62%). 'H-NMR (400 MHz, CDC13) δ: 8.33 (1Η, t, J = 6 Hz), 7.46 (2H, d, J.= 8 Hz), 7.42 -7.3 5 (3 H, m), 7.20 ( 2H, d, J = 8 Hz), 7.10 (2H, d, J - 8 Hz), 5.49 (1H, s), 5.08 (1H, d, J = 10 Hz), 4.86 (1H, d, J = 10 Hz), 4.24 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 6 Hz), 3.65 (3H, s), 2.71 (3H, s), 2.31 (3H, s), 1.30 ( 3H, t, J = 7 Hz). -136- 201141839 (2)({[5-Hydroxy-2-methyl-6-(4-methylbenzyl)pyrimidin-4-yl]carbonyl}amino) Acetic acid according to Example 72-(2) ' and using [({5_(benzyloxy)_6_[2-methoxy-1-(4-methylphenyl)-2-yloxyethyl]_2 _Methylpyrimidin-4-yl}carbonyl)amino]acetate (0.16 g) in place of [((5(benzyloxy)_6_[2_ethoxy]-2-yloxy-1-(3) , 4,5-Difluorophenyl)ethyl]-2-methylpyrimidin-4-ylsulfonylcarbonyl)amino]ethyl acetate' gave the title compound ( 〇〇64 g, yield 6%) as a white solid. 17 7 °C ; H-NMR (400 MHz, CDC13) δ: 11.28 (1Η, s), 8.43 (1H, t, J = 6 Hz), 7.26 (2H, d, J = 8 Hz), 7.08 (2H , d, J = 8 Hz), 4.27 (2H, d, J = 6 Hz), 4.14 (2H, s), 2.62 (3H, s), 2.29 (3H, s). ( Example 75) ({[5-Hydroxy-2-methyl --6- (3-methylbenzyl) pyrimidin--4_ yl] carbonyl} amino) acetate

(1) [({5-(Benzyloxy)-6-[2-ethoxy-indole-(-)-methylphenyl)-2-yloxyethyl]-2-methylpyrimidine-4- Ethyl}carbonyl)amino]ethyl acetate

According to Example 72-(1), using (3-methylphenyl)acetate (0.11 mL) and Example 1-(3) ({[5-(benzyloxy)-2-) Ethyl acetate-6--137- 201141839 Ethyl fluorophenyl), the title compound was obtained as the title compound {[(dimethylmethyl) ortho]oxy)pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5- (0.1 5 g, yield 61%) 'H-NMR (400 MHz, CDci3) &amp; 8 34 (ih, == 6 Hz), 7.45-7.42 ( 2H,m),7.4l,7 34 (3H,m),7 18 (1H,t,; = 8 Hz), 7.11-7.05 (3H,m),5 47 ( 1 H,s),5 〇7 (1H,d,; = 1〇HZ), 4.73 (1H,d,J = l〇Hz), 4.27 -4.0 9 (6H, m), 2.71 (3H, s), 2.28 (3H, s)

•29 (3H, t, J

Hz), 1.17 (3 H, t, J = 7 Hz). Methylbenzyl)pyrimidin-4-yl]carbonyl}amino) (2)({[5-hydroxy-2-methyl-6-( 3_Acetic acid according to fr Example 72-(2), and using [({5(benzyloxy)6[2ethoxy-1-(3-methylphenyl)-2-yloxyethyl]2A Pyrimidine I-based fluorenylcarbonyl)amino]acetic acid ethyl acetate (〇·ΐ5 g) in place of benzyloxyethoxy_2-o-oxy-1-(3,4,5-trifluorophenyl)ethyl </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; -NMR (400 MHz, CDClj) δ: 11.42 (1Η, s), 8.43 (1H, t, J = 6 Hz), 7.27-7.17 (3H, m), 7.02 (1H, d, J = 7 Hz), 4.27 (2H, d, J = 6 Hz), 4.21 (2H, s), 2.68 (3H, s), 2.31 (3H, s). (Example 76) ({[6-(4-chlorobenzyl)) -5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid-138- 201141839

(1) [({5-(Benzyloxy)-6-[l-(4-chlorophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidine-4- Ethyl}carbonyl)amino]ethyl acetate

({[5-(Benzyloxy)-2-methyl) according to Example 72-(1), using (4-chlorophenyl)acetate (0.12 mL) and Example 1-(3) -6-{[(Trifluoro(φ)methyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5-trifluorophenyl) Ethyl acetate gave the title compound (0.17 g, yield: 64%). 'H-NMR (400 MHz, CDC13) δ: 8 _ 3 4 (1 Η, t, J = 6 Η ζ), 7.45 - 7.3 6 (5 Η, m), 7.24-7.20 (4Η, m), 5.44 (1Η, s), 5.10

(1 H, d, J = 1 1 Hz), 4.92 (1 H, d, J = 11 Hz), 4.25 (2H, q, J -7 Hz), 4.22 (2H, d, J = 6 Hz), 4.17-4.09 (2H, m), 2.70

(3H, s), 1.30 (3H, t, J = 7 Hz), 1.17 (3H, t, J = 7 Hz). (2)({[6-(4-chlorobenzyl)-5-hydroxy- 2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 72-(2), and using [({5-(benzyloxy)-6-[1-(4-chlorophenyl)) -2-Ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.17 g) in place of [({5-(benzyloxy)) -6-[2-ethoxy-2-p-oxy-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid The title compound (0.061 g, yield 56%) -139- 201141839 mp : 2 0 3 °C ; 'H-NMR (400 MHz, CDC13) δ: 11.34 (1H, s), 8.44 (1H, t, J = 6 Hz), 7.31 (2H, d, J = 8 Hz), 7.24 (2H, d, J = 8 Hz), 4.28 (2H, d, J = 6 Hz), 4.15 (2H, s), 2.64 (3H, s). (Example 77) ({ [5-Hydroxy-6-(4-methoxybenzyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1) [({5-(Benzyloxy)-6-[2-ethoxy-1-(4-methoxyphenyl)-2-yloxyethyl]-2-methylpyrimidine- 4-yl}carbonyl)amino]ethyl acetate

According to Example 72_(1), and using (4-methoxyphenyl)acetate (0.18 mL) and Example 1-(3) ({[5-(benzyloxy)-2-) Ethyl 6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) in place of (3,4,5-trifluorophenyl) Ethyl acetate gave the title compound φ (〇·········· 'H-NMR (400 MHz, CDC13) δ: 8.34 (1Η, t, J = 6 Hz), 7.47 (2H, d, J = 8 Hz), 7.42- 7.3 5 ( 3 H, m), 7.24 (2H , d, J = 9

Hz), 6.82 (2H, d, J = 9 Hz), 5.46 (1H, s), 5.08 (1H, d, J = 11 Hz), 4.83 (1 H, d, J = 1 1 Hz), 4.25 ( 2H, q, J = 7 Hz), 4.22 (2H, d, J = 6 Hz), 4.18-4.09 (2H, m), 3.78 (3H, s), 2.71 (3H, s), 1.30 (3H, t , J = 7 Hz), 1.17 (3H, t, J = 7

Hz). -140- 201141839 (2) ({[5-Hydroxy-6-(4-methoxybenzyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 72- (2) and using [({5-(benzyloxy)-6-[2-ethoxy-1-(4-methoxyphenyl)-2-yloxyethyl]-2-yl) Ethyl pyrimidin-4-yl}carbonyl)amino]acetate (0.19 g) in place of [({5-(benzyloxy)-6-[2-ethoxy-2-oxo-l-() Ethyl acetate, 3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl} carbonyl)amino], the title compound (0.03 3 g, yield 59%) . Mp : 19 1 °C ; 'H-NMR (400 MHz, CDCI3) δ: 11.29 (1Η, s), 8.44 (1H, t, J = 6 Hz), 7.30 (2H, d, J - 9 Hz), 6.82 (2H, d, J = 9 Hz), 4.27 (2H, d, J = 6 Hz), 4.12 (2H, s), 3.76 (3H, s), 2.63 (3H, s). (Example 78) ({[6-(3,4-difluorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)

(1) [({5-(Benzyloxy)-6-[1-(3,4-difluorophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidine -4-yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), using (3,4-difluorophenyl)acetate (0.20 g) and Example 1-(3) ({[5-(benzyloxy)-2) -methyl-6-{[(-141 - 201141839 trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead (3,4, Ethyl 5-(trifluorophenyl)acetate gave the title compound (j.j. !H-NMR (400 MHz, CDC13) δ: 8.35 ( 1 Η, t, J = 4 Η ζ), 7.44-7.3 6 ( 5 Η, m), 7.19-7.16 (1Η, m), 7.06-7.00 ( 1 Η, m), 6.96-6.93 ( 1 H, m), 5.39 (1H, s), 5.12 (1H, d, J = 8 Hz), 4.96 (1 H, d, J = 8 Hz), 4.25 ( 2H, q, J = 7 Hz), 4.22 (2H,

d, J = 4 Hz), 4.12 (2H, q, J = 7 Hz), 2.71 (3H, s), 1.31 (3H, t, J = 7 Hz), 1.17 (3H, t, J = 7 Hz) (2) ({[6-(3,4-Difluorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to Example 72-(2), and using [({5-(benzyloxy)-6-[1-(3,4-difluorophenyl)-2-ethoxy-2-oxoethoxy) Ethyl acetate 2-(methylpyrimidin-4-yl}carbonyl)amino]acetate (0.18 g) in place of [({5-(benzyloxy)-6-[2-ethoxy-2-) Ethyl-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound (1. Yield 88%) yellow solid. Mp: 200-202 °C; 'H-NMR (400 MHz, CD3〇D) δ: 7.30-7. 1 2 (3H, m), 4.13 (2H, s), 4.12 (2H, s), 2.62 ( 3H, s). (Example 79) ({[6-(3,5-Difluorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid-142- 201141839

OH Ο F

Octaco2hoxy(l)[({5-(benzyloxy)-6-[l-(3,5-difluorophenyl)-2-ethoxy-2-lateral ethyl]-2-methyl Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), and using (3,5-difluorophenyl)acetic acid (0.20 g) and Example 1-(3) ({[5-(benzyloxy)-2-methyl) --φ Trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid (0.24 g) in place of ethyl (3,4,5-trifluorophenyl)acetate Title (0.25 g, yield 94%). 'H-NMR (400 MHz, CDC13) δ: 8_36 ( 1 H, t, J = 6 7.44-7.3 7 (5 H, m), 6.80 (2H, dd, J = 8 Hz, 2 Hz), (1H , dd, J = 9 Hz, 2 Hz), 5.38 (1H, s), 5.13 (1H, d, J Hz), 4.95 (1H, d, J = 11 Hz), 4.28 -4.22 (4H, m), 4.10 (2H, m), 2.71 (3H, s), 1.31 (3H, t, J = 7 Hz), (3H, t, J = 7 Hz). (2)({[6-(3,5- Difluorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl-3-yl)acetic acid according to Example 72-(2), using [({5-(benzyloxy)-6-[ 1 difluorophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl)amino]acetate (0.25 g) instead of [({5-( Benzyloxy)-6-[2 yl-2-yloxy- l-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidine-carbonyl)amino]acetate, The title compound was obtained (0.13 g,yield of yellow solid. ethyl ester 6-{[(ethyl esters Hz), 6.7 1 =11 4.18-1.18 s) amine (3,5-i) carbonyl-ethoxy"} 9%) -143- 201141839 mp : 17 9 °C ; 'H-NMR (400 MHz, CDC13) δ: 11.33 (1H, s), 8.45 (1H, t, J = 6 Hz), 6.90 (2H, d , J = 6 Hz), 6.65 (1H, t, J = 9 Hz), 4.3 0 (2H, d, J = 6 Hz), 4.15 (2H, s), 2.64 (3H, s). ( Example 80) [({5-Hydroxy-2-methyl-6-[4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

(1) ({[5-(Benzyloxy)-6-{2-ethoxy-2-oxoyl-1-[4-(trifluoromethyl)phenyl]ethyl) 2-methyl Pyrimidine-4-yl]carbonyl}amino)ethyl acetate

According to Example 72-(1), using [4-(trifluoromethyl)phenyl]acetate (0.23 g) and Example 1-(3) ({[5-(benzyloxy)) -2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5- Ethyl trifluorophenyl)acetate gave the title compound (0.25 g, yield 91%). 'H-NMR (400 MHz, CDC13) δ: 8.34 (1Η, t, J = 6 Hz), 7.52 (2H, d, J = 8 Hz), 7.44- 7.3 6 ( 7 H, m), 5.50 (1 H, s), 5.12

(1 H, d, J = 1 1 Hz), 4.95 (1 H, d, J = 1 1 Hz), 4.25 (2H, q, J =7 Hz), 4.22 (2H, d, J = 6 Hz) , 4.20-4.11 (2H, m), 2.70 (3H, s), 1.30 (3H, t, J = 7 Hz), 1.18 (3H, t, J = 7 Hz). (2) [({5-hydroxyl) -2-Methyl-6-[4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid-144- 201141839 According to Example 72-(2), and using (U5_( Benzyloxy)-6_{2_ethoxy-2-axyloxytrifluoromethyl)phenyl]ethyl}-2.methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate (0.25 g) in place of [({5-(benzyloxy)_6_[2-ethoxy-2-oxoyl-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidine) 4-Methyl}carbonyl)amino]ethyl acetate' gave the title compound (0.14 g,iel. Mp : 19 6 ° C ; *H-NMR (400 MHz, CDC13) δ: 11.33 (1H, s), 8.43 (1H, t, J = 6 Hz), 7.53 (2H, d, J = 8 Hz), 7.48 (2H, d, J = 8 Hz), 4.28 (2H, d, J = 6 Hz), 4.23 (2H, s), 2.63 (3H, s). (Example 81) [({5 - Hydroxy- 2-methyl-6-[4-(trifluoromethoxy)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

φ (^({[5-(Benzyloxy)_6-{2·methoxy-2-oxoyl-1-[4-(trifluoromethoxy)phenyl]ethyl}-2-) Ethylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

Me02C ΟΒη Ο

({[5-(Benzyloxy)) according to Example 72-(1)' and using [4-(trifluoromethoxy)phenyl]acetic acid methyl ester (0.23 g) and Example 1-(3) • 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxypyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5- Ethyl trifluorophenyl)acetate gave the title compound (0·25 g, yield: 78%). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 7.44-7.3 6 (5H, m), 7.31 (2H, d, J = 9 Hz), 7.11 (2H, d, J – 9 Hz), 5.48 (1H, s), 5.12 (1H, d, J = 11 Hz), 4.95 (1H, d, J = 11 Hz), 4.25 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 6

Hz), 3.66 (3H, s), 2.71 (3H, s), 1.30 (3H, t, J = 7 Hz). (2)[({5-hydroxy-2-methyl- 6- [4_(three) Fluoromethoxy)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid was used according to Example 72-(2)' and ({[5-(benzyloxy)-6-{2-methoxy-) 2-Ethyloxy-1-[4-(trifluoromethoxy)phenyl]ethyl-2-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.25 g) in place of [({ 5-(Benzyloxy)-6-[2-ethoxy-2-oxo-l-(3,4,5-trifluorophenyl)ethyl]_2-methylpyrimidin-4-yl}carbonyl The title compound (0.15 g, yield 93%) ofyield Mp : 15 6 ° C ; ^-NMR (400 MHz, CDClj) δ: 11.32 (1 Η, s), 8.44 (1H, t, J = 6 Hz), 7.40 (2H, d, J = 9 Hz), 7.12 (2H, d, J = 9 Hz), 4.29 (2H, d, J = 6 Hz), 4.18 (2H, s), 2.63 (3H, s). (Example 82) ({[6-(3, 5-dichlorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl)amino)acetic acid

(1) [({5-(Benzyloxy)-6-[1-(3,5-dichlorophenyl)-2-methoxy-2-oxoethyl]-2-methylpyrimidine -4-yl}carbonyl)amino]ethyl acetate-146- 201141839 ΟΒη Ο

M8 according to Example 7 2 - (1), and using (3,5-dichlorophenyl)acetic acid methyl ester (0.22 g) and Example 1-(3) ({[5-(benzyloxy) Instead of (3,4, ethyl-2-methyl-6·{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) Ethyl 5-(trifluorophenyl)acetate gave the title compound (0 - 22 g, yield 78%).

H-NMR (400 MHz, CDC13) δ: 8.37 (1 H, t, J = 6 Hz), 7.44- 7.3 7 (5 H, m), 7.26 (1H, m), 7.14 (2H, d, J = 2 Hz), 5.35 (1H, s), 5.15 (1H, d, J = 11 Hz), 4.95 (1H, d, J = 11 Hz), 4.26 (2H, q, J = 7 Hz), 4.23 (2H , d, J = 6 Hz), 3.66 (3H, s), 2.72 (3H, s), 1.31 (3H, t, J = 7 Hz). (2)({[6-(3,5-Dichloro) Benzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 72-(2), and using [({5-(benzyloxy)-6-[1] -(3,5-φ Dichlorophenyl)-2-methoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.22 g) Instead of [({5-(hydroxy)-6-[2-ethoxy-2-oxo-l-(3,4,5-trifluorophenyl)ethyl]-2-methyl) Ethylpyrimidin-4-yl}carbonyl)amino]acetate gave the title compound (0.13 g, yield: Mp : 204-206 ° C ; ^-NMR (400 MHz, CDC13) δ: 11.34 (1 Η, s), 8.45 (1H, t, J = 6 Hz), 7.26 (2H, d, J = 2 Hz), 7.21 (1H, t, J = 2 Hz), 4.30 (2H, d, J = 6 Hz), 4.12 (2H, s), 2.64 (3H, s). -147- 201141839 (Embodiment 83) ({[ 5-hydroxy-2-methyl-6-(2-naphthylmethyl)pyrimidin-4-yl] acid

八C02H (1)[({5-(Benzyloxy)-6-[2-ethoxy-1-(2-naphthyl)-2-2-methylpyrimidin-4-yl}carbonyl)amino group Ethyl acetate

EtO,C ΟΒη Ο iTc〇2Et According to Example 72-(1), and using (2-naphthyl)acetic acid and Example 1-(3) ({[5-(Benzyloxy)-2-) Ethyl (-)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid ethyl acetate (3,4,5-trifluorophenyl)acetate was used to obtain the titled quantitative yield. 'H-NMR (400 MHz, CDC13) δ: 8.34 (1 H, t carbonyl}amino) ethyl ΟΗ Ο

Side oxyethyl]-

Ethyl ester (0.21 g) 5-{[(trifluoromethyl ester (0.24 g) as a compound (0.27 g, J = 6 Hz), (1 H, s), 7.5 1 5.67 (1 H, s ), 11 Hz), 4.24 16 (2H, q, J = 1.18 (3H, t, J ]carbonyl}amino) 7.82 -7.76 (2H, m),: 7.73-7 .70 (1 H, m), 7.65 (1H, dd, J = 8 Hz, 2 Hz), 7.46-7.35 (7H, m), 5.11 (1H, d, J = 1 1 Hz), 4.79 (1H, d, J = (2H, q, J : -7 Hz), 4. 2 1 (2H,d, J = 6 Hz) , 4 · 7 Hz), 2.73 (3H, s), 1.29 (3H, t, J =7 Hz), = 7 Hz). (2) ({[5-Hydroxy-2-methyl-6-(2-naphthylmethyl)pyrimidine-4-g acetic acid-148- 201141839 according to Example 72-(2), and used [({5-(Hydroxy)-6·[2-ethoxy-1(2 τ))2 oxyethyl]_2_methylpyrimidin-4-yl}mineral)amino]acetic acid Ethyl ester (0.27 g) in place of [({5-(ethoxy ethoxy ethoxy]·teroxy-1-(3,4,5-fluorophenyl)ethyl b-2-methylpyrimidine) 4-Methyl}carbonyl)amino]ethyl acetate' gave the title compound (4 g, m.

H-NMR (400 MHz, CDC13) δ: 11.34 (1H, s), 8.44 (1H, t, J = 6 Ηζ), 7.8 0-7.74 (4 Η, m), 7.51 (1Η, dd, J = 8 Ηζ ,2

Hz), 7.46- 7.3 9 (2H, m), 4.35 (2H, s), 4.27 (2H, d, J = 6 Hz), 2.64 (3H, s). (Example 84) ({[5 - -6-(4-isopropylbenzyl)-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid OH Ο

N^co2h (1)[({5-(Benzyloxy)-6-[1-(4-isopropylphenyl)_2-methoxy-2-oxoethyl]-2-methyl Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

MeO^C ΟΒη Ο

y 八C02Et 依照 according to Example 7 2 - (1), using (4-isopropylphenyl)acetic acid methyl ester (0.19 g) and Example 1-(3) ({[5_(benzyloxy) ) 2-(methyltrifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) in place of (3,4,5-trifluorophenyl)acetic acid The title compound (0.25 g, yield 95%) was obtained. -149- 201141839 'H-NMR (400 MHz, CDC13) δ: 8.32 (1 H, t, J = 6 Hz), 7.46-7.43 (2H, m), 7.41-7.35 (3H, m), 7.23 (2H , d, J = 8 Hz), 7.14 (2H, d, J = 8 Hz), 5.50 ( 1 H, s), 5.08 (1 H, d, J = 11 Hz), 4.85 ( 1 H, d, J = 1 1 Hz), 4.25 (2H, q, J = 7 Hz), 4.2 1 (2H, d, J = 6 Hz), 3.66 (3H, s), 2.87 (1H, m), 2.71 (3H, s ), 1.30 (3H, t, J = 7 Hz), 1.22 (6H, d, J = 7 Hz). (2)({[5-hydroxy-6-(4-isopropylbenzyl)-2-) Methylpyrimidin-4-yl]carbonyl}amine

Acetic acid according to Example 72-(2), and using [({5-(benzyloxy)-6-[1-(4-isopropylphenyl)-2-methoxy-2- sideoxy) Ethyl ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (〇·25 g) in place of [({5-(benzyloxy)-6-[2-ethoxy] Ethyl 2-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound (0.091 g , yield 55%) light yellow solid. Mp: 67-69 °C;

'H-NMR (400 MHz, CDCI3) δ: 11.34 (1H, s), 8.44 (1H, t, J = 6 Hz), 7.32 (2H, d, J = 8 Hz), 7.14 (2H, d, J = 8 Hz), 4.27 (2H, d, J = 6 Hz), 4.18 (2H, s), 2.86 (1H, m), 2.65 (3H, s), 1.2 1 (6H, d, J = 7 Hz) (Example 8 5 ) ({[6-(Biphenyl-4-ylmethyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid hydrazine Ο

-150- 201141839 -2 -Sideoxyethyl(1)({[5-(benzyloxy)-6-(1-biphenyl-4-yl-2-methoxy)-2-methylpyrimidine) _4_yl]carbonyl}amino)ethyl acetate

({[5-(Benzyloxy)-2-methyl)ylsulfonyl) obtained according to Example 72-(1), using biphenyl-4-yl g) and Example 1-(3) Oxy}pyrimidin-4-yl]carbonyl}•amino)acetamidine in place of ethyl (3,4,5-trifluorophenyl)acetate afforded g, yield 91%). 'H-NMR (400 MHz, CDC13) δ: 8.35 (1Η, t,: (2H, d, J = 8 Hz), 7.51 (2H, d, J = 8 Hz), 7 m), 5.56 (1 H , s), 5.12 ( 1 H, d, J = 11 Hz), 4 11 Hz), 4.25 (2H, q, J = 7 Hz), 4.22 (2H, 3.68 (3H, s), 2.73 (3H, s ), 1.30 (3H, t, J = (2) ( {[6-(biphenyl-4-ylmethyl)-5-hydroxy-2-methylpyrimidinyl)acetic acid according to Example 72-(2), And ({[5-(benzyloxy-4-yl-2-methoxy-2-oxoethyl)-2-methylpyrimidinyl)acetate (0.25 g) was used instead of [({5 Ethyl-(benzyloxy)-p-oxy-1 -(3,4,5-trifluorophenyl)ethyl]-2-methylpyridinyl]acetate gave the title compound (0.14 g, Mp : 2 14 ° C ; methyl acetate (0.23 base-6-{[(trifluoromethyl ethyl ester (0.24 g)) compound (〇· 2 5 \ = 6 Hz), 7.56 .48 - 7.3 0 ( 1 0H, •92 (1H, d, J = d, J = 6 Hz), 7 Hz). -4-yl]carbonyl}amino)-6 - (1-biphenyl-_4_yl)carbonyl}amine 6-[2-ethoxy-2-D疋-4-yl} group) Yield 83%) Light yellow-151 - 201141839 'H-NMR (400 MHz, CDC13) δ: 11.34 (1H, s) , 8.45 (1H, t, J = 6 Hz), 7.5 6- 7.5 0 (4H, m), 7.46 -7.3 9 (4H, m), 7.32 (1H, t, J = 7 Hz), 4.28 (2H, d, J = 6 Hz), 4.23 (2H, s), 2.65 (3H, s). (Example 86) ( {[6-(3,4-Dimethylbenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid hydrazine Ο

(1) [({5-(Benzyloxy)-6-[1-(3,4-dimethylphenyl)-2-ethoxy-2-oxoethyl]-2-methyl) Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), using (3,4-dimethylphenyl)acetate (0.19 g) and Example 1-(3) ({[5-(benzyloxy)-) 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5-three Ethyl fluorophenyl)acetate afforded the title compound (0.27 g, yield quantitative). 'H-NMR (400 MHz, CDCI3) δ: 8.33 (1 H, t, J = 6 Hz), 7.4 6-7.43 (2H, m), 7.41-7.35 (3H, m), 7.06-7.04 (3 H , m), 5.4 5 (1H, s), 5.07 (1H, d, J = 10 Hz), 4.77 (1H, d, J = 10 Hz), 4.25 (2H, q, J = 7 Hz), 4.2 1 (2H, d, J = 6 Hz), 4.16-4.08 (2H, m), 2.71 (3H, s), 2.21 (3H, s), 2.19 (3H, s), 1.30 (3H, t, J = 7 Hz), 1.17 (3H, t, J = 7 Hz). -152- 201141839 (2)({[6-(3,4-Dimethylbenzyl)-5-hydroxy-2-methylpyrimidine-4 -yl]carbonyl]amino)acetic acid according to Example 72-(2), and using [({5-(benzyloxy)-6-[1-(3,4-dimethylphenyl))-2- Ethyl ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.27 g) in place of [({5-(benzyloxy)-6-) [2-Ethoxy-2-oxo-l-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate, The title compound (0.14 g, mp. Mp : 1 8 2 - 1 8 3 °C ; ^-NMR (400 MHz, CDC13) δ: 11.29 (1H, s), 8.44 (1H, t, J - 6 Hz), 7.14 (1H, s), 7.11 (1H, d, J = 7 Hz), 7.04 (1H, d, J - 7 Hz), 4.27 (2H, d, J = 6 Hz), 4.12 (2H, s), 2.63 (3H, s), 2.22 (3H, s), 2.20 (3H, s). (Example 87) [({5-Hydroxy-2-methyl-6-[3-(trifluoromethyl)benzyl]pyrimidin-4-yl} Carbonyl) #amino]acetic acid

(1) ({[5-(Benzyloxy)-6-{2-methoxy-2-oxoyl-1-[3-(trifluoromethyl)phenyl]ethyl}-2-) Ethylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

According to Example 7 2 - (1), and using [3-(trifluoromethyl)phenyl]acetic acid methyl ester (0.22 g) and Example 1-(3) ({[5-(benzyloxy) -2-methyl--153- 201141839 6-{[(Trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead (3 Ethyl acetate, 4,5-trifluorophenyl) gave the title compound (0.25 g, yield 93%). • H-NMR (400 MHz, CDC13) δ: 8.36 (1Η, t, J = 6 Hz), 7.5 5 - 7.5 2 (2 H, m), 7.48 (1H, d, J = 8 Hz), 7.45 - 7.3 7 (6H, m), 5.50 (1H, s), 5.13 (1H, d, J = 11 Hz), 4.99 (1H, d, J = 11 Hz), 4.25 (2H, q, J = 7 Hz) , 4.23 (2H, d, J = 6 Hz), 3.66 (3H, s), 2.71 (3H, s), 1.31 (3H, t, J = 7 Hz).

