WO1999032459A1 - Chymase inhibitors - Google Patents

Abstract

Heterocyclic amide compounds represented by general formula (I), or pharmacologically acceptable salts thereof; drug compositions containing the same; and use thereof as drugs (wherein each symbol is as defined in the description). The compounds exhibit an excellent chymase-inhibiting activity for mammals including Homo sapiens, and are therefore useful as orally or parenterally administrable chymase inhibitors and thus effective in preventing or treating various diseases caused by angiotensin II or other diseases caused by chymase.

Description

 Specification

 Chimase inhibitor

 Technical field

 The present invention relates to a novel heterocyclic amide compound and a pharmacologically acceptable salt thereof, a pharmaceutical composition thereof, and a pharmaceutical use thereof. In particular, the present invention relates to pyridone and pyrimidonacetoamide derivatives and pharmacologically acceptable salts thereof, which are useful in pharmacological, diagnostic and disease prevention / treatment.

 Background art

 Angiotensin II has physiological activities such as increasing blood pressure by strongly constricting blood vessels and stimulating secretion of aldosterone, which has a sodium-retaining action from the adrenal cortex, and has high blood pressure, cardiac hypertrophy, myocardial infarction, It is considered a causative agent or risk factor for diseases such as arteriosclerosis, diabetic and non-diabetic renal disease, and vascular restenosis after PTCA (percutaneous transluminal coronary angioplasty).

 This angiotensin 11 is produced by cleavage of two amino acids from angiotensin I, which is a peptide consisting of 10 amino acids present in a living body, and the cleavage involves angiotensin conversion. It is known that an enzyme (ACK) is involved, and many ACE inhibitors have been developed as prophylactic and therapeutic agents for the above diseases.

 By the way, in recent years, the action of a group of chimase groups, including human heart chymase, human mast cell chymase and human skin chymase, which are one of the subfamilies of the serine oral teat, has been demonstrated. Attention has been paid.

Chymase has been shown to be involved in the process of angiotensin H formation that is not based on ACE in the above-mentioned conversion of angiotensin I to angiotensin H (Okuni shi et al., Jpn. J. Pharmacol. 1993, 62. p07, etc.), and many other physiologies such as extracellular matrix, site force proteins, substance P, VIP (basoactive 'intestinal' polypeptide), and apoprotein B. It is known that the active substance is used as a substrate, and the activity of other proteases such as collagenase is also known. Involvement in sex has also become apparent (Miyazaki et al., History of Medicine 19 95. 172, p559).

 Therefore, chimase inhibitors are expected to be inhibitors of angiotensin II action by suppressing the ACE-independent production of angiotensin II, as well as various diseases caused by chimaze. It is also expected as a therapeutic agent.

 The present inventors have already filed a patent application based on these ideas, and in W096

COO e

And the like.

 An object of the present invention is to provide a novel compound having a more excellent chimase inhibitory activity than the above-mentioned compound, a pharmaceutical composition thereof, and a chymase inhibitor.

 Disclosure of the invention

The present inventors have disclosed in the above-mentioned W〇96 / 339974 to achieve the above object. The structural transformation of the compound was studied in various ways. As a result, it has been surprisingly found that amidation of the terminal carboxyl group can improve the chimase inhibitory activity and impart excellent blood stability, thereby completing the present invention.

 That is, the present invention provides a compound represented by the formula (I):

[Wherein R is a hydrogen atom, alkyl, one CH0, -C ONH2, — CORl, one C 00R ¹ , -C 0NH0R ¹ , -C ONHR ¹ , one CONRl Rl ', one CONH S 0 ₂ R ¹ , one COSRl, -C 0 C OR2, one COCO oR ^2, one C_〇_NHC 00 R2, one COCONR ³ R4, one C SXRl, - S 0 ₂ WR], - S O2 N Rl Rl ¹ or a SO2 E (the above formula Wherein R ¹ and Rl ′ may be the same or different and each independently represents alkyl, cycloalkyl, cycloalkyl, alkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl. R ² , R ³ and R ⁴ may be the same or different and each independently represents a hydrogen atom, an alkyl or an arylalkyl, and one NR ³ R4 together forms a heterocycle. X may represent a single bond, 10ΝΗ, 10 0 or 1S S. , W. is a single bond, one ΝΗ-, -Ν HC0-, shows an NHC00- or a NHC0NH-, E denotes a hydroxyl group or § amino) indicates,

R5, R6, R7 are the same or different or was or hydrogen atom an alkyl and each may independently have, or R ^5, R6, 1 Tsu is Ariru of R7, Ari Ruarukiru, § Li one Ruarukeniru, Heteroa Reel, heteroaryl alkyl Or a heteroarylalkenyl, and the rest are hydrogen atoms,

 M represents a carbon atom or a nitrogen atom, provided that when M is a nitrogen atom, R6 does not exist;

 Y represents cycloalkyl, aryl or heteroaryl,

R ⁸ represents a hydrogen atom, alkyl or arylalkyl,

R9 and R1 () may be the same or different and each independently represents a hydrogen atom, an alkyl, an alkenyl, a cycloalkyl, a cycloalkylalkyl, a heterocyclealkyl, an aryl, an arylalkyl, an arylalkenyl, a heteroaryl, A heteroarylalkyl or a heteroarylalkenyl, and one NR ⁹ R10 together may exhibit a heterocycle;

Z is the equation (i)

R ¹¹

(C) _m- i (i)

(In the formula, _R U and R] 2 may be the same or different and are each independently a hydrogen atom. Represents an alkyl, arylalkyl or heteroarylalkyl; and R ¹¹ and R12 together form a carbon atom May represent 2 to 6 methylene chains, m represents an integer of 丄 to 6), the formula i)

One (CH ₂ ) _p Q one (CH ₂ ) _r —

{Wherein Q represents —0—, one S—, a direct bond or the formula: one NR13— (where R! ³ represents a hydrogen atom, alkyl or arylalkyl), and P and r are the same Or may be different and each independently represents an integer of 0 to 3} or formula (Πί)

(Wherein, s and t each represent an integer such that the sum thereof is 1 to 6, and Q, p and r have the same meanings as described above).

n represents 0 or J.

Of the above groups, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, heterocyclylalkyl each have a substituent. (May have)

Or a pharmacologically acceptable salt thereof (hereinafter also referred to as compound (I)).

 The present invention also relates to a pharmaceutical composition comprising compound (I) or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier, and a pharmaceutical use, particularly a chymase inhibitor.

 The symbols used in the present specification are described below.

 Alkyl in R, Rl, Rl 'and R2 to R13 preferably has 1 to 6 carbon atoms and may be linear or branched, for example, methyl, ethyl, n-propyl pill, isobutyl pill, n-butyl, isobutyl, sec-butyl, tert-butyl, π-pentyl, isopentyl, η-hexyl and the like.

 The cycloalkyl in Rl, Rl ', R9 and RlOγ preferably has a carbon number of

: To 7, for example, cyclopropyl, cyclobutyl, cyclobentyl, cyclohexyl, cycloheptyl and the like.

The cycloalkylalkyl in R 1, Rl \ R9, R] 0 is the same as the cycloalkyl portion described above, and the alkyl portion preferably has 1 to 3 carbon atoms and may be linear or branched. For example, cyclopropylmethyl, 2-cycloα-butylethyl, 3-cyclobentylpropyl, cyclohexylmethyl, 2-cyclohexyl And butyl methyl.

 Aryl in Rl, Rl ', R5-R7, R9, RlO, γ is preferably phenyl, naphthyl, or ortho-fused; a bicyclic radical having at least one ring atom having at least one ring atom and at least one ring atom. Those in which the ring is an aromatic ring (eg, indenyl and the like) and the like can be mentioned.

Arylalkyl in R 丄 and R ¹ R2 to R13 has the same aryl moiety as described above, and the alkyl moiety preferably has 1 to 3 carbon atoms and may be linear or branched. Benzyl, phenyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3- (1-naphthyl) propyl, 3- (2 —Naphthyl) Probi'nole and the like.

 Arylalkenyl in R5 to R7 means that the aryl part is the same as described above, and the alkenyl part is preferably C6 to C6 and may be linear or branched, for example, styryl, 3 —Phenyl 1-probenyl, 4-phenyl 3-butenyl, 5-phenyl-1-41-pentenyl, 6-phenyl 5-hexenyl, 3- (丄 -naphthyl) 1-2-pro Benil, 4- (2-naphthyl) 1: Babel and the like.

 The arylalkenyl in R9 and RlO means that the aryl moiety is the same as described above, and the alkenyl moiety thereof preferably has 3 to 6 carbon atoms and may be linear or branched. 2-ru 1-l-provenil, 4-huen 2-ru 3-butenyl and the like.

The heteroaryl in RI, R1, R5 to R7, R9, R〗 0, Y is preferably a heteroaryl having 5 carbon atoms and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen atoms). 6-membered or ortho-fused bicyclic heteroaryls having 8 to 10 ring atoms derived therefrom, especially those derived from Benz, or α-benylene, trimethylene or tetramethylene groups. Examples include those derived by fusion, and stable そ の -oxides thereof. For example, pyrrolyl, frill, thi Enyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, vilazolyl, triazolyl, tetrazolyl, 1,3.5-oxaziazolyl, 2,4,1-oxaziazolyl, 2,4-thiadiazolyl, pyridyl Vilanyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2.4—triazinyl, L.2,3—triazinyl, and 3,5—triazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, thianaphthenyl, isothienyl Anaphthyl, benzofuranyl, isobenzofuranyl, chromenil, isoindrill, indrillyl, indazolyl, isoquinolinol, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzoxazinyl, etc. You.

R], R ^, and the Heteroa reel alkyl in ^{R 5 ~ R 7, R 9} ~R 1 2, Teroa re Ichiru portion to that is the same as above, properly favored the alkyl portion is 1 to carbon atoms 3 may be linear or branched, such as 2-pyrrolylmethyl, 1-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-phenylphenyl, 2- (2-pyridyl) ethyl, 1- ( 3- (pyridyl) ethyl, 2- (4-pyridyl) ethyl, 3- (2-pyrrolyl) propyl and the like.

 The heteroarylalkenyl in R 5 to R 7 has the same meaning as the above, and the alkenyl part thereof is preferably a straight-chain or branched-chain having 6 to 6 carbon atoms. For example, 2- (2-pyridyl) ether, 3- (2-pyridyl) -1-2-provenyl, 4- (3-pyridyl) -1,3-butyr, 5- (2-pyrrolyl) -14 1-pentenyl, 6- (2-phenyl) -1-5-hexenyl and the like.

 R!) And the heteroarylalkenyl in has the same meaning as the heteroaryl portion described above, and the alkenyl portion preferably has 3 to 6 carbon atoms and may be linear or branched. 2-pyridyl)-2-probenyl, 4-(2-pyridyl) 13-butyr and the like.

The heterocycle represented by R l and R! ′ Is a 4- to 6-membered ring group having a carbon atom and 1 to 4 hetero atoms (oxygen atom, sulfur atom or nitrogen atom), for example, azetidinyl, Pyrrolidinyl, Piberidinyl, Piberidino, Piberazinil, Morpho Examples include linyl, morpholino, thiomorpholinyl, oxothiomorpholinyl, dioxothiomorpholinyl, tetrahydroviranyl, and dioxacyclohexyl.

^{- NR 3 R 4, - NR} 9 and Heterosai cycle represented by R ^10, have the coal桌原terminal and at least yet another heteroatom having a single nitrogen atom (oxygen atom or a sulfur atom) A 4- to 7-membered ring group which may be selected, for example, azetidinyl, pyrrolidinyl, biperidino, piperazinyl, hexahi draw I [1-azebine-diyl, morpholino, thiomorpholino, oxothiomorpholino, Oxothiomorpholino.

R l, R卩, the Heterosai Kuruarukiru in R 9, R〗 0, Terosa Lee barrel portion to the above (R l, R ¹ ') similar, and the like as the, the alkyl portions lay good or May have 1 to 3 carbon atoms and may be linear or branched, for example, azetidinylethyl, pyrrolidinylpropyl, piberidinylmethyl, piberidinoethyl, biberazinylethyl, morpholinylpropyl, morpholinomethyl, Examples thereof include thiomorpholinylethyl, oxothiomorpholinylethyl, dioxothiomorpholinylethyl, tetrahydrobiranylpropyl, hexoxymethyl methyl and the like.

 The alkenyl in R 9 and R 10 preferably has 3 to 6 carbon atoms and may be linear or branched, and includes, for example, 2-phenyl-phenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like. No.

 Of the above substituents, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylaryl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocycle, heterocyclealkyl are Each may be substituted with one or more substituents shown below.

Examples of the substituent of these S-substituents include, for example, nitrogen, hydroxyl, nitro, cyano, trifluoromethyl, alkyl, alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, COORa, -CH 2 C 0 0 Ra, -0 CH ₂ C 00 Ra, one C ONRb Rc, -CH 2 CONRb Rc, -OC H ₂ C ONRb Rc, one C OO (CH2) 2 Re Rf, one S〇2 T], -C ONRd SOT ^1, -NRe Rf, one NRg CH_〇, - Rg C OT2, -N Rg C 0 OT2, -NRh CQNRi Rj, -N Rk S O2 T 3, - S O2 N Rl Rm, - S O2 NRn C OT ^ And the like.

 Here, in the substituents of the above substituents, alkyl and arylalkyl are the same as those described above. Halogen includes fluorine, chlorine, bromine and iodine. The alkoxy preferably has 1 to 6 carbon atoms and may be linear or branched and includes, for example, methoxy, ethoxy, ethoxy, butoxy, butoxy, hexoxy and the like. The alkylthio preferably has 1 to 6 carbon atoms and may be linear or branched, and examples thereof include methylthio, ethylthio, propylthio, butylthio, pentylthio, and hexylthio. The acyloxy may preferably be linear or branched having from i to 6 carbon atoms, and includes, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, vivaloyloxy, hexanoyloxy and the like.

 Ra to Rn are a hydrogen atom, alkyl (as described above), arylalkyl

(As above). In addition, one NRb Rc, -NRe Rf, one NRi Rj, and -N Rl Rm are taken together to form a heterocycle (similar to those exemplified for the one NR ³ R ⁴ and the one N RIO described above, And NRe Rf may be a heteroaryl having = 0.

(For example, 2-pyrrolidinone-11-yl, succinimide, oxazolidin-2-one-3-yl, 2-benzoxazolinone-3-yl, phthalimid, cis-1-hexahydrophthalate, etc.) Can also. 】 -44 represent the same groups as Rl described above, which may be substituted by the substituents described above. Q indicates = 0 or -S.

The compound (I) can exist as an optically active substance and a racemic form by an asymmetric carbon atom to which one (CH ₂ ) n one Y group is bonded. Each of the optically active substances can be separated by a known method. Also, if these compounds have additional asymmetric carbon atoms, the compounds can exist as a mixture of diastereomers or as a single diastereomer, but these may also be present. Each of them can be separated by a method known per se.