(2) [({5-Hydroxy-2-methyl-6-[3-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 72-(2), And using ({[5·(benzyloxybubu)methoxy-2-oxooxytrifluoromethyl)phenyl]ethyl 2methylpyrimidin-4-yl]-based}amino)acetic acid Ethyl vinegar (0.25 leopard instead of [({5_(pre-oxy)_6_[2_ethoxy-2-yloxy-1-(3,4,5-trifluorophenyl)ethyl]_2_A Ethyl pyridyl}carbyl)amino]acetic acid ethyl acetate gave the title compound ( 〇 14 g, yield: 5%) as a pale yellow solid.

Mp: 16 6 °C; H-NMR (400 MHz, CDCl3) u 33 (1H, s), 8 44 ( 1 H, t, J = 6 Hz), 7.64 (1H, s), 7.56 (iH, d , j = 8 Hz)j 7.47 (1H, d,...HZ), 7.39 (1H,t,...Hz), 4 2 9 (2H,d,... Hz), 4.23 (2H,s), 2.63 (3H, S)· (Example 88) ({[6-(4-ethoxycarbonyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid-154- 201141839 OH Ο Ο

Octaco2h (l)[({5-(Benzyloxy)-6-[l-(4-ethoxyphenyl)-2-methoxy-2-oxoethyl]-2-methyl Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), and using (4-ethoxyphenyl)acetic acid methyl ester (0.19 g) and Example 1-(3) ({[5-(benzyloxy)-2-) Methyl-6-{[((trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5-trifluoro) Phenylacetic acid ethyl acetate gave the title compound (0.25 g, yield 97%).

[H-NMR (400 MHz, CDC13) δ: 8.34 (1H, t, J = 6 Hz), 7_47 (2H, d, J = 7 Hz), 7.47-7.3 5 (3 H, m), 7.22 (2H , d, J = 9 Hz), 6.81 (2H, d, J = 9 Hz), 5.47 (1H, s), 5.08 (1H, d, J = 10 Hz), 4.84 (1 H, d, J = 10 Hz), 4.25 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 6 Hz), 4.00 (2H, q, J = 7 Hz), 3.65 (3H, s), 2.71 (3H, s), 1.39 (3H, t, J = 7 Hz), 1.30 (3H, t, J = 7 Hz). (2)({[6-(4-ethoxybenzyl)-5-hydroxy-2) -Methylpyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 72-(2), and using [({5-(benzyloxy)-6-[1-(4-ethoxyphenyl) -2-methoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.25 g) in place of [({5-(benzyloxy) -6-[2-ethoxy-2-oxo-l-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}-155- 201141839 carbonyl The title compound (〇14 g, yield 85%) was obtained as pale yellow solid. Mp : 18 0 ° C ; 'H-NMR (400 MHz, CDC13) δ: 11.30 (1H, s), 8.44 (1H, t, J = 6 Hz), 7.28 (2H, d, J = 9 Hz), 6.80 (2H, d, J = 9 Hz), 4.27 (2H, d, J = 6 Hz), 4.12 (2H, s), 3.98 (2H, q, J = 7 Hz), 2.63 (3H, s), 1.37 (3H, t, J = 7 Hz). (Example 89) ({[6-(4-chloro-2-fluorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl} Amino) acetic acid

(1) [({5-(Benzyloxy)-6-[1-(4-chloro-2-fluorophenyl)-2-ethoxy-2-oxoethyl]-2-methyl Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), and using (4-chloro-2-fluorophenyl)acetate (0.22 g) and Example 1-(3) ({[5-(benzyloxy)_2) -methyl-6·{[(trifluoromethyl)sulfonyl]oxy}pyrimidinyl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5-trifluorophenyl) The title compound (〇_21 g, yield 79%) was obtained from ethyl acetate. 'H-NMR (400 MHz, CDC13) δ: 8.3 4 (1Η, t, J = 6 Η ζ), 7.44-7.42 (2H, m), 7.3 8 - 7.3 3 (3H, m), 7·24 ( 2H,d,J = 8

Hz), 7.0 8 -7.03 ( 1 H, m), 5.78 (1H, s), 5.14 (1H, d, J = 11 201141839

Hz), 4.98 (1H, d, J = 11 Hz), 4.26 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 4.16-4.08 (2H, m), 2.69 ( 3H, s), 1.31 (3H, t, J = 7 Hz), 1.16 (3H, t, J = 7 Hz). (2)({[6-(4-chloro-2-fluorobenzyl)-5 -hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to Example 72-(2), and using [({5-(benzyloxy)-6-[1-(4-chloro-2-fluorophenyl)-2-ethoxy-2-oxooxy) Ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.21 g) in place of [({5-(benzyloxy)-6-[2-ethoxy-2- Ethyloxy-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound (1. , yield 74%) White solid. Mp : 18 4 ° C ; j-NMR (400 MHz, CDC13) δ: 11.31 (1H, s), 8_45 (1H, t, J - 6 Hz), 7.18 (1H, t, J = 8 Hz), 7.09 -7.04 (2H, m), 4.29 (2H, d, J = 6 Hz), 4.18 (2H, s), 2.61 (3H, s). φ (Example 9〇) ({[6-(3-Chlorine) -4-methylbenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1) [({5-(Benzyloxy)-6-[1-(3-chloro-4-methylphenyl)-2-ethoxy-2-oxoethyl]-2-yl) Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

-157-201141839 According to Example 72-(1), using (3-chloro-4-methylphenyl)acetate (0.21 g) and Example 1-(3) ({[5-( Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead (3, Ethyl 4,5-trifluorophenyl)acetate gave the title compound (0.23 g,iel. • H-NMR (400 MHz, CDC13) δ: 8.35 (1Η, t, J = 6 Η ζ),

7.46-7.42 (2Η, m), 7.42 -7.3 6 (3 Η, m), 7.27 (1Η, d, J = 2 Hz), 7.13 ( 1 H, d, J = 8 Hz), 7.08 ( 1 H, Dd, J = 8 Hz, 2 Hz), 5.40 (1H, s), 5.10 (1H, d, J = 10 Hz), 4.86 (1H, d, J = 10 Hz), 4.25 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 6 Hz), 4.16-4.10 (2H, m), 2.71 (3H, s), 2.33 (3H, s), 1.30 (3H, t, J = 7 Hz) , 1.17 (3H, t, J = 7 Hz). (2) ({[6-(3-Chloro-4-methylbenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl} Amino)acetic acid

According to Example 72-(2), and using [({5-(benzyloxy)-6-[1-(3-chloro-4-methylphenyl)-2-ethoxy-2-oxoxy) Ethyl ethyl 2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.23 g) in place of [({5-(benzyloxy)-6-[2-ethoxy-2) -ethyloxy-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound (0.12 g. Rate 8 3%) white solid. Mp : 18 8 ° C ; h-NMR (400 MHz, CDC13) δ: 1 1 _ 7 1 ( 1 Η, s ), 8. 3 7 (1 Η, brs), 7.43 (1Η, s), 7.31- 7.29 (1H, m), 7.15 (1H, d, J = 8 -158- 201141839

Hz), 4.30 (2H, S), 4.25 (2H, d, J = 5 Hz), 2 2.32 (3H, s). (Example 9 1) [({6-[(4'-Fluorobiphenyl)- 4_yl)methyl]_5_hydroxy-2-methylzincylamino)acetic acid•76 (3H, s), 1 steep-4-yl}羯

OH 〇

(1) [({5-(Benzyloxybromophenyl)-2-ethoxy-2]_2.methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate Et〇2C ΟΒη Ο , co2Et

({[5-(Benzyloxy)-2-methyl)sulfonyl) obtained according to Example 72-(1), using (4-bromophenyl)ethylg) and Example 1-(3) Alkyloxy]pyrimidin-4-yl]carbonyl]amino)acetic acid; substituting ethyl (3,4,5-trifluorophenyl)acetate to give the title g, yield 81%) . 'H-NMR (400 MHz, CDC13) δ: 8.35 (1Η, t, d (2H, dd, J = 8 Hz, 2 Hz), 7.41-7.36 (5H, m), J = 8 Hz), 5.42 ( 1H, s), 5.11 (1H, d, J = - side oxyethyl (1H, d, J = 10 Hz), 4.25 (2H, q, J = 7 Hz), 4. =6 Hz), 4.13 (2H, q, J = 7 Hz), 2.70 (3H, s), J = 7 Hz), 1.17 (3H, t, J = 7 Hz). (2)[({5-(Benzyloxy)- 6-[2-Ethoxy-l-(4'-fluorobiphenyl-4-ylethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid ethyl acetate (0.24 • 6- {[(Trifluoromethyl: ester (0.22 g) compound (0.2 3 6 Hz), 7.44 7-16 (2H, d, 〇Hz), 4.92 22 (2H, d, J 1.30 (3H, t, -yl) -2_ side oxygen-159- 201141839

N χο2β H [({5-(Benzyloxy)-6-[l-(4.bromophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidine-4 -yl}carbonyl)amino]acetate (〇3 g) and (4-fluorophenyl)boronic acid (〇.〇32 g) are dissolved in 1,2-dimethoxyethane (35 mL). After adding palladium acetate (0.0052 g), triethylenediamine (0.0052 g) and potassium carbonate (0.095 g) under a nitrogen atmosphere, the mixture was heated under reflux for 4 hours. The reaction solution was cooled to room temperature and then water was added. The organics were extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the residue obtained was purified by silica gel column chromatography to give the title compound (yel. 13 g, yield 97%) as white solid. 'H-NMR (400 MHz, CDC13) δ: 8.35 (1Η, t, J = 6 Hz), 7.5 3 - 7.3 4 (9H, m), 7.16 (2H, d, J = 9 Hz), 7.10 (2H ,t,J =9 Hz), 5.53 (1H,s),5.11 (1H,d,J = l〇Hz), 4.91 (1H, d,J = 1 0 H z),4 · 2 6 (2 H ,q,J = 7 H z),4 2 2 (2 H,d,]=6 Hz),4_17 (2H,q,J = 7 Hz), 2_72 (3H,s),1.30 (3H,t, J =

Hz).

7 Hz), 1.19 (3H, t, (3H({6-[(4'-fluorobiphenyl-4-yl)methyl)hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid According to Example 72-(2), and using [({5_(oxy).6·[2·Ethyl-indenyl 4'-fluorobiphenyl-4-yl)-2-yloxyethyl] Winter methyl hydrazide steeply fluorenyl)amino]acetic acid ethyl acetate (0.13 g) instead of [((Μ 氧基 oxy)·6·[2 ^ oxy 2 _ _ oxy group (3, 4, 5-triphenylphenyl)ethyl]-2-methylpyrimidine_4_3-160-201141839} carbonyl)amino]acetic acid ethyl acetate gave the title compound (0.06 3 g, yield 72%) as a yellow solid. mp: 219 -221 °C; 'H-NMR (400 MHz, CDC13) δ: 11.33 (1H, s), 8.45 (1H, t, J = 6 Hz), 7.5 2 -7.42 (6H, m), 7.10 (1 H , d, J = 9 Hz), 7.08 (1H, d, J = 9 Hz), 4.28 (2H, d, J = 6 Hz), 4.22 (2H, s), 2.65 (3H, s). (Example 92) [({6-[(3 chlorobiphenyl-4-yl)methyl]-5.hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid]

(1) [({5-(Benzyloxy)-6-[1-(3'-chlorobiphenyl-4-yl)-2-ethoxy-2-oxoethyl]-2-yl) Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

[({5-(Benzyloxy)-6-[1-() obtained according to Example 91-(2) and using (3-chlorophenyl)boronic acid (0.12 g) and Example 91-(1) 4-bromophenyl)-2.ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.21 g) instead of (4-fluoro Phenyl)boronic acid gave the title compound (0.22 g, yield 97%) as a yellow solid.

'H-NMR (400 MHz, CDCI3) δ: 8.36 (1Η, t, J = 6 Hz), 7.53 (1 H, d, J - 2 Hz), 7.4 8 -7.2 9 ( 1 2H, m), 5.53 ( 1 H, s), 5.12 (1 H, d, J = 1 1 Hz), 4.9 1 (1 H, d, J = 11 Hz), 4.26 (2H, q, J -161 - 201141839 =7 Hz) , 4.22 (2H, d, J = 6 Hz), 4.17 (2H, q, J = 7 Hz), 2.73 (3H, s), 1.30 (3H, t, J = 7 Hz), 1.19 (3H, t, J = 7

Hz). (2) [({6-[(3'-chlorobiphenyl-4-yl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Example 72-(2), and using [({5-(benzyloxy)-6-[1-(3'-chlorobiphenyl-4-yl)-2-ethoxy-2- sideoxy) Ethyl ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (〇·22 g) in place of [({5-(benzyloxy)-6-[2-ethoxy] 2-Ethyloxy-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound. 〇 4 5 g, yield 27%) yellow solid. Mp : 1 92 - 1 9 3 °C ; 'H-NMR (400 MHz, CDC13) δ: 11.33 (1Η, s), 8.45 (1H, t, J = 6 Hz), 7.53-7.41 (6H, m) , 7.3 5 -7.26 (2 H, m), 4.29 (2H, d, J = 6 Hz), 4.22 (2H, s), 2.65 (3 H, s).

(Example 93) [({6-[(4'_chlorobiphenyl-4-yl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid]

(1) [({5-(Benzyloxy)-6-[1-(4'-chlorobiphenyl-4-yl)-2-ethoxy-2-oxoethyl]_2-methyl Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

-162- 201141839 [({5-(Benzyloxy)_6_π_(4) obtained according to Example 91-(2), using (4-chlorophenyl)boronic acid (〇12 3) and Example 91-U) _Bromophenyl)_2_ethoxy-2-alkoxyethyl]-2-methylpyrano-4_yl}carbonyl)amino]acetic acid ethyl acetate (0·2! g) instead (4 Benzene acid, the title compound (〇Μ g, yield 89%) was obtained as a yellow amorphous solid. 'H-NMR (400 MHz, CDC13) δ: 8 3 S (1 u . τ UH, t, J = 6 Hz)) 7.49-7.45 (6H,m),7.42-7.3 6 (7H,5 ” , ' ,S), 5ll Lu (1H, d, J = 10 Hz), 4.92 (1H,d, J= 1〇Hz), 4 26 (2H,q ^ =7 Hz), 4.22 (2H, d, J = 6 Hz), 4.17 /·〇Η a τ nw UH, q, J = 7 Hz),

2_72 (3H, s), 1.30 (3H, t, J = 7 Hz), 119 (3H ′ , , t, J = 7

Hz). Anthracene-2.methylpyrimidin-4-yl}carbonyl)amino]acetic acid was used according to Example 72-(2), and [({5•(oxy))_6_π_(仏气苯苯_ 4_yl)-2-ethoxy·2· side oxygen

W oxyethyl]-2-methylpyrimidine _4·yl

Ethyl acetate]acetate (0.20 X Μ in place of [({5-(benzyloxy)-6_[2·7 per yl-2-yloxy-1-(3,4,5-^ _) ~Amino)Ethyl]-2-methylpyrimidine-4_carbamoyl)amino]acetate, magnetic &amp; 1 silly title compound (0·〇35 g stem 26%) yellow solid. Mp: 236-238 °C; 1 H-NMR (4 00 MHz, CD ci 3) δ: 11.32 (1H, s), 8.45 (iH' t J = 5 Hz), 7.49 - 7·45 (6H ' ' , work), 7.38 (2H, d, J = 9 HZ), 4.28 (2H, d, J = 5 Hz), 4.22 s), 2.64 (3H, s). Ί63- 201141839 (Embodiment 9 4) [( {6-[(6-fluoro-2-naphthyl)methyl]-5-yl-2-methylpyrano-4-yl}p-amino)amino]acetic acid

(1) (6-fluoro-2-naphthyl)methanol

Methyl 6-fluoro-2-naphthoate (1.0 g) was dissolved in tetrahydrofuran (15 mL), and lithium aluminum hydride (〇 · 19 g) was slowly added at 〇 ° C under a nitrogen atmosphere. 〇 Stir for 30 minutes' and stir at room temperature for 1 hour. The reaction solution was cooled to 〇t, and a few drops of water and hydrochloric acid (1 Torr) were added dropwise, followed by vigorous stirring. The resulting precipitate was filtered through EtOAc (EtOAc)EtOAc. 'H-NMR (400 MHz, CDC13) δ: 7.84-7.82 (2Η, m), 7.79 (1H, d, J = 9 Hz), 7.51 (1H, d, J = 9 Hz), 7.45 (1H, dd , J = 10 Hz, 3 Hz), 7.27 (1H, dt, J = 9 Hz, 3 Hz), 4.86 (2H, d, J = 5 Hz), 1.75 (1 H, d, J = 5 Hz). (2) 2-(bromomethyl)-6-fluoronaphthalene

(6-Fluoro-2·naphthyl)methanol (0.89 g) was dissolved in tetrahydrofuran (15 mL), and phosphorus tribromide (0.24 mL) was added dropwise at 〇 ° C under a nitrogen atmosphere, and then stirred at the same temperature. In a minute, stir at room temperature for 1.5 hours. After a saturated aqueous sodium hydrogencarbonate solution was added to the mixture, the organic layer was extracted with ethyl acetate. The organic-164-201141839 layer was washed with a saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to afford the title compound (1.1 g, yield quantitative). 'H-NMR (400 MHz, CDC13) δ: 7.8 3 - 7.8 0 (2Η, m), 7.78 (1H, d, J = 9 Hz), 7.53 (1H, d, J = 9 Hz), 7.45 (1H , dd, J = 10 Hz, 2 Hz), 7.29 (1H, dt, J = 9 Hz, 2 Hz), 4.65 (2H, s). (3) (6-fluoro-2-naphthyl)acetonitrile

2-(Bromomethyl)-6-fluoronaphthalene (1.1 g) was dissolved in dichloromethane (10 mL), sodium cyanide (0.49 g), tetrabutylammonium bromide (0.16 g) and water (5) After 5.5 mL, the mixture was vigorously stirred at room temperature for 5 hours under a nitrogen atmosphere. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. H-NMR (400 MHz, CDC13) δ: 7.8 5 -7.8 0 (3 Η, m), 7.45 (1H, dd, J = 10 Hz, 3 Hz), 7.41 (1H, d, J = 9 Hz), 7.30 (1H, dt, J = 9 Hz, 3 Hz), 3.91 (2H, s). (4) (6-Fluoro-2-naphthyl)acetic acid benzyl acetate

(6-Fluoro-2-naphthyl)acetonitrile (〇·8 8 g) was suspended in water (5 m L), concentrated sulfuric acid (5 mL) was added, and the mixture was refluxed for 3 hours. After the reaction mixture was cooled to room temperature and water was added, the organic layer was extracted with diethyl ether, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the precipitated solid was collected by filtration, whereby (6-fluoro-2-naphthalenyl)acetic acid (0.97 g, yield quantitative) was obtained as a pale red solid-165-201141839 (6) -Fluoro-2-naphthalenyl)acetic acid (0.51 g) was dissolved in acetonitrile (10 mL). After adding benzyl bromide (0.36 mL) and potassium carbonate (0.83 g), the mixture was heated to reflux for 1 hour under nitrogen atmosphere. After water was added to the reaction mixture and the mixture was evaporated. After the solvent was evaporated under reduced pressure. 'H-NMR (400 MHz, CDC13) δ: Ί .19-Ί .12 (3Η, m), 7.45-7.42 (2Η, m), 7.36-7.31 (5Η, m), 7.25 (1H, dt, J = 9 Hz, 3 Hz), 5.15 (2H, s), 3.82 (2H, s). ^ (5)[({5-(Benzyloxy)-6-[2-(benzyloxy)-1- (6-fluoro-2-naphthyl)-2-oxoethylethyl-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), and using (6-fluoro-2-naphthyl)acetic acid benzyl ester (0.29 g) and Example 1-(3) ({[5-(benzyloxy)-2) -methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5·trifluoro Ethyl phenyl)acetate gave the title compound (yield: 27 g, yield: 85%). 'H-NMR (400 MHz, CDC13) δ: 8.33 (1Η, t, J = 5 Hz), 7.71-7.65 (2H, m), 7.62 (1H, s), 7.51 (1H, dd, J = 9 Hz , 2 Hz), 7.40 (1H, dd, J = i〇Hz, 2 Hz), 7.36-7.19 (11H, m), 5.68 (1H, s), 5.22 (1H, d, J = 13 Hz), 5.11 (1H, d, J = 13

Hz), 5.08 (1H, d, J = π Hz)&gt; 4.79 (ih, d, J = 11 Hz), 4.24 (2H, q, J = 7 Hz), 4.20 (2H, d, J = 5 Hz) ), 2.68 (3H, s), 1.29 (3H, t, J = 7 Hz). -166 - 201141839 (6) [({6-[(6-fluoro-2-naphthyl)methyl]-5- Hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[({5-(Benzyloxy)-6-[2-(benzyloxy)-1-(6-fluoro-2-naphthyl)-2-yloxyethyl]-2-methylpyrimidine) Ethyl acetate (0·27 g) was dissolved in ethyl acetate (5 mL), 5% palladium-activated carbon (0.050 g) was added, and then stirred at room temperature under hydrogen atmosphere. 5 . 5 hours. After the reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give [({6-[(6-fluoro-2-naphthalenyl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amine Ethyl acetate (0.16 g, yield 92%) as a white solid. This was dissolved in methanol (3 mL), and aqueous sodium hydroxide (1 M, 1.5 mL) was added at room temperature, and the mixture was stirred for one hour and then left overnight. Hydrochloric acid (1 M) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. solid. Mp : 2 0 6 ° C ; *H-NMR (400 MHz, CDClj) δ: 11.33 (1H, s), 8.44 (1H, t, J = 6 Hz), 7.79 (1H, s), 7.77 (1H, Dd, J = 9 Hz, 6 Hz), 7.70 (1H, d, J = 8 Hz), 7.54 (1H, d, J - 8 Hz), 7.39 (1H, dd, J = 10 Hz, 2 Hz), 7.22 (1H, dt, J = 9 Hz, 2 Hz), 4.33 (2H, s), 4.28 (2H, d, J = 6 Hz), 2.64 (3H, s). (Example 95) [({6 -[3-chloro-4-(trifluoromethyl)benzyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid-167- 201141839

Co2h (l) 4-(bromomethyl)-2-chloro-1-(trifluoromethyl)benzene

2-Chloro-4-methyl-1-(trifluoromethyl)benzene (0.98 g) was dissolved in cyclohexane (15 mL), N-bromosuccinimide (0.99 g) and 2,2 were added. After _ azobis(isobutyronitrile) (AIBN) (0.041 g), it was heated under reflux for 3 hours under a nitrogen atmosphere.