 Compound (I) can exhibit polymorphism, can exist as more than one tautomer, and can have a solvate (eg, ketone solvate). Products, hydrates, etc.).

 Therefore, the present invention includes any stereoisomers, optical isomers, polymorphs, tautomers, solvates, and any mixtures thereof as described above. When compound (I) is an acidic compound, its pharmacologically acceptable salts include alkali metal salts (eg, salts with lithium, sodium, potassium, etc.), alkaline earth metal salts (eg, Salts with calcium, magnesium, etc.), aluminum salts, ammonium salts, salts with organic bases (eg, salts with triethylamine, morpholin, piperidine, triethanolamine, etc.).

 When compound (I) is a basic compound, its pharmacologically acceptable salts include inorganic acid addition salts (for example, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.) ), Organic acid addition salts (eg, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoalphaacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipine) Acid, maleic acid, tartaric acid, succinic acid, mandelic acid, linoleic acid and the like), and salts with amino acid (for example, salts with glutamic acid, aspartic acid and the like).

In the compound (I) of the present invention, a preferable compound is a compound wherein 式 in the formula (（) is an aryl which may have a substituent: a compound wherein 式 in the formula (I) is a formula (i); A compound in which one of R ⁵ , R ⁶ , and R ⁷ in (I) may have a substituent, and a compound in which the remainder is a hydrogen atom (however, when M is a hydrogen atom, R 6 does not exist) And the like. More preferred compounds include those described in Examples 3, 4, 7, 8, 1K12, 17, 18, 18, 21-38, and 42-48. 55 and 59.

The production method of the wood compound (I) is shown in the following scheme 1 (1-0), 1-②, and 1-③).

Scheme 1 ー ①

Scheme 1

(0 Scheme 1—③

(I) (R = cbz)

(I) (R-H)

(I) (R ≠ H)

[In the formula, R14 represents a protecting group for a hydroxyl group (for example, tert-butyldimethylsilyl, triisobromovirsilyl, tert-butyldiphenylsilyl group, etc.), cbz represents a benzyloxycarbonyl group, Ru represents a hydrogen atom or Na or Represents an alkali metal such as K, and other symbols are as defined above)

 First, as shown in Scheme 1-II, the ability to condense compound (III) with amine (A) and lead to compound (Vil), and the ability to condense compound (11) with amine (A,) (Vila) to lead to compound (VII) via compound (Vllb) by hydrolysis, or to condense compound (II I) with amine (A ") to give compound (IV).

Compound (III) is a compound described in the literature (JP-A-6-56785, JP-A-5-286946, Warner et al. J. Med. Chem. 1994. 37, p3O90, Damewood et al. Med. Chem. 994 , 37, p3303, Veale et al., Med. Chem. 1995. 38, p98, WO 3/21210, etc.), or prepared by conventional methods based on these documents. It is made. Moreover, § Mi emissions (A), § Mi emissions (A '), § Mi emissions (eight ") and § Mi emissions: HNR ⁸ Preparation of ZC ONR9 R 10 will be described later.

Condensation of compound (1ί1) with amine (Α), amine (Α '), amine (Α "), compound (VI lb) and amine: HN R8 ZC ONR9 R ¹ " Examples of the condensing agent for activating the carboxylic acid of compound (III). Compound (VUb) include dicyclohexylcarbodiimide (DCC) / hydroxybenztriazole (H0BT), N- (3 -Dimethylaminopropyl)-Ν'-ethylcarbodiimide (WSC1) or its hydrochloride / HOB, WSC1 or its hydrochloride / 4-dimethylaminopyridine (DMAP), 2-ethoxy-ethoxycarbonyl -1.2 -Dihydroquinoline (EEDQ), carbonyldiimidazole (CDI) / H0BT. Getyl phosphoryl cyanide, benzotriazole-1-yloxytris (dimethylamino) phosphonium hexaoxafluophosphate (B0P) , Phenyl N— Eniruhosuhorami skull Ride one bets, and the like as a preferable example.

 The reaction is generally carried out in an inert solvent, and the inert solvent used may be any non-protonic solvent, and is preferably acetate nitrile, dichloromethane, or the like. Black form, N, N-dimethylformamide and the like.

 In addition, the condensation is usually performed at a temperature of -30 to 80 ° C, and preferably at 0 to 25 ° C.

The hydroxyl group of the obtained compound (VII) may be protected and converted to the compound (IV). Conversely, the protective group (R ¹⁴ ) of the hydroxyl group of compound (! V) may be deprotected to give compound (VII).

 Next, as shown in Scheme i-②, the benzyloxycarbonyl group in compound (IV) can be removed by a usual method such as hydrogenolysis, and converted to compound (V).

The compound can be obtained by, for example, converting the amino group bonded to carbon on the heterocycle (pyridone ring or pyrimidone ring) in compound (V) by the following method. R force, '-CHO,-C 0 NH 2, C ORl,-COOR ¹ ,-C ONH 0 R ^1.- CONHR ¹ ,-C QNRl R',-C ONH S O2 R ¹ ,-COS Rl,

- C 0 CO R2, - C 0 C 00 R2, - CONHC QOR 2 or - The synthesis of C OCO NR ³ R4, compound (VI), using the activation force carboxylic acid derivative such as an acid payments de And a method using a carboxylic acid and a coupling agent.

When synthesizing the compound (VI) in which R is -CONH ₂ , -C 0 NHR ¹ , ~ C ONHS 0 ₂ R ¹ or -CON H CO 2, a method using an isocyanate may, for example, be mentioned. Further, for example, carbonyldiimidazole, phosgene, diphosgene (trichloromethyl chromate formate) or triphosgene Lbis (trichloromethyl) hydrogen carbonate is represented by the formula R ¹ OH. that alcohol, wherein R ¹ thiols or formula R ¹ NH2 represented by SH, include ⁽¹⁾ 2 NH, and § Mi emissions represented by Rl ONH _2, method, etc. for use with a base such as Bok Ryechiruami emissions are .

R is - synthesizing CS XR ^1, compound a (VI), a method of using activated Chiokarubon acid derivatives (e.g., lower alkyl esters such as Chioirukurorai de Ya Jichioikku acid), a Chioi click acid and couplings agent Examples include the method used. Further, for example, dimethyl Bok Li Chio carbonate, an alcohol of the formula R ¹ 0H, and a method for use with Amin represented by thiols or formula R ¹ NH2 formula Rl SH and the like. Further, in the case of synthesizing the compound (VI) in which X is -NH, a method using isothiocyanate and the like can be mentioned.

There - S 0 ₂ WRL, - S_rei_2 NR ¹ Rl 'or - case of synthesizing S 0 ₂ E, compound (VI), there is a method described below as a preferred method of sulfonylating example, formula _{H0 - S 0 2 WRl, HO-} S 0 2 NRl Rl ' or H_〇 - - S 0 ₂ sulfonic acid represented by E or the corresponding acid halide, particularly the formula C 1 - S 0 ₂ WRl, C 1 - S_rei_2 NR ¹ Rl 'or CI - and sulfonyl (or sulfamoyl) chloride Li de represented by S 0 ₂ E, organic bases (Bok Riechiruami down, pyridine, etc.) or an inorganic base (carbonate Na Application Benefits um , Potassium carbonate, etc.), inert Use in solvents (dichloromethane, tetrahydrofuran, toluene, etc.)

 When compound (VI) has C 00 Ra (carboxyl group) in which Ra is a hydrogen atom as a substituent of each substituent in R, for example, a corresponding compound synthesized using an acid protecting group suitably removed By decomposing the ester (compound (VI) having CO ORa in which Ra is not a hydrogen atom as a substituent of the substituent), the compound is obtained. This decomposition can be performed by any of various methods well known in organic chemistry, for example, basic hydrolysis using lithium hydroxide or sodium hydroxide, or hydrogenolysis of benzyl ester. .

Compound (VI) is, C 00 Ra as substituents for each substituent at R, - C ON Rb Rc, if having a _{-C OO (CH 2) 2 NRe} Rf or a C QNRd S 0 _2, for example, the formula HORa _{, HNRb Rc, HO (CH 2} ) 2 NRe Rf or HNRd S 0 the compound represented by the ₂ Tl and (if Ra to Ri 'is not hydrogen atom), it is Ra is hydrogen atom as the substituent of the substituted group one The compound (VI) having C 00 Ra (carboxy group) or an activated derivative thereof can be reacted to obtain the compound.

When the compound (VI) has OCH ₂ C OORa or O CH2 C ONRbRc as a substituent of each substituent in R ^{5 to} R ⁷ and R, for example, the compounds represented by the formulas B r C H2 C OORa, I CH C OORa, B r C H2 CON Rb Rc or I CH ₂ C ONRb Rc compound represented by (in the case Ra to Rc is not hydrogen atom), the compound having a hydroxyl group as a substituent of substituent (VI), hydrogenated diisocyanato Li um By reacting in the presence of such a base, the compound can be derived.

Compound (VI) is, R5 through R7, the substituent of each substituent in ^{R - NRg COT 2, - NRg} C 00 T2, - N Rh CQNRi Rj, - NRk case with S 0 ₂ T3 or Ashiruokishi group, e.g. , hydroxyl group as the substituent of the substituted group, or is NHRg, - NHRh or - the corresponding compound having an amino group NHRk with (VI), formula ^{HO C OT2, HOC OOT 2,} HOC QNRi Rj or H_〇 By reacting with an activated derivative of an acid represented by S 0 ₂ T ³ or the like, the compound is obtained.

Compound (VI) is, R ⁵ ~ R ^7, Heteroari Ichiru into R - Okisai a de base case including, R ⁵ ~R ^7, R or the corresponding compounds containing Heteroariru groups in Z (VI) Is oxidized using a common oxidizing agent such as dioxysilane in acetate to obtain the compound.

 Here, the conversion and the like of each substituent in R and the like have been described with reference to the case of compound (V [). However, such conversion and the like are not possible only in the case of compound (VI). This is also possible for various compounds as long as they do not affect other functional groups present in the chemical structure (for example, the substituent of each substituent in R etc. is an amino group, a hydroxyl group, etc.). In such a case, the conversion is preferably performed not in the state of compound (VI) but in the state of compound (I)). In each conversion, it is preferable to appropriately protect the functional group with a known protecting group in consideration of the reaction conditions and the like.

Next, the compound (II) is obtained by removing the protecting group (R ¹⁴ ) of the hydroxyl group in the compound (VI).

 The removal of the hydroxyl-protecting group can be performed using tetrabutylammonium fluoride or the like in an inert solvent such as tetrahydrofuran, and at this time, the reaction solution is buffered with an acid such as acetic acid. Is preferred.

 Next, the hydroxyl group of the compound (1) is oxidized to lead to the target compound (I).

As a preferable method of this oxidation, for example, there is a method of using excess dimethyl sulfoxide and water-soluble carbodiimide at about room temperature in an inert solvent such as toluene and using acetic acid as a catalyst. . Other useful methods include, for example, a method using an aqueous solution of potassium permanganate: a method using oxalyl chloride, dimethyl sulfoxide, and a tertiary amine: acetic anhydride and dimethyl. Method using sulfoxide: Method using pyridine trioxide complex and dimethyl sulfoxide: Method using chromium oxide (VI) pyridine complex in methylene chloride Method: 1, 1, tritolyacetoxy-1, 1, 2, 3, 4 dihydro-1.2-benzidodotool-3 (1H) -Hypervalent hyperiodine reagents such as perodinane, etc. N-N-dimethylformamide can be used.

 In addition, as shown in Scheme I-③, the compound (1Π) is condensed with amine (A) or the compound (HI) is condensed with amine (Α ') ( In the compound (VIί) derived through the hydrolysis compound (VI lb) of the compound (VIla) or obtained by deprotecting the hydroxyl group of the compound (IV), The compound (I) having an amino group protected with a benzyloxycarbonyl group can be obtained by oxidation.

 Then, the benzyloxycarbonyl group of this compound is removed (deprotected) under mild reaction conditions to obtain a compound (I) in which R is a hydrogen atom. For example, deprotection is carried out by an acid decomposition reaction in which trifluoromethanesulfonic acid or trifluoroacetic acid acts in the presence of anisol or thioanisole, or a hydrogenolysis reaction using palladium carbon or the like as a catalyst. Will be

 Further, the compound (I) in which R is other than a hydrogen atom can also be obtained by performing the above acylation reaction or the like.

Another method for producing the compound (I) of the present invention is shown in the following scheme 2 (2-①, 2-②, 2-③).

Scheme 2—①

(1) Scheme 2—③

HNR ^B R ¹⁰

 ((R = cbZ)

(I) (= H)

(In the formula, R15 represents a straight-chain or branched alkyl having i to 6 carbon atoms, or a group forming an ether serving as a protecting group for a carboxyl group, and other symbols are as defined above. )

As shown in Scheme 2—①, compound (ΙΠ) is condensed with amine (B) (XIV), the compound (Π!) Is condensed with an amide (Α ') to form a compound (VI la), and the compound (Vllb) is hydrolyzed to the compound (XIV). Alternatively, the compound (111) is condensed with an amine (C) to give a compound (Vlli).

Incidentally, § Mi emission (beta), § Mi emission (C) and § Mi emissions: HNR8 Preparation tone ZC 02 R ¹⁵ will be described later.

Compound ([pi!) And § Mi emission (beta), condensation with § Mi emission (C), compound (VI ib) and Amin: HNR8 ZC 02 Chijimigo剂used in the condensation with R ^15, and reaction solvent The same ones as those used in the production shown in Scheme 1 can be used.

 The conversion of compound (VIII) to compound (XIV) and the conversion of compound (XIV) to compound (VI (1)) can be carried out in the same manner as in the production method shown in Scheme 1.

 Next, as shown in Scheme 2-②, Compound (VIII) is converted to Compound (XI [) through Compound (IX), Compound (X) and Compound (XI) in the same manner as in Scheme 1-②. The protecting group (R15) of the carboxyl group of the obtained compound (XII) is eliminated to give a compound (XHI), which is reacted with an amamine: HNR9R10 to lead to a compound (I).

 Further, as shown in Scheme 2-3, compound (XV) is obtained from compound (1Π) via compound (XIV) in the same manner as in Scheme 1-3. This is converted into a compound (XVI) by deprotection of the carboxyl group, and by amidation, a compound (I) (wherein R represents bbz and other symbols are as defined above) is obtained.

 Further, the benzyl group of this compound is removed by the above-mentioned method, and the compound is converted into a compound (I) (wherein R is hydrogen and the other symbols are as defined above). A compound ([) in which R is other than a hydrogen atom can be obtained by a chemical reaction or the like.

 The compound (VIII) and the compound (X) are reacted with an amide: HN R9 RIO via carboxyl group deprotection to give a compound (IV) and a compound (X), respectively.

(VI).

Scheme 3 shows another method for producing compound UV). In this method, if M is a carbon field Used only when

Scheme 3

Wherein each symbol is as defined above. ]

As shown in the above scheme 3, compound (XVII) [Compound described in the literature (Japanese Patent Publication No. 6-56785, Warner et al., J. Med. Chem. 1994, 37, p3090, Dameood et al., J. Med. Chem. 1994, 37, p3303) or a compound prepared by a conventional method based on these documents] and compound (D) to obtain compound (IV). Can be. The method for preparing compound (D) will be described later. As described in, for example, JP-A-6-56785 and J. Med. Chem. 1994, 37, p3303, this reaction is carried out by converting compound (XVII) into a non-protonic solvent, especially N, Inactive solvents such as N-dimethylformamide, tetrahydrofuran, etc., bases such as sodium hydride, hydrogenation power, etc., -30 to 80 ° C, preferably 0 to 30 ° After treating with C, this is carried out by reacting with compound (D) at −30 to 8 (TC: preferably at 0 to 30 ° C.).

 The compound (IV) thus obtained is derived into the compound (ί) by the method described in Scheme II.

 Two

 Five

In addition, compound (V111) can also be obtained in the same manner as in scheme 3, using compound (II) as shown in scheme 4. Scheme 4

The obtained compound (VIH) is led to compound (I) by the method described in Scheme 2. The method for preparing compound (Ε) will be described later.

The amide (Α), amine (Λ ') and amine (Α ") necessary for the above-mentioned synthesis are synthesized by the method shown in the following scheme 5. Scheme 5

 (XVIII) 2

 6

RvHN Roh, C0 ₂ R _w

R _V HN

 (XXI)

(A) (A ") [Wherein, R _V represents an amino-protecting group (for example, a benzyloxycarbonyl group (bzz), a tert-hydroxycarbonyl group (B0C), etc.), and Rw represents an alkyl group having 1 to 5 carbon atoms. And other symbols are as defined above.]

 First, the compound (XViil) is esterified to give a compound (XIX).

 Examples of the esterification method include a method in which Rw is reacted with an alkyl halide corresponding to Rw in the presence of a base such as hydrogen carbonate and a reaction method with a diazoalkane.

 The amino group-protected α-amino acid represented by the formula (XV111) is commercially available in many cases, but the other one is obtained by the method of Strecker synthesis from aldehyde Υ— (CΗ2) nCHO or other methods. After obtaining an amino acid by the obvious method described above, the amino acid can be protected and protected.

 Next, when the compound (XIX) is reduced using, for example, diisobutylaluminum hydride, the compound (XXI) can be easily obtained. In addition, as reported in a report by Fehrent'z et al. (Synthes is. 1983, p676), an amide derivative obtained by condensing a compound (XV HI) with N, 0-dimethylhydroxylamine is converted to lithium aluminum hydride. Compound (XX!) Can also be synthesized by reduction with

 As another method, the compound (XIX) is reduced with, for example, sodium borohydride Z to give compound 00, and then described in the conversion of compound (Π) to compound ([). Compound (XX) can also be obtained by oxidizing compound (XX) by an oxidation method.

Next, compound (XXI) was prepared by the method described in (i) Hal 1 inan and Fried (Tetrahedron Lett. 1984, 25. p2301) and Thai rivongs et al. U. Med. Chem. 1986, 29, ρ2ϋ80). (2) reacting with chlorodifluoroacetate in the presence of zinc powder according to the method of ang and Schaub (Tetrahedron Lett. 1988, 29, p2943), or (3) According to the method of Hoover (US Pat. No. 4,855,303), compound (XXU) is synthesized by reacting with ethyl promodifluoroacetate, zinc dust and titanium tetrachloride. can do.

The compound (XXI 1) pro Bokun polar solvent, preferably ethanol or methanol, § Mi emissions: Itanyukappa8 reacted with ZC ON R ⁹ R ^10, compound (XXI V) is obtained.

 In the compound (XXIV), the amide (A) is obtained by removing the protecting group Rv of the amino group.

Further, the corresponding carboxylic acid compound () I) obtained by hydrolyzing the compound (、) is converted into an amide: HNR ⁸ ZCONR9R10 by the method described in the synthesis of the compound (I). Condensation gives compound (XXIV), and then removal of protecting group Rv also gives amide (A).

Amines (Α ') can be obtained by removing the protecting group Rv of the compound (XXH). <Amin (A ") can be obtained by converting the hydroxyl group of the compound (XXIV) to a protecting group (R ¹⁴ ), followed by removal of the protecting group Rv of the amino group.

Amin (B) and amine (C) are synthesized by the method shown in Scheme 6.

(O

I

Compound (XX [pi) or the compound (XXI II) in § Mi emissions: HN R8 ZC 00 to R ¹⁵ are reacted to give compound (XXVI), § Mi down in the same procedure as obtaining a § Mi emissions (Alpha) (Β) is obtained. Further, an amine (C) is obtained via the compound (XXV! 1) by the same procedure as that for obtaining the amine (Α ″) from the compound (XXVI).

Ζ9 § Mi emissions: HN R ⁸ ZC ONR ⁹ RlO is § Mi emissions: HN R8 ZC O2 H (R¾ = H) a § Mi amino group of the general group used in (base Nji as a protecting group for amino amino acid Protected with a carbonyl group, tert-butoxycarbonyl group, etc., then condensed with amide: HN R9 RlO by the method described in Scheme 1-①, and deprotected to give HNR ⁸ ZC 0 NR9 RlO (R8 -H) is obtained. HN R8 ZCONR ^ 10 in (R8 = H), the presence of an alkylating or reducing agent used Arukiruharai de, after reductive alkylation reaction with aldehydes, if deprotection, HNR 8 ZC ON R ⁹ R ¹⁰ (R ⁸ ≠ H) is obtained.

§ Mi emissions: The HN R ⁸ ZC 0 ₂ R ¹⁵ is greater commercially available, otherwise it is synthesized as follows. Amines: HNR ⁸ ZC 02H (R ⁸ = H) is replaced with a group generally used as an amino-protecting group for amino acids such as benzyloxycarbonyl and tert-butoxycarbonyl. , And then esterified by a known method and deprotected to obtain HNR ⁸ ZC 02 R ¹⁵ (R ⁸ = H).

Alkylation of ZC 0 ヮ R ¹⁵ (R ⁸ = H) using an alkyl halide or reductive alkylation in the presence of a reducing agent and then deprotection followed by deprotection yields HNR ⁸ ZC 02 R ¹⁵ (R ⁸ H) is obtained.

Scheme 7 shows the synthesis of compound (D).

scheme

H ゥ N

(D)

(In the formula, each symbol is as defined above.)

The synthesis of this compound (D) is carried out, for example, according to the report of Damewood et al. U. Med. Chem. 1994. 37, P3303). First, the amine (A) is reacted with N-methylmorpholine or the like in an inert solvent such as tetrahydrofuran. Reaction with chloroacetyl chloride at −20 to 60 ° C., preferably at 0 to 30 ° C. in the presence of an organic base gives compound (XXVI II). The compound (XXIX) is obtained by protecting the hydroxyl group of this compound (XXV1H) with the above-mentioned protected amino group (Ri4), preferably a silyl group such as a tert-butyldimethylsilyl group. This, for example, When reacted with sodium iodide or lithium iodide in an inert solvent such as acetone at -20 to 60 ° C, preferably at 0 to 30, the desired compound (D) is obtained. The resulting Scheme 8 shows a method for synthesizing compound (E). Scheme 8

(E)

(In the formula, each symbol is as defined above.)

Compound (E) can be obtained by using compound (XXX) and then compound (ΧΧΧΠ) in the same procedure as starting compound (D) from compound (A), starting from compound (B). Can be. The compound (I) of the present invention thus synthesized can be purified to any desired purity by appropriately performing known separation and purification means, for example, concentration, extraction, chromatography, reprecipitation, and recrystallization. Can be collected as

 Also, a pharmacologically acceptable salt of the compound (I) can be produced by a known method. Further, various isomers of the compound (I) and the like can also be produced by a known method.

 The compound (I) of the present invention and a pharmacologically acceptable salt thereof have excellent inhibitory activity against a mammal (for example, human, dog, cat, etc.) against the chimaze group.

 Therefore, the compound (I) of the present invention and a pharmacologically acceptable salt thereof are ffl as inhibitors of the chymase group including human heart chymase, and it is considered that angiotensin 11 is present. Prevention of possible diseases (eg, hypertension, cardiac hypertrophy, myocardial infarction, arteriosclerosis, diabetic and non-diabetic renal disease, vascular restenosis after PTCA, etc.) Useful for prevention and treatment.

 When the compound (I) of the present invention and a pharmacologically acceptable salt thereof are used as a drug, a pharmacologically acceptable carrier or the like may be used, and granules, tablets, capsules, injections, ointments, creams, aerosols and the like may be used. And can be administered orally or parenterally. An effective amount of compound (I) or a pharmacologically acceptable salt thereof is incorporated into the above preparation.

 The administration site of the compound (e) and a pharmacologically acceptable salt thereof varies depending on the administration route, the patient's symptoms, rest, age, and the like, and can be appropriately set depending on the purpose of administration. Usually, for oral administration to adults, 0.01 to l OOOmg / kg body weight /, preferably 0.05 to 500 mg / kg rest / day should be administered in 1 to several times a day. preferable.

 BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the change in the concentration of the unchanged compound in plasma when the compound of the present invention and the conventional compound were orally administered to rats in Experimental Example 2, respectively. FIG. 1 shows plasma in the case where the compound of the present invention was orally administered to dogs in Experimental Example 3. It is a graph showing the transition of the unchanged substance concentration of _n

 Example

 Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Analytical instruments and reagents

 One NMR spectrum of each product was measured using a Bruker AMX-500 nuclear magnetic resonance apparatus (500 MHz) or a Bruker DPX-300 nuclear magnetic resonance apparatus (300 MHz) using tetramethylsilane (TMS) as an internal standard. IR spectra were measured using a Shimadzu IR-420 infrared spectrophotometer or a Perkin Elmer FT-IR 1725X infrared spectrophotometer. The mass spectrum was measured using a Hitachi M-2000 double focusing mass spectrometer or PE Sciex API165 liquid chromatograph mass spectrometer, and the melting point was measured using a Yanagimoto MP-S3 trace melting point analyzer. It was measured. As a packing material for column chromatography, Silica gel 60 (230 to 400 mesh) for column chromatography manufactured by Merck was used. Reagents and solvents used were JIS special grade or primary grade.

Reference example 1

 Synthesis of [5-benzyloxycarbonylamino-2- (4-fluorophenol) -1,6-dihydro-6-oxo-1-pyrimidinyl] acetic acid

 (1) Hydrogen chloride was blown into a solution of 4-fluorobenznitryl (50.8 g, 0.407 mol) in ethanol (500 ml) under ice-cooling, and saturated, then at room temperature for 16 hours Stirred. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with ether and dried under vacuum to obtain 82.1 g (99%) of ethyl 4-fluorobenzimidate hydrochloride as colorless crystals. .

(2) A solution of the desired compound (50.0 g, 0.246 mol) in step (1) in ethanol (200 ml) was added under ice-cooling to an aminoacetaldehyde aldehyde dodecyl acetal (43 ml, 0.30 ml). It was added dropwise mo 1), and stirred for 12 h at 4 ^D C. Ethanol was distilled off under reduced pressure, and the obtained concentrate was added to a 1N aqueous sodium hydroxide solution (500 ml), and extracted with a chloroform form. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and N- (2,2- A colorless oily substance containing 4-hydroxyfluorinated benzoamidine was obtained.

 (3) To a solution of the target compound of Step (2) (the crude product obtained in the above reaction) in ethanol (100 ml), add dropwise at room temperature dimethyl ether methylene carbonate (55 ml, 0.27 mol). did. After the dropwise addition, the mixture was stirred at room temperature for 30 minutes, heated to 9 CTC, and stirred for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (1: 1 ethyl acetate-hexane), and ethyl 1- (2,2-jetoxetyl) -2- 70.2 g of (4-fluorophenyl) pyrimidin-6 (1H) -one 5-carboquinate was obtained as a pale yellow oily substance.

(4) Lithium iodide (49.0 g, 0.366 mol) was added to a solution of the target compound (55.0 g, 0.145 mol) in pyridine (200 ml) in step (3), and the mixture was heated to 100 and stirred for 16 hours. After evaporating the organic solvent under reduced pressure, toluene (200 ml) was added and the remaining traces of pyridine were distilled off under reduced pressure. The residue was added to a saturated aqueous sodium hydrogen carbonate solution (500 ml), and ethyl acetate was added. The organic substances other than carboxylic acid were extracted with. The insoluble matter was removed by filtration, and 3N hydrochloric acid (400 ml) was added to the aqueous layer to make 2 and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1- (2,2-jetoxethyl) -2- (4-fluorophenyl) pyrimidine-6. (14.5 g of 110-one-5-carboxylic acid was obtained as a pale yellow oily substance. The insoluble matter obtained above was added to 2N hydrochloric acid (500 ml) and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 29.7 g of the target compound as a pale yellow oily substance (total yield: 87%) ₍ ;

(5) A solution of the target compound (43.6 g, 0.124 mol) in step (4) and triethylamine (35 ml, 0.25 mol) in 1,4-dioxane (400 ml) was added at room temperature to diphenylphosphoryl azide (31 ml, 0.14 mol) was added dropwise over 20 minutes. After the dropwise addition, the mixture was gradually heated, and benzyl alcohol (26 ml, 0.25 mol) was added at 100 ° C. The reaction solution was stirred at the same temperature for 18 hours, cooled to room temperature, and 1,4-dioxane was distilled off under reduced pressure. The residue was added to a saturated aqueous solution of ammonium chloride (500 ml), and the oil was distilled off with ethyl ethyl acetate. The extract was washed successively with a 1N aqueous solution of sodium hydroxide and a saturated saline solution. After drying under reduced pressure, the solution was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (chloroform), and [5-benzyloxycarbonylamino-2- (4-fluorophenyl) -1,6-dihydro-6-hydroxy-1- A mixture of pyrimidinyl] acetaldehyde dodecyl acetal and benzyl alcohol was obtained as a light brown oily substance, 45, 2 g (65% obtained).

 (6) To a solution of the target compound (mixture with benzyl alcohol, 44.6 g, 79.1 ol) in step (5) in tetrahydrofuran (THF) (350 ml), add IN hydrochloric acid (250 ml), and add Stirred for hours. The reaction solution was cooled to room temperature, and THF was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained concentrated solution to adjust the pH to pH 7, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained solid was washed with 1: 1 hexane-ether, and -benzyloquincarbonylamino-2_ (4fluorophenyl) -1,6-diphenyl 20.7 g (55%) of a mixture of dro-6-oxo-1-pyrimidinyl] acetaldehyde and benzyl alcohol was obtained as a colorless solid.

 (7) The target compound of step (6) (mixture with benzyl alcohol, 20.2 g, 42.3 mmol). 2-Methyl-2-propanol (300 ml) and 2-methyl-2-butene (50 ml.