. After the organic layer was extracted with n-hexane, the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to give the title compound (0.28 g, yield: 21%) oily material "H-NMR (400 MHz, CDC13) δ: 7.67 (1Η, d, J = 8 Hz), 7.55 (1H, s), 7.38 (1H, d, J = 8 Hz), 4.44 (2H, s). (2) [3-Chloro- 4- (trifluoromethyl)phenyl]acetonitrile

In accordance with Example 94-(3), and using 4-(bromomethyl)-2-chloro-1-(trifluoromethyl)benzene (0.28 g) instead of 2-(bromomethyl)-6-fluoronaphthalene, Obtained the title compound (0.19 g, yield: ield: , d, J = 8 Hz), 3.81 (2H, s). (3) [3-Chloro-4-(trifluoromethyl)phenyl]acetate

-168- 201141839 Dissolve [3-chloro-4-(trifluoromethyl)phenyl]acetonitrile (0.19 g) in ethanol (4 mL), add concentrated sulfuric acid (1 mL), and then warm to reflux under nitrogen atmosphere 9.5 hour. Water was added to the reaction mixture, and the organic layer was evaporated. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to afford the title compound (1. 7 g, yield: 6%). !H-NMR (400 MHz, CDC13) δ: 7.65 (1Η, d, J = 8 Hz), 7.45

(1H, s), 7.29 (1H, d, J = 8 Hz), 4_18 (2H, q, J = 7 Hz), 3.64 (2H, s), 1.27 (3H, t, J = 7 Hz). 4) ({[5-(Benzyloxy)-6-{l-[3-chloro-4-(trifluoromethyl)phenyl)2-ethoxyethyl}_2-methylindole D-based Carbonyl guanamine)ethyl acetate Ει〇2〇ΟΒη Ο

C02Et obtained according to Example 7 2 - (1), using [3 _ chloro- 4 </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Ethyloxyl-2-methyl_6_{[(difluoromethyl)sulfonyl]oxypyrimidin-4-yl]carbonyl)amino)acetate (0.16 g) instead of (3,4,5- Ethyl trifluorophenyl)acetate gave the title compound (0·16 g, H-NMR (400 MHz, CDC13) δ: 8.36 (1Η, t, J = 5 Hz), 7.56 (1H, d, J = 8 Hz), 7.43 -7.3 6 (6H, m), 7.26-7.23 ( 1 H, m), 5.41 (1H, s), 5.15 (1H, d, J = h hz), 5.00 (1H, d' J = 11

Hz), 4.26 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 5 Hz), 4.17- 4.10 (2H, m), 2.71 (3H, s), 1.3i (3H, t, j = 7 Hz),! 18 (3H, t, J = 7 Hz). -169- 201141839 (5)[({6-[3 -Chloro-4-(trifluoromethyl)benzyl]-5-hydroxy-2-methylpyrimidine -4 -yl}carbonyl)amino]acetic acid

According to Example 72-(2), and using ({[5-(benzyloxy)_6_{1_[3_chloro-4-(trifluoromethyl)phenyl]-2-ethoxy-2-oxooxy) Ethyl ethyl 2-ethyl-pyrimidin-4-yl]carbonyl}amino)acetate (0.23 g) in place of [({5_(benzyloxy)_6_[2-ethoxy-2-yloxy) 1-(3,4,5-trifluorophenyl)ethyl]_2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate' gave the title compound (0.076 g, yield 49%) Yellow solid. Mp: 193-194 °C; 'H-NMR (400 MHz, CDC13) δ: 11.58 (1 H, s), 8.49 (1 Η, brs), 7.59 (1H, d, J = 8 Hz), 7.51 (1H , s), 7.36 (1H, d, J = 8 Hz), 4.18 (2H, s), 4.17 (2H, d, J = 6 Hz), 2.63 (3H, s). (Example 96) ({[ 6-(4-chloro-3-methylbenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1) (4-chloro-3-methylphenyl)methanol

4 -Bromo-chloro-2-methylbenzene (0.66 mL) was dissolved in tetrahydrofuran (15 mL) under nitrogen atmosphere, and n-hexane solution of n-butyllithium (1.6 M) was added dropwise at -78 °C for 20 minutes. After 3.8 mL), stir at the same temperature for 4 minutes. After adding paraformaldehyde (0.20 g) to the reaction solution, the temperature was slowly raised to room temperature over a period of 2.5 hours. The organic layer was taken up in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by EtOAc EtOAc (EtOAc). 'H-NMR (400 MHz, CDC13) δ: 7.32 (1Η, d, J = 8 Hz), 7.23 (1H, s), 7.12 (1H, d, J = 8 Hz), 4.64 (2H, s), 2.38 (3H, s), 1.64 (1 H, brs). (2) (4-Chloro-3-methylphenyl)acetate

Cl^Xc〇2Et was used in accordance with Examples 94-(2), 94-(3) and 95-(3), and (4-chloro-3-methylphenyl)methanol (〇.45g) was used instead. -Fluoro-2-naphthyl)methanol gave the title compound (0.41 g, yield 62% 'H-NMR (400 MHz, CDCI3) δ: 7.28 (1Η, d, J = 8 Hz), 7.15 (1H, d, J - 2 Hz), 7.05 (1H, dd, J = 8 Hz, 2 Hz) , 4.15 (2H, q, J = 7 Hz), 3.54 (2H, s), 2.36 (3H, s), 1.25 (3H, t, J = 7 Hz). φ (3)[({5-(benzyl Oxy)-6-[l-(4-chloro-3-methylphenyl)-2-ethoxyxoethyloxyethyl]-2-methylpyrimidin-4-yl}carbonyl)amine Ethyl acetate

According to Example 72-(1), and using (4-chloro-3-methylphenyl)acetate (〇·21 g) and Example 1-(3) ({[5-(benzyloxy) Ethyl 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead (3,4,5 Ethyl trifluorophenyl)acetate afforded the title compound (m. -171- 201141839 'H-NMR ( 5 00 MHz, CDC13) δ: 8.34 ( 1 H, t, J = 5 Hz), 7.44-7.3 6 (5H, m), 7.24 ( 1 H, d, J = 8 Hz), 7.10 (1 H, d, J = 2 Hz), 7.06 (1H, dd, J = 8 Hz, 2 Hz), 5.41 (1H, s), 5.10 (1 H, d, J = 1 1 Hz ), 4.84 (1 H, d, J = 11 Hz), 4.25 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 5 Hz), 4.17-4.10 (2H, m), 2.71 ( 3H, s), 2.28 (3H, s), 1.30 (3H, t, J = 7 Hz), 1.17 (3H, t, J = 7 Hz). (4)({[6-(4 -chloro-3) -Methylmercapto)-5-carbyl-2-methylindole-4-yl]fluorenyl}amino)acetic acid according to Example 72-(2), and using [({5-(benzyloxy) 6-[1-(4-Chloro-3-methylphenyl)-2-ethoxyxoethyloxyethyl]-2-methylpyrimidin-4-yl}carbonyl)amino Ethyl acetate (0.27 g) in place of [({5-(benzyloxy)-6.[2-ethoxy-2-yloxy-1-(3,4,5-trifluorophenyl)) Ethyl ethyl-2-methylpyrimidin-4-yl}carbonyl)amino]acetate gave the title compound (0.09 5 g, yield 55%). Mp : 19 2 ° C ; 'H-NMR (400 MHz, CDCI3) δ: 11.30 (1Η, s), 8.44 (1H, t, J = 6 Hz), 7.24-7.22 (2H, m), 7.13 (1H , dd, J = 8 Hz, 2 Hz), 4.28 (2H, d, J = 6 Hz), 4.11 (2H, s), 2.63 (3H, s), 2.3 3 (3H, s). (Example 97 [({5-hydroxy-2-methyl-6-[(2'-methylbiphenyl-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid-172- 201141839

fC〇2H (l)[({5-(Benzyloxy)-6-[2-ethoxy-oxime-(2,-methylbiphenyl-4)) 2-oxo H] Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

, C02Et [({5_(benzyloxybromophenyl)-2-ethoxy-2-oxoethoxyethyl) 2-methylpyrimidin-4-ylcarbonyl) obtained in Example 91-(1) Ethyl]acetate (0.17 g) and (2-methylphenyl)boronic acid (〇〇49 g) are dissolved in hydrazine, 2-dimethoxyethane (6. mL) under nitrogen After adding ruthenium (triphenylphosphine) palladium complex (0·0 3 5 g) and cesium fluoride (〇·〇9 1 g ), it was heated under reflux for 4 hours. After the reaction mixture was filtered over Celite, the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) Lu 7.48-7.19 (13H, m), 5.56 (1H, s), 5.12 (1H, d, J = 12 Hz), 4.87 (1H,d,J = 12 Hz), 4.25 (2H,q,J = 8 Hz), 4.22 (2H, d, J = 4 Hz), 4.20 (2H, q, J = 8 Hz), 2.74 (3H, s), 2.25 (3H, s), 1.32 (3H, t, J = 8 Hz), 1.20 (3H, t, J = 8 Hz). (2) [({5-Hydroxy-2-methyl-6-[(2'-methylbiphenyl-4-yl)methyl]pyrimidine -4·yl}carbonyl)amino]acetic acid according to Example 7 2 - (2), and using [({ 5 _ (benzyloxy)-6 _ [ 2 -ethoxy-1-(2'-A) Benzyl-4-yl)-2-oxoethylethyl-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.094 g) in place of [({5_(benzyloxy)) _6_[2_ -173- 201141839 Ethoxy-2-oxo-l-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino] Ethyl acetate gave the title compound (0.050 g,iel. MS m/z: 3 92 (M + H) + ; 'H-NMR (400 MHz, CD3〇D) δ: 7.40-7.14 (8H, m), 4.21 (2H, s), 4.09 (2H, s) , 2.63 (3H, s), 2.21 (3H, s). (Example 98) [({6-[(2'-fluorobiphenyl-4-yl)methyl]-5-hydroxy-2-methyl Pyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-(Benzyloxy)-6-[2-ethoxy-1-(2'-fluorobiphenyl-4-yl)-2-yloxyethyl]-2-yl) Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

[({5-(Benzyloxy)-6-[ 1-() obtained according to Example 97-(1), using (2-fluorophenyl)boronic acid (0.067 g) and Example 91-(1) Instead of (2-A), 4-bromophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.23 g) Phenyl phenyl)boronic acid gave the title compound ( 〇········· *H-NMR (400 MHz, CDC13) δ: 8.35 (1 H, t, J = 4 Hz), 7.48-7.19 (13H, m), 5.54 (1H, s), 5.12 (1H, d, J = 12 Hz), 4.8 6 ( 1 H, d, J = 1 2 Hz), 4.25 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 4 Hz), 4.20 (2H, q, J = 8 Hz), 2.73 (3H, s), 1.30 (3H, t, J = 8 Hz), 1.20 (3H, t, J = 8 Hz). -174- 201141839 (2)[({6-[(2 '-Fluorobiphenyl-4-yl)methyl]_5, hydroxy-2-methylpyrimidin-4-yl)carbonyl)amino]acetic acid

According to Example 72-(2), and using [({5_(benzyloxy)_6-[2-ethoxyfluorobiphenyl-4-yl)-2-yloxyethyl b-2-methyl Ethyl acetate (0.13 g) of carbonyl)amino)] in place of [({5·(benzyloxy)-6-[2-ethoxy-2-sideoxy-1-(3, Ethyl acetate of 4,5-trifluorophenyl)ethyl]-2-methylpyrimidinyl-carbonyl}carbonyl)amino]] gave the title compound (m. Mp: 1 6 3 - 1 64 °C ; H-NMR (400 MHz, CD3〇D) δ: 7.49-7.12 (8H, m), 4.21 (2H, s), 4.13 (2H, s), 2.63 (3H , s). (Example 9 9 ) [({6-[(2'-chlorobiphenyl-4-yl)methyl]_5-hydroxy-2-methylpyrimidin-4-yl)carbonyl)amino] Acetic acid OH 0

According to Examples 91-(2) and 72-(2), and using (2-chlorophenyl)boronic acid (0.075 g) and the benzyloxybromophenyl)-2·B obtained in Example 91-(1) Ethyl oxy-2-oxoethyl] 2 -methylpyrimidin-4-yl hydrazinylcarbonyl)amino]acetate (0.23 g) in place of (4-fluorophenyl)boronic acid to give the title compound (0· 061 g, yield 30%) yellow solid. Mp: 106-109 °C; 'H-NMR (400 MHz, CD3〇D) δ: 7.5 0-7.29 (8H, m), 4.22 (2H, s), 4.13 (2H, s), 2.63 (3H, s). -175- 201141839 (Example 1 0 0) ({[6-(4-Bromobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid hydrazine Ο

[({5_(Benzyloxy)-6-[1·(4-bromophenyl)-2-ethoxy-2-) obtained according to Example 72_(2)' and using Example 91 (1) Ethyloxyethyl] 2 -methylpyrimidin-4-yl}carbonyl)amino]acetate (0.31 g of Uj instead of [({5-(benzyloxy)-6-[2-ethoxy-2-) Ethyl-1-(3,4,5-tri-triazide 1)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate, obtained ~ ~ title compound (0.14 g, yield 69%) yellow solid. mp: 211-213 ° C; 'H-NMR (400 MHz, CDjOD) δ: 7.41 (2Hs d 7.25 (2H, d, (3H, s). hz), 4.13 (2H,s)'4.12(2h,.s),

Hz), 2.6 1 (Example 101) [({6-[(2-Chlorobiphenyl-4-yl)methyl]_5_hydroxy-2-methyl)amino]acetic acid OH Ο N^C02H Η Aridin-4-yl}carbonyl

CI Br chlorophenyl)ethyl acetate (1) (4-bromo-3-

C02Et In accordance with Example 9 5 - (1 ), 9 4 - ( 3 ) and 9 5 - ( 3 ), 1-bromo-2-chloro-4-methylbenzene (2.5 g) was used instead of 2-chloro- 4-Methyl-1-(=ung~fluoromethyl)benzene gave the title compound (yield: -9 g, yield 3%). -176- 201141839 'H-NMR (400 MHz, CDC13) δ: 7.55 (1H, d, J = 8 Hz), 7.39 (1H, d, J = 2 Hz), 7.05 (1H, dd, J = 8 Hz) , 2 Hz), 4.16 (2H, q, J = 7 Hz), 3.55 (2H, s), 1.26 (3H, t, J = 7 Hz). (2) [({5-(Benzyloxy)- Ethyl 6-[1-(4-bromo-3-chlorophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl

EtO,C ΟΒη Ο Cl

Br

According to Example 72-(1), using (4-bromo-3-chlorophenyl)acetate (0.30 g) and Example 1-(3) ({[5-(benzyloxy)-) 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5-three) Ethyl fluorophenyl)acetate gave the title compound (0-25 g, yield: 79%). 'H-NMR (400 MHz, CDC13) δ: 8.35 (1Η, t, J - 6 Hz), 7.49 (1 H, d, J = 8 Hz), 7.44- 7.3 7 (5 H, m), 7.35 ( 1H, d, J = 2 Hz), 7.04 (1H, dd, J = 8 Hz, 2 Hz), 5.36 (1H, s), 5.13

(1 H, d, J = 1 1 Hz), 4.96 (1 H, d, J = 11 Hz), 4.25 (2H, q, J =7 Hz), 4.23 (2H, d, J = 6 Hz), 4.13 (2H, q, J = 7 Hz), 2.70 (3H, s), 1.30 (3H, t, J = 7 Hz), 1.17 (3H, t, J = 7

Hz). (3) [({5-(Benzyloxy)-6-[l-(2-chlorobiphenyl-4-yl)-2-ethoxy-2-oxoethyl]-2 -methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

Et02C ΟΒη Ο

.丨..., NT, C02Et -177- 201141839 According to Example 91-(2), and using phenylboronic acid (0.05 4 g) instead of (4-fluorophenyl)boronic acid, and using [({5-(benzyloxy)) 6-[1-(4.bromo-3-chlorophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino] Ethyl acetate (0.24 g) in place of [({5-(benzyloxy)-6-[1-(4-bromophenyl)-2-ethoxy-2-oxoethyl]-2- Ethyl acetate of methylpyrimidin-4-yl}carbonyl)amino] gave the title compound (0.18 g, yield 77%).

*H-NMR (400 MHz, CDC13) δ: 8.38 (1Η, t, J = 6 Hz), 7.47 (2H, dd, J = 8 Hz, 2 Hz), 7.41-7.34 (9H, m), 7.25 ( 2H, d, J = 6 Hz), 5.46 ( 1 H, s), 5.15 (1 H, d, J = 11 Hz), 4.96 (1 H, d, J = 11 Hz), 4.25 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 4.17 (2H, q, J = 7 Hz), 2.73 (3 H, s), 1.30 (3 H, t, J =7 Hz) , 1.20 (3H, t, J = 7 Hz). (4) [({6-[(2-chlorobiphenyl-4-yl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl) }carbonyl)amino]acetic acid

According to Example 72-(2), and using [({5-(benzyloxy)-6-[ 1-(2-chlorobiphenyl-4-yl)-2-ethoxy-2-oxooxy) Ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.18 g) in place of [({5-(benzyloxy)-6-[2-ethoxy-2-) Ethyl acetoxy-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound (0.070 g, yield 5 7%) white solid. Mp: 195-197 °C; 'H-NMR (400 MHz, CDC13) δ: 11.34 (1H, s), 8.45 (1H, t, J = 6 Hz), 7.49 - 7.2 3 (8 H, m), 4.29 (2H,d,J = 6 Hz), 4. 19 (2H, s), 2.65 (3H, s). -178- 201141839 (Example 102) [({6_[4_氯- 3- (three Fluoromethyl)benzyl-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Examples 9 6 - ( 1 ), 9 4 - ( 2 ), 9 4 - ( 3 ) and 9 5 - ( 3 ), and using 4-bromo-1-chloro-2-(trifluoromethyl)benzene (〇74 g) The title compound (0.79 g, yield 60%)yiel. 'H-NMR (400 MHz, CDC13) δ: 7.61 (1Η, d, J = 2 Hz), 7.47 (1H, d, J = 8 Hz), 7.41 (1H, dd, J = 8 Hz, 2 Hz) , 4.18 (2H, q, J = 7 Hz), 3.64 (2H, s), 1.27 (3H, t, J = 7 Hz). (2)({[5-(oxygen)-6-{1_ [4_Chloro_3 (trifluoromethyl)phenyl]_2ethoxy-2-alkoxyethyl}-2-methylpyrimidinyl]carbonyl}amino) ethyl acetate ethyl acetate (〇. 27 g) and Example 1 - (3) to obtain ethyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine acid (〇.24 g) instead of (3,4,5_3 ({[5_(Benzyloxy)-2-methyl)oxy}pyrimidin-4-yl] obtained from fluorophenyl ridge and using [4-chloro-3-(trifluoromethyl)phenyl]^(3) Ethyl carbonyl]amino)ethyl [,5-trifluorophenyl)acetate gave the title compound (0.29 g, yield 96%). H-NMR (5 00 MHz

(7H, m), 5.4 1

Hz), 7.59 (1H, s), 7.44-7.37 (1H, s), 5.13 (1H, d, J = -179- 201141839 11 Hz), 5.04 (1H, d, J = 11 Hz), 4.28-4.21 (4H, m), 4.17-4.11 (2H, m), 2.70 (3H, s), 1.31 (3H, t, J = 7 Hz), 1.17 (3H, t, J = 7 Hz). (3)[ ({6-[4-chloro-3-(trifluoromethyl)benzyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Example 72-(2), and using ({[5·(benzyloxy)-6-{l-[4-chloro-3-((difluoromethyl)phenyl)ethoxy-2) side oxygen Ethyl ethyl hydrazine - 2 - methyl hydrazino - 4 - yl] carbonyl} amino) ethyl acetate (0 · 29 g) instead of [({5_(benzyloxy)-6-[2-ethoxy -2 -Sideoxy-1-(3,4,5-tris-phenyl)ethyl]_2-methylpyrimidin-4-yl}carbonyl)amino]acetate's title compound (0.10 g, yield 5 2 %) white solid mp: 19 8 ° C; j-NMR (400 MHz, CDC13) δ: 1 1 fly &lt; δ 44 ( 1 Η, t, 5 (1 Η, s) , J = 6 Ηζ), 7.71 (1Η, d, J = 2 Ηζ), 7 5〇 (ιΗ, dd, J = 8 Ηζ, 2 HZ), 7.41 (1H, d, J = 8 Hz), 4.29 ( 2h dj = 6 Hz), 4·19

(2H, s), 2.63 (3H, s). (Example 1 〇3) [({6-[(4'·chlorobiphenyl-3-yl)methyl]-5-hydroxymethylpyranidine _4-yl}carbonyl)amino]acetic acid (1)[({5-(decyloxy)-6-[1-(3-bromophenyl&amp;oxy-2-sideoxyethyl]_2) ·Methylpyrimidin-4-yl}carbonyl)amino]acetic acid ethyl vinegar-180- 201141839

According to Example 72-(1), and using (3-bromophenyl)acetate (1·8 g) and Example 1-(3), ({[5-(hydroxy))-2 Methyl-6-{[(difluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (1.8 g) instead of (3,4,5-trifluorobenzene Ethyl acetate gave the title compound (1.0 g, yield 44%). 'H-NMR (400 MHz, CDC13) δ: 8 · 3 4 (1Η,t,J = 5 Η ζ), 7.49-7.34 (7H, m), 7.16 (2H, d, J = 8 Hz), 5.42 (1H, s), 5.10 (1H, d, J = 10 Hz), 4.92 (1H, d, J = 10 Hz), 4.25 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 5 Hz), 4.13 (2H, q, J = 8 Hz), 2.70 (3H, s), 1.30 (3H, t, J = 8 Hz), 1.17 (3H, t, J =8 Hz). (2) [({5-(Benzyloxy)-6-[1-(4'-chlorobiphenyl-3-yl)-2-ethoxy-2-oxooxyethyl]-2-methylpyrimidine- 4-yl}carbonyl)amino]ethyl acetate

In accordance with Example 91-(2), and using (4-chlorophenyl)boronic acid (0.11 g) instead of (4-fluorophenyl)boronic acid, and using [({5-(benzyloxy)-6-[ 1-(3-Bromophenyl)-2-ethoxy-2-oxoethoxyethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.34 g) instead ({5-(Benzyloxy)-6-[1-(4-bromophenyl)-2-ethoxy-2-epoxyethyl]-2-methylpyrimidin-4-yl}carbonyl) The title compound (0.26 g, yield 72%) was obtained. -181 - 201141839 'H-NMR (400 MHz, CDC13) δ: 8.34 (1 H, t, J = 4 Hz), 7.4 7- 7.2 9 ( 1 3 H, m), 5.55 (1H, s), 5.10 (1H, d, J = 12 Hz), 4.8 6 ( 1 H, d, J = 12 Hz), 4.24 (2H, q, J = 8 Hz), 4.2 1 (2H, d, J = 4 Hz), 4.20 (2H, q, J = 8 Hz), 2.72 (3 H, s), 1.30 (3H, t, J = 8 Hz), 1.19 (3H, t, J = 8 Hz). (3)[({ 6-[(4'-Chlorobiphenyl-3-yl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 72-(2), and used [({5-(Benzyloxy)-6-[1-(4'-chlorobiphenyl-3-yl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidine- 4-(yl}carbonyl)amino]acetate (0.26 g) in place of [({5-(benzyloxy)-6-[2-ethoxy-2-yloxy-l-(3,4) Ethyl acetate of 5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl]amino]] gave the title compound (j. MS m/z : 4 12 (M + H) + ; 'H-NMR (400 MHz, CD3OD) δ: 7.5 9-7.5 6 (3 H, m), 7.42-7.32 (3H, m), 7.17-7.12 (2H, m), 4.22 (2H, s), 4.12 (2H, s), 2.62 (3H, s). (Example 104) [({2-ethyl-5-hydroxy-6-[4-( Trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

(1) ({[5-(Benzyloxy)-2-ethyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)ethyl acetate -182- 201141839

ΟΒη Ο TfO

^C02Et In accordance with Example 1 - (1) to 1 - (3 ) ' and using propane imine decylamine hydrochloride (3.5 g) in place of ethaneimine decylamine hydrochloride, the title compound (4.6 g, yield The rate is 40%). 'H-NMR (500 MHz, CDC13) δ: 8.19 (1Η, t, J = 5 Hz), 7.51 (2H, dd, J = 7 Hz, 2 Hz), 7.41-7.35 (3H, m), 5.23 ( 2H, s), 4.28 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 5 Hz), 2.98 (2H, q, J = 7 Hz), 1.36 (3H, t, J = 7 Hz), 1.33 (3H, t, J = 7 Hz). (2)({[5-(Hydroxy)-6-{2-(hydroxy))_2_oxytrifluoromethyl) Ethylpyrimidinyl]carbonyl oxime amino)ethyl acetate

, C02Et according to Example 72-(1), and using benzyl [4-(trifluoromethyl)phenyl]acetate (0.29 g) instead of (3,4,5·trifluorocage) Ethyl acetate, and using ({[5-(benzyloxy)-2-ethyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino) Ethyl acetate (0.25 in place of ({[5-(benzyloxy)-2_methyl-6-{[(trifluoromethyl)sulfonyl)oxy}pyrimidin-4-yl]carbonyl}amine Ethyl acetate gave the title compound (yield: 8 g, yield, 5 5 %). 'H-NMR (400 MHz, CDC13) δ· R ^ (2H, d, J = 8 HZ), 7.39 (2H, d, jm), 7.31-7.30 (3H, m), 7.22-7.20 5.18 (1H, d, J = 11 Hz), 5.I6 〇H (1H,d,J = 12 Hz), 5.09 (1H, d , j, -183- (1 H, t, J = 6 Hz), 7.5 1 8 Hz), 7.3 8 -7.3 3 (5H, (2H, m), 5.55 (1H, s),

d, J = 12 Hz), 5.09 1 1 Hz), 4.25 (2H, q, J 201141839 =7 Hz), 4.22 (2H,d,J = 6 Hz), 2.94 (2H,q,J = 7 Hz) , 1.32 (3H, t, J = 7 Hz), 1.30 (3H, t, J - 7 Hz). (3) [({2 -ethyl-5 -hydroxy-6-[4-(trifluoromethyl) Benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 94-(6), and using ({[5-(benzyloxy)_6_{2_(benzyloxy)-2-) side oxygen Ethyl-1 -[ 4 -(trifluoromethyl)phenyl]ethyl b 2-ethylpyrimidin-4-yl]carbonyl}amino)acetate (0.18 g) in place of [({5-(benzyl) Oxy)-6-[2-(benzyloxy)-1-(6-fluoro-2-naphthyl)-2-yloxyethyl]-2-methylpyrimidin-4-yl}yl) The title compound (0.068 g, yield 64%) was obtained as a white solid. Mp: 181-183 °C; 'H-NMR (5 00 MHz, DMSO-d6) δ: 12.88 (1H, s), 12.04 (1H, s), 9.47 (1H, t, J = 6 Hz), 7.56 (2H, d, J = 8 Hz), 7.51 (2H, d, J = 8 Hz), 4.24 (2H, s), 4.00 (2H, d, J = 6 Hz), 2.84 (2H, q, J = 8 Hz), 1 .2 8 (3 H, t, J = 8 Hz). (Example 105) ({[6-(3,4-Dichlorobenzyl)-2-ethyl-5-hydroxypyrimidine) -4-yl]carbonyl}amino)acetic acid OH Ο

(1) ({[5-(Hydroxy)-6-[2-(hydroxy)-1-(3,4-dichlorophenyl)-2-yloxyethyl]-2-ethyl) Ethylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

BnOjC ΟΒπ Ο 201141839 In accordance with Example 7 2 - (1) 'and use benzyl (3,4 -dichlorophenyl)acetate (〇·29 g) instead of (3,4,5-H fluorophenyl) Ethyl acetate, and ({[5-(benzyloxy)_2ethyl_6_{[(trifluoromethyl)sulfonyl)oxy}pyrimidine _4 obtained using Example 1〇 4-(1) Ethyl]carbonyl]amino)acetate (〇25 instead of ({[5-(decyloxy)-2-methyl·6_{[(trifluoromethyl)sulfonyl]oxypyrimidine.

The rate of 4-ethyl]carbonyl}amino)acetic acid ethyl acetate was 79%). MS m/z: 63 6 (M + H) + (2) ({[6-(3,4-dichlorobenzyl))acetic acid afforded the title compound (0.25 g, ethyl-5-hydroxypyrimidine _yl]carbonyl)amine according to Example 94-(6), 彳 彳 田# ) and using ({[5·(卞oxy)-6-[2-(oxy)-1·(3, 4 - chlorophenyl)-2, side each of its 7 9 7 η η 侧 氧基 ethoxyethyl ethyl 2-(ethylpyrimidin-4-yl) end group} amino) ethyl acetate (0.44 g Instead of [({5_(benzyloxy)6[2 gasbenzyloxy)-1-(6-fluoro-2-naphthyl)-2-yloxyethyl b-2-methylpyrimidine_4_ Ethyl acetate was added to the title compound (o3 g, yield: 85%) as a white solid. MS m/z: 3 84 (M + H) + ; *H-NMR (400 MHz, DMSO-d5) δ: 12.86 (1H s, , 0 '4u, sj,12.〇2(lH, s), 9.43 (1H, t, J = 6 Hz), 7.56 (1H, d, J = 2 Hz) η 55 (1H, dd, J = 8 Hz, 2 Hz), 7.25 (1H, d, J = 8 Hz) 4 ^

(2H, s), 3.99 (2H, d, J = 6 Hz), 2.83 (2H η τ - δ TT , 4, J - 8 Hz), 1.27 (3H, t, J = 8 Hz). -185- 201141839 (Example 106) ({[6-(3,4-Dichlorobenzyl)-5-hydroxy-2-propylpyrimidin-4-yl]carbonyl}amino)

(1) ({[5-(Benzyloxy)-6-[2-(benzyloxy)-1-(3,4-dichlorophenyl)_2-sideoxyethyl]-2-propyl) Pyrimidine-4-yl]carbonyl}amino)ethyl acetate

In accordance with Example 7 2 - (1), and using (3,4-dichlorophenyl)acetic acid benzyl ester (0.59 g) in place of (3,4,5-trifluorophenyl)acetate, and using Example

(-[1)-(Benzyloxy)-2-propyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino group Ethyl acetate (〇.50 g) instead of ({[5-(benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl) Ethyl acetate of carbonyl}amino) gave the title compound (0.57 g, yield 88%). MS m/z: 650 (M + H) + (2) ({[6-(3,4-dichlorobenzyl)-5-hydroxy-2-propylpyrimidin-4-yl]carbonyl}amino) Acetic acid was used according to Example 94-(6)' and ({[5-(benzyloxy)·6-[2-(benzyloxy)-1-(3,4-dichlorophenyl)-2) side oxygen Ethyl ethyl 2-(2-propylpyrimidin-4-yl)carbonyl}amino)acetate (〇.57 g) in place of [({5-(benzyloxy)-6-[2-(benzyloxy)) 1-(6-fluoro-2-naphthyl)-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate' gave the title compound (0.29 g, Yield 81%) white solid. -186- 201141839 MS m/z: 3 9 8 (M + H) + ; 'H-NMR (400 MHz, DMSO-d6) 6: 12.84 (1H, s), 12.02 (1H, s), 9.43 (1H , t, J = 6 Hz), 7.56 (1H, s), 7.54 (1H, d, J - 8 Hz), 7.25 ( 1 H, d, J = 8 Hz), 4.15 (2H, s), 3.99 ( 2H, d, J = 6 Hz), 2.79 (2H, t, J = 8 Hz), 1.76 (2H, tq, J = 8 Hz, 7

Hz), 0.90 (3H, t, J - 7 Hz). (Embodiment 1 07)

[({5-Hydroxy-2-propyl-6-[4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid ΟΗ Ο

rTc〇2H In accordance with Examples 72-(1) and 94-(6), and using [4-(trifluoromethyl)phenyl]acetic acid benzyl ester (0.59 g) instead of (3,4,5-trifluoro Phenyl)acetate, and ({[5-(benzyloxy)-2-propyl-6-{[(trifluoromethyl)sulfonyl)oxy) obtained using Example 12-(1) Ethyl pyrimidine-4-yl]carbonyl}amino)acetate (0.50 g) instead of ({[5-(benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl) Ethyl acetate of oxy}pyrimidin-4-yl]carbonyl}amino) gave the title compound (0.28 g, yield: MS m/z: 3 9 8 (M + H) + ; 'H-NMR (400 MHz, DMSO-d6) δ: 12.85 (1H, s), 12.02 (1H, s), 9.43 (1H, t, J = 6 Hz), 7.65 (2H, d, J = 8 Hz), 7.49 (2H, d, J = 8 Hz), 4.23 (2H, s), 3.99 (2H, d, J = 6 Hz), 2.79 ( 2H, t, J = 8 Hz), 1.77 (2H, tq, J = 8 Hz, 7 Hz), 0.90 (3H, t, J = 7 Hz). -187- 201141839 (Embodiment 108) ({[6 -(4-chloro-3-ethylbenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid hydrazine Ο

n&quot;^co2h Η (1) 4-chloro-3-ethylphenyl trifluoromethanesulfonate

OTf

4-Chloro-3-ethylphenol (0.78 g) was dissolved in dichloromethane (10 mL), triethylamine (0.84 mL) was added under nitrogen, and then trifluoromethanesulfonic anhydride was added dropwise at -78 °C. (1.0 m L)' was stirred at the same temperature for 4 hours. After the organic layer was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified mjjjjlililililililililililili

'H-NMR (400 MHz, CDC13) δ: 7.41 (1Η, d, J = 9 Hz), 7.15 (1H, d, J = 3 Hz), 7.07 (1H, dd, J = 9 Hz, 3 Hz) , 2.78 (2H, q, J = 7 Hz), 1.25 (3H, t, J = 7 Hz). (2) Methyl 4-chloro-3-ethylbenzoate

4-chloro-3-ethylphenyl trifluoromethanesulfonate (1.4 g) is dissolved in a mixed solvent of N,N-dimethylformamide (10 m L) and methanol (1 〇m L). After adding palladium(II) chloride diphenylphosphinoferrocene-dichloromethane complex (0.17 g) and triethylamine (1.3 mL), it was placed at 60 ° under a carbon monoxide (1 atm) atmosphere. C was stirred for 4 hours. Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate - 188 - 201141839, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure. *H-NMR (400 MHz, CDC13) δ: 7.92 (1Η, d, J = 2 Hz), 7.80 (1H, dd, J = 8 Hz, 2 Hz), 7.40 (1H, d, J = 8 Hz) , 3.91 (3H, s), 2.80 (2H, q, J = 7 Hz), 1.26 (3H, t, J = 7 Hz). (3) (4-Chloro-3-ethylphenyl)acetic acid phenyl ester

Following the procedure of Example 94-(1) to 94-(4), using 4-chloro-3-ethylbenzoic acid methyl ester (0.81 g). g, yield 70%) colorless oily material. !H-NMR (400 MHz, CDC13) δ: 7.3 8 - 7.29 (5Η, m), 7.28 (1H, d, J = 8 Hz), 7.14 (1H, d, J = 2 Hz), 7.05 (1H, Dd, J = 8 Hz, 2 Hz), 5.13 (2H, s), 3.62 (2H, s), 2.72 (2H, q, J = 7 Hz), 1.21 (3H, t, J = 7 Hz). ^ (4) [((5-(Benzyloxy)-6-[2_(benzyloxy)-1-(4-chloro-3-ethylphenyl)-2-yloxyethyl]-2-yl) Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

BnQ2C ΟΒη Ο

According to Example 72-(1), and using (4-chloro-3-ethylphenyl)acetic acid benzylacetate (0.29 g) and Example 1-(3) ({[5-(benzyloxy)) -2 -Methyl-6-[[(trifluoromethyl)alkyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead (3,4,5_ Ethyl trifluorophenyl)acetate gave the title compound (0.28 g, yield 91%). -189- 201141839 Ή-NMR (400 MHz, CDC13) δ: 8.32 (1H, t, J = 6 Hz), 7.3 9 - 7.2 9 (8 H, m), 7.23-7.2 1 (3H, m), 7.13 (1H, d, J = 2 Hz), 7.05 (1H, dd, J = 8 Hz, 2 Hz), 5.47 (1H, s), 5.18

(1 H, d, J = 1 3 Hz), 5.09 ( 1 H, d, J = 1 3 Hz), 5.05 ( 1 H, d, J =11 Hz), 4.87 (1 H, d, J = 1 1 Hz), 4.24 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 6 Hz), 2.71 (2H, q, J = 7 Hz), 2.67 (3H, s), 1.31 (3H , t5 J = 7 Hz), 1.14 (3H, t, J = 7 Hz). (5)({[6-(3-chloro-3-ethylbenzyl)-5-hydroxy-2-methylpyrimidine) 4-yl]carbonyl]amino)acetic acid according to Example 94-(6), and using [({5-(benzyloxy)-6-[2-(benzyloxy)-1-(4-chloro) -3-ethylphenyl)-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (〇_28 g) instead of [({5-( Benzyloxy)-6-[2-(benzyloxy)-1-(6-fluoro-2-naphthyl)-2-yloxyethyl]-2-methylpyrimidin-4-yl}carbonyl) The title compound (0.11 g, yield: 64%) Mp : 17 2 ° C ; 'H-NMR (400 MHz, CDC13) δ: 11.31 (1Η, s), 8.44 (1H, t, J = 6 Hz), 7.25 (1H, d, J = 2 Hz), 7.22 (1H, d, J = 8 Hz), 7.13 (1H, dd, J = 8 Hz, 2 Hz), 4.29 (2H, d, J = 6 Hz), 4.13 (2H, s), 2.71 (2H, q, J = 7 Hz), 2.63 (3H, s), 1.20 (3H, t, J = 7 Hz). (Example 109) [({6-[(6-methyl-2-naphthyl))) 5-yl-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid-190- 201141839 OH Ο

(1) Trifluoromethanesulfonic acid (6-methyl-2-naphthyl ester)

The title compound (1 3 g, yield 94%) oil was obtained according to Example 108-(1) using 6-methyl-2-naphthalene (0.77 g) instead of 4-chloro-3-ethylphenol. Shaped matter.

^-NMR (400 MHz, CDC13) δ: 7.83 (1Η, d, J = 9 Hz), 7.77 (1H, d, J = 8 Hz), 7.70 (1H, d, J = 2 Hz), 7.66 (1H , s), 7.42 (1H, d, J = 8 Hz), 7.33 (1H, dd, J = 9 Hz, 2 Hz), 2.53 (3H, s). (2) (6-methyl-2-naphthalene) Ethyl acetate r^V&quot;Y^co2a Difluoride (6-methyl-2-naphthalene vinegar) (1.3 g) was dissolved in ν, Ν-dimethylformamide (20 mL) 'Add bis(pinacolyl)diboron (1.4 g), palladium(II) chloride [1,1'-bis(diphenylphosphino)ferrocene]-dichloromethane complex (0.17 g) and potassium acetate (1.4 g), and the mixture was stirred at 90 ° C for 5 hours. Water was added to the mixture, and the organic layer was extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to give 6-methyl-2-naphthylboronic acid pinacol ester as an oily substance, which was dissolved in tetrahydrofuran (2 0 m L ), after adding ethyl bromoacetate (0.77 mL), palladium acetate (0.05 2 g), tris(o-tolyl)phosphine (0.21 g), potassium carbonate (3.2 g) and water (0.17 mL), Warm stirring 24 small After the organic layer was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The title compound (0.31 g, yield 30%) was obtained as a white solid. <H-NMR (400 MHz, CDC13) δ: 7.73 - 7.67 (3 Η, m), 7.58 (1H, s ), 7.38 (1H, dd, J = 8 Hz, 2 Hz), 7.30 (1H, d, J = 8 Hz), 4.16 (2H, q, J = 7 Hz), 3.75 (2H, s), 2.50 ( 3H, s), 1.25 (3H, t, J = 7 Hz). (3) Benzyl (6-methyl-2-naphthyl)acetate

Ethyl acetate (6-methyl-2-naphthyl) (0.31 g) was dissolved in a mixed solvent of methanol (3 mL) and tetrahydrofuran (.5 mL), and then aqueous potassium hydroxide (2 Μ,1. After m L), it was stirred at room temperature for 1 hour. Hydrochloric acid (1 M) was added to the reaction mixture, and the organic layer was extracted with diethyl ether. The solvent was evaporated under reduced pressure to give (6-methyl-2-naphthyl)acetic acid as a white solid. This was dissolved in acetonitrile (5 mL), benzyl bromide (0.19 mL) and potassium carbonate (0.36 g). Water was added to the reaction mixture, and the organic layer was evaporated. After the solvent was evaporated under reduced pressure. 'H-NMR (400 MHz, CDC13) δ: 7.72 (1Η, d, J = 9 Hz), 7.69-7.67 (2H, m), 7.59 (1H, s), 7.38 (1H, dd, J = 8 Hz , 2 Hz), 7.3 4-7.29 (6H, m), 5.15 (2H, s), 3.81 (2H, s), 2.50 (3H, s). -192- 201141839 )-2- Side Oxygen (4)[ ({5-(Benzyloxy)-6-[2-(benzyloxy)-1-(6-methyl-2-naphthylethyl)-2-methylpyrimidin-4-yl}carbonyl)amine Ethyl acetate

According to Example 72-(1), and using (6-methyl-2-naphthyl (0.21 g) and Example 1-(3) ({[5-(benzyloxy)-2-f Fluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino) (0.17 g) in place of ethyl (3,4,5-trifluorophenyl)acetate, obtained (〇. 1 5 g, yield 6 6 %). 'H-NMR (400 MHz, CDC13) δ: 8.33 (1Η, t, J = 6 (1H, d, J = 9 Hz), 7.61-7.56 (3H, m), 7.45 (1H, Hz, 2 Hz) , 7.3 7-7.22 ( 1 1 H, m), 5.70 (1H, s), 5.: J = 13 Hz), 5.10 (1 H, d, J = 1 3 Hz), 5.06 (1 H, Hz) , 4.7 1 ( 1 H, d, J = 1 0 Hz), 4.24 (2H, q, J = 7 (2H, d, J = 6 Hz), 2.68 (3H, s), 2.49 (3H, s), 1. J = 7 Hz). (5) [({6-[(6-Methyl-2-naphthyl)methyl)-5-hydroxy-2-methyl 13⁄4 carbonyl)amino]acetic acid according to the examples 94-(6), and using [({5-(benzyloxy)-yl)-1-(6-methyl-2-naphthyl)-2-yloxyethyl]-2-methylcarbonyl) Ethyl acetate ethyl acetate (0.15 g) in place of [({5-(benzyloxyoxy)-1-(6-fluoro-2-naphthyl)-2-yloxyethyl]-2 - The title compound (0.058 67%) was obtained as white crystal. Benzyl acetate Yinky-6-{[(ethyl acetate heading Hz), 7.67 dd, J = 9 U (1H, d, d, J = 10 Hz), 4.20 29 (3H, t, ί pyridine - 4-yl} ;-[2_(benzyloxypyridin-4-yl})-6-[2-(benzylfyridin-4-yl} g, yield -193-201141839 mp : 17 4 ° C ; 'H -NMR (400 MHz, CDC13) δ: 11.31 (1H, s), 8.44 (1H, t, J = 6 Hz), 7.74 (1H, s), 7.78 (1H, d, J = 8 Hz), 7.66 ( 1H, d, J = 8 Hz), 7.55 (1H, s), 7.47 (1H, d, J = 8 Hz), 7.28-7.26 ( 1 H, m), 4.32 (2H, s), 4.27 (2H, d, J = 6 Hz), 2.64 (3H, s), 2.47 (3H, s). (Example 1 1 〇)

[({6-[(4',6-Dichlorobiphenyl)carbonyl)amino]acetic acid

Br Cl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl (1)(3-bromo-4-chlorophenyl)acetate

C02Et

In accordance with Examples 94-(3) and 95-(3), 2-bromo-4-(bromomethyl)-1-chlorobenzene (1.9 g) was used instead of 2-(bromomethyl)-6-fluoronaphthalene. The title compound (2.0 g, yield 87%) was obtained. 'H-NMR (400 MHz, CDC13) δ: 7.56 (1Η, s), 7.40 (1H, d, J = 8 Hz), 7.18 (1H, d, J = 8 Hz), 4.16 (2H, q, J = 8 Hz), 3.56 (2H, s), 1.26 (3H, t, J = 8 Hz). (2) [({5-(Benzyloxy)-6-[1-(3-bromo-4-) Chlorophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

EtO?C ΟΒη Ο

Γ - - -194- 201141839 According to Example 72-(1), using (3-bromo-4-chlorophenyl)acetate (0.56 g) and Example 1-(3) ({[5-( Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.48 g) instead (3, Ethyl 4,5-trifluorophenyl)acetate gave the title compound (3. 'H-NMR (400 MHz, CDC13) δ: 8.34 (1Η, t, J = 4 Hz), 7.50 (1 H, s), 7.44-7.15 (7H, m), 5.36 (1H, s), 5.12 ( 1H, d, J = 12 Hz), 4.95 (1 H, d, J = 12 Hz), 4.2 5 (2H, q, J = 8 Hz), Lu 4.21 (2H, d, J = 4 Hz), 4.12 (2H, q, J = 8 Hz), 2.70 (3H, s), 1.30 (3H, t, J = 8 Hz), 1.17 (3H, t, J = 8 Hz). (3)[({5- (Benzyloxy)-6-[l-(4',6-dichlorobiphenyl-3-yl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidine-4- Ethyl}carbonyl)amino]ethyl acetate

In accordance with Example 97-(1), and using (4-chlorophenyl)boronic acid (0.11 g) instead of (2-methylphenyl)boronic acid, and using [({5-(benzyloxy)-6-) [1-(3-Bromo-φ 4-chlorophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate ( 0.36 g) instead of [({5-(benzyloxy)-6-[1-(4-bromophenyl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidine- Ethyl 4-ethyl}carbonyl)amino]acetate gave the title compound (0.096 g, yield 26%). *H-NMR (400 MHz, CDC13) δ: 8.36 (1 Η, t, J = 4 Hz), 7.41-7.20 (12Η, m), 5.45 (1H, s), 5.10 (1H, d, J = 10 Hz), 4.95 (1H, d, J = 10 Hz), 4.25 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 4 Hz), 4.15 (2H, q, J = 8 Hz) , 2.70 (3H, s), 1.30 (3H, t, J = 8 Hz), 1.19 (3H, t, J = 8 Hz). -195- 201141839 (4)[({6-[(4',6 -dichlorobiphenyl-3-yl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

[({5-(Benzyloxy)-6-[1-(4',6-dichlorobiphenyl-3-yl)·2·ethoxy-2-oxoethyl]-2- Ethyl acetate (0.0 84 g) of methylpyrimidin-4-yl}carbonyl)amino] was dissolved in ethanol (1 mL), and concentrated hydrochloric acid (0.60 mL) was added, and the mixture was stirred at 60 ° C for 5 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to give [({6-[(4',6-dichlorobiphenyl-3-yl)methyl]-5-hydroxyl Ethyl -2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.039 g, yield 62%). This was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (2 mL), and then aqueous sodium hydroxide (1 M, 2.0 mL) was added at room temperature and then stirred at 40 ° C for 1 hour. Hydrochloric acid (1 M) was added to the reaction mixture, and the obtained solid was filtered, and dried under reduced pressure to give the title compound (0.33 g, yield:

MS m/z: 446 (M + H) + ; 'H-NMR (400 MHz, CD3〇D) δ: 7.44-7.34 (7H, m), 4.18 (2H, s), 4.10 (2H, s), 2.61 (3H, s). (Example 1 1 1) [({5-Hydroxy-2-methyl-6-[(4'-methylbiphenyl-4-yl)methyl]pyrimidin-4-yl) }carbonyl)amino]acetic acid

-196- )-2- 201141839 (1)[({5-(Benzyloxy)-6-[2-(benzyloxymethylbiphenyl-4-yloxyethyl)-2-methyl) Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