0.47 mol) of sodium dihydrogen phosphate dihydrate (51.4 g, 0.329 mol) and sodium chlorite (85% content, 36.6 g, 0.329 mol) in water (130 ml ) The solution was added, and the mixture was stirred at room temperature for 3 hours. The organic solvent was distilled off under reduced pressure, and the obtained concentrated solution was added to 2N hydrochloric acid (200 ml), followed by extraction with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Ether was added to the residue for crystallization, and 15.5 g (86 化合物!) Of a mixture of the title compound and benzyl alcohol was obtained as a colorless solid.

 iH-NMR (500MHz, DMSO-dg) <5 13.3 (brs, 1H), 8.99 (s, III), 8.46 (s, 111), 7.56 Cdd, J-5.4, 8.9 Hz, 211), 7.44 (d, J-7.2 Hz, 211), 7.30-7.42 (m, 5H), 5.19 (s, 2H), 4.53 (s, 2H)

IR (KBr) 3650-2300, 1720, 1660, 1600 cm " ¹ Reference example

 Synthesis of [5-benzyloxycarbonylamino-6-oxo-2- (3-methylphenyl) -1,6-dihydro-1-pyrimidinyl] acetic acid

 (1) Ethyl 3-methylbenzimid hydrochloride was synthesized in the same manner as in Reference Example I. That is, m-tolunitrile (25.2 g, 0.1π) is treated with hydrogen chloride in a solution of ethanol (250 ml) to give the target compound as colorless crystals, 41.7 g (97%)

7

 (2) Synthesis of N- (2,2-jetoxetyl) -3-methylbenzamidine was performed in the same manner as in Reference Example I. That is, the target compound (25-0 g, 0.125 mol) of the step (1) is reacted with aminoacetoaldehyde decyl acetal (21 ml, 0.14 mol) in a solution of ethanol (00 ml) in ethanol, and the target compound is obtained. 40.1 g of a colorless transparent oil containing was obtained.

 (3) Ethyl (2,2-jetoxetyl) -2- (3-methylphenyl) pyrimidin-6 (1H) -one-5-carboxylate was synthesized in the same manner as in Reference Example II. That is, the target compound of step (2) (the crude product obtained in the above reaction) was reacted with getylethoxymethylene malonate (28 ml, O. Umol) in an ethanol (50 ml) solution, 35.8 g of the target compound was obtained as a pale yellow oil.

 (4) Synthesis of 1- (2.2-methoxethyl) -2- (3-methylphenyl) pyrimidine-6 (111) -one-5-carboxylic acid was performed in the same manner as in Reference Example 3. That is, the target compound (34.8 g, 92.9 mmol) of the step (3) was reacted with iridium iodide (30.0 g, 244 mmol) in a pyridine (140 ml) solution to obtain 22.7 g of the target compound as brown crystals. 7 1¾) obtained.

(5) [5-Benzyloxycarbonylamino-6-oxo-2- (3-methylphenyl) -1,6-dihydro-1-pyrimidinyl] acetaldehyde Synthesis of dodecyl acetal is for reference Performed in the same manner as in Example 1. That is, the target compound (22.0 g. 63.5 mmol) of the step (4) was dissolved in 1,4-dioxane (200 ml) in the presence of triethylamine (18 ml, 0.13 moi) in the presence of diphenylphosphoryl azide (16 fd, 71 mmol) and benzyl alcohol (10 ml, 97 mmol). A mixture of coles was obtained as a pale yellow oil, 30.1 g (86%).

 (6) Synthesis of {5-benzyloquincarbonylamino-6-oxo-2- (3-methylphenyl) -l, 6-dihydro-l-pyrimidinyl] acetaldehyde is the same as in Reference Example 1. A similar procedure was used. That is, the target compound of Step (5) (mixture with benzyl alcohol, 29.4 g, 53.6 mmol) was treated with IN hydrochloric acid (150 ml) in THF (200 ml), and the mixture containing the target compound was converted to a colorless solid. 26.1 g was obtained.

 (7) [5-benzyloxycarbonylamino-6-oxo-2- (3-methylphenyl) -1,6-dihydro-1-pyrimidinyl] Acetic acid was synthesized in the same manner as in Reference Example 1. That is, the target compound of Step (6) (the crude product obtained in the above reaction, 26, 1 g) was mixed with 2-methyl-2-propanol (350 ml) and water (150 ml) in a mixed solvent. In the presence of -methyl-2-butene (60 ml, 0.57 mol) and sodium dihydrogen phosphate (58.5 g, 0.375 mol), sodium chlorite (containing 85, 41.6 g, 0.391 mol) mol) to give 18.9 g of the title compound as colorless crystals.

mp 183-185. C

 Ill-NR (500MHz, DMSO-d6) δ 13.27 (brs, 111), 8.97 (s, 111), 8.46 (s, 1H), 7.44 (d, J = 7.3 Hz, 2H), 7.32-7.42 (m , 5H), 7.31 (s, III), 7.27

(d, J 7.4 Hz, 111), 5.19 (s, 211), 4.51 (s, 2H), 2.35 (s, 3H)

IR (KBr) 3600-2300, 1720, 1655, 1600, 1515 cm- ¹

Reference example 3

 Synthesis of [5-benzyloxycarbonylamino-6-oxo-2 (3-pyridyl) -1,6-dihydroxy-1-pyrimidinyl] acetic acid

(1) Acetyl chloride (190 ml, 2.67 mol) was added dropwise to a mixture of black-mouthed form (100 ml) and ethanol (200 ml) over 1 hour under ice-cooling. After stirring at 0 ° C for 30 minutes, a solution of 3-cyanopyridine (25.5 g, 245 mmol) in chloroform (300 ml) was added dropwise over 1.5 hours. After stirring at room temperature for 17 hours, the precipitate was collected by filtration, washed with chloroform and dried under vacuum, and 50.5 g (92%) of ethyl 3-pyridinecarboximidyl dihydrochloride was obtained as colorless crystals. :)Obtained. (2) A solution of the target compound (50.0 g, 0.224 mol) in step (1) in ethanol (200 ml) was added under ice-cooling to an aminoacetaldehyde aldehyde dodecyl acetal (37 ml, ϋ.25 mol). After addition of triethylamine (35 ml, 0.25 mol), the mixture was stirred at room temperature for 5 hours. Ethanol was distilled off under reduced pressure, and the obtained concentrate was added to an aqueous IN sodium hydroxide solution (6 (0 ml)) and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 55.0 g of a yellow oil containing N- (2,2-jetoxetyl) -3-pyridinecarboxamidine.

 (3) Ethyl (2,2-jetoxyl) -2- (3-pyridyl) pyrimidin-6 (1H) -one-5-carboxylate was synthesized in the same manner as in Reference Example II. . That is, the target compound of n (2) (the crude product obtained in the above reaction, 55.0 g) was reacted with getylethoxymethylene malonate (51 m and 0.25 mol) in an ethanol (100 ml) solution. 53.0 g of the desired compound was obtained as colorless crystals.

 (4) 1- (2.2-Jetoxicetyl) -2- (3-pyridyl) pyrimidin-6 (1H) -one-5-carboxylic acid was synthesized in the same manner as in Reference Example 3. That is, the target compound (50.2 g. 139 mmol) in the step (3) was reacted with lithium iodide (43.1, 322 rnmol) in a pyridine (200 ml) solution, and the target compound was converted into a brown solid in 33.0 g ( 66%).

 (5) Synthesis of [5-benzyloxycarbonylcarbonyl-6-oxo-2- (3-pyridyl) -1,6-dihydropyrimidinyl] acetaldehyde dodecyl acetal is a reference example. Performed in a similar manner to 1. That is, the target compound (32.5 g, 7.5 mmol) of the step (4) was dissolved in 1,4-dioxane (250 ml) solution in the presence of triethylamine (27 tn and 0.19 mol) in the presence of diphenylphosphoryl azide 6 Then, it was reacted with benzyl alcohol (15 ml, 0.14 mol) to obtain 30.8 g (72%) of the target compound as colorless crystals.

(6) [5-benzyloxycarbonylamino-6-oxo-2- (3-pyridyl) -1,6-dihydro-1-pyrimidinyl] acetoaldehyde was synthesized in the same manner as in Reference Example 1. I went. That is, the target compound of step (5) (29.9 g, 68.2 irnnol) was added to THF (250 ml). The solution was treated with IN hydrochloric acid (180 ml) to obtain 25.4 g of a brown solid containing the target compound. (7) [5-benzyloxycarbonylamino-6-oxo-2- (3-pyridyl) [1,6-Dihydropyrimidinyl] acetic acid was synthesized in the same manner as in Reference Example 1. That is, the target compound obtained in the step (6) (crude product obtained in the above reaction, 25.4 g) was treated with 2-methyl- _{2 in} a mixed solvent of 2-methyl- ₂ -propanol (O ml) and water (180 ml). -In the presence of butene (72 ml, 0.68 mol) and sodium dihydrogen phosphate (74.5 g, 478 mmol), sodium chlorite (85% content, 53.%) g, 498 mmol) to give 17.4 g of the title compound as colorless crystals.

m 189-190 ° C

iH- 麵 (``) 00 MHz, DMS0-d6) δ 13.3 (brs, 1H), 9.06 (s, IH). 8.74 (dd, J = 4.9. 1.6 Hz.IH), 8.70 (d, J = 1.8 Hz , IH) .8.50 (s.1H), 7. <On.1H) .7.56 (dd, J = 7.9.4.9 Hz.111), 7.Ί5 (d, J = 7.1 Hz, 2H), 7.40 (t, J = 7.1 Hz, 2H), 7.34 (t.J = 7.1 Hz. IH) .5.20 (s, 2H), .57 (s, 2H)

IR (Br) 3380,〗 720. 1660.1600, 1510 cm— ¹

Reference example 4

 Synthesis of (5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-topyrimidinyl) acetic acid

 (1) Hydrogen chloride was blown into a solution of benzonitrile (60.0 g, 0.582 inol) in ethanol (500 mi) under ice-cooling with hydrogen chloride, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with ether and dried under vacuum to obtain 73.6 g (68%) of ethylbenzimidate hydrochloride as colorless crystals.

(2) To a solution of the target compound (72.0 g, ϋ.388 mol) in step (L) in ethanol (300 ml) was added dropwise aminoacetoaldehyde dejtylacetal (68 ml, 0.47 mol) under ice-cooling. Thereafter, the mixture was stirred for 18 hours at 4 hours. Ethanol was distilled off under reduced pressure, and the obtained concentrate was added to an aqueous solution of sodium hydroxide IN (800 ml), and the oil was distilled off using a chloroform form. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. -Jetoxetil) 141.2 g of a colorless transparent oil containing benzamidine was obtained.

 (3) To a solution of the desired compound (about half the amount of the crude product obtained in the above reaction, 70.6 g) of ethanol (10 ml (3 ml)) as described in I (2) under ice-cooling, getyl ethoxymethylene malonate ( ! 38 m and 0.29 fnol) was added dropwise, and the mixture was heated to 100 and stirred for 2 hours. The solvent was distilled off under reduced pressure, and the obtained concentrated solution was added to a saturated aqueous solution of ammonium chloride (fiOO ml). The extract was washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue obtained by concentrating the extract was subjected to silica gel column chromatography (50:50 hexane-acetic acid). And 58.2 g of ethyl 1- (2,2-jetoxetyl) -2-phenylpyrimidine-6 (1H) -one-5-carboxylate as a pale yellow oil was obtained. .

 (3) To a solution of the desired compound (57.7 g, 0.160 mol) in step (3) in tetrahydrofuran (THF) (500 ml) was added a 0.5N aqueous sodium hydroxide solution (360 ml), and the mixture was stirred at room temperature for 1 hour. After the reaction solution was washed with chloroform, IN hydrochloric acid (200 ml) was added to the aqueous layer, and the oil was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow oil containing 1- (2,2-jetoxetyl) -2-phenylpyrimidine-6 (111) -one-5-carboxylic acid. 39 g were obtained.

(5) A solution of diphenylphosphoryl azide (27.5 ml, 0.123 tnol) in 1.4-dioxane (100 ml) was heated to 110 ° C, and the mixture was stirred and the target compound of step (4) (obtained by the above reaction) was added. Of the crude product, 3fi.9 g) and triethylamine (34.0 ml, 0.244 mol). A dioxane (300 ml) solution was added dropwise over 1.5 hours. After stirring for 1 hour under reflux with heating, benzyl alcohol (25 ml, 0.24 mol) was added, and the mixture was further stirred for 14 hours under reflux with heating. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the obtained oil was added to a saturated aqueous solution of ammonium chloride (500 ml) and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium hydroxide (600 ml) and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the extract was separated and purified by silica gel gel chromatography (50:50 hexane-ethyl acetate), and the residue was purified using (5-benzyloxycarbonylamino-6-oxo). -2-Phenyl-1,6-diethyl 24.7 g of a mixture of pyrimidinyl) acetoaldehyde decyl acetal and benzyl alcohol was obtained as a light brown oil.

 (6) A mixed solution of the target compound of step (5) (mixture with benzyl alcohol, 24.3 g, 47.1 mmol) in THF (210 ml) and IN hydrochloric acid (150 ml) was heated to 60 ° C and left for 18 hours Stirred. The THF was distilled off under reduced pressure, and the concentrated solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution (PH 7), and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give (5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl). ) 22.4 g of a light brown oil containing acetoaldehyde was obtained.

(7) The target compound of step (6) (crude product obtained in the above reaction, 22.4 g), 2-methyl-2-propanol (300 ml) and 2-methyl-2-butene (50 ml, 0.47 g) mol), a solution of sodium dihydrogen phosphate dihydrate (51.4 g, 0.329 mol) and sodium chlorite (containing 85! ¾, 36.6 g, 0.344 mol) in water (130 ml) was added to the mixture at room temperature. Stir for 3 hours. The organic solvent was distilled off under reduced pressure, and 3N hydrochloric acid was added to adjust the pH to 3, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crystals. The crystals were washed with hexane-ether (1: 1) and dried under vacuum to give 16.0 _{g of the} title compound as colorless crystals.

mp 179-183 ⁿ C

iH-NMR (200MHz, DMSO-d ₆ ) S 13.1 (brs, 1H), 8.99 (s, 1H), 8.47 (s, 1H), 7.2-7.6 (m, 10II), 5.19 (s, 211), 4.51 (s, 2H)

IR (KBr) 3600-2200, 1720, 1655, 1605, 1510 cm— ¹

Reference example 5

 Synthesis of L5-benzyloxycarbonylamino-6-oxo-2- (4-methylphenyl) -1,6-dihydro-1-pyrimidinyl] acetic acid

(1) Ethyl 4-methylbenzimidyl hydrochloride was synthesized in the same manner as in Reference Example 1. That is, P-tolutritril (25.6 g, 0.219 mol) is treated with hydrogen chloride in an ethanol (250 ml) solution, and the target compound is converted to colorless crystals as 42.3 g (97%). Obtained.

 (2) Synthesis of N- (2,2-diethoxyshetyl) -4-methylbenzamidine was performed in the same manner as in Reference Example 1. That is, the target compound (25.0 g, 0.125 mol) of the step (1) is reacted with aminoacetoaldehyde dodecyl acetal (21 ml. 0.14 mol) in a solution of ethanol U00 ml) to contain the target compound. 40.ϋ s of a clear, colorless oil was obtained.

(3) Ethyl (2.2-jetoxetyl) -2- (4-methylphenyl) pyrimidine-6 (1H) -one-5-carboxylate was synthesized in the same manner as in Reference Example 1. That is, the target compound of the step (2) (the crude product obtained in the above reaction) is reacted with getylethoxymethylenemalonone (28 ml, 0-14 mol) in a solution of ethanol (50 ml), the desired compound as a pale yellow oil was obtained 36. I _g.

 (4) The synthesis of 1- (2,2-diethoxyshetyl) -2- (4-methylphenyl) brimidine-6 (111) -one-5-carboxylic acid was performed in the same manner as in Reference Example 3. That is, the target compound (35.0 g, 93.5 mmol) in the step (3) was reacted with lithium iodide (30.0 g, 244 irnnol) in a pyridine (140 ml) solution to obtain 24.0 g of the target compound as pale brown crystals. (745 obtained.

 (5) [5-benzyloxycarbonylamino-6-oxo-2- (4-methylphenyl)-]. 6-dihydropyrimidinyl] acetaldehyde Dodecyl acetal is a reference example. Performed in the same manner as i. That is, the target compound (23.0 g. 66.4 mmol) of the step (4) was dissolved in 1,4-dioxane (200 ml) in the presence of triethylamine (18.5 m and 133 mmol 1) in the presence of difuninyl phosphoryl azide (16.5 ml, 79.8 mmol) and further reacted with benzyl alcohol (10 ml. 97 mmol) to obtain 29.8 g (86%) of a mixture of the target compound and benzyl alcohol as a colorless solid.

(6) The synthesis of [5-benzyloxycarbonylamino-6-oxo-2- (4-methylphenyl) -1.6-dihydro-]-pyrimidinyl] acetaldehyde was the same as in Reference Example 1. The method was performed. That is, the target compound (mixture with benzyl alcohol, 29.1 g, 55.mol) in step (5) was treated with hydrochloric acid (150 ml) in THF (200 ml), and the mixture containing the target compound was obtained. 25.3 _{g were} obtained as a colorless solid. (7) [5-benzyloxycarbonylamino-6-oxo-2- (4-methylphenyl) -1,6-dihydro-1-pyrimidinyl] acetic acid was synthesized in the same manner as in Reference Example 1. went. That is, the target compound of the step (6) (the crude product obtained in the above reaction, 25.3 g) was mixed with 2-methyl-2-propanol (350 ml) and water (150 ml) in a mixed solvent of 2-methyl-2 -In the presence of butene (60tnl, 0.57 mol) and sodium dihydrogen phosphate dihydrate (61.0 g, 0.391 mol), sodium chlorite (85% content, 43 g, 0.408 mol) ) To give 17.5 g of the title compound as colorless crystals.

nip 251-254 ° C

lll-NMR (500 MHz, DMS0-d ₆ ) δ 13.27 (brs, 1H), 8.95 (s, 1H). 8.45 (s, 1H), 7.44 (d, J = 7.4 Hz, 2H), 7.37-7.42 (m , 411), 7.31-7.35 (m, 3H),

5.19 (s, 2H), 4.52 (s, 211), 2.38 (s, 3H)

IR (KBr) 3600-2300, 1735, 1715, 1660, 1605, 1525 cm— ¹

Reference example 6

 [Synthesis of [5-benzyloxycarbonylamino-6-oxo-2- (4-pyridyl) -1,6-dihydroxy-1-pyrimidinyl monoacetic acid]

 (1) To a solution of 4-cyanopyridine (23.9 g, 0.230 mol) in methanol (200 ml) was added a methanol solution of sodium methoxide (5.0 M, 5.0 ml. 25 mraol). The mixture was stirred at room temperature for 7 hours. After acetic acid (1.5 ml, 26 minol) was added to stop the reaction, aminoacetoaldehyde decyl acetal (38 ml, 0.26 mol) was added under ice cooling, followed by stirring at room temperature for 14 hours. The methanol was distilled off under reduced pressure, and the obtained concentrate was added to a 0.5N aqueous sodium hydroxide solution (500 ml) and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 80.6 g of a colorless solid containing N- (2,2 diethylquinethyl) -4-viridinecarboxamidine;

(2) Ethyl (2,2-dietoquinethyl) -2- (4 pyridyl) -pyrimidin-6 (1H) -one-5-carboxylate was synthesized in the same manner as in Reference Example 1. That is, the target compound of step (1) (the crude product obtained in the above reaction, 80.6 g) was mixed with getyl ethoxyquinmethylene malonate (52 ml, 0.26 mol) in a solution of ethanol (100 ml). The reaction was performed to obtain 54.9 g of the desired compound as colorless crystals.

 (3) Synthesis of 1- (2,2-ethoxyxethyl) -2- (4-pyridyl) -pyrimidine-6 UH) -one-5-carboxylic acid was performed in the same manner as in Reference Example 3. . That is, the target compound (56.7 g, 179 mmol) of the step (2) was reacted with lithium iodide (57.5 g, 430 mmol) in a pyridine (220 ml) solution to obtain 32.1 g of the target compound as pale reddish brown crystals. (54%).

 (4) Synthesis of [5-benzyloxycarbonylamino-6-oxo-2- (4-pyridyl) -6-dihydro-1-pyrimidinyl] acetaldehyde dodecyl acetal is referred to in Reference Example 1. Was performed in the same manner as described above. That is, the target compound (3.8 g, 92.4 mmol) of the step (3) was dissolved in diphenylphosphoryl azide (26 ml, 0.19 mol) in 1,4-dioxane (230 ml) in the presence of triethylamine (26 ml, 0.19 mol). The resulting compound was reacted with benzyl alcohol (U ml, 0.14 mol) to obtain 28.4 g (70 mg) of the target compound as colorless crystals.

(5) [5-benzyloxycarbonylamino-6-oxo-2- (4-pyridyl) -1.6-dihydro-1-pyrimidinyl] acetoaldehyde was synthesized in the same manner as in Reference Example i. I went. That is, the target compound (27.7 g, 63.2 related) in the step (4) was treated with 1N hydrochloric acid (180 ml) in a THF (250 ml) solution to obtain 24.7 _{g of} a colorless solid containing the desired compound.

(β) [5-Benzyloxycarbonylamino-6-oxo-2-pyridyl) -1,6-dihydro □ -1-pyrimidinyl] acetic acid was synthesized in the same manner as in Reference Example 1. Was. That is, the target compound of the step (5) (crude product obtained in the above reaction. 24.7 g) was treated with 2-methyl-2-propanol (400 ml) and water (170 ml) in a mixed solvent of 2-methyl- In the presence of 2-butene (67 ml, 0.63 mol) and sodium dihydrogen phosphate dihydrate (69.0 g, 442 mmol), sodium chlorite (containing 85¾; 49.1 g, 461 mmol) to give 21.7 _{g of the} title compound as yellow crystals.

mp 216-219 ° C

 iH-NMR (500 MHz, dg) δ 13.3 (brs, 1H), 9.09 (s.1H), 8.76 (d.

J = 6.0 Hz.2H), 8.50 (s, 1H), 7.51 (d.J-6.0 Hz, 2H), 7.45 (d, J = 7.1 Hz. 2H), 7.40 (t, J = 7.1 \, 2H) .7.34 (t, J = 7.) Hz, 1H), 5.20 (s. 2H) .4.55 (s. 211)

 1R (KBr) 3370, 3260. 1725. 1665. 1595, 1525 cm

Reference Example 7

 [Γ) -Synthesis of benzyloxycarbonyl-2-amino-4- (4-methoxyfujyl) -6-oxo-1,6-dihydropyrimidinyl] acetic acid

 ()) The synthesis of ethyl methoxybenzimid hydrochloride was performed in the same manner as in Reference Example 1. That is, anisonitrile (25.6 g. 0.199 mol) was treated with hydrogen chloride in an ethanol (250 ml) solution to obtain 40. ") g (ί) 4) of the target compound as pale red crystals.

 (2) Ν- (2,2-Jetoxyshetyl) -4-methoxybenzamidine was synthesized in the same manner as in Reference Example ί. That is, the target compound of step (1) (38.8 g, 0.180 mol) is reacted with aminoacetoaldehyde decyl acetal (29 ml, 0.20 mol) in an ethanol (130 ml) solution to give a colorless and transparent mixture containing the target compound. 60.2 g of oil was obtained.

(3) Ethyl (2.2-jetoxyl) -2- (4-methoxyphenyl) pyrimidin-6 (1H) -one-5-carboxylate was synthesized in the same manner as in Reference Example II. . That is, the target compound of the step (2) (the crude product obtained by the above reaction; 60.2 g) was dissolved in ethanol (70 ml) solution to obtain a mixture of dimethyl ether, methylene chloride (M 0.5 m) and 0.20 mol ) To give 33.6 _{g of} the target compound as a pale yellow oil.

 (4)]-(2.2-Methoxyxyl) -2- (4-methoxyphenyl) pyrimidine-6 (1H) -one-5-carboxylic acid was synthesized in the same manner as in Reference Example 3. That is, the process

The target compound (33.0 g. 84.5 mmol) of (3) was reacted with lithium iodide (27.1 g, 202 mmol) in a solution of pyridine (120 ml) to give the target compound as colorless crystals. %)Obtained.

(5) [5-benzyloxycarbonylamino-2- (4-methoxyquinphenyl) -6-oxo-1,6-dihydropyrimidinyl] acetaldehyde Synthesis Was performed in the same manner as in Reference Example I. That is, the target compound (24.6 g, 67.9 mmol) in the step (4) was dissolved in 1,4-dioxane (2 () 0 ml) solution in the presence of triethylamine (Iil ml, 0.14 mol) in the presence of diphenylphosphorylazide. (16.8 mi, 74.9 mmol) and further reacted with benzyl alcohol (9.1 ml, 88 mmo!) To obtain 18.8 g (59%) of the target compound as colorless crystals.

 (6) [5-Benzyloxycarbonylamino-2- (4-methoxyphenyl) -6-oxo-], dihydropyrimidinyl] acetoaldehyde was synthesized in the same manner as in Reference Example 1. I went in. That is, the target compound (I8. Ig., 38.7 mmon) in step (5) was treated with 1N hydrochloric acid (100 ml) in a THF (130 ml) solution to obtain 16.5 of a mixture containing the target compound as a colorless solid.

 (7) The synthesis of [5-benzyloxycarbonylamino-2- (4-methoxyphenyl) -6-oxo-1,6-dihydro-1-pyrimidinyl] acetic acid was the same as in Reference Example 1. Made by the way. That is, the target compound of step (6) (crude product obtained in the above reaction, 16.5 g) was mixed with 2-methyl-2-propanol (240 ml) and water (] 00 ml) in a mixed solvent of 2-methyl In the presence of 2-butene (4i ml, 0.39 mol) and sodium dihydrogen phosphate dihydrate (4] g. 283 mmol), sodium chlorite (85% content, 28.8 g, 271 mmol) to give 4.4 g of the title compound as colorless crystals.

m 195-200 ° C

iH-NMR (500 MHz, D S0-d ₆ ) δ 13.2 (brs, 1H). 8.93 (s, 1H), 8.U (s,] 11), 7.47-7.42 (m, 4H), 7.39 J = 7.1 II z, 2H) .7.34 (t, J = 7.1 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 5.19 (s.2H) .4.5 (s, 2H), 3.82 (s, 3H)

IR (KBr) 3300.1725, 1660.1600 cm- ¹

Reference Example 8

 Synthesis of [5-benzyloxycarbonylamino-2- (4-chlorophenyl) -6-oxo-1,6-dihydropyrimidinyl] acetic acid

(1) Synthesis of ethyl 4-chlorobenzimide hydrochloride is the same as in Reference Example 1. Was performed in the manner described above. That is, benzonitrile (25.6 g, 0.18 mol) was treated with hydrogen chloride in a solution of ethanol (250 ml) to obtain 36.8 g (90%) of the target compound as colorless crystals.

 (2) | -Curoguchi-N- (2,2-jetoxyl) Benzamidine was synthesized in the same manner as in Reference Example 1. That is, the target compound (35.6 g. 0.162 mol) of the step (1) is reacted with aminoacetoaldehyde dodecyl acetal (26 ml, 0.18 tnol) in a solution of ethanol (120 ml) to obtain a compound containing the target compound. 43 g of a yellow oil were obtained.

 () Ethyl 2- (4-α-α-phenyl) -1- (2,2-jetoxyl) pyrimidine-6 (1Η) -one-5-carboxylate was synthesized in the same manner as in Reference Example 1. Was. That is, the target compound (48.3 g of the crude cow obtained in the above reaction, 48.3 g) obtained in the step (2) was dissolved in a solution of ethanol (70 ml) in dimethyl ether (70 ml). 0.18 mol) to obtain 46.3 g of the desired compound as a pale yellow oil.

 () 2- (4-cyclohexyl) -toluene (2,2-jetoxethyl) pyrimidine-6 (1H) -one-5-carboxylic acid was synthesized in the same manner as in Reference Example 3. Was. That is, the target compound (45.7 g, 116 mmol) in the step (3) was reacted with lithium iodide (37.2 g. 278 mmol) in a pyridine (165 ml) solution to obtain 33.0 g of the target compound as pale brown crystals.

(78%).

 (5) The synthesis of [5-benzyloxycarbonylamino-2- (4-chlorophenyl) -6-oxo-], 6-dihydropyrimidinyl] acetaldehyde aldehyde docetyl acetal The procedure was performed in the same manner as in Reference Example 1. That is, the target compound (32.2 g. 87.8 mmol) of the step (4) was dissolved in 1,4-dioxane (260 ml) solution in the presence of triethylamine (24.5 id, 176 mmol) in the presence of diphenylphosphoryl azide (21.5 ml, 95.9 mmol) and further reacted with benzyl alcohol (12 ml, 0.16 mol) to obtain 39.3 g (85%) of a mixture of the target compound and benzyl alcohol as a colorless solid.

(6) The synthesis of [5-benzyloxycarbonylamino-2- (4-chlorophenyl) -6-oxo-1,6-dihydro-1-pyrimidinyl] acetaldehyde The procedure was the same as in Reference Example 1. That is, the target compound of step (5) (mixture with benzyl alcohol, 3 ^W ° ^99/32459 PC so-called 麵 86

8.7 g (73. ol) was treated with IN hydrochloric acid (190 ml) in a THF (250 ml) solution to obtain 36.8 _g of a mixture containing the target compound as a colorless solid.