According to Example 7 2 - (1)' and using (4'-methylbiphenyl-4-yl)benzyl acetate (0.48 g) and Example 1-(3) ({[5-(benzyloxy) In place of (3,4, ethyl)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.36 g) Ethyl 5-(trifluorophenyl)acetate gave the title compound (0.28 g, m. 'H-NMR (400 MHz, CDC13) δ: 8.34 (1Η, t, J = 6 Hz), 7.58 (1H, d, J = 7 Hz), 7.49 (2H, d, J = g Hz), 7.45 ( 2H, d, J = 8 Hz), 7.41-7.29 (l〇H, m), 7.24 (3H, t, J = 8 Hz), 5.58 (1H, s), 5.23 (1H, d, J = 13 Hz ), 5.10 (1H, d, J = 13 Hz), 5.07 (1H, d, J = 10 Hz), 4.83 (1H, d, J = 10 Hz), 4.25 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 6 Hz), 2.68 (3H, s), Lu 2.38 (3H, s), 1.30 (3H, t, J = 7 Hz). (2)[({5-hydroxy-2 -Methyl-6-[(4'-methylbiphenyl-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 9 4 - (6) 'and using [({ 5-(Benzyloxy)-6-[2-(benzyloxy)-1-(4'-methylbiphenyl-4-yl)-2-yloxyethyl]-2-methylpyrimidine- 4-(yl}carbonyl)amino]acetate (〇.28 g) in place of [({5·(benzyloxy)-6-[2-(benzyloxy)-1-(6-fluoro-2-) Naphthyl)-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate' gave the title compound (0.070 g,iel. -197- 201141839 MS m/z: 3 92 (M + H) + ; 'H-NMR (5 00 MHz, DMSO-d6) δ: 12.88 (1H, s), 12.03 (1H, s), 9.47 (1H , t, J = 6 Hz), 7.55 (2H, d, J = 8 Hz), 7.52 (2H, d, J = 8 Hz), 7.35 (2H, d, J = 8 Hz), 7.25 (2H, d , J = 8 Hz), 4.15 (2H, s), 3.99 (2H, d, J = 6 Hz), 2.59 (3H, s), 2.33 (3H, s). (Example 1 1 2)

(S)-2-[({5-Hydroxy-2-methyl-6-[4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]propanoic acid

(1) 5-(Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine-4-carboxylic acid tert-butyl ester

5-(Benzyloxy)-6-hydroxy-2-methylpyrimidine-4-carboxylic acid tert-butyl ester (3.2 g) obtained according to Example 1-(3) and using Example 1-(1) Instead of ({[5-(benzyloxy)-6-hydroxy-2-methylpyrimidin-4-yl)carbonyl}amino)acetic acid ethyl acetate, the title compound (2.9 g, yield 81%) Shaped solid. 'H-NMR (400 MHz, CDC13) δ: 7.4 3 - 7.3 8 (5 Η, m), 5.12 (2H, s), 2.71 (3H, s), 1.57 (9H, s). (2)5- (benzyloxy)-6-{2-methoxy-2-oxo-l-[4-(trifluoromethyl)phenyl]ethyl}-2-methylpyrimidine-4-carboxylic acid Tributyl ester-198- 201141839

In accordance with Example 72-(1), and using [4-(trifluoromethyl)phenyl]acetic acid methyl ester (1. 9 g) in place of hydrazine, 4,5-trifluorophenyl)acetate, and Instead of ({[5-(benzyloxy)) 2 methyl group), oxy))-2-methyltrifluoromethyl)sulfonyl]oxy)pyrimidine-4carboxylic acid second butyl vinegar (1-9 g) was used instead. 6{[((Trifluoromethyl))]oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid ethyl acetate afforded the title compound (1. H-NMR (400 MHz CDC13) δ: 7.54 (2Η, d, 7.42-7.3 9 (5H, m), 7.35 (2H, dd, J = 8 Hz, 2 Hz), 5.44 (1H, s), 5.03 ( 1H, d, J = 11 Hz), 4.84 (1H, d, J= 11 Hz), 3-68 (3H, s), 2.73 (3H, s), 1.59 (9H, s). U)(S) _2-[({5_(Benzyloxy)_2methyl-6-[4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]propionic acid ethyl ester

5-(Benzyloxy)-6-{2-methoxy-2-oxo-l-[4-(trifluoromethyl)phenyl]ethyl}-2-methylpyrimidine-4- The carboxylic acid tert-butyl ester (1.7 g) was dissolved in methanol (50 mL), and aqueous sodium hydroxide (1 M, 17 mL) was added and then stirred at 6 ° C for 2 hours. After adding hydrochloric acid (1 M, 30 mL) to the reaction mixture, the resulting precipitate was filtered off and dried under reduced pressure to obtain 5-(benzyloxy)-2-methyl-6-[4-(3) Fluoromethyl)benzyl]pyrimidin-4·carboxylic acid (1.1 g, yield 87%) was obtained as a white solid. -199- 201141839 5-(Benzyloxy)-2-methyl-6-[4-(trifluoromethyl)benzyl]pyrimidin-4carboxylic acid (0.19 g) and ethyl L-alaninate The acid salt (0.15 g) was dissolved in N,N-dimethylformamide (5 mL), and benzotriazole-1 -yloxy ginseng (dimethylamino)sodium hexafluorophosphate (PyB〇P) was added. (〇.44 g) and triethylamine (0.32 mL), and the mixture was stirred for 2 hr. TC was added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated brine. After the solvent was evaporated to dryness crystals crystals crystals crystals crystals crystalssssssssssssssssssssssssssssss , t, J = 7 Hz), 7.46 (2H, d, J = 8 Hz), 7.42-7.36 (5H, m), 7.28 (2H, d, J = 9

Hz), 5.09 (1H, d, J = 11 Hz), 4.99 (1H, d, J = 11 Hz), 4.76 (1H, q, J = 7 Hz), 4.25 (2H, q, J = 7 Hz) , 4.08 (2H, s), 2.71 (3H, s), 1.54 (3H, d, J = 7 Hz), 1.30 (3H, t, J = 7 Hz). (4)(S)-2-[( {5-Hydroxy-2-methyl-6-[4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]propionic acid according to Examples 7 - (2) and 1 - (6) And using (S) - 2 - [( { 5 -(benzyloxy)-2methyl-6 [4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino] Ethyl propionate (0.15 g) in place of [({5_(benzyloxy)_2-methyl-6-[3.(trifluoromethyl)phenyl]pyrimidine-4-yl}carbonyl)amino] The title compound (0.11 g, yield 98%) Mp: 161 -200- 201141839 'H-NMR (400 MHz, CDC13) δ: 11.41 (1H, s), 8.41 (1H, d, J = 7 Hz), 7.53 (2H, d, J = 9 Hz), 7.48 (2H, d, J = 9 Hz), 4.76 (1H, m), 4.22 (2H, s), 2.64 (3H, s), 1.62 (3H, d, J = 8 Hz). (Example 1 1 3) ({[6-(4-Chlorobenzyl)-2-ethyl-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid

(1) [({5-(Benzyloxy)-6-[1-(4-chlorophenyl)-2-ethoxy-2-oxoethyl]-2-ethylpyrimidine-4- Ethyl}carbonyl)amino]ethyl acetate

In accordance with Example 72-(1), (4-chlorophenyl)acetic acid ethyl acetate (〇32 g) was used instead of (3,4,5-trifluorophenyl)acetate, and Example 1 was used. 4_ U) (U5-(Hydroxy)-2-ethyl-6-{[(trifluoromethyl)indoleyl]oxy}pyrimidin-4-yl]carbonyl}amino)ethyl acetate (0.39 g) instead of ({[5(hydroxy))-2-methyl·6_{[(difluoromethyl)))]}}}]]]] Ester 'obtained the title compound (0.22 g, yield 51 &lt;) /). 'H-NMR (400 MHz, CDCI3) δ: 8.41 Γ1Η ♦ t5 j = 4 Hz),

7.46-7.3 6 (5 H, m), 7.23 (4H, s), 5.44 (1H , , r , , , 1U ' 5.11 (1H, d, J = 10 Hz), 4.89 (1H,d, J = 10 Hz), 4.25 (2h qj = 8

Hz), 4.22 (2H, d, J = 4 Hz), 4.12 (2H α τ ,, q, J = 8 Hz), 2.98 (3H,t,J = (2H, q, J = 8 Hz), 1.35 (3H, t, J = 8 Hz), 1 8 Hz), 1.17 (3H, t, J = 8 Hz). -201 - 201141839 Ethyl-5-hydroxypyrimidin-4-yl]carbonyl}amino) According to the embodiment (4), and using [({5-(benzyloxy)-6-[1-(4-chloro)

Ethyl 3-(yl)-2-ethoxy-3 _ oxoethyl bromide 2 _methylpyrimidine _ 4 _yl}carbonyl)amino]acetate to give the title compound (〇1() g , yield 72%) of a white solid. MS m/z: 3 5 0 (M + H) + ; 'H-NMR (400 MHz, CD3 〇D) δ: 7.33 (2H, d, J = 8 Hz), 7.27 (2H, d, J = 8 Hz), 4.16 (2H, s), 4.14 (2H, s), 2.90 (2H, q, J = 8 Hz), 1.34 (3H, t, J = 8 Hz). (Example 1 14) ({[ 2-ethyl-5-hydroxy-6-(4-methylbenzyl)pyrimidin-4-yl]carbonyl)amino)acetic acid

(1) [({5-(Benzyloxy)-2-ethyl-6-[2-methoxy-1-(4-methylphenyl)-2-yloxyethyl]pyrimidine-4 -yl}carbonyl)amino]ethyl acetate

In accordance with Example 72-(1), and using (4-methylphenyl)acetic acid methyl ester (〇·26 g) in place of (3,4,5-trifluorophenyl)acetate, and using the examples 10 4-(1) Obtained ({[5·(benzyloxy)·2·ethyl-6_{[(trifluoromethyl)sulfonyl] 201141839 yl]oxy} Mouth 'Shen-4-yl]carbonyl Ethyl acetate ethyl ester (〇 39 g) instead of ({[5-(kilooxy)-2-methyl-6_{[(trifluoromethyl)sulfonyl]oxy}pyrimidine·4 - The title compound (〇17 g, yield 41%) was obtained. 'H-NMR (400 MHz, CDC13) δ: 8.39 (1Η, t, J = 4 Hz), 7.48 -7.3 5 (5H, m), 7.21 (2H, d, J = 8 Hz), 7.09 (2H, d, J 8 Hz), 5.50 (1H, s), 5.08 (1H, d, J = 12 Hz), 4.83 (1H, Lu d, J = I2 Hz), 4.24 (2H, q, J = 8 Hz) , 4.22 (2H, d, J = 4 Hz), 3.65 (3H, s), 2.98 (2H, q, J = 8 Hz), 2 31 (3H, s), 1.36 (3H, t, J = 8 Hz ), 1.3i (3H, t, j = 8 Hz) (2) ({[2-ethyl-5-hydroxy-6-(4-methylbenzyl)pyrimidin-4-yl]carbonyl}amino) Acetic acid according to Example 110-(4), and using [({5_(benzyloxy)_2_ethyl_6_[2-methoxy-1_(4-methylphenyl)_2_ oxyethyl) Pyrimidine, _yl}carbonyl)amino]acetate (0.17 g) in place of [({5_(benzyloxy)·6 [丨_(4,,6_二φ氯联本_3_)) _2_Ethoxy-2-oxoethylethyl-2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate' gave the title compound ( 〇〇 75 g, yield 68%) as white solid . Mp: 1 5 5 - 1 5 6 ° C ; 'H-NMR (400 MHz, CD3OD) δ: 7.i9 (2H, d, j = 8 Hz) 7.06 (2H, d, J = 8 Hz), 4.12 (2H, s), 4 n (2h, s), 2.88

Hz) (2 H,q,J = 8 H z ), 2.2 7 ( 3 H,s ),1 . 3 3 ( 3 H,t,j = (Example 115) ({[6-(3-chloro) Benzyl)-2-ethyl-5-hydroxypyrimidin-4-yl]carbonyl)amino)acetic acid-203 - 201141839

(1) [({ 5-(Benzyloxy)-6-[1-(3-chlorophenyl)-2-ethoxy-2-oneoxyethyl]-2-ethylpyrimidine-4- Ethyl}carbonyl)amino]ethyl acetate

In accordance with Example 72-(1)' and using (3-chlorophenyl)acetic acid ethyl acetate (〇32 g) in place of (3,4,5-trifluorophenyl)acetate, and using Example 1 4-(1) Obtained ({[5-(decyloxy)-2-ethyl-6-{[(trifluoromethyl))]oxy}pyrimidin-4-yl]carbonyl}amino) Ethyl acetate (0.39 g) instead of ({[5_(hydroxy))-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amine Ethyl acetate' gave the title compound (0. ug, yield 26%). 'H-NMR (400 MHz, CDC13) δ: 8.41 (1H, t) J = 4 Hz), 7.46 -7.40 (5 H, m), 7.30 (1H, s), 7.23-7.16 (3H, m), 5.43 (1H, s), 5.12 (1H,d, 4·24 (2H,q, &gt; J = 4 Hz), 4.14 (2H,

J = 1 2 Hz), 4.85 (1 H, d, Hz), 4.22 (2H, d, J = 4 Hz according to Example 110-(4), using phenyl)-2-ethoxy-2- Ethyloxyethyl]2-yl]acetic acid ethyl acetate (0.H g) in place of [({5_biphenyl-3-yl)-2-ethoxy, 2-galene]ethyl acetate (0.1 1 And using [((5-(benzyloxy)-6-[1-(3-chloroethyl)-2-ethylpyrimidin-4-ylindolecarbonyl)) in place of [({5_(benzyloxy) -6-[1-(4,6-Dichloro'-oxyethyl]-2-methylpyrimidin-4-yl}carbonyl-204- 201141839 yl)amino]ethyl acetate' obtained the title compound (0050 g, yield 70%) mp.m. (3H,m), 4.16 (2H,s),4_13 (2H,s), 2.90 (2H,q,J = 8

Hz), 1.33 (3H, t, J = 8 Hz). (Embodiment 1 1 6)

({[2-ethyl-5-hydroxy-6-(2-naphthylmethyl)pyrimidin-4-yl]carbonyl}amino)acetic acid OH 0

(^[({5-(Hydroxy)-6-[2-(benzyloxy)-1-(2-naphthyl)) 2_ oxyethylate)

]-2-ethylpyrimidin-4-yl}carbonyl)amino]

In accordance with Example 72-(1), and using 2-benzyl-naphthylacetate (0.44 g) in place of (3,4,5-dihydrocarbyl)acetic acid ethyl acetate, and using Example ι〇4·(ι Obtained ({[5_(benzyloxy)-2_ethyl-6-{[(trifluoromethyl)sulfonyl)oxy) oxen-4-yl]p-)}amino)acetic acid Ester (0.39 g) instead of ({[5-(octyloxy)-2-methyl-6-{[(difluoromethyl)sulfonyl)oxy)pyrimidin-4-yl]carbonyl)amino)acetic acid The title compound (〇 2 g, yield Μ%) was obtained from ethyl ester. ^-NMR (400 MHz, CDC13) δ: 8.40 (1Η ... ς u, v 1 ? t, J = ) η Z j , 7.81-7.75 (2H, m), 7.72 - 7.65 ( 2H, m), 7.54- 7.5〇(1H, m), 7.47-7.41 (2H,m),7.3 9 -7.20 (1 0H,m),5 7 3 (ih,s), 518 -205 - 201141839 (1H, d, J = 13 Hz), 5.11 (1H, d, J = l3 Hz), 5.08 (1H, d, J =11 Hz), 4.74 (1H, d, J = 11 Hz), 4.24 (2H, q, J = 8 Hz) , 4.20 (2H, d, J = 5 Hz), 2.96 (2H, q, j = g Hz), 1.34 (3H, t, J = 8 Hz), 1.29 (3H, t, J = 8 Hz) (2) ({[2-ethyl-5-carbyl-6-(2-naphthylmethyl)pyran-4)-based)amino)acetic acid according to Example 94-(6), And using [((5_(benzyloxy)_6_[2_(oxy))-1-(2-naphthyl)-2-yloxyethyl]-2-ethylpyrimidin-4-ylcarbonyl) Ethyl acetate ethyl acetate (0.12 g) in place of [({5-(benzyloxy)_6_[2-(oxy))-1-(6-fluoro-2-naphthalenyl)-2-yloxy) </RTI> <RTIgt; + ; 'H-NMR (400 MHz, CD3〇D) δ: 7.78-7.41 (7H, m), 4.34 (2H, s), 4.12 (2H, s), 2 .89 (2H, q, J = 8 Hz), 1.33 (3H, t, J = 8 Hz). (Example 1 17) ({[6-(biphenyl-4-ylmethyl)-2-ethyl) Glycosyl-p-butyl-4-yl]amino}amino)acetic acid

(1) ({[5-(decyloxy)-6-(1-biben-4-yl-2-methoxy-2-yloxyethyl)-2-ethylpyrimidin-4-yl) Carbonyl}amino)ethyl acetate-206- 201141839

In accordance with Example 72-(1), and using methyl 4-biphenyl-4-ylacetate (0.36 g) in place of ethyl (3,4,5-trifluorophenyl)acetate, and using Example 104- (1) ({[5-(Benzyloxy)-2-ethyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid obtained Ethyl ester (0.39 g) instead of ({[5-(benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl)oxy}pyrimidin-4-yl]carbonyl}amine Ethyl acetate gave the title compound (0.19 g, yield 42%). H-NMR (400 MHz, CDC13) δ: 8.4 1 (1 Η, t, J = 4 Η ζ), 7.5 7-7.3 5 ( 1 4H, m), 5.56 (1H, s), 5.13 (1H, d , J = 12 Hz), 4.90 (1 H, d, J = 1 2 Hz), 4.25 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 4 Hz), 3.68 (3H, s ), 3.00 (2H, q, J - 8 Hz), 1.38 (3H, t, J = 8 Hz), 1.30 (3H, t, J = 8 Hz). (2)({ [6-(biphenyl)- 4-ylmethyl)-2-ethyl-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 1 1〇-(4), and using ({[5-(benzyloxy)) Ethyl 6-(1-biphenyl-4-yl-2-methoxy-2-oxoethyl)-2-ethylpyrimidin-4-yl]carbonyl}amino)acetate (0.19 g) Instead of [({5-(benzyloxy)-6-[1-(4',6-dichlorobiphenyl-3-yl)-2-ethoxy-2-oxoethyl]-2 Ethyl acetate of -methylpyrimidin-4-yl}carbonyl)amino]] gave the title compound (0.097 g,iel. MS m/z: 3 9 2 (M + H)+; -207 - 201141839 'H-NMR (400 MHz, CD3OD) δ: 7.57 (2H, d, J = 8 Hz), 7.52 (2H, d, J = 8 Hz), 7.41-7.29 (5H, m), 4.21 (2H, s), 4.13 (2H, s), 2.91 (2H, q, J = 8 Hz), 1.34 (3H, t, J = 8 Hz (Example 1 18) ({[6-(4-chloro-3-methylbenzyl)-2-ethyl-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid

(1) [({5-(Benzyloxy)-6-[1-(4-chloro-3-methylphenyl)-2-ethoxy-2-oxoethyl]-2-ethyl Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

In place of (3,4,5-trifluoro), according to Example 72-(1), and using (4-chloro-3-methylphenyl)acetate (0.34 g) obtained in Example 96-(2). Phenyl)acetate, and using the compound obtained in Example 104-(1) ({[5-(benzyloxy)_2-ethyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine- 4-(yl)carbonyl]amino)acetate (0.39 g) in place of ({[5-(benzyloxy)_2-methyl-6-{[(trifluoromethyl)sulfonyl)oxy} Ethyl pyrimidine-4-yl-carbonyl]amino)acetate gave the title compound (0.039 g, yield 9%). 'H-NMR (400 MHz, CDCI3) δ: 8.4 0 ( 1 Η, t, J = 4 Η ζ), 7.45-7.38 (5H, m), 7.24 (1H, d, J = 8 Hz), 7.12 ( 1H, s), 7.07 (1H, d, J = 8 Hz), 5.42 (1H, s), 5.12 (1H, d, J = 12 Hz), 4.83 (1H, d, J =: 12 Hz), 4.25 (2H, q, J = 8 Hz), 4.22 -208- 201141839 (2H, d, J = 4 Hz), 4.16-4.12 (2H, m), 2.98 (2H, q, J = 8 Hz), 2.28 ( 3H, s), 1.36 (3H, t, J = 8 Hz), 1.30 (3H, t, J = 8 Hz), 1.17 (3H, t, J = 8 Hz). (2)({[6-( 4-Chloro-3-methylbenzyl)-2-ethyl-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 1 1 〇-(4), and using [({ 5 - (Benzyloxy)-6 - [ 1 · (4-chloro-3-methylphenyl)-2-ethoxy-2-oxoethylethyl]-2-ethylpyrimidin-4-yl}carbonyl Ethyl acetate] (0.039 g) in place of [({5-(benzyloxy)-6-[1-(4',6-dichlorobiphenyl-3-yl)-2-ethoxy) Ethyl acetate of 2-ethyloxyethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]] gave the title compound (0.015 g, yield MS m/z: 3 64 (M + H) + ; 'H-NMR (400 MHz, CD3〇D) δ: 7.25 (1H, s), 7.23 (1H, d, J -8 Hz), 7.12 (1H , d, J = 8 Hz), 4.12 (2H, s), 4.11 (2H, s), 2.89 (2H, q, J = 8 Hz), 2.31 (3H, s), 1.34 (3H, t, J = 8

Hz). (Example 1 19) [({6-[(5-fluoro-2-naphthyl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) Benzyl (5-fluoro-2-naphthyl)acetate

- 209- 201141839 (5-Fluoro-2-naphthyl)acetonitrile (0-34 g) was dissolved in acetic acid (3 mL), concentrated hydrochloric acid (6 mL), and the mixture was stirred at 1 ° C for 1.5 hours. After the organic layer was extracted with diethyl ether, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, whereby (5-fluoro-2-naphthyl)acetic acid was obtained. This was dissolved in acetonitrile (5 mL), benzyl bromide (0.26 mL) and potassium carbonate (0.50 g). After the organic layer was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. H. - NMR (500 MHz, CDCI3) δ : 8.07 (1 H, d, J = 9 Hz), 7.75 (1H, O, 7.57 (1H, d, J = 8 Hz), 7 • 48 ( 1 H, d, J = 9 Hz), 7.4 1- 7.3 2 (6H, m), 7.13 ( 1 H , dd, J = 11 H2 :, 8 Hz), 5.16 (2H, s), 3.85 (2H, s 0· (2) [({5-(Benzyloxy)-6-[2-(benzyloxy)-1-(5-fluoro-2-naphthyl)-2-yloxyethyl]-2-yl) Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), and using (5-fluoro-2-naphthyl)acetic acid benzyl ester (〇·29 g) and Example 1-(3) ({[5-(benzyloxy)) -2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (〇·24 g) instead of (3,4 Ethyl 5-(trifluorophenyl)acetate gave the title compound (0.21 g, yield 67%). 'H-NMR (500 MHz, CDC13) δ: 8.34 (1Η, t, J - 5 Hz), 8.02 (1H, d, J = 9 Hz), 7.65 (1H, s), 7.54 (1H, d, J = 9 Hz), -210- 201141839 7.48 (1 H, d, J = 9 Hz), 7.3 9- 7.3 0 (9 H, m), 7.2 5 - 7.2 3 (2H, m), 7.12 ( 1 H, Dd, J = 11 Hz, 8 Hz), 5.70 (1 H, s), 5.21 (1 H, d, J = 1 2 Hz), 5.11 (1 H, d, J = 1 2 Hz), 5.08 ( 1 H, d, J = 10 Hz), 4.80 (1H, d, J = 10 Hz), 4.24 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 5 Hz), 2.69 (3H, s), 1.28 (3H, t, J = 7

Hz).

(3) [({6-[(5-fluoro-2-naphthyl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 94-(6) And using [({5-(benzyloxy)-6-[2-(benzyloxy)-1-(5-fluoro-2-naphthyl)-2-yloxyethyl]-2- Ethyl acetate (0.21 g) of methylpyrimidin-4-yl}carbonyl)amino] in place of [({5-(benzyloxy)-6-[2-(benzyloxy)-1-(6-fluoro) Ethyl acetate of 2-naphthyl)-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino], the title compound (1. g, yield: 79%) White solid. Mp: 1 93 - 1 9 6 ° C ; 'H-NMR (400 MHz, CDC13) δ: 11.36 (1H, s), 8.45 (1H, t, J = 6 Hz), 8.02 (1 H, d, J = 9 Hz), 7.82 ( 1 H, s), 7.59-7.56 (2H, m), 7.38-7.33 (1H, m), 7.08 (lH, dd, J = 11 Hz, 8 Hz), 4.35 (2H, s), 4.27 (2H, d, J = 6 Hz), 2.64 (3H, s). (Example 120) [({6-[(6-chloro-2-naphthyl)methyl]-5-hydroxyl -2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid OH Ο

-211 - 201141839 (1) Benzyl (6-chloro-2-naphthyl)acetate

In accordance with Examples 1-8-(1), 108-(2) and 94-(1) to 94-(4), and using 6-chloro-2-naphthol (1.3 g) instead of 4-chloro-3- Ethylphenol, the title compound (0.40 g, yield 31%) 'H-NMR (400 MHz, CDC13) δ: 7.81 ( 1 Η, d, J = 2 Η ζ), 7.74- 7.7 0 (3 Η, m), 7.45 (1Η, dd, J = 9 Hz, 2 Hz ), 7.42 (1H, dd, J = 9 Hz, 2 Hz), 7.3 6- 7.3 0 (5 H, m), 5.16 (2H, s), 3.83 (2H, s). (2)[({5 -(benzyloxy)-6-[2-(benzyloxy)-1-(6-chloro-2-naphthalenyl)-2-yloxyethyl]-2-methylpyrimidin-4-yl} Carbonyl)amino]ethyl acetate

According to Example 72-(1), and using (6-chloro-2-naphthyl)acetic acid benzyl ester (0.31 g) and Example 1-(3) ({[5-(benzyloxy)-2) -methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidinyl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5-trifluorophenyl) Ethyl acetate gave the title compound (0.33 g, yield quantitative).

'H-NMR (400 MHz, CDC13) δ: 8.35 (1Η, t, J = 6 Hz), 7.78 (1H, d, J = 2 Hz), 7.68 (1H, d, J = 8 Hz), 7.6 3 - 7.5 9 (2H, m), 7.51 (1H, dd, J = 8 Hz, 2 Hz), 7.38 (1H, dd, J = 9 Hz, 2 Hz), 7.35-7.29 (8H, m), 7.25- 7.22 (2H, m), 5.68 (1H, s), 5.22 (1H, d, J = 13 Hz), 5.11 (1H, d, J = 13 Hz), 5.08 (1 H, d, J = 1 0 Hz ), 4.78 (1 H, d, J = 1 0 Hz), 4.24 (2H, q, J -212- 201141839 =7 Hz), 4.21 (2H, d, J = 6 Hz), 2.68 (3H, s) , 1.29 (3H, t, J = 7 Hz). (3) [({6-[(6-Chloro-2-naphthyl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl} Carbonyl)amino]acetic acid according to Example 1 1〇-(4), and using [({5-(benzyloxy)-6-[2-(benzyloxy)-1-(6-chloro-2-) Naphthyl)-2-oxo-ethylidene]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.33 g) in place of [({5-(benzyloxy)-6) -[1-φ(4',6-Dichlorobiphenyl-3-yl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino Ethyl acetate gave the title compound (0.048 g, yield 26% Mp : 207-2 1 0 °C ; ^-NMR (400 MHz, CDC13) δ: 11.35 (1H, s), 8.44 (1H, t, J = 6 Hz), 7.7 8 -7.76 (2H, m), 7.72 (1H, d, J - 9 Hz), 7.68 (1H, d, J = 9 Hz), 7.54 (1H, d, J = 9 Hz), 7.38 (1H, dd, J =9 Hz, 2 Hz) , 4.33 (2H, s), 4.28 (2H, d, J = 6 Hz), 2.64 φ (3H, s). (Example 1 2 1 ) [({6-[(2-Fluorobiphenyl-4-) Methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-(Benzyloxy)-6-[1-(2-fluorobiphenyl-4-yl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidine -4-yl}carbonyl)amino]acetate-213- 201141839

According to Example 72-(1), and using (2-fluorobiphenyl-4-yl)acetate (0.26 g) and Example 1-(3) ({[5-(benzyloxy)-) Ethyl 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.26 g) instead of (3,4,5- Ethyl trifluorophenyl)acetate gave the title compound (0.096 g, m. 'H-NMR (400 MHz, CDC13) δ: 8.37 (1Η, t, J = 6 Hz), 7.51 (2H,d, J = 9 Hz), 7.47-7.31 (9H, m), 7.14 (1H, dd , J = 12 Hz, 2 Hz), 7.10 (1H, dd, J = 8 Hz, 2 Hz), 5.49 (1H, s), 5.14 (1 H, d, J = 11 Hz), 4.95 ( 1 H, d, J = 11 Hz), 4.25 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 4,19 (2H, q, J = 7 Hz), 2.73 (3H, s), 1.28 (3H, t, J = 7 Hz), 1.20 (3H, t, J = 7 Hz). (2) [({6-[(2-Fluorobiphenyl-4-yl)methyl]] -5-Hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 72-(2), and using [({5-(benzyloxy)-6-[1-(2) -Fluorobiphenyl-4-yl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.096 g) in place of [ ({5-(Benzyloxy)-6-[2-ethoxy-2-o-oxy-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidine-4 Ethyl acetate of <RTI ID=0.0># </RTI> carbonyl) </RTI> <RTI ID=0.0> Mp: 208-209 °C; -214- 201141839 H-NMR (400 MHz, CDC13) δ: 11.35 (1H, s), 8.46 (1H, t, J = 6 Hz), 7.51 (2H, d, J = 8 Hz), 7.42 (2H, t, J = 7 Hz), 7.35 (2H, t, J = 8 Hz), 7.22 (1H, dd, J = 8 Hz, 2 Hz), 7.18 (1H, d, J = 11 Hz), 4.30 (2H, d, J = 6 Hz), 4.21 (2H, s), 2.65 (3H, s). (Example 122) ({[6-(3 - chloro-4-) Propylbenzyl)-5-hydroxy-2-methylpyrimidin-4yl]carbonyl}amino)acetic acid

(I) 2-Gas-1-isopropenyl-4_methoxybenzene

The methyltriphenylphosphonium bromide (3.5 g) was suspended in tetrahydrofuran (1 〇m L). A solution of lithium hexamethyldiamine in tetrahydrofuran was added dropwise at -7 8 °C under nitrogen atmosphere (1 · 0 Μ, 1 2 m L), stir at the same temperature for 15 minutes, then stir for 40 minutes at 〇〇c. After a solution (3 mL) of ι_(2·chloro-4-methoxyphenyl)ethanone (0.91 g) in tetrahydrofuran (3 mL) was added to the mixture, and the mixture was stirred at room temperature for 4 hours. After the organic layer was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, crystals crystals crystals crystals crystals !H-NMR (400 MHz, CDCI3) δ: 7.12 (1Η, d, J = 9 Hz), 6.91 (1H, d, J = 3 Hz), 7.76 (1H, dd, J = 9 Hz, 3 Hz) , 5.20 (1H, s), 4.94 (1H, s), 3.79 (3H, s), 2.08 (3H, s). -215 - 201141839 (2) 3-Chloro-4·isopropylphenol

2-Chloro-1·isopropenyl-4-methoxybenzene (0-78 g) was dissolved in ethyl acetate (5 mL), 5% palladium-activated carbon (10 mg) was added, and then placed in a hydrogen atmosphere Stir for 1.5 hours. 5% palladium-activated carbon (0.17 g) was added to the reaction mixture, followed by stirring for 1 hour. After the reaction mixture was filtered over Celite, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 2-chloro-1-isopropyl-4-methoxybenzene. This was dissolved in dichloromethane (8 mL), and a solution of boron tribromide in dichloromethane (1.0 M, 5 · 7 mL) was added dropwise at -78 ° C under a nitrogen atmosphere. temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the organic layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give crystals crystals. 'H-NMR (400 MHz, CDC13) 6: 7.15 (1H, d, J = 9 Hz), 6.86 (1H, d, J = 3 Hz), 6.72 (1H, dd, J = 9 Hz, 3 Hz) , 4.73 (1H, s), 3.32 (1H, m), 1.21 (6H, d, J = 7 Hz). (3) (3-Chloro-4_isopropylphenyl)acetic acid benzyl ester

According to the examples 1 0 8 - (1 ), 1 0 8 - (2 ) and 9 4 - (1 ) to 9 4 - (4), and using 3-chloro-4-isopropylphenol (0.65 g) instead 4-Chloro-3-ethylphenol, the title compound (0.58 g, yield 50%) JH-NMR (400 MHz, CDC13) δ: 7.39-7.31 (5Η, m), 7.28 (1Η, d, J = 2 Hz), 7.24 (1H, d, J = 8 Hz), 7.15 (1H, dd, J -216- 201141839 =8 Hz, 2 Hz), 5.14 (2H, s), 3.61 (2H, s), 3.38 (1H, m), 1.23 (6H, d, J = 7 Hz). (4)[ ({5-(Benzyloxy)-6_[2_(benzyloxychloro_4_isopropylphenyl) 2_ oxo Bafc 〇 〇 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 Amino]acetic acid ethyl vinegar

According to Example 72-(1)' and using (3_chloro-4-isopropylphenyl)acetic acid^narrow vinegar (0·30 g) and Example 1-(3) ({[5-(( Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy)pyrimidin-4-yl]carbonylguanidino)acetic acid ethyl acetate (0.24 g) instead (3, Ethyl acetate 4,5-trifluorophenyl) gave the title compound (0.28 g, yield: 89%). !H-NMR (400 MHz, CDC13) δ: 8.34 (1Η, t, J = 6 Hz), 7.3 9 -7.29 (8 H, m), 7.26-7.18 (4H, m), 7.14 (1H, dd, J = 8

Hz, 2 Hz), 5.44 (1H, s), 5.20 (iH) d, J = 13 Hz), 5.08

(1H,d,J = 13 Hz), 5.07 (1H,d,J = 11 Hz), 4.83 (1H,d,J • = 11 Hz), 4.25 (2H, q, J = 7 Hz), 4.21 ( 2H, d, J - 6 Hz), 3.35 (1H, m), 2.67 (3H, s), l, 3 〇 (3H, t, J = 7 Hz), 1.21 (6H, d, J = 7 Hz) (5) ({[6-(3-Chloro-4-isopropylbenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid according to Example 72-(2) And using (benzyloxy)_6_[2_(benzyloxy)-1-(3-chloro-4-isopropylphenyl)-2_sideoxyethyl]_2-methylpyrimidin-4-yl }]]============================================================================================= Ethyl]ethyl]-2-methylpyrimidine-4_-217-201141839 yl}carbonyl)amino]ethyl acetate' gave the title compound (0.079 g,iel. m p : 9 4 - 9 7 ° C ;

'H-NMR (5 00 MHz, CDC13) δ: 11.29 (1H, s), 8.44 (1H, t, J = 6 Hz), 7.34 (1H, d, J = 2 Hz), 7.24 (1H, dd, J = 8 Hz, 2 Hz), 7.19 (1H, d, J = 8 Hz), 4.29 (2H, d, J = 6 Hz), 4.H (2H, s), 3.34 (1H, m), 2.64 (3H, s), 1.21 (6H, d, J = 7 Hz). (Example 123) [({5-]-yl-2-methyl-6-[(2-methylbiphenyl-4-yl) Methyl]pyrimidin-4_yl}indenyl)amino]acetic acid

(1) [({5-(Benzyloxy)-6-[2-ethoxy-1-(2-methylbiphenyl-4-yl)-2-yloxyethyl]-2-yl) Ethylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), and using (2-methylbiphenyl-4-yl)acetate (〇.5〇g) and Example 1-(3) ({[5-(benzyl) Ethyl oxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.45 g) instead of (3,4 Ethyl 5-(trifluorophenyl)acetate gave the title compound (yield: 47 g, yield 79%) as a yellow amorphous solid. 'H-NMR (400 MHz, CDC13) δ: 8.37 (1Η, t, J = 6 Hz), 7.46 (2H, d, J = 8 Hz), 7.41-7.27 (8H, m), 7.19-7.13 (3H ,m), 5.51 (1H, s), 5.12 (1H, d, J = 11 Hz), 4.84 (1H, d, J= 11 -218- 201141839

Hz), 4.25 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 4.19 (2H, q, J = 7 Hz), 2.74 (3H, s), 2.19 (3H, s), 1.30 (3H, t, J = 7 Hz), 1.2 1 (3H, t, J = 7 Hz). (2)[({5-hydroxy-2-methyl- 6-[(2-A) Benzyl-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

According to Example 72-(2), and using [({5-(benzyloxy)-6-[2-ethoxy-1-(2-methylbenben-4-yl)-2-yloxy) Ethyl]-2-methyl-butyl 4-amino}carbonyl]amino]acetate (0.47 g) in place of [({5-(benzyloxy)-6-[2-ethoxy]- 2-Ethyloxy-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound (0.26 g, Yield 81%) white solid. Mp : 95 -96 ° C ; 'H-NMR (400 MHz, CDC13) δ: 11.37 (1Η, s), 8.46 (1H, t, J = 6 Hz), 7.38 (2H, t, J = 7 Hz) , 7.3 2- 7.2 3 (5H, m), 7.14 (1H, d, J - 7 Hz), 4.28 (2H, d, J = 6 Hz), 4.20 (2H, s), Ref. 2.66 (3H, s) , 2.23 (3H, s). (Example 124) ({[2-cyclopropyl-6-(3,4-dichlorobenzyl)-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid

CI CI

iTc〇2H (1)({[5-(benzyloxy)-2-cyclopropyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino) Ethyl acetate-219- 201141839 ΟΒη Ο , C02Et

Tf〇^ According to Example i - (1) to 1 - (3) ' and using cyclopropanecarboxyamine decylamine hydrochloride (2.8 g) in place of ethaneimine decylamine hydrochloride' to give the title compound (6.5 g , yield 53%) yellow oily substance. *H-NMR (400 MHz, CDC13) δ: 8.15 (1Η, t, J = 5 Hz), 7.51-7.35 (5H, m), 5.19 (2H, s), 4.27 (2H, q, J = 7 Hz ), 4.22 (2H, d, J = 5 Hz), 2.29-2.25 ( 1 H, m), 1.33 (3H, t, J =7 Hz), 1.19-1.13 (4H, m). (2)({ [2-cyclopropyl-6-(3,4-dichlorobenzyl)-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid according to Examples 72-(1) and 94-(6), And (3,4-dichlorophenyl) benzyl acetate (〇.47 g) was used instead of (3,4,5-trifluorophenyl)acetate, and ({[5-(benzyloxy)) was used. )·2·Cyclopropyl-6-{[((trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.40 g) instead ({[5_( Benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidinyl-4-yl]carbonyl}amino)acetic acid ethyl acetate' gave the title compound (0.19 g, yield 60%) white solid. MS m/z: 3 96 (M + H) + ; 'H-NMR (400 MHz, CD3OD) δ: 7.48 (1H d J = 2 Hz), 7.41 (1H, d, J = 8 Hz), 7.24 ( 1H, dd, j = 8 Hz, 2 Hz), 4.12 (2H, s), 4.11 (2H, s), 2.22-2.15 (ih, m), 1.05-0.96 (4H, m). -220- 201141839 ( Example 1 2 5 ) [({2-Ethyl-6-[(6-fluoro-2-naphthyl)methyl]·5-hydroxypyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-(Benzyloxy)-6-[2-(benzyloxy)-1_(6-fluoro-2_naphthalenyl)_2_ oxyethyl]-2-ethylpyrimidine) _4-yl}carbonyl)amino]ethyl acetate

In place of (3,4,5-trifluoro), according to Example 7 2 - (1 ), and using (6-fluoro-2-naphthyl)acetic acid benzyl ester (0.47 g) obtained in Example 9 4 - (4) Phenyl)acetate, and ({[5-(benzyloxy)-2-ethyl-6-{[(trifluoromethyl)sulfonyl)oxy) obtained using Example 104-(1) } pyrimidine-4-yl]carbonyl}amino)acetate (〇·39 g) in place of ({[5-(benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonate) Ethyl benzyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate gave the title compound (0.18 g, yield 35%). !H-NMR (400 MHz, CDC13) δ: 8.39 (1Η, t, J - 5 Hz), 7.73-7.60 (3H, m), 7.5 6-7.5 0 ( 1 H, m), 7.43-7.18 (12H , m), 5.69 (1H, s), 5.17 (1H, d, J = 13 Hz), 5.10 (1H, d, J = 13 Hz), 5.08 (1H, d, J = 10 Hz), 4.74 (1H , d, J = l〇Hz), 4.23 (2H, q, J = 8 Hz), 4.20 (2H, d, J = 5 Hz), 2.95 (2H, q, j = 8

Hz), 1.33 (3H, t, J = 8 Hz), 1.29 (3H, t, J = 8 Hz). (2)[({2-ethyl-6-[(6-fluoro-2-naphthyl) )methyl]-5-hydroxypyrimidin-4-yl}carbonyl)amino]acetic acid-221 - 201141839 According to Example 94-(6), and using [({5·(benzyloxy)·6_[2_( Benzyloxy)-1-(6-fluoro-2-naphthyl)-2-yloxyethyl]_2-ethylpyridin-4-yl}yl)amino]acetate (〇·18 g) in place of benzyloxy(benzyloxy)-1 -(6-fluoro-2-naphthyl)-2-yloxyethyl]-2-pyrimidin-4-yl)carbonyl)amine] Ethyl acetate gave the title compound (0.071 g, yield: 65%) White solid mp : 222 -22 3 ° C; 'H-NMR (400 MHz, CD3OD) δ: 7.8 5 -7.8 0 ( 1 Η, m ), 7.79 (1H, s), 7.74 (1H, d, J = 8 Hz), 7.52 (1H, d, J = 8 Hz), 7.45 (1H, dd, J = 8 Hz, 4 Hz), 7.24 ( 1H, dt, J = 8 Hz, 4 Hz), 4.32 (2H, s), 4.12 (2H, s), 2.90 (2H, q, J = 8 Hz), 1.3 3 (3H, t, J = 8 Hz (Example 126) [({6-[4-Chloro-3-(trifluoromethyl)benzyl]_2-ethyl-5-hydroxypyrimidin-4-yl}p-)amino)acetic acid

Π)({[5-(Benzyloxy)-6-{1-[4-chloro-3-(trifluoromethyl)phenyl) 2-ethoxy

In place of (3,4) [4. chloro-3-(trifluoromethyl)phenyl]acetate (0.43 g) obtained according to Example 72-(1) and using Example 1〇2_(1) , 5-trisylphenyl)acetate, and obtained using Example 1〇4-(1) ({[5-(benzyloxy-222- 201141839))-2-ethyl-6-{[(trifluoro Methyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (〇·39 g) instead of ({[5-(benzyloxy)-2-methyl-6-) Ethyl acetate of [[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino) / title compound (0.23 g, yield 47%). 'H-NMR (400 MHz, CDC13) δ: 8.41 (1Η, t, J = 4 Hz), 7.64 (1H, s), 7.4 5 - 7.3 5 (7H, m), 5.42 (1H, s), 5.14 (1H, d, J = 12 Hz), 5.03 (1H, d, J = 12 Hz), 4.25 (2H, q, J = 8 Hz), • 4.2 1 (2H, d, J = 4 Hz), 4.14 (2H, m), 2.97 (2H, q, J = 8

Hz), 1.34 (3H, t, J - 8 Hz), 1.30 (3H, t, J = 8 Hz), 1.17 (3H, t, J = 8 Hz). (2)[({6-[4- Chloro-3-(trifluoromethyl)benzyl]-2-ethyl-5-hydroxypyridin-4-yl}carbonyl)amino]acetic acid according to Example 1 1〇-(4), and used ({ [5-(Benzyloxy)-6-{1-[4-chloro-3-(trifluoromethyl)phenyl]-2.ethoxy-2-oxoethyl}-2-ethyl Acetylpyrimidin-4-yl]carbonyl}amino)acetate (0.23 g) in place of [({5-(benzyloxy)_6_[1-(4',6-dichlorobiphenyl-3-yl) Ethyl acetate 2-ethyloxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino], the title compound (0.11 g, yield 72%) solid. Mp : 1 7 3 - 1 74 °C ; 'H-NMR (400 MHz, CD3〇D) δ: 7.77 (1H, s), 7.56 (1H, d, J =8 Hz), 7.51 (1H, d, J = 8 Hz), 4.23 (2H, s), 4.13 (2H, s)? 2.89 (2H, q5 J = 8 Hz), 1.32 (3H, t, J = 8 Hz). -223 - 201141839 (Example 1 2 7 ) [({6-[3-Fluoro-4-(trifluoromethyl)benzyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1"[3-Fluoro-4-(trifluoromethyl)phenyl]acetic acid benzyl acetate

The title compound was obtained according to Example 94-(4), using [3-fluoro-4-(trifluoromethyl)phenyl]acetonitrile (1.0 g) instead of (6-fluoro-2-naphthyl)acetonitrile. 1.3 g, yield 87%) beer oily substance 'H-NMR (400 MHz, CDC13) δ: 7.56 (1Η, t, J = 8 Hz), 7.39-7.31 (5H, m), 7.18-7.15 (2H, m), 5.16 (2H, s), 3.72 (2H, s). (2)({[5-(Benzyloxy)-6-{2-(benzyloxy)-l-[3- Ethyl fluoro-4-(trifluoromethyl)phenyl]-2-oxoethyl}-2-methylpyrimidin-4-yl]carbonyl}amino)acetate

According to Example 72-(1)' and using [3-fluoro-4-[(trifluoromethyl)phenyl]acetic acid benzyl ester (0.31 g) and Example 1-(3) ({[5-(benzyl) Oxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidinyl]carbonyl}amino)acetate (0.24 g) instead (3,4,5 Ethyl trifluorophenyl)acetate gave the title compound (0.27 g,yield 85%). 'H-NMR (400 MHz, CDC13) δ: 8.34 (1H, t, J = 6 Hz), 7.45 (1H, t, J = 8 Hz), 7.3 8 -7.3 0 ( 8 H, m), 7.24 7.20 (2H,m), -224- 201141839 7.13 (1H, d, J = 11 Hz), 7.04 (1H, d, J = 8 Hz), 5.46 (1H, s), 5.18 (1H, d, J = 13 Hz), 5.10 (1H, d, J = 11 Hz), 5.08 (1 H, d, J = 1 3 Hz), 4.99 (1 H, d, J = 1 1 Hz), 4.25 (2H, q, J = 7 Hz), 4.22 (2H, d, J - 6 Hz), 2.66 (3H, s), 1.30 (3H, t, J = 7 Hz). (3)[({6-[3-Fluorine- 4-(Trifluoromethyl)benzyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Example 94-(6), and using ({[5-(benzyloxy)-6-{2-(benzyloxy)-1-[3-fluoro-4-(trifluoromethyl)phenyl) [-2-(oxyethyl}-2-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.27 g) in place of [({5-(benzyloxy)-6-[2 -(Benzyloxy)-1-(6-fluoro-2-naphthyl)-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate, obtained the title Compound (0.11 g, yield 67%) was obtained as a white solid. Mp: 2 0 5 °C; H-NMR (400 MHz, CDC13) δ: 11.36 (1 Η, s), 8.44 (1H, t, J = 6 Hz), 7.51 (1H, d, J = 8 Hz), 7.25 (1H, d, J = 8 Hz), 7.23 (1H, d, J = 11 Hz), 4.30 (2H, d, J = 6 Hz), 4.21 (2H, s), 2.64 (3H, s). (Example 128) [({5-Hydroxy-2-methyl-6-[3-methyl-4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid hydrazine Ο

-225 - 201141839 (1) 4-(Bromomethyl)-2-methyl-1-(trifluoromethyl)benzene

In accordance with Examples 94-(1) and 94-(2), and using methyl 3-methyl-4-(trifluoromethyl)benzoate (2.3 g) in place of methyl 6-fluoro-2-naphthoate, The title compound (2.5 g, yield 94%) was obtained. A-NMR (400 MHz, CDC13) δ: 7.58 (1H, d, J = 8 Hz), 7.3 2-7.2 8 (2HS m), 4.45 (2H, s), 2.49 (3H, s). (2) [3-methyl-4-(trifluoromethyl)phenyl]acetonitrile

Dissolve 4-(bromomethyl)-2-methyl-1-(trifluoromethyl)benzene (2.5 g) in acetonitrile (20 mL), add tetraethylammonium hydride (1.8 g), and then nitrogen Stir at room temperature for 2 · 5 hours under the atmosphere. Saturated brine was added to the reaction mixture, and the organic layer was extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to afford the title compound (1.1 g, yield: 7%). 'H-NMR (400 MHz, CDC13) δ: 7.62 (1H, d, J = 8 Hz), 7.2 9- 7.2 3 (2 H, m), 3.78 (2H, s), 2.51 (3H, s). (3) [3-Methyl 4-(trifluoromethyl)phenyl]acetic acid benzyl acetate

[3-Methyl-4-(trifluoromethyl)phenyl]acetonitrile (1.1 g) was dissolved in ethanol (5 mL), added with aqueous potassium hydroxide (2 M, 10 mL) and stirred at 80 ° C 20 minutes, followed by one night at room temperature. After the reaction mixture was stirred at 80 ° C for further 4 hours, concentrated hydrochloric acid was added, and the organic layer was extracted with diethyl ether, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give [3-methyl-4-[(trifluoromethyl)phenyl]acetic acid. This was dissolved in acetonitrile (1 mL), benzyl bromide (1.3 mL) and potassium carbonate (1.5 g). After adding water to the reaction mixture and extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to afford the title compound ( 〇 5 2 g, yield 31%).