 (7) The synthesis of [5-benzyloxycarbonylamino-2- (4-chlorophenyl) -6-oxo-1,6-dihydro-]-pyrimidinyl] acetic acid was the same as in Reference Example i. Made by the way. That is, the target compound of Step (6) (crude product obtained in the above reaction; 36.8 g) was added to a mixed solvent of 2-methyl-2-butanol (460 ml) and water (190 ml), In the presence of methyl-2-butene (78 m !, 0.74 mol) and sodium dihydrogen phosphate dihydrate (34.2 g, 540 mmol), sodium chlorite (containing 80¾; 58.5 g) , 517) to give 26.6 g of the title compound as colorless crystals.

mp 220-224 ° C

iH-NMR (500 MHz.DMSO-d ^) δ 13.29 (brs, HI), 9.01 (s, 111), 8.47 (s, 1H), 7.60 (d, J = 8.5 Hz.2H), 7.53 (d, J-8.5 Hz, 2H), 7.44 (d.J-7.1 Hz, 2H). 7.39 (t, J = 7.1 Hz, 2H), 7.34 (t, J = 7.1 Hz, 1H),

5.19 (s, 2H), 4.53 (s, 2H)

1R (KBr) 3320, 1725, 1665, 1610, 1515 cm- ¹

Reference Example 9

 Synthesis of [5-benzyloxycarbonylamido J-I- (4-nitrophenyl) -6-oxo-1,6-dihydroα-1-pyrimidinyl] acetic acid

 (1) Synthesis of ethyl 4-hydroxybenzoic acid hydrochloride was performed in the same manner as in Reference Example 1. That is, 4-benzotribenzoyl (26.5 g, 0.179 mol) was treated with hydrogen chloride in an ethanol (250 ml) solution to give the target compound as colorless crystals: --7 g (86 mg).

 (2) Synthesis of N- (2,2-jetoxetyl) -4-nitrobenzamidine was performed in the same manner as in Reference Example 1. That is, the target compound (34.7 g, 0.150 mol) of the step (Π) is reacted with aminoacetoaldehyde decyl acetal (24 ml, 0.17 mol) in a solution of ethanol (120 ml) in a solution of ethanol (120 ml) to obtain a pale yellow color containing the target compound 42.4 g of a solid was obtained.

(3) Ethyl 1- (2,2-jetoxyl) -2- (4-nitrophenyl) pyrimidine- 6 (1H) -one-5-carboxylate was synthesized in the same manner as in Reference Example I. That is, the target compound of step (2) (the crude product obtained in the above reaction, 42.4 g) was added to ethylethoxymethylene malonate (34 ml, 0.17 mol) in a solution of ethanol (65 ml). The reaction was carried out to obtain 49.0 g of the desired compound as pale yellow crystals.

 (4) Synthesis of 1- (2,2- ethoxyxyl) -2- (4-nitrophenyl) pyrimidine-6-on-5-carboxylic acid was performed in the same manner as in Reference Example 3. That is, the target compound of the step (3) (41 g. 0.119 mol) was reacted with iridium iodide (38.1 g, 0.285 mol) in a pyridine (160 ml) solution to obtain 26.7 g of the target compound as colorless crystals. (59 ¾) obtained.

 (5) [5-benzyloxycarbonylamino-2- (4-nitrophenyl) -fi-oxo-1,

6-Dihydropyrimidinyl] acetaldehyde dodecyl acetal was synthesized in the same manner as in Reference Example 1. That is, the target compound (22 g, B9.4 ol) of the step (4) was dissolved in 1,4-dioxane (220 ml) solution in the presence of triethylamine (19 ml, 0.14 mol) in the presence of diphenylphosphoryl. It was reacted with azide (17, 9 ml. 79.8 mmol) and further reacted with benzyl alcohol (10.5 ml. 0.101 mol) to obtain 24.5 g (73%) of the target compound as pale yellow crystals.

 (6) [5-benzyloxycarbonylamino-2- (4-nitrophenyl) -6-oxo-1

6-Dihydropyrimidinyl] acetaldehyde was synthesized in the same manner as in Reference Example i. That is, the target compound (24.0 g, 49.7 ol) in Step (5) was treated with 1N hydrochloric acid (40 ml) in a THF (] 85 ml) solution to give 20.4 g (100 mg) of the target compound as pale yellow crystals. Obtained.

(7) [5-benzyloxycarbonylamino-2- (4-nitrophenyl) -6-oxo-16-dihydro-1-pyrimidinyl] acetic acid was synthesized in the same manner as in Reference Example 1. I went in. That is, the target compound (20.2 g. 49.5 mmol) of the step (6) was mixed with 2-methyl-2-butene (52) in a mixed solvent of 2-methyl-2-propanol (: Π0 ml) and water (130 ml). ml, 0.49 mol) and sodium dihydrogen phosphate (56.4 g. 362 mmol) in the presence of sodium chlorite (containing 85¾, 36.9 g, 347 mmol) to give the title compound. 20.3 g (97%) were obtained as colorless crystals.

mp 240- 243 ° ji

lli-NMR (500 MHz, DMS0-d ₆ ) δ 13.3 (brs, 1Η), 9.10 (s, 1H), 8.51 (s, 1H), 8.37 (d, J = 8.8 Hz, 2H), 7.79 (d, J-8.8 Hz, 2H), 7.45 (d, J-7.1 Hz, 2H), 7.40 (t, J = 7.1 Hz, 2H), 7.34 (t, J = 7.1 Hz, 1H), 5.20 (s , 2H) .4.53 (s, 2H)

 I (KBr) 3650-2800, 1720, 1670, 1610, 1530, 1505 cm-l

 The following compounds were synthesized in the same manner as in Reference Example 1.

Reference example 10

 “5-benzyloxycarbonylamino-2- (3-fluorophenyl) -1,6-dihydro-6-oxo-pyrimidinyl] acetic acid

White crystals

 mp 194-196 ° C

lil NMR (300MHz, DMSO-d ^) <5 9.06 (s, 1H), 8.48 (s, III), 7.59 (dt, J-5.9, 8.0Hz, III), 7.47-7.31 (m, 810, 5.20 (s, 211), 4.54 (s, 2H) IR (KBr) 3700-2200, 1725, 1660, 1605, 1585, 1520 cm- ¹

Reference example 1 1

 [5-benzyloxycarbonylamino-2- (3-chlorophenyl) 1,6-dihydro-6-oxo-1-pyrimidinyl] acetic acid

White crystals

 mp 193-195. C

 lH NMR (300MHz, DMSO-) δ 9.07 (s, III), 8.48 (s, 1H), 7.66-7.53 (m, 3H), 7.49-7.31 (m, 611), 5.20 (s, 2H), 4.53 ( s, 2H)

IR (KBr) 3600-2200, 1725, 1660, 1605, 1520 cm— ¹

Reference example 1 2

[5-Benzyloxycarbonylamino-1,6-dihydro-2 (3-methoxyphenyl) -6-oxo-1-pyrimidinyl] acetic acid White crystals

 tnp 227-230 ° C

iH NMR (300MHz, DMSO-d ₆ ) ό 9.02 (s, III), 8.46 (s, III), 7.48-7.31 (m, 6H), 7.15-7.02 (m, 3H), 5.20 (s, 2H), 4.51 (s, 2H), 3.78 (s, 3 II)

IR (KBr) 3600-2200, 1735, 1720, 1655, 1605, 1580, 1525 cm— ¹ Reference example 1 3

 [5-benzyloxycarbonylamino-1,6-dihydro-2- (3-nitrophenyl) -6-oxo-1-pyrimidinyl] acetic acid

White crystals

 mp 245-253. C

III NMR (300 MHz, DMSO-d ₆ δ 9.11 (s, 1H), 8.52 (s, IH), 8.43-8.35 (m, 211), 7.96 (d, J—8.0 Hz, IH), 7.83 (ΐ , J-8.0Hz, IH), 7.48-7.31 (m, 5H), 5.21 (s, 2H), 4.56 (s, 2H)

IR (KBr) 3420, 3300, 3070, 1730, 1665, 1610, 1515 cm ^-1

Reference example 1 4

 Synthesis of 2- [4 (S) -amino-2,2-difluoro-3-hydroxy-5-phenylpentanoylamino] acetic acid tert-butyl hydrochloride

 (1) To a suspension of fenaralaninol (152.7 g, 1.01 mol) in THF (1200 ml) was added sodium hydrogen carbonate (161.5 g, 1.52 mol), and the mixture was added with water. After cooling to C, a THF solution of benzil formate (153 ml, 1.07 mmol) was added dropwise over 1 hour, and the mixture was stirred at room temperature for 3 hours. Water (11) and 6 M hydrochloric acid (500 ml) were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated saline (500 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give 247.3 g (86 mg) of N-benzyloxycarbonyl-diphenylaraninol as white needles.

(2) Triturate the above compound (25.0 g, 87.6 mmol) in dichloromethane solution (220 ml). Ethylamine (48.9 ml) was added and cooled to -10. To this mixture was added a solution of sulfur trioxide-pyridine complex (41.0 g, 258 ol) in DMSO (220 ml), and the mixture was reacted for 2 hours. The reaction mixture was poured into a saturated aqueous sodium chloride solution (1000 ml) and extracted with getyl ether (200 ml × 5). The ether layer was washed with 1M hydrochloric acid (100 ml x 3) and saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated to give N-benzyloxycarbonyl-diphenylalanil. 24.8 g (quant.) Was obtained as a yellow solid.

 (3) The above compound was added to a suspension of zinc dust (17.2 g, 263 mmol) and copper acetate monohydrate (1.70 g, 8.51 dragonol) in TIIF (250 ml) under a nitrogen atmosphere by ultrasonic irradiation. (24.8 g, 87.6 mmol) and a solution of ethyl bromodifluoroacetate (34.0 ml, 265 mmol) in THF (250 ml) were added dropwise over 10 minutes. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a 1M aqueous solution of potassium hydrogen sulfate (500 ml) and ethyl acetate (1 mixture). After separating the ethyl acetate layer, the aqueous layer was washed with ethyl acetate (200 ml x 5). The combined ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (80:20, hexane-ethyl acetate). 25.6 g (72%) of 4 (S) -L (benzyloquincarbonyl) amino ェ -2,2-difluoro-3-hydroxy-5-phenylpentanoate as a pale yellow solid was obtained.

 (4) An aqueous solution (150 ml) of potassium carbonate (13.8 g) was added to a solution of the above compound (10.2 g, 25.0 ol) in THF (100 ml) and methanol (150 ml), and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, water (100 ml) was added to the residue, and getyl ether (100 ml x

Extracted in 3). The aqueous layer was adjusted to pH 3 by adding 6M hydrochloric acid, and extracted with ethyl acetate (100 ml × 4). The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (100 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-hexane to give 4 (S)-[( Benzyloxycarbonyl) amino] -2,2-difluoro 3-hydroxy-5-phenylpentanoic acid was obtained as a pale yellow powder in 8 · 21 g (86%),

(5) The above compound (8.19 g, 21.6 mmol), glycine tert-butyl ester hydrochloride N-ethylmorpholine (3.0 ml) and WSCI hydrochloride were added to the MF solution of the salt and IIOBT-hydrate, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water (300 ml), extracted with ethyl acetate (400 ml x 3), and the combined organic layers were combined with a 10% aqueous solution of citric acid (300 ml). The extract was washed with an aqueous solution of sodium chloride (300 ml) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was crystallized from ethyl acetate-hexane to give 2- [4 (S)-[(benzyloxycarbonyl) amino 2,2-difluoro-3-hydroxy-5- [Phenylpentanoylamino] tert-butyl acetate (8.39 g, 79 mg) was obtained as a pale yellow powder ₍ :

(6) The above compound (8.15 g, 16.6隨ol) methanol (110 ml) nitrogen Kiri囲gas under the solution, 101¾ palladium on carbon (1.64 ₈₎ and 1¾1 under a hydrogen atmosphere by adding hydrochloric acid (16.9 ml),

Stir for 3 hours. The catalyst was removed by filtration, and the catalyst was washed with methanol (50 ml × 7). The filtrate and the washings were combined and concentrated under reduced pressure to obtain 6.21 g (95%) of the title compound as a white solid. This compound was used as is in the next reaction.

Reference example 1 5

 N-!. 2- [4 (S) -Amino-2,2-difluoro-3-hydroxy-5-phenylpentanoylamino] acetyl I Synthesis of getylamine

 (1) Using 2- (tert-butoxycarbonyl) aminoacetic acid and getylamine, [2- (tert-butoxycarbonyl) aminoacetyl] getylamine was obtained as a white powder by the same reaction as in Reference Example 14- (5). g (30¾).

 () The above compound (3.92 g) was dissolved in 4MHC1 / dioxane and stirred at room temperature for 2 hours. Dioxane was distilled off under reduced pressure, and the obtained residue was obtained from getyl ether-hexane as a powder, to obtain 2.73 g (96 2.7) of (2-aminoacetyl) getylamine as a white solid.

C 3) To a solution of the compound obtained in Reference Example 14- (3) (21.3 g, 52.3 mmol) in TIIF (00 ml) was added a 1M aqueous solution of sodium hydroxide (52.3 ml), and the mixture was stirred overnight. . TIIF was distilled off under reduced pressure, water (200 ml) was added to the obtained residue, and the mixture was washed with ethyl acetate (200 ml) and getyl ether (200 ml). After concentrating the aqueous layer under reduced pressure to 100 ml, water (300 ml) And freeze-dried, and sodium 2- (2-difluoro-3-)-σ-sigma-5-phenylenesulfonate as a white powder is added to 4 (S)-[(benzyloxycarbonyl) amino. 19.5 g (93¾) was obtained.

 (4) Using the compound obtained in (2) and the compound obtained in (3) in the same reaction as in Reference Example 14- (5), [2- [4 (S)-[(benzyloxycarbonyl) ) Amino] -2,2-Difluoro-3-hydroxy-5-phenylpentanoirileamino acetyl J Jethylamine was obtained as a white solid (2.02 g, 42%).

 (5) By the same reaction as in Reference Example 14- (6) using the above compound, 1.18 g (97%) of the title compound was obtained as a white solid.

 1H NMR (300MHZ, DMSO-) δ 9.02 (br, 1H), 8.18 (br, 311), 7.37-7.19 (m, 511), 6.78 (d, J = 6.1Hz, 2H), 4.15 -3.80 (m, 4H), 3.42-2.85 (m, 6H), 1.17-1.01 (m, 611)

 IR (KBr) 3300, 2900, 1675, 1640 cm "!

The title compound of Reference Example 15 was also synthesized by the following method.

 (1) Suspension of dioxane (100 g, 661 ol) in dioxane UO0O ml) was cooled to 0 :, and di-tert-butyl dicarbonate (159 g, 729 mmol) in dioxane (200 ml) was added. ) The solution was added dropwise, and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the residue was recrystallized from ethyl acetate hexane to obtain 150 g (90! ¾) of N-tert-butoxycarbonyl-L-phenylalanol as white cotton.

 (2) Using the above compound and performing the same reaction as in Reference Example 14- (2), 18.2 g (73%) of N-tert-butoxycarbonyl-phenylanilanal was obtained as a pale yellow solid.

(3) 4 (S) -L (te-butoxycarbonyl) amino] -2,2-difluoro-3-hydroquine-5 by the same reaction as Reference Example 14- (3) using the above compound. -18.4 g (68%) of ethyl phenylpentanoate was obtained as a pale yellow solid.

(4) 4 (S)-[(tert-butoxycarbonyl) amino "-2,2-difluoro-3-hydroxy-5 by the same reaction as in Reference Example 15- (3) using the above compound. -18.0 g (99%) of sodium phenylpentanoate was obtained as a white solid. (5) L2- [4 (S)-(tert-butoxycarbonyl) amino] -2,2-difluoro-3-hydroxy-L- [4 (S)-(tert-butoxycarbonyl) amino] by the same reaction as in Reference Example 15- (4) using the above compound 5-Phenylpentanoylamino] acetyl ”8.56 g (85 mg) of getylamine was obtained as a pale yellow powder.

 (6) By the same reaction as in Reference Example 15- (2) using the above compound, 5.46 g (79%) of the title compound was obtained as a white solid.

Reference Example 1 6

 Synthesis of N- [3- [4 (S) -amino-2,2-difluoro-3-hydroxy-5-phenylpentanoylamino] propionyl] getylamine

 (1) Using [3- (benzyloxycarbonylamino) propionic acid and getylamine, in the same reaction as in Reference Example 14- (5), [3- (benzyloxycarbonylamino) propionyl] getylamine Was obtained as a pale yellow oil (2.49 g, 96%).

 (2) Using the above compound and performing the same reaction as in Reference Example 14- (6), 1.57 g (97%) of (3-aminopropionyl) getylamine was obtained as a white solid. .

 (3) Using the above compound and the compound (605 mg) obtained in Reference Example 14- (4), a reaction similar to that of Reference Example 14- (5) was performed to obtain [3-i4 (S) _ [(benzyl 529 mg (665) of (oxycarbonyl) amino] -2,2-difluoro-3-hydroquin-5-phenylpentanoylaminopropionyl] getylamine as a white solid.

 (4) Using the above compound, a reaction similar to that of Reference Example 14- (6) was carried out to give 3- [4 (S) -amino-2,2-difluoro-3-hydroxy-5-phenylpentane. [Nylamino] propionyl 1 getylamine was obtained as a white oil (407 mg, quant.) This compound was used as such in the next reaction.

Example 1

 2- [5-benzyloquincarbonylamino-2- (4-fluorophenyl) -1,6-dihydrido-6-oxo-1-pyrimidinyl] -N- [1-benzyl-3,3 -Gifolo- 2-oxo-

Synthesis of 3- [N-[(N-Ethylcarbamoyl) methyl] dirubamoyl] propyl "acetamide (1) HOBT-hydrate (2.24 g, 14.6 mmo 1) was added to a solution of the title compound of Reference Example 1 (2.32 g, 5.85 mmol) and the title compound of Reference Example 14 (2.20 g 5.57 mmol) in DMF (30 ml). And WSCI hydrochloride (1.40 g, 7.31 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Water (150 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml × 4). The extract was washed successively with 10% citric acid (50 ml × 3), a saturated aqueous sodium hydrogen carbonate solution (50 ml × 3) and a saturated saline solution (50 ml), dried over magnesium sulfate, and then dried under reduced pressure. It was concentrated. The obtained residue was purified by silica gel column chromatography (3: 2, porcine monoethyl acetate) to give 2- “5-benzyloxycarbonylamino-2- (4-fluoroporous). Phenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl! -N- [1-benzyl-3,3-difluoro-2--2-hydroxy-3- [N- (tert-butoxy 3.74 g (91%) of carbonylmethyl) lubamoyl {propyl] acetamide was obtained as a white solid.

 (2) Dess-Martin periodinaneCl. 70 g, 4.01 ol) was added to a dichloromethane (60 ml) suspension of the above compound (1.74 g, 2.36 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with diethyl ether (100 ml), and a saturated aqueous solution of sodium hydrogen carbonate (50 ml) containing sodium thiosulfate (25 g / 100 ml) was added, and the mixture was stirred at room temperature for 3 hours. Stirred. After separating the organic layer, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed successively with a saturated aqueous solution of sodium hydrogencarbonate (20 ml × 3) and a saturated aqueous solution of sodium chloride (20 ml). After drying over magnesium, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2: 1, chloroform-ethyl acetate) to give 2--benzyloquincarbonylamino-2- (4-fluorophenyl) -1,6-dihydroxyl. Dro-6-oxo-pyrimidinyl-N- [1-benzyl-3,3-difluoro-2-oxo-3- [N- (te rt-butoxycarbonylmethyl) rubamoyl] propyl " 1.61 g (93¾) was obtained as brown morphus.

(3) The above compound (1.50 g, 2.04 mmol) was dissolved in 4M HC1 / dioxane (45 ml) and stirred at room temperature for 18 hours. After concentrating the reaction solution under reduced pressure, the operation of adding getyl ether to the residue and concentrating under reduced pressure was repeated three times. The resulting residue was dried under reduced pressure using a vacuum pump, and the residue was dried with 2- [5-benzyloxycarbonylamino-2 (4-furo-chloro- Phenyl) -1,6-Dihydro-6-oxo-:: L-pyrimidinyl] -N- [tribenzyl-3,3-difluoro-2-oxo-3--3- (carboxymethyl) caprubamoyl] propyl 1.39 g (quant.) Of yellow amide was obtained as yellow amorphous.

(4) To a solution of the above compound (418 mg, 0.615 mmol) in DMF (20 ml) was added ethylamine hydrochloride (100 mg, 1.23 mmol). N-methylmorpholine (0.142 ml, 1.29 mmol), HOBT-hydration objects (236 mg, 1.54 mmol) and WSCI hydrochloride (141 mg, 0.738 mmol) was added, water (100 ml) was added to the _c reaction mixture was stirred for 18 hours at room temperature, extracted with acetic acid Echiru (50 ml X 3) The organic layers were combined, washed sequentially with 1M hydrochloric acid (20 ml x 3), saturated aqueous sodium hydrogen carbonate solution (20 ml x 3) and saturated saline (20 ml x 2), and dried over anhydrous magnesium sulfate. It was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (1: 3, chloroform-ethyl acetate), and the obtained oil was crystallized from chloroform-hexane to give the title compound as a pale yellow color 302 mg (69%) were obtained as a powder.

m 100.0-105.0 ^C C

iH NR (500MHz, DMS0-d 6 + D2 0) <5 8.44 (s, 1H), 7.45-7.16 (m, 14 H), 5.19 (s. 211), 4.43, 4.27 (ABq, J-16.3Uz, 2H), 4.31 (m, 111), 3.75

(s, 2H), 3.13 (dd, J = 2.3, 14.2Hz, 111), 3.06 (q, J-7.0Hz, 2H), 2.61 (dd, J--11.5, 14.2Hz, 1H), 0.98 (t , J = 7.0Hz, 3H)

IR (KBr) 3250, 3050.2900, 1650, 1600, 1520 cnT ¹

 MS (SIMS (RI 'on glycerol) m / z 725, 707

Example 2

 2- [5-amino-2- (4-fluorophenyl) -1, 6-dihydro-6-hexoxo-: l-pyrimidinyl nitrate N- [1-benzyl-3,3- Synthesis of difluoro-2-oxo-3-[[N-((N-ethylcarbamoyl) methyl] dylbamoyl j propyl] acetamide

A mixed solution of the title compound of Example 1 (165 rag, 0.233nunol) in THF (5 ml) and methanol (20 ml) was ice-cooled, and 10% palladium on carbon (33 mg) was added under a nitrogen atmosphere. Stirred at room temperature for 18 hours. After filtering off the catalyst, the residue obtained by concentration under reduced pressure is removed. The title compound was crystallized from chloroform-hexane as a yellow powder (126 mg, 94 mg

%) Obtained.

 m 100.0-103.0 V

Ml NM (500MHz, DMS0-d ₆ D ₂ ° ⁵ 7.31-7.07 (m, 9H), 7.30 (s, III),

4.35, 4.16 (ABq, J = 16.2Hz, 2H), 4.25 (m, 1H), 3.72 (s, 211), 3.12-3.00 (m, 3H), 2.57 (m, 1H), 0.93 ( t.J = 7.31Iz, 3H)

IR (KBr) 3250, 3050, 1750, 1640, 1605, 1540, 1500 cm— ¹

 MS (SIMS (ten), on glycerol) m / z 591, 573

Example 3

 2-"5-benzyloxycarbonylamino-2-(4-fluorophenyl)-1, 6-dihydro-6-oxo-1-pyrimidinyl]-N- [1-benzyl-3, 3- difluoro- 2-oxo-

Synthesis of 3-IN-[(N, N-Jetylcarbamoyl) methyl] carbamoyl, propyl ”acetamide

 To a solution of the compound obtained in Example 1- (3) (418 nig, 0.625 mmol) in DMF (20 ml) was added getylamine (0.127 ml, 1.23 minol), H0BT-hydrate (236 mg, 1.54 mmo 1) And 'SCI hydrochloride (141 rag, 0.738 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Water (100 ml) was added to the reaction mixture, extracted with ethyl acetate (50 ml x 3), and the organic layers were combined. Wash with 1M hydrochloric acid (20 ml x 3), saturated aqueous sodium hydrogen carbonate solution (20 ml x 3), and saturated saline (20 ml x 2), dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. did. The obtained residue was purified by silica gel column chromatography (3: 2, chloroform-formyl acetate), and the obtained oil was crystallized from chloroform-hexane to give the title compound as a pale-yellow powder (330 mg) (73%) obtained.

 mp 90.0-93.0 V

 iH NMR (500MHz, DMSO- + D20) δ 8.41 (s, HI), 7.45-7.15 (m, 14H), 5.19 (s, 211), 4.39 (d, J = 16.3Hz, 111), 4.30, 4.07 (ABq, J = 16.3Hz,

2H), 4.29 (m, III), 3.97 (d, J-16.7Hz, 1H), 3.32-3.24 (m, 411), 3.13 (dd, 2.1, 13.9Hz, 1H), 2.61 (dd, J = ll) .5, 13.9Hz, 1H), 1.11 (t, J = 7. OIIz, 3H), 1.02 (t, J-7.0Hz, 3H)

 IR (KBr) 3250, 3000, 2950, 1650, 1600, 1520 cra-1

 MS (SIMS (ten), on glycerol) m / z 753, 735

Example 4

 2- [5-Amino-2- (4-fluorophenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl] -N-butyl benzyl-3,3-difluoro mouth -2-Oxo-Synthesis of 3- [Ν-[(Ν, Ν-Jetylcarbamoyl) methyl] -lubamoyl] propyl] acetamide

 Using the title compound of Example 3 and reacting in the same manner as in Example 2, 133 mg (94%) of the title compound was obtained as a yellow powder.

 mp 92.5-96.5 "C

 iH NMR (500MHz, DMSO-10) δ 7.31-7.08 (m, 911), 7.28 (s, 1H).

4.31, 4.20 (ABq, J-16.3Hz, 2H), 4.26 (dd, J = 2.8, 11.3Hz, 111), 4.02 (d, J = 16.8IIz, III), 3.93 (d, J: 16.8ilz, 1H ), 3.30-3.20 Cm, 411), 3.08 (dd, J = 2.8, 14.2Hz, 110.2.58 (dd, J-ll.3, 14.2Ilz, III), 1.07 (t, J = 7.1Hz, 3H ), 0.99 (3H, t, J = 7.1Hz)

IR (KBr) 3250, 2950, 1750, 1620, 1600, 1530, 1500 cm— ¹

 MS (SIMS (ten), on glycerol) m / z 619, 601

Example 5

 2- [5-benzyloxycarbonylamino-2- (4-fluorophenyl) -1, 6-dihydrido-6-oxo-tripyrimidinyl] L1-benzyl-3,3- Jifuru 2-b-oxo-

3-CN-C rubamoylmethyl) rivavamoyl ”Provir: Synthesis of Jacetamide To a solution of the compound obtained in Example 1- (3) (455 mg, 0.669romol) in DMF (20 ml) was added ammonium chloride (Π). .7 mg, 1.23 nraol), N-methylmorpholine (0.155 ml, 1.41 orchid ol), ΗϋΒΤ-hydrate (257 mg, 1.67 mmol) and WSCI hydrochloride (154 mg, 0.803 mmol) were added. Stirred at room temperature for 18 hours. Water (100 ml) was added to the reaction mixture, extracted with ethyl acetate (50 ml × 3), and the combined organic layers were combined with 1M hydrochloric acid (20 ml × 3) and a saturated aqueous solution of sodium bicarbonate (20 ml × 3). ) And washed with saturated saline (20 ml x 2) The extract was washed, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was suspended in chloroform-ether and collected by filtration to obtain 216 rag (48%) of the title compound as a white powder.

 mp 119.0-121.0 V

iH NMR (500MHZ, DMS0-d ₆ ID ₂₀ ) δ 8.41 (s, 1H), 7.45-7.14 (m, 14

II), 5.19 (s, 211), 4.41, 4.29 (ABq, J- 16.5Hz 211), .30 (m, III), 3.73 (m, 2H), 3.12 (dd, J = 2.3, 13.9Uz, 1H ), 2.60 (dd, J-ll.6, 13.9Hz 1 il)

I (KBr) 3250, 3050, 1650, 1600, 1520 cm— ¹

 MS (SIMSC +), on glycerol) m / z 697, 679

Example 6

 2-1.5-Amino-2- (4-fluorophenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl] -N- [1-benzyl-3,3-difluoro-2 -Oxo -3- "N- (Rubamoylmethyl) Rubamoyl" Provir]

 By a reaction similar to that of Example 2 using the title compound of Example 5, 89 mg (82%) of the title compound was obtained as a pale yellow powder.

 mp 110.0-113.5 C

_{iH NMR (500MHz, DMSO- d 6} 1 D 2 0) δ 7.31-7.06 (m 911), 7.29 (s, 1H), 4.33, 4.17 (ABq, J-16.4Hz, 2H), 4.24 (dd, J: 2.6, 11.4Hz, 1H), 3.75 (d J = 16.7Hz, 1H), 3.68 (d, J-16.7IIz, 1H), 3.07 (dd, J: 2.6 13.8Ilz,

III), 2.56 (dd, J = ll.4 13.811 z, 1H)

IR (KBr) 3250, 1750, 1650, 1600, 1535, 1500 cm— ¹

 MS (SI SC +), on glycerol) m / z 563, 545

Example Ί

2- [5-benzyloxycarbonylamino-2- (4-fluorophenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl] -N- [1-benzyl-3 , 3-Difluoro-2-oxo-3-[N-[(N, N_dimethylcarbamoyl) methyl] methyllvamoyl] propyl " Synthesis of mid