1 H-NMR (400 MHz, CDCh) δ: 7. 55 (1H, d, J = :8 Hz), 7.38-7.3 1 ( 5 H , m), 7.19-7.17 (2H, m), 5.15 (2H , s), 3.67 (2H, s), 2.46 (3H, s )- (4)({[5-(benzyloxy)-6- -{2-(benzyloxy)-1 -[3- Ethyl-4-(trifluoromethyl)phenyl]-2·-sideoxyethyl}-2-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate Bn02C ?Bn§ 八C02Et f3c^ Ι Ι Ν M

According to Example 7 2 - (1), and using [3-methyl-4-(trifluoromethyl)phenyl]acetic acid benzyl ester (0.31 g) and Example 1-(3) ({[5 Instead of (-benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid ethyl acetate (0.24 g) Ethyl acetate (3,4,5-trifluorophenyl) gave the title compound (0. ^-NMR (400 MHz, CDC13) δ: 8.34 (1Η, t, J = 6 Hz), 7.49 (1H, d, J = 8 Hz), 7.3 6-7.3 0 (8 H, m), 7.24-7.22 (2H, m), 7.16 (1H, d, J = 8 Hz), 7.12 (1H, s), 5.49 (1H, s), 5.20

(1H, d, J = 13 Hz), 5_〇9 (1H&gt; d, J = 13 Hz), 5.08 (1H, d, J - 227- 201141839 =11 Hz), 4.85 (1 H, d, J = 1 1 Hz), 4.25 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 6 Hz), 2.67 (3H, s), 2.37 (3H, s), 1.30 (3H, t, J = 7 Hz). (5) [({5-Hydroxy-2-methyl-6-[3-methyl-4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino group Acetic acid according to Example 72-(2), and using ({[5-(benzyloxy)-6-{2-(benzyloxy)-1-[3-methyl-4-(trifluoromethyl)) Ethyl phenyl]-2-oxoethylethyl 2-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.29 g) in place of [({5-(benzyloxy)-6-) [2-Ethoxy-2-oxooxy-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate, The title compound (0.14 g, mp. Mp : 16 9 ° C ; W-NMR (400 MHz, CDC13) δ: 11.33 (1H, s), 8.45 (1H, t, J = 6 Hz), 7.51 (1H, d, J = 9 Hz), 7.2 8 - 7.2 5 (2H, m), 4.29 (2H, d, J = 6 Hz), 4.18 (2H, s), 2.64 (3H, s), 2.44 (3H, s). (Example 1 2 9 ) [({6-[(4'·fluoro-2-methylbiphenyl-4-yl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid]

(1) Methyl 4'-fluoro-2-methylbiphenyl-4-carboxylate

-228 - 201141839 Methyl 4-bromo-3-methylbenzoate (3.8 g) and (4-fluorophenyl) succinic acid (3_5 g) were dissolved in toluene (8 〇mL)' under nitrogen atmosphere. (Triphenylene) Palladium complex (〇·97 g) and sodium carbonate (3_6 g) were heated under reflux for 3 hours. After adding water to the reaction mixture and extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified to silica gel column chromatography to afford the title compound (4.5 g, yield quantitative).

^-NMR (400 MHz, CDC13) δ: 7.95 (1Η, s), 7.89 (1H, d, J = 8 Hz), 7.3 0- 7.2 6 (3 H, m), 7.13 (1H, d, J = 8 Hz), 7.11 (1H, d, J = 8 Hz), 3.93 (3H, s), 2.30 (3H, s). (2) (4fluoro-2-methylbiphenyl-4-yl)acetic acid ester

According to Examples 94-(1), 94-(2), 128-(2) and 95-(3), and using 4'-fluoro-2-methylbiphenyl-4-carboxylate (4.5 g The title compound (2.7 g, yield 54%) was obtained as a colorless amorphous solid. *H-NMR (400 MHz, CDC13) δ: 7.27 (1Η, d, J = 6 Hz), 7.25 (1H, d, J = 6 Hz), 7.18 (1H, s), 7.16 (2H, d, J = 2 Hz), 7.09 (2H, t, J = 9 Hz), 4.18 (2H, q, J = 7 Hz), 3.62 (2H, s), 2.24 (3H, s), 1.29 (3H, t, J = 7 Hz). (3) [({5-(Benzyloxy)-6-[2-ethoxy-oxime-.,-fluoro-2-methylbiphenyl-4))

201141839 According to Example 72-(1), and using (4, _fluoro-2-methylbiphenyl-n-yl)ethyl acetate (0.53 g) and Example by) ({[5_(benzyl) Instead of (3,4,5) oxymethyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl)amino)acetic acid ethyl acetate (0·45 g) Ethyl trifluorophenyl)acetate gave the title compound (0.54 g, yield 88%) as a yellow amorphous solid. 'H-NMR (400 MHz, CDC13) δ: 8.37 (1H, t, J = 5 Hz) J5 *7,4 7 (2H, dd, J = 8 Hz, 2 Hz), 7.42 -7.3 6 (3 H ,m),7 , 5 ' -26-7.〇5 (7H, m), 5.50 (1H, s), 5.12 (1H, d, J = 11 Hz) 4 〇- ^-87 (1H, d, J= 11 Hz), 4.26 (2H, q, J = 7 Hz), 4.23 (2H ht

5 U 5 J = J

Hz), 4.18 (2H, q, J = 7 Hz), 2.73 (3H, s), 2.17, H, s), 1.31 (3H, t, J = 7 Hz), 1.21 (3H, t, J = 7 Hz). (4) [({6-[(4'-Fluoro-2-methylbiphenyl-4-yl)methyl]_5_yl)-2-methyl-4-yl}carbonyl)amino Acetic acid according to Example 72-(2), and using [({5_(benzyloxy)_6_[2•ethyl]-l-(4'-fluoro-2-methylbiphenyl-4-yl)- 2-ethyloxyethyl]J-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.54 g) in place of [({5_(oxygen)-6-[2-ethoxy-2] -ethyloxy-1-(3,4,5-trifluorophenyl)ethyl]_2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound 3 _ 8 &gt; Rate 84%) white solid. Mp : 9 9- 1 00 ° C ; 'H-NMR (400. MHz, CDC13) δ: 11.37 (iH&gt; s), 8.46 (lH, t J = 6 Hz), 7.2 7 -7.2 2 (4H, m ), 7.11 (iH, d, J = 8 Hz), 7 〇 7

(2H, t, J = 9 Hz), 4.29 (2H, d, J = 6 HZ), 4.20 (2H 2.67 (3H, s), 2.2 1 (3H, s). -230- 201141839 (Embodiment 130) {[(5-Hydroxy-2-methyl-6-{[2-(trifluoromethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid

[4-Chloro-3-(trifluoromethyl)phenyl]methanol (1.1 g) was dissolved in tetrahydrofuran® (80 mL), sodium hydride (0.25 g) was added at 〇 ° C and stirred for 1 hour. Chloromethyl methyl ether (0.45 mL) was added at the same temperature and stirred for 3 hours. The reaction liquid was poured into water, and the organic substance was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, crystals crystals crystals crystals crystals ^-NMR (400 MHz, CDC13) δ: 7.69 (1Η, s), 7.50-7.44 (2H, • m), 4.72 (2H, s), 4.60 (2H, s), 3.41 (3H, s). 2) 4-[(Methoxymethoxy)methyl]-2-(trifluoromethyl)biphenyl

1-Chloro-4-[(methoxymethoxy)methyl]_2-(trifluoromethyl)benzene (0.56 g) was dissolved in tetrahydrofuran (30 mL). Tetrahydrofuran solution (1.1 M, 4.1 mL) and 1,3-bis(2,6-diisopropylphenyl)imidazolyl)-(3-chloropyridyl)palladium dichloride (0.0015 g), heated and refluxed 3 hours. After the reaction solution was cooled to room temperature and water was added, the organic layer was extracted with ethyl acetate -231 - 201141839. After the solvent was evaporated under reduced pressure, crystals crystals crystals crystals crystals 'H-NMR (400 MHz, CDC13) δ: 7.75 (1Η, s), 7.55 (1H, d, J = 8 Hz), 7.41-7.38 (3H, m), 7.3 4-7.3 0 (3 H, m ), 4.77 (2H, s), 4.69 (2H, s), 3.45 (3H, s). (3) [2-(Trifluoromethyl)biphenyl-4-yl]methanol

Dissolve 4-[(methoxymethoxy)methyl]_2-(trifluoromethyl)biphenyl (0.84 g) in methanol (20 mL), add hydrochloric acid (1%, 4.0 mL) and heat Reflux for 4 hours. After the reaction solution was cooled to room temperature and water was added, the organic layer was extracted with ethyl acetate. After the solvent was evaporated under reduced pressure, crystals crystal crystal crystal crystal crystal crystal crystal

'H-NMR (400 MHz, CDC13) δ: 7.76 (1H, s), 7.57 (1H, d, J = 8 Hz), 7.42-7.3 8 (3 H, m), 7.35-7.31 (3H, m) , 4.82 (2H, d, J = 6 Hz), 1.80 (1H, t, J = 6 Hz). (4) [2-(Trifluoromethyl)biphenyl-4-yl]ethyl acetate

In accordance with Examples 94-(2), 128-(2) and 95-(3), and using [2-(trifluoromethyl)biphenyl-4-yl]methanol (0.64 g) instead of (6-fluoro -2-Naphthyl)methanol' gave the title compound (0.39 g, yield 50%) as a colourless oil. -232- 201141839 Ή-NMR (400 MHz, CDC13) δ: 7.66 (1H, d, J = 2 Hz), 7.49 (1 H, dd, J = 8 Hz, 2 Hz), 7.41-7.37 (3H, m ), 7.32-7.29 (3H, m), 4.21 (2H, q, J = 7 Hz), 3.71 (2H, s), 1.30 (3H, t, J = 7 Hz). (5)({[5- (Benzyloxy)-6-{2-ethoxy-2-oxo-l-[2-(trifluoromethyl)biphenyl-4-yl]ethyl}-2-methylpyrimidine-4 -yl]carbonyl]amino)ethyl acetate

According to Example 72-(1), and using [2-(trifluoromethyl)biphenyl-4-yl]acetate (0.39 g) and Example 1-(3) ({[5-( Instead of (3, benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.28 g) Ethyl 4,5-trifluorophenyl)acetate gave the title compound (0.34 g,iel. 'H-NMR (400 MHz, CDC13) δ: 8.38 (1Η, t, J = 6 Hz), 7.66 (1H, d, J = 2 Hz), 7.49- 7.4 5 (3 H, m), 7.4 3 - 7.3 7 (6H, m), • 7.29 (2H, dd, J = 7 Hz, 3 Hz), 7.23 ( 1 H, d, J = 8 Hz), 5.51 (1 H, s), 5.15 (1H, d , J = 11 Hz), 5.05 (1 H, d, J= 11

Hz), 4.26 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 4.18 (2H, q, J = 7 Hz), 2.73 (3H, s), 1.31 (3H, t, J = 7 Hz), 1.2 1 (3H, t, J = 7 Hz). (6) {[(5-Hydroxy-2-methyl-6-U2-(trifluoromethyl)biphenyl-4 -yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid according to Example 72-(2), and using ({[5-(benzyloxy)-6-{2-ethoxy-2) -Phenoxy-1-[2-(trifluoromethyl)biphenyl-4-yl]ethyl}-2-methylpyrimidine 201141839 淀-4-yl]hydrazino}amino)ethyl acetate (0.34 g) in place of [({5_(hydroxy)-6-[2-ethoxy-2]-oxy-1-(3,4,5-trifluorophenyl)ethyl b 2•methyl Ethyl pyrimidin-4-yl}carbonyl)amino]acetate gave the title compound (m.p. Mp : 1 42- 1 43 °C ; 'H-NMR (400 MHz, CDC13) δ: 11.35 (iHj s), 8.46 (1H, t) J = 6 Hz), 7.76 (1H, d, J = 2 Hz ), 7.56 (iH} d, J = 8 Hz),

7.3 9 - 7.3 5 (3 H,m), 7.28 (2H, dd, J = 8 Hz, 2 Hz), 7.24 (1H, d, J - 8 Hz), 4.30 (2H, d, J = 6 Hz) , 4.27 (2H, s) 2.66 (3H, s). (Example 131) [({5-hydroxy-2-methyl- 6-[4-methyl-3-(trifluoromethyl)benzyl] Pyrimidine _4_yl} carbonyl)amino]acetic acid ΟΗ Ο

n^co2h

(1) [4-methyl-3-(trifluoro)

0〇2&amp;11 methyl)phenyl]acetic acid benzyl ester was used in accordance with Example 119-(1), and [4-methyl-3-(trifluoromethyl)phenyl]acetonitrile (0.86 g) was used instead. 5-fluoro-2-naphthyl)acetonitrile to give the title compound (1.7 g, yield, yield) as a colorless oily material. 'H-NMR (400 MHz, CDC13) δ: 7.52 (1 Η, s), 7.38-7.31 (6H, m), 7.24 J = g Hz), 5.14 (2H, s), 3.68 (2H, s), 2.46 (3H, s). -234- 201141839 (2) ({[5-(benzyloxy) - 6-{2-(Benzyloxy)-l-[4-methyl-3-(trifluoromethyl)phenyl]-2-oxoethyl}-2-methylpyrimidine-4- Ethyl acetate

Obtained according to Example 72-(1)' and using [4-methyl-3-(trifluoromethyl)phenyl]acetic acid benzyl ester (0.31 g) and Example 1-(3) ({[5- (benzyloxy) 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead (3 Ethyl acetate, 4,5-trifluorophenyl) gave the title compound (0.31 g, yield 97%). 'H-NMR (400 MHz, CDC13) δ: 8.34 (1Η, t, J = 6 Hz), 7.52 (1H, s), 7.3 9-7.29 (9H, m), 7.2 3 -7.20 (2H, m) , 7.18 (1H' d, J = 8 Hz), 5.48 (1H, s), 5.18 (1H, d, J = 13 Hz), 5.08

(1H, d, J = 13 Hz), 5.06 (1H, d, J = 11 Hz), 4.92 (1H, d, J =11 Hz), 4.25 (2H, q, J = 7 Hz), 4.21 (2H , d, J = 6 Hz), 2.66 (3H, s), 2.43 (3H, s), 1.30 (3H, t, J = 7 Hz). (3) [({5-hydroxy-2-methyl- 6-[4-Methyl-3-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 94-(6), and used (丨[5-(benzyloxy) Base)_6_{2_(hydroxyl)-1-[4-methyl-3-(trifluoromethyl)phenyl]-2-oxoethyl}_2•methyl sulphonate-4·yl Instead of [((5-(benzyloxy)-6-[2-(benzyloxy)-1-(6-fluoro-2-naphthyl))] carbonyl]amino)acetic acid ethyl acetate (〇·3 g) Ethyl acetate of 2-oxoethylethyl] 2 -methylpyrimidin-4-yl}carbonyl)amino], the title compound ( 〇 15.8: yield 82%) of white solid. H-NMR (400 MHz, CDC13) δ: 11.31 (1H, s), 8.45 (1H, t, J = 6 Hz), 7.62 (1H, s), 7.42 (1H, d, J = 8 Hz), 7.19 (1H, d, J = 8 Hz), 4.29 (2H, d, J = 6 Hz), 4.18 (2H, s), 2.63 (3H, s), 2.43 (3H, s). (Example 132) ( {[6-(4-Chloro-3-fluorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1) [({5-(Benzyloxy)-6-[1-(4-chloro-3-fluorophenyl)-2-ethoxy-2-oxoethyl]-2-methyl Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

According to Example 72-(1), and using (4-chloro-3-fluorophenyl)acetate (0.22 g) and Example 1-(3) ({[5-(benzyloxy)-) 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) instead of (3,4,5-three Ethyl fluorophenyl)acetate gave the title compound (0.26 g, yield 94%). 'H-NMR (400 MHz, CDC13) δ: 8 3 7 (1 Η, t, J = 5 Hz), 7.45 - 7.3 7 ( 5 H, m), 7.27 (1H, t, J = 8 Hz), 7.12 (1H, dd, J =11 Hz, 2 Hz), 6.96 (1H, dd, J = 8 Hz, 2 Hz), 5.39 (1H, s), 5.13 (1 H, d, J = 1 1 Hz) , 4.46 (1H, d, J = 1 1 Hz), 4.26 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 5 Hz), 4.16-4.10 (2H, -236 - 201141839 m) , 2.71 (3H, s), 1.31 (3H, t, J = 7 Hz), 1.17 (3H, t, J = 7 Hz). (2)({[ 6-(4-chloro-3-fluorobenzyl) )-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

According to Example 1 1〇-(4), and using [({5-(benzyloxy)-6-[ 1-(4-chloro-3-fluorophenyl)-2-ethoxy-2- side) Ethyl ethoxy]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (〇·26 g) in place of [({5-(benzyloxy)-6-[1-(4) Ethyl acetate of '6-dichlorobiphenyl-3-yl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino] Compound (0.047 g, 28% yield) of white solid. Mp : 209-2 1 0 °C ; *H-NMR (400 MHz, CDC13) δ: 11.33 (1H, s), 8.45 (1H, t, J = 6 Hz), 7.30 (1H, d, J = 8 Hz), 7.17 ( 1 H, dd, J - 10 Hz, 2 Hz), 7.10 (1H, dd, J = 8 Hz, 2 Hz), 4.30 (2H, d, J = 6 Hz), 4.14 (2H, s), 2.63 (3H, s). (Example 133) [({6-[(2-chloro-4'-fluorobiphenyl-4-yl)methyl]-5-hydroxy-2-methylpyrimidine -4-yl}carbonyl)amino]acetate ΟΗ Ο

iTc〇2H (1) 2-chloro-4'-fluoro-4-methylbiphenyl

-237 - 201141839 1-Bromo-2-chloro-4-methylbenzene (2.5 g) was dissolved in tetrahydrofuran (loo mL), and n-hexane solution of n-butyllithium was added dropwise at -78 °C under a nitrogen stream. (1.6 M, 8.6 mL) was stirred at the same temperature for 2 hours. Trimethyl borate (4 · 1 mL) was added dropwise to -78 in the reaction mixture, and the mixture was stirred at room temperature for 3 hours, and then slowly warmed to room temperature. Hydrochloric acid (1% by weight, 30 mL) was added to the reaction mixture, and the organic layer was extracted with diethyl ether. The solvent was evaporated under reduced pressure to give (2-chloro-4-methylphenyl)boronic acid (2.0). g, yield 96%) of white solid. 1-Fluoro-4-iodobenzene (3.0 g) and (2-chloro-4-methylphenyl)boronic acid (2.0 g) were dissolved in toluene (100 mL)' under a nitrogen atmosphere at room temperature (three) Phenylphosphine)palladium complex (0·70 g) and sodium carbonate (2.6 g) were heated under reflux for 3 hours. After the organic layer was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure. 'H-NMR (400 MHz, CDC13) δ: 7.62 (1Η, dd, J = 9 Hz, 5 Hz), 7.39 (1H, dd, J = 9 Hz, 5 Hz), 7.29 (1H, s), 7.20 (1H, d, J = 8 Hz), 7.12-7.08 (3H, m), 2.37 (3H, s). (2) (2-Chloro-4'-fluorobiphenyl-4-yl)acetate

In accordance with Examples 95-(1), 128-(2) and 95-(3), and using 2-chloro-4'-fluoro-4-methylbiphenyl (2.2 g) instead of 2-chloro-4-methyl The title compound (0.38 g, yield 13%) was obtained as a colorless oil. 201141839 'H-NMR (400 MHz, CDC13) δ: 7.47 (1H, s), 7.44-7.31 (3H, m), 7.30 (1H, dd, J = 8 Hz, 2 Hz), 7.13 (2H, t, J = 9 Hz), 4.21 (2H, q, J = 7 Hz), 3.78 (2H, s), 1.29 (3H, t, J = 7 Hz). (3)[({5-(Benzyloxy)) -6-[l-(2-chloro-4'-fluorobiphenyl-4-yl)_2-ethoxy-2-ethyloxyethyl]-2-methylpyrimidin-4-yl}carbonyl)amine Ethyl acetate

According to Example 72-(1), and using (2-chloro-4'-fluorobiphenyl-4-yl)acetate (0.38 g) and Example 1-(3) ({[5-( Instead of (3, benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.29 g) Ethyl acetate 4,5-trifluorophenyl) gave the title compound (0.21 g, yield 54%) j-NMR (400 MHz, CDC13) δ: 8.37 (1H, t, J = 6 Hz), 7.47 (2H, dd, J = 8 Hz, 2 Hz), 7.43 -7.3 5 (6H, m), 7.25- 7.20 • (2H,m), 7. 10 (2H,t,J = 9 Hz), 5.45 (1H, s), 5.14 (1H, d, J = 11 Hz), 4.98 (1H, d, J= 11 Hz), 4.26 (2H, q, J ^ 7 Hz), 4.24 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 6 Hz), 2.73 (3H, s), 1.31 (3H, t, J = 7 Hz), 1.20 (3H, t, J = 7 Hz). (4) [({6-[(2-Chloro-4,-fluorobiphenyl-4-yl)methyl]-5 -Hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 72-(2), and using [({5-(benzyloxy)-6-indole-(2-chloro-) 4'-Fluorobiphenyl-4-yl)-2-ethoxy-2-oxoethylethyl-2-methylpyrimidine-4--239- 201141839 base] ortho)amino]acetate (〇.2丨g) instead of [({5 (hydroxy)6 [2_ethoxy-2-oxo-l-(3,4,5·difluorophenyl)ethyl] 2 A) The title compound (〇〇7〇g, yield 47%) was obtained as a white solid. Mp: 1 5 6- 1 5 7 ° C ; 'H-NMR (400 MHz, CDC13) δ: π.35 (1Η, s), 8.46 (1Η, t, J = 6 Hz), 7.48 (1H, d , J = 2 Hz), 7.37 (2H, dd, J = 9 Hz, 6 Hz), 7.32 (1H, dd, J = 8 Hz, 2 Hz), 7.22 (1H, d, J = 8 Hz), 7.09 (2H, t, J = 9 Hz), 4.30 (2H, d, J = 6 Hz), 4.19 (2H, s), 2.66 (3H, s). (Example 134) [({6-[(2 -Chloro-3'-fluorobiphenyl-4-yl)methyl]_5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

According to Example 1 3 3 · (1), 9 5 - (1 ), 1 2 8 - (2) and 9 5 - ( 3 ) ' and use 1-fluoro-3-iodobenzene (2.7 g) instead of 1- The title compound (0.42 g, yield 12%) was obtained as a colorless oily material. 1H-NMR (400 MHz, CDCI3) δ: 7.42-7.3 7 (2 Η, m), 7.29 (1H, d , J = 8 Hz), 7.25 (1H, d, J = 8 Hz), 7.21 (1H, d, J =

8 Hz), 7.16 (1H, dd, J = 8 Hz, 2 Hz), 7.09 (1H, t, J = 8 -240- 201141839

Hz), 4.20 (2H, q, J = 7 Hz), 3.64 (2H, s), 1.29 (3H, t, J = 7 Hz). (2)[({5-(Benzyloxy)·6- [1. (2-Chloro-3,-fluorobiphenyl-4-yl)-2-ethoxy-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino] Ethyl acetate

According to Example 72-(1), and using (2·chloro-3,-fluorobiphenyl-4-yl)acetate (0.42 g) and Example 1-(3) ({[5-( Benzyloxy)·2·methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.32 g) instead (3, Ethyl 4,5-trifluorophenyl)acetate gave the title compound (0.20 g, m. 'H-NMR (400 MHz, CDC13) δ: 8.37 (1Η, t, J = 6 Hz), 7.47 (2H, dd, J = 8 Hz, 2 Hz), 7.43 -7.3 5 (5H, m), 7.24 (2H, d, J = 2 Hz), 7.18 (1H, d, J = 7 Hz), 7.14 (1H, dt, J = 10 Hz, 2 Hz), 7.07 (1H, dt, J = 10 Hz, 2 Hz), 5.45 (1H, s), 5.15 (1H,d,J = 11 Hz), 4.98 (1H,d, J= 11 Hz), 4.27 (2H, q, J =7 Hz), 4.24 (2H, q, J = 7 Hz), 4.20 (2H, d, J = 6 Hz), 2.73 (3H, s), 1.31 (3H, t, J = 7 Hz), 1.20 (3H, t, J = 7

Hz). (3) [({6-[(2-Chloro-3'-fluorobiphenyl-4-yl)methyl) 5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino] Acetic acid according to Example 72-(2), and using [({5_(benzyloxy)-6-[1·(2-chloro-3-pyrene-4-yl)-2-ethoxy-2- Ethyloxyethyl]-2-methylpyrano_4_yl}carbonyl)amino]acetate (〇·20 g) in place of [({5-(benzyloxy)-6_[2_-241-) 201141839 Ethyloxy-2-oxo-l-l-(3,4,5-trifluorophenyl)ethyl]_2-methyl-methyl 4-amino}carbonyl)amino]acetate to give the title compound 0〇6〇g, yield 4 1%) white solid. Mp: 1 8 9- 1 90 °C ; 'H-NMR (400 MHz, CDC13) δ: 11.36 (1H, s), 8.46 (1H t J = 6 Hz), 7.49 (1H, s), 7.40- 7.3 2 (2H,m), 7.24 (ih dj =8 Hz), 7.18 (1H,d,J = 8 Hz), 7.13 (1H,d,J = 8 Hz) 7.05 (1H, t, J = 8 Hz) , 4.30 (2H, d, J = 6 Hz), 4.19 (2H s), 2.66 (3H, s). (Example 1 3 5 ) [({6-[(3'_Fluorobiphenyl-4-yl) )methyl]-5-hydroxy-2-methylpyrimidin-4-yl}ironyl)amino]acetic acid

(1) [({5-(卞-oxy)-6-[2-ethoxyindole-(3'-fluorobiphenyl-4-yl)_2-sideoxyethyl]-2-methyl Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

Et02C ΟΒη Ο

|j 八C02Et [({5·(benzyloxy)_6_π·) obtained according to Example 91-(2) 'and using (3-fluorophenyl)boronic acid (ob g) and Example 91-(1) 4-(bromophenyl)2-ethoxylated 2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (〇·26 g) instead of (4- Fluorophenyl)boronic acid 'obtained the title compound ( 〇 19 g, yield 70%) as a yellow solid. -242 - 201141839 Ή-NMR (400 MHz, CDC13) δ: 8.3 7 ( 1 Η, t, J = 6 Η z ), 7.5 0-7.46 (2H, m), 7.43 -7.3 2 (8 H, m), 7.25 (2H, dd, J = 10 Hz, 2 Hz), 7.01 (1H, dt, J = 8 Hz, 2 Hz), 5.54 (1H, s), 5.12 (1 H, d, J = 11 Hz), 4.91 ( 1 H, d, J = 11 Hz), 4.27 (2H, q, J = 7 Hz), 4.23 ( 2H, q, J = 7 Hz), 4.19 (2H, d, J = 6

Hz), 2.72 (3H, s), 1.29 (3H, t, J - 7 Hz), 1.19 (3H, t, J = 7 Hz).

(2) [({6-[(3'-Fluorobiphenyl-4-yl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid] according to Example 72- (2) and using [({5-(benzyloxy)-6-[2-ethoxy-:l-(3'-fluorobiphenyl-4-yl)-2-yloxyethyl]] Ethyl 2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.19 g) in place of [({5-(benzyloxy)-6-[2-ethoxy-2-yloxy) Ethyl acetate of -1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]] gave the title compound (0.07 g, ) White solid. • mp: 214-216 °C; 'H-NMR (400 MHz, CDCI3) δ: 11.34 (1H, s), 8.45 (1H, t, J = 6 Hz), 7.49 (2H, d, J = 9 Hz ), 7.46 (2H, d, J = 9 Hz), 7.40- 7.3 2 (2H, m), 7.26-7.2 3 ( 1 H, m), 7.01 (1 H, d, J = 8 Hz), 4.29 ( 2H, d, J = 6 Hz), 4.23 (2H, s), 2.65 (3H, s). (Example 136) [({5-hydroxy-6-[(6-methoxy-2-naphthyl) )methyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid- 243 - 201141839 OH Ο

(l) [({5-(Benzyloxy)-6-[2-ethoxy-1-(6-methoxy-2-naphthyl)-2-yloxyethyl]-2-yl) Ethylpyrimidin-4-yl}carbonyl)amino]acetic acid ethyl ester according to Example 7 2 - (1), using (6-methoxy-2-naphthyl) ethyl acetate (〇_14 g) and ({[5-(Benzyloxy)-2-methyl.-6-{[(trifluoromethyl)sulfonyl)oxy}pyrimidin-4-yl]carbonyl) obtained in Example 1-(3) The title compound (0.11 g, yield 66%) was obtained as a colourless amorphous solid. *H-NMR (400 MHz, CDC13) δ: 8.36 (1Η, t, J = 6 Hz), 7.67 (1H, d, J = 9 Hz), 7.65 (1H, s), 7.61 (1H, d, J = 9 Hz), 7.59 (1H, d, J = 7 Hz), 7.47 (1H, dd, J = 9 Hz, 2 Hz), 7.4 3 -7.3 5 (4H, m), 7.13 (1H, d, J = 9 Hz), 7.10 (1H, s), 5.64 (1H, s), 5.10 (1H, d, J = ii Hz), 4_75 (1H, d, J = 11 Hz), 4.25 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 6 Hz), 4.16 (2H, q, J = 7 Hz), 3.90 (3H, s), 2.73 (3H, s), 1.29 (3H, t, J = 7 Hz), 1.18 (3H, t, J = 7 Hz). (2) [({5-Hydroxy-6-[(6-methoxy-2-naphthyl)methyl]-2-methyl) Pyrimidin-4-yl}carbonyl)amino]acetic acid according to Example 72-(2)' and using benzyloxyethoxy-1-(6-methoxy-2-naphthyl)-2-oneoxy Ethyl]2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.11 g) in place of [({5·(benzyloxy)_6·[2_B-244- 201141839 oxy- 2-Ethyloxy-1-(3,4,5-trifluorophenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound (0.05 6 g , yield 80%) white solid. Mp : 2 12-213 ° C ; ^-NMR (400 MHz, CDC13) δ: 11.33 (1H, s), 8.45 (1H, t, J = 6 Hz), 7.73 (1H, s), 7.66 (2H, t, J = 9 Hz), 7.48 (1H, dd, J = 9 Hz, 2 Hz), 7.12-7.08 (2H, m), 4.31 (2H, s), 4.29 (2H, d, J = 6 Hz) , 3.90 (3H, s), 2.64 (3H, s). (Example 137) ({[6-(1-benzothiophen-3-ylmethyl)-5-hydroxy-2-methylpyrimidine-4 -carbonyl]carbonyl}amino)acetic acid

(1) [({6-[1-(1-Benzothiophen-3-yl)-2-ethoxyxoethyloxyethyl]-5-(benzyloxy)-2-methyl Pyrimidine-4-yl}carbonyl)amino]ethyl acetate

According to Example 7 2 - (1), using 1-benzothiophen-3-ylacetic acid ethyl ester (0.44 g) and Example 1-(3) ({[5-(benzyloxy)-2) -methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.44 g) instead of (3,4,5-trifluoro Phenylacetic acid ethyl acetate gave the title compound (0.19 g, yield: 35%). • H-NMR (400 MHz, CDC13) δ: 8.37 (1Η, t, J = 6 Hz), 7.83 (1H, d, J = 8 Hz), 7.61 (1H, d, J = 7 Hz), 7.38 ( 1 H, s), -245 - 201141839 7.34-7.27 (7H, m), 5.94 (1H, s), 5.10 (1H, d, J = 10 Hz), 4.91 (1H, d, J = 10 Hz), 4.26 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 4.18 (2H, q, J = 7 Hz), 2.71 (3H, s), 1.30 (3H, t, J = 7 Hz), 1.18 (3H, t, J = 7 Hz). (2) ({[6-(l-benzothiophen-3-ylmethyl)_5_hydroxy-2-methylpyrimidine-4- [carbonyl]amino)acetic acid according to Example 72-(2), and using [({6_[Bu(1-benzothiophen-3-yl)-2-ethoxy-2-oxoethyl) 5-(-benzyloxy)-2-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.19 g) in place of [({5·(benzyloxy)_6_[2_ethoxy] Ethyl-2-yloxy-1-(3,4,5-trifluorophenyl)ethyl]_2-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate' gave the title compound (〇. 1 〇 g, yield 86%) of a white solid. Mp : 1 44- 1 45 °C ; 'H-NMR (400 MHz, CDCI3) 5: 11.41 (1Η, s), 8.44 (1H, t, J = 6 Hz), 8.01 (1H, d, J = 8 Hz), 7.82 (1H, d, J = 8 Hz), 7.40-7.31 (2H, m), 7.28 (1H, S), 4.41 (2H, s), 4.25 (2H, d, J = 6 Hz), 2.62 (3H, s). (Example 138) [({5. hydroxy-2-methyl-6-[(3'-methylbiphenyl-4-yl)methyl]pyrimidin-4-yl)carbonyl) Amino]acetic acid

According to Examples 72-(1) and 72-(2), and using (3,-methylbiphenyl-4-yl)acetate (0.48 g) and Example i_(3) ({[5_(( Anodeoxy) — -246 -

COaMe 201141839 2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidineacetate (0.36 g) in place of (3,4,5-trifluorobenzene title compound (0.13 g) , yield 43%) white solid I mp: 1 48- 1 49 ° C; 'H-NMR (500 MHz, DMS 〇-d6) δ: 12.88 s), 9.47 (1H, t, J = 6 Hz), 7.56 (2H, (1H, s), 7.40 (1H, d, J = 8 Hz), 7.36 7.32 (1H, t, J = 8 Hz), 7.16 (1H, d, J s), 3.99 (2H, d , J = 6 Hz), 2.59 (3H, s) (Example 130) {[(5-Hydroxy-2-methyl-6-{[6-(trifluoromethyl)-2-yl)carbonyl]amine }}Acetate ΟΗ Ο N^COjH Η (1) 6-(Trifluoromethyl)-2-naphthoic acid methyl ester

Methyl 6-iodo-2-naphthoate (2.5 g) was dissolved in (25 mL), and methyl chlorodifluoroacetate (1.7 mL) was added to copper iodide (1) (1.8 g) at 120 ° After stirring 20 / J water, the resulting precipitate was separated and filtered, and the organic matter was vigorously poured into the filtrate. The organic layer was washed with water and saturated brine to dryness. After distilling off the solvent under reduced pressure, crystals crystals crystals crystals crystalssssssssssssssssssssssssssssssssss Ethyl acetate 'obtained Ϊ 0 (1Η, s), 12.04 (1Η, d, j = 8 Hz), 7.43 (2H, d, J = 8 Hz), =8 Hz), 4.16 (2H, , 2.26 ( 3H, s). Naphthyl]methyl}pyrimidin-4 · N,N-dimethylacetamide, potassium fluoride (〇.55 g) in time. After adding ethyl acetate to the reaction solution and extracting the polyester, The residue of anhydrous sulfuric acid is 98% white solid, s), 8.19 (1H, s), -247- 201141839 8.17 (1H, d, J = 9 Hz), 8_〇8 (1H, d , J = 9 Hz), 8.00 (1H, d, J = 9 Hz), 7.72 (1H, d, J = 9 Hz), 4.01 (3H, s) (2) [0-(trifluoromethyl)- Benzyl 2-naphthyl]acetate

ΟΟ^Βπ according to Examples 94-(1), 94-(2), 128-(2) and 119-(1)' and using 6-(dimethylmethyl)-2-naphthoic acid methyl vinegar (2. 〇g) The title compound (0.83 g, yield 31%) 'H-NMR (400 MHz, CDC13) δ: 8.13 (1Η, s), 7.91-7.88 (2H, m), 7_79 (1H, s), 7.64 (ih, d, J = 8 Hz), 7.53 (1H , d, J = 8 Hz), 7.3 6-7.3 2 (5H, m), 5.16 (2H, s), 3.87 (2H, s). (3) ({[5-(Hydroxy)-6- {2-(Benzyloxy)_2_sideoxy-oxime-"trifluoromethyl)_2-naphthylethylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

({[5_Γ卡oxy)·2_methyl-) obtained according to Example 72-(1) 'and using [6_(trifluoromethyl)_2-naphthyl]acetate vinegar g) and Example W3) Ethyl 6-{[(difluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.24 g) in place of (3,4,5-trifluorophenyl)acetic acid The title compound (0.24 g, yield 71%) was obtained. H-NMR (400 MHZ, CDC13) δ: 8.34 (1Η, t, J = 6 Hz), 8.10 OH, s), 7.85 (1H, d, J = 9 Hz), 7.79 (1H, d, j = 9 Hz), 7.67 (1H, s), 7.62-7.57 (2H, m) # 7.37.7.29 (8H, m), 7.25-7-23 (2H, m), 5.70 (1H) s), 5.22 (1H) d, J = 12 Hz), 5.11 (1H, d, J 12 Hz), 5.09 (1H, d, j = n Hz), 4 8 3 ( 1 H,d,j -248- 201141839 =11 Hz), 4.24 (2H, q, J = 7 Hz), 4.20 (2H, d, J = 6 Hz), 2.68 (3H, s), 1.29 (3H, t, J = 7 Hz). (4){[(5 -hydroxy-2-methyl-6-{[6-(trifluoromethyl)-2-naphthalenyl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid according to Example 9 4 - (6) And using ({[ 5 -(benzyloxy)-6 - { 2 -(benzyloxy)-2-yloxy-1-[6-(trifluoromethyl)-2-naphthalenyl]ethyl Ethyl acetate of 2-methylpyrimidin-4-yl]carbonyl}amino) (0.24 g) in place of [({5-(benzyloxy)-6-I [2-(benzyloxy))-1) -(6-Fluoro-2-naphthyl)-2-oxoethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetate to give the title compound (0.10 g, yield 67 %) White solid. Mp : 18 7 ° C ; 'H-NMR (400 MHz, CDC13) δ: 11.38 (1Η, s), 8.44 (1H, t, J = 6 Hz), 8.09 (1H, s), 7.89 (1H, d , J = 9 Hz), 7.86-7.83 (2H, m), 7.63 - 7.5 8 (2H, m), 4.37 (2H, s), 4.27 (2H, d, J = 6 Hz), 2.64 (3H, s Φ (Example 140) [({5-Hydroxy-2-methyl-6-[(5-phenyl-2-thienyl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-(Benzyloxy)-6-[2-ethoxy-2-yloxy-1-(5-phenyl-2-thienyl)ethyl]-2-methylpyrimidine _4-yl}carbonyl)amino]ethyl acetate

-249 - 201141839 According to Example 72-(1), using (5-phenyl-2-thienyl)ethyl acetate (〇·46 g) and Example 1-(3) ({[5- (benzyloxy)-2-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.44 g) instead (3 Ethyl acetate, 4,5-trifluorophenyl) gave the title compound (0.39 g, yield 70%) as a yellow solid. 'H-NMR (400 MHz, CDC13) δ: 8.36 (1Η, t, J = 6 Hz), 7.56 (2H, d, J = 8 Hz), 7.50 (2H, dd, J = 8 Hz, 2 Hz) , 7.4 1- 7.33 (5H, m), 7.25 (1H, t, J = 8 Hz), 7.12 (1H, d, J = 4

Hz), 6.87 (1H, d, J = 3 Hz), 5.79 (1H, s), 5.15 (1H, d, J = 11 Hz), 5.02 (1H, d, J = 11 Hz), 4.26 (2H, q, J = 7 Hz), 4.23 (2H, d, J = 6 Hz), 4.17 (2H, q, J = 7 Hz), 2.74 (3H, s), 1.30 (3H, t, J = 7 Hz) , 1.18 (3H, t, J = 7 Hz). (2) [({5-Hydroxy-2-methyl-6-[(5-phenyl-2-thienyl)methyl]pyrimidin-4-yl) }carbonyl)amino]acetic acid according to Example 72_(2), and using [({5-(benzyloxy)-6-[2-ethoxy-2-epoxy-1-(5-phenyl) -2-Thienyl)ethyl]-2-methylpyrimidin-4-yl} oryl]amino]acetic acid ethyl acetate (〇.39 g) instead of [({5-(henyloxy)_6_[2 • Ethoxy 2-bromooxyl small (3,4,5-trioxaphenyl)ethyl]-2-methylpyran-4-yl}carbonyl)amino]acetate to obtain pepper B ^ ni1 The title compound (0.0 3 1 g, yield 12%) was obtained as a yellow solid. Mp : 15 3 ° C ; 'H-NMR (400 MHz, CDC13) δ = 6 Hz), 7.53 (2H, dd, J = 9 1 1 .28 (1H, s), 8.45 (1H, t, J 2 Hz), 7.33 (2H, t, J = 8 '250. 201141839

Hz), 7.23 (1H,m), 7.12 (1H,d,J = 4 Hz), 6.95 (1H,d,J = 4 Hz), 4.37 (2H, s), 4.29 (2H, d, J = 6 Hz), 2.65 (3H, s). (Test Example 1) The usefulness (pharmacological activity) of the compound of the present invention was confirmed by the following test. The in vitro erythropoietin (EPO)-inducing activity of the test compound was evaluated using a Hep3B cell line derived from human liver cancer (ATCC, Manassas, VA). Hep3B cells were cultured in DMEM (Dulbecco's Modified Eagle Medium) in the presence of i〇% FBS (fetal calf serum) overnight at 37 ° C (24 well plates, 1.0 OxlO5 cells/well). Replace with fresh D Μ E Μ ( + 1) containing the test compound (concentrated at 12.5 μM) dissolved in 〇. 5 % DM SO (dimethyl hydrazine) or solvent control (control: 〇.5% DMSO) After 0% FBS), it was incubated at 37 ° C for 24 hours. After the culture supernatant was recovered, and the human EPO ELISA kit (StemCell Technologies) was used to quantify the EP0 concentration in the culture supernatant. The EPO concentration of the test compound is expressed as a multiple of the EP 〇 concentration in the control. The results are shown in Table 1. The compound of the present invention or a pharmacologically acceptable salt thereof exhibits excellent EPO-producing ability and is useful as a medicine for the treatment or prevention of anemia. 201141839 [Table η Test compound ΕΡΟ concentration (times) Control group (0 · 5 % DMS 0) 1 Example 17 98 Example 44 49 Example 54 37 Example 69 18 Example 73 43 Example 90 16 Example 94 29

[Industrial use possibility]

The novel compound having the structure of 5-hydroxypyrimidine-4-carboxyguanamine of the present invention has excellent EPO-producing ability and is useful for diseases caused by low EPO. Specifically, the compound of the present invention, as anemia, is preferably renal anemia (dialysis period and shelf life), anemia of premature infants, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, or treatment of cancerous anemia or A prophylactic agent is useful, and can also be used as a therapeutic or preventive agent for ischemic brain diseases and the like. [Simple description of the diagram] Μ 〇

JXW [Main component symbol description] None. -252-

Claims (1)

201141839 VII. Patent application scope: 1. A compound represented by formula (1) or a pharmacologically acceptable salt thereof R1 [In the formula (1), R1 represents a Ci-Ce alkyl group, a halogenated C^-Cs alkyl group, or a cyclopropyl group, R2 represents a Ct-Cs alkyl group, or a -Χ-Q1 or -X-Qi-Y -Q2 means Further, Q1 is a monocyclic or bicyclic hydrocarbon ring group independently selected from the substituent group A and having 1 to 3 substituents (the hydrocarbon ring group contains 3 to 10 membered aromatic hydrocarbon rings and non-aromatic hydrocarbons) a monocyclic or bicyclic heterocyclic group which may have 1 to 3 substituents independently selected from the substituent group A (the heterocyclic group contains 4 to 10 members of an aromatic heterocyclic ring and a non-aromatic heterocyclic ring) And comprising one or two atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom), and Q2 is a monocyclic or bicyclic ring which may be independently selected from the substituent group A and may have 1 to 3 substituents. a hydrocarbon ring group (the hydrocarbon ring group contains a 3 to 10 member aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring), or a monocyclic or bicyclic ring which may be independently selected from the substituent group A and may have 1 to 3 substituents. a heterocyclic group (the heterocyclic group contains 4 to 10 membered aromatic heterocyclic rings and non-aromatic heterocyclic rings, and contains 1 or 2 atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom), X Representative, -0-, -S·, -NH-, or -N(CH3)-, -253 - 201141839 η represents an integer from 1 to 6, Υ represents a single bond, -CH2-, -(CH2)2-, -(CH2)3- -CH2〇-, -OCH2-, or -Ο ' R3 represents a hydrogen atom or a methyl group, and the substituent group A represents a halogen atom, a hydroxyl group, an amine group, a nitro group, a cyano group, a CrCe alkyl group, a halogenated CrC; a group consisting of a propyl group, a cyclopropyl group, a Cl-C6 alkoxy group, a halogenated C1-C3 alkoxy group, and a C2-C7 compound thiol group. 2. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein (:, -(:4 alkyl, or cyclopropyl, Κ8 alkyl' or aryl, 013 And a phenyl group which may be substituted, a naphthyl group which may be substituted (the substituent of the phenyl or naphthyl group is 1 to 3 groups independently selected from the substituent group Aa), a thienyl group, or a benzothienyl group. Q2a represents a phenyl group which may also be substituted (the substituent of the phenyl group is 1 to 3 groups independently selected from the substituent group Aa) 'Xa represents a single bond, -(CH2)n-, -〇(CH2) N-, -(CH2)nO-, or -S-, Y 3 represents a single bond ' _ C Η 2 〇-, or * 0 C Η 2 -, the substituent group Aa represents a fluorine group, a chlorine group, a bromine group a group consisting of Cl-C4 alkyl, trifluoromethyl, cyclopropyl, C1-C3 alkoxy, and trifluoromethoxy. -254 - 201141839 3. A compound of claim 1 or A pharmacologically acceptable salt thereof, wherein the compound is selected from the group consisting of: ({[6-(3,5-dichlorophenyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl) }amino)acetic acid, [({6-[2-(4-fluorophenyl)ethyl]-5-hydroxyl Benzyl-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, [({6-[2-(2,5-Dimethylphenyl)ethyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid], [({5-hydroxyl) - 6-[2-(2-Isopropylphenyl)ethyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, ({[5-hydroxy-2-methyl- 6- (5-methylhexyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[6-(3,4-dichlorobenzyl)-5-hydroxy-2-methylpyrimidin-4-yl] Carbonyl}amino)acetic acid, [({5-hydroxy-2-methyl-6-[4-(trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, ({[5 -hydroxy-2-methyl-6-(2-naphthylmethyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, ({[6-(biphenyl-4-ylmethyl)-5-hydroxyl) -2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid '({[6-(3,4-dimethylbenzyl)-5-hydroxy-2-methylpyrimidin-4-yl)carbonyl) } Amino)acetic acid, ({[6-(3- gas-4-methylindolyl)-5-yl-yl-2-methyl-methyldin-4-yl]-based group} - 255 - 201141839 Amino )acetic acid, [({6-[(6-fluoro-2-naphthyl)methyl)-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, [({6-[ 3-chloro-4-(trifluoromethyl)benzyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, ({[6-(( 4-(Chloro-3-methylbenzyl)-5-hydroxy-2-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, [({6-[(2-chlorobiphenyl-4-yl)) Methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, [({6-[(5-fluoro-2-naphthyl)methyl]-5-hydroxy-2) -methylpyrimidin-4-yl}carbonyl)amino]acetic acid, [({6-[(6-chloro-2-naphthyl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl} Carbonyl)amino]acetic acid, [({2-ethyl-6-[(6-fluoro-2-naphthyl)methyl]-5-hydroxypyrimidin-4-yl}carbonyl)amino]acetic acid, [( {6-[3-Fluoro-4-(trifluoromethyl)benzyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, [({6-[(3') -fluorobiphenyl-4-yl)methyl]-5-hydroxy-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, [({5-hydroxy-6-[(6-methoxy) -2-Naphthyl)methyl]-2-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, and, {[(5-hydroxy-2-methyl-6-{[6-(trifluoro) Methyl)-2_naphthyl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid. - 256 - 201141839 4 - A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 3 or a pharmacologically acceptable salt thereof as an effective ingredient. 5 · A pharmaceutical composition as claimed in item 4 of the patent application for the treatment or prevention of anemia. 6 _ For example, the pharmaceutical composition of claim 5, wherein anemia is gluteal anemia, anemia of premature infants, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, or cancer anemia. 7. A pharmaceutical composition as claimed in claim 4, which is used to produce erythropoietin. A use of a compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition. 9 • For the purposes of application No. 8 of the patent application, wherein the pharmaceutical composition is used for the treatment or prevention of anemia. 10. The use of claim 9 in the scope of patent application, wherein anemia is renal anemia, anemia in premature infants, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, or cancer anemia. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, is used in a method for treating or preventing a disease. A compound according to claim 11 or a pharmacologically acceptable salt thereof, wherein the disease is anemia. -257 - 201141839 1 3. For example, the compound of Patent No. 12 or its pharmacologically permissible salt, wherein anemia is renal anemia, anemia of premature infants, anemia associated with chronic diseases, and chemotherapy with cancer Anemia, or cancerous anemia. A method for treating or preventing a disease by administering a pharmacologically effective amount of a compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof to a mammal or a bird. 15. The method of claim 14, wherein the disease is anemia. 1 6 · The method of claim 15, wherein anemia is renal anemia, anemia of premature infants, anemia associated with chronic diseases, anemia associated with cancer chemotherapy 0, or cancer anemia. The method of any one of claims 1 to 16, wherein the mammal is a human, a horse, a cow or a pig, and the bird is a chicken. 18. The method of any one of clauses 14 to 16, wherein the mammal or bird is a human. A method for producing erythropoietin, which comprises administering a pharmacologically effective amount of a compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof to a mammal or a bird. - 258 - 201141839 IV. Designation of Representative Representatives (1) The representative representative of the case is: None. (2) A brief description of the symbol of the symbol of this representative figure: 4fB-. j \ w V. If there is a chemical formula in this case Co2h N N Please reveal the chemical formula that best shows the characteristics of the invention: (1)