 In a DMF (1.5 ml) solution of the compound (279 mg, 0.410 iMiol) obtained in Example 3 (3), dimethylamine hydrochloride (36.4 m. 0.446 mraol), N-ethyl morpholine (0.058 ml, 0.456 mmol), I10BT-hydrate (126 mg, 0.823 mmol) and WSCI hydrochloride (86.7 m. 0.452 mmol) were added, and the mixture was stirred at room temperature for 21 hours. Ethyl acetate (20 ml) was added to the reaction mixture, which was poured into water (10 ml), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (20 ml × 2), and the combined organic layers were combined with a 10% aqueous solution of citric acid (20 ml), an aqueous solution of sodium hydrogencarbonate (20 ml), and a saturated aqueous solution of sodium chloride (20 ml). ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (39: 1, chloroform-methanol) to obtain 198 mg (68%) of the title compound as a white powder.

 iH NMK (300MHz, DMSO-) δ 9.13 (m, 1H), 8.94 (s, 1H), 8.88 (d, J--7.7Hz, 1H), 8.44 (s, 1H), 7.50-7.10 (ra, 14H ), 5.19 (s, 211), 4.98 Cm, 111), 4.47, 4.35 (ABq, J = 16.611z, 211), 4.03 (d, -3.8Hz, 2H), 3.18 (dd, J-3.9, 14.4Hz) , 1H), 2.95 (s, 311), 2.82 (s, 3H), 2.71 (dd, J-9.8,

(14.4Hz, 1H)

IR (KBr) 3375, 3050, 2925, 1690, 1650, 1605, 1520, 1500 cm— ¹

 MS (SIMS (f), on glycerol) m / z 725, 707

Example 8

 2-L5-Amino-2- (4-fluorophenyl) -1,6-dihydro-6-oxo-tripyrimidinyl N-il-benzyl-3,3-difluoro-2-oxo-3- Synthesis of LN-[(Ν, Ν-dimethylcarbamoyl) methyl] -lubamoyl〗 propyl ”acetamide

 The same reaction as in Example 2 was carried out using the title compound of Example 7 to obtain 103 mg (80%) of the title compound as a white powder.

 mp 214.0-215.0. C

iH NMR (300MHZ, DMSO-de) <5 9.14 (m, 1H), 8.84 (d.J = 7.7Hz, 1H), 7.40-7.08 (m, 9H), 5.19 (brs, 2H), 4.98 (m, 1H), 4.42, 4.32 (ABq, J = 16. 6Hz, 2 (1), 4.05 (d, J = 5.3Hz, 2H), 3.18 (dd, J = 3.6, 1.4Hz.1H), 2.96 (s, 3H). 2.S3 (s, 3H). 2.72 (dd, J = 9.8, 14.4Hz, 111)

 1R (KBr) 3450, 3350.3250, 3025, 2925, 1755, 1690. 1655. 1630, 1615,

1560. 1530, 1500 cm— 1

 MS (SIMS (+), on glycerol) m / z 573

Example 9

 2- [5-benzyloxycarbonylamino-], 6-dihydro-6-oxitz-2- (3-pyridyl)-]-pyrimidinyl] -N- [tribenzyl-3,3-difluoro -Synthesis of 2-oxo- 3- [N-[(N-ethylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

(1) Using the title compound of Reference Example 2 and the compound shown in Table 14 of Reference Example 14, 2- [5-benzyloxycarbonylamino-1.6-dihydro- 6-oxo-2- (3-pyridyl) -topyrimidinyl] -N- [1-benzyl-3,3-difluoro-2-hydroxy-3- [N- (tert-butoxycarbonylmethyl) 2.97 g (789) were obtained as a light brown solid.

 (2) Using the above compound, 2- [5-benzyloxycarbonylamino-1, 6-dihydro-6-oxo-2- (3-pyridyl) was obtained in the same reaction as in Example (2). ) 1-Pyrimidinyl] -N- [l-benzyl-3,3-difluoro-2-oxo-3--3- [N- (tert-butoxycarbonylmethyl) -l-bamoyl] propyl] acetamide 2.05 g (70%) was obtained.

 (3) Using the above compound and performing the same reaction as in Example 1- (3), 2- [5-benzyloxycarbonylamino-1,6-dihydro 6-oxo-2- (3-pyridyl) -Topirimidinyl] -N- [1-benzyl-3,3-difluoro-2-oxo-3-[[N- (carboxymethyl) caprubamoyl] propyl] acetamide as a brown solid 1.76 g (99% ) Obtained.

(4) The title compound was obtained in a similar reaction to that of Example 1- (4) using the above compound to give 419 mg (83%) of the title compound as a white solid.

lH NMR (300MHz, D S0-d ₆ ) δ 9.29 (t, J = 5.9Hz.1H), 9.01 (s, 1H), 8.92 (d, J = 7.6Hz.1H), 8.70 (dd, J = l .5, 4.8Hz, [H), 8.65 (d, J = 2.0Hz, fi3 IH), 8.48 (s, 1H), 7.94 (t, J = 5.4Hz.Hi), 7.76 (dt, J = l.9, 8.OH /, 1H), 7.47-7.09 (m, 11H), 5.19 (s, 2H). 4.95 (m. 1Π), 4.51. .40 (Αβη,

J = 16.8Hz, 2H), 3.75 (d, J = 5.2Hz.210, 3.16 (dd, j = 3.7, 14.2Hz, IH) .3.05 (m.2H). 2.69 (dd.J = .9. 14.3 Hz, 1H), 0.97 (t, J = 7.2Hz. H)

IR (KBr) 3250. 3050, 1655, 1600. 1510 cm— ¹

 MS (SIMS (+), on glycerol) m / z 708, 690

Example 10

 2- [5-amino-1.6-dihydro-6-oxo-2- (3-pyridyl) -topyrimidinyl] -N- [1-benzyl-3,3-difluoro-2-oxo-3 Synthesis of-[N-[(N-ethylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

 The same reaction as in Example 2 was carried out using the title compound of Example 9 to give 151 mg (805) of the title compound as a white powder.

 mp 122-128 ΐ

 NMR (300MHz, DMSO-dg) n 9.31 (t.J = 5.5Hz, 1H), 8.88 (d, J = 7.4Hz. IH), 8.64 (dd, J = l.5, 4.8Hz, IH), 8.58 7.93 (t, 3Hz, IH), 7.68 (dt.J = 1.9, 7.9Hz.IH), 7.38 (dd, J = 4.9, 7.5Hz.HI) .7.34 (s.) 10, 7.30-7.09 (m, 5H), 5.28 (s.2H), 4.95 (m,) H), 4, 47, 4.38 (ABq, J = 16.7Hz, 2H). 3.75 (d. 3.16 (dd, J = 3.6, 14.2Hz.IH), 3.05 (m, 2H), 2.71 (dd.J = .8, 14.2Hz, IH), 0.98 (t, J = (7.2Hz. 3H)

 IR (KBr) 3275, 3050, 1650. 1610, 1540 cm-1

 MS (SIMS (+) .on glycerol) m / z 556

Example 1 1

2- [5-benzyloxycarbonylamino-1,6-dihydro-6-oxo-2- (3-pyridyl) -1-pyrimidinyl] -N- [1-benzyl 3,3-difluoro -2-year-old oxo-Synthesis of 3- [N-[(N, N- getylcarbamoyl) methyl] -caprolbamoyl] propyl] acetamide Example 9-Example using compound obtained in (3) Titled by the same reaction as 3 The compound was obtained as a light brown solid in a quantity of 251 mg (47%).

 iH NMR (300MHz, DMSO-dfi) δ 9.12 (t.J = 5.5Hz, 111) .9.00 (s. Ul), <S.9i (d, J = 7.GHz.HI), 8.70 (dd, J 4.8Hz, 1H), 8.65 (d, J = l.9l! z, iH), 8.48 (s, IH), 7.76 (dt.J = l.9, 7.9Hz, IH), 7, 49-7.08 On.11H).

5.19 (s, 2H), 4.95 (m, 111) .4.51..40 (ABq, J = 16.6Hz, 2H), 4.02 (m,

3.30-3.20 (m, 4H). 3.17 (dd, J = 3.8, 14.3Hz, IH), 2.69 (dd, J = 9.4, 13.8Hz. IH). 1.10 (t, J = 7.0Hz , 3H), 1.00 (t.J = 7.0Hz, 3H)

1R (Br) 3300, 16 ") 0, 1600, 1510 cm one ¹

 MS (SIMS (+), on glycerol) m / z 736, 718

Example i 2

 2-[5-Amino-1,6-dihydro-6-oxo- 2- (3-pyridyl) -topyrimidinyl] -N- [I-benzyl-3,3-difluro-2- Synthesis of oxo-3- [N-[(NN-Jetylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

 The title compound was obtained as a white powder in the same manner as in Example 2 using the title compound of Example U as a white powder (1 M mg, 76%).

 m 102.5-105.5. C

 iH hidden (300MHz, D S0-d6) δ 9.14 (t, J = 5.4Hz, IH), 8.86 (d, J = 7.6Hz, IH), 8.63 (dd, J = l.5, 4.8Hz, IH) 8.58 (d, J = l.9Hz.Ill), 7.68 (dt,

J = 1.9. 7.9Hz. IH), 7.37 (dd. J = 4.9. 7. Hz, IH). 7.34 (s, HI). 7.30-7.09 (m, 5H), 5.28 (s, 2H), 4.94 ( m, IH), 4.48, 4.37 (ABq, J = 16.9Hz. 211) .4.03 (d.J = 5.0Hz.2H), 3.31-3.21 (m.4H). 3.17 (dd.J = 3.8, 14.3H z.IH), 2.71 (dd, J = 9.8, 14.2Hz, IH), 1.12 (t.J = 7.0Hz, 3H), 1.01 (t,

(J = 7.0Hz, 3H)

IR (KBr) 3275, 3025, 2950. 1750, 1690. 1630, 1605, 1520 cm— ¹

 MS (SIMS (+), on glycerol) m / z 584

Example 13

2- [5-benzyloxycarbonylamino-1, 6-dihydro-6-oxo-2- (3-pyr Synthesis of Jill) -Topyrimidinyl] -N- [1-benzyl-3,3-difluoro-2-oxo-3--3- [N- (l-rubamoylmethyl) l-rubamoyl] propyl] acetamide

 Using the compound obtained in Example 9- (3), and in the same reaction as in Example 5, 471 mg (71%) of the title compound was obtained as a white solid.

 Ή NMR (300 MHz, D SO-de) δ 9.24 (t, J = 5.8 Hz, 1H), 9.02 (s, 1H).

8.91 (d. J = 7.5 Hz, 1H), 8.70 (dd, J = 1.5, 4.9 Hz, 1H), 8.65 (d, J =] .8 Hz, IH), 8.48 (s, 1H). 7.76 ( dt, J = 1.9, 8.0Hz, 1H), 7.50-7.08 (m, 13H), 5.19 (s, 2H), 4.95 (m, 1H), 4.5.1, 4.40 (ABq, J = 16.9Hz, 2H) , 3.75 On, 2H). 3.17 (dd, J = 3.9. 14.3Hz, 1H). 2.69 (dd, J = .8, 14.1Hz, 111) 1R (KBr) 3275, 3050,〗 660, 1600.1510 cm — ¹

 MS (SIMS (+). On glycerol) m / z 680, 662

Example 丄 4

 2-[5-Amino-1,6-dihydro-6-oxo-2-(3-pyridyl) -topyrimidinyl]-N-[1-Benzyl-3,3-difluoro-2-oxo -Synthesis of 3- [N- (carbamoylmethyl) carbamoyl] propyl] acetamide

 The same reaction as in Example 2 was carried out using the title compound of Example 13 to give 153 mg (81%) of the title compound as a white powder.

iH NMR (300MHz, DMS0-d 6) δ 9.24 (t, J = 5.8Hz, IH), 8.87 (d, J = 7.5 Hz, 1H), 8.64 (dd, J = l.5, 4.8Hz. ] H ), 8.58 (d, J = 2.1Hz, IH), 7.69 (dt,

J = 1.8, 7.9Hz. IH). 7.45 (brs, IH). 7.37 (dd.J = 4.9, 7.8Hz, IH) .7.34 (s.IH) .7.30-7.07 (m, 6H). s. 2H), 4.94 (m, IH), 4.46, 36 (ABq, J = 16.7 Hz, 2H), 3.75 (d, J = 5.4 Hz. ZH), 3.17 (dd, J = 3.8. 14.1 Hz,

IH), 2.70 (dd, J = 9.8, 14.2Hz, IH)

1R (KBr) 3300. 1660. 1605. 1535 cm— ¹

 MS (SIMS (+), on glycerol) m / z 546, 528

Example i 5

2- [5-benzyloxycarbonylamino-6-dihydro-2- (3-methylphenyl) -6-oxo-tripyrimidinyl] -N- [tribenzyl-3,3-difluoro-2-oxo-3-3- [N-[(N-ethylcarbamoyl) methyl] pyrubamoyl] propyl] acetamide Synthesis

 (1) Using the compound shown in Table 3 of Reference Example 3 and the title compound of Reference Example 14, the same reaction as in Example (2) was carried out to give 2- [5-benzyloxycarbonylamino-1,6-dihydroxy. -2-(3-Methylphenyl) -6-oxo-pyrimidinyl]-N- [1-benzyl-3,3-difluoro-2--2-hydroxy-3- [N- (tert-butoxy There was obtained 3,55 g (66%) of carbonylmethyl) lebamoyl] propyl] acetamide as a light brown solid.

 (2) By using the above compound and conducting the same reaction as in Example 1- (2), 2- [5-benzyloxycarbonylamino-1,6-dihydro-2- (3-methylphenyl) ) -6-Oxo-1-pyrimidinyl] -N- [tribenzyl-3,3-difluoro- mouth-2-oxo-3- [N- (tert-butoxycarbonylmethyl) pyruvamoyl] provir] acetami 3.50.) As a brown solid.

(3) By using the above compound and performing the same reaction as in Example 1- (3), 2- [5-benzyloxycarbonylamino-1,6-dihydroxyα-2- (3-methylphenyl) -6-oxo-tripyrimidinyl]-Ν- [1 c-benzyl-3,3-difluo mouth-2-oxo-3- [Ν- (carboxymethyl) carbamoyl] bropyl] 2.87 _g (S ⁽ J¾)).

 (4) Using the above compound and performing a reaction similar to that of Example 1- (4), 339 mg (59%) of the title compound was obtained as a white solid.

iH NMR (500MHZ.DMS0-d ₆ + D20) δ 8.43 (s, 1H), 7.45-7.07 (m, 14

5.19 (s, 2H), 4.45-4.26 (m, 3H). 3.77 (d,

2H), 3.1 (dd, J = 2.2, 13.9Hz, 1H), 3.09-3.06 (m, 2H), 2.61 (dd, J-ll. .13.9ik.1H) .2.31 (s, 3H), 0.97 (t.J = 7.3Hz, 3H)

 IR (Br) 3290. 3050, 2950, 1650, 1510

 MS (SIMS (ten). On gl cerol) m / z 721, 703

Example 16 2- [5-amino-1.6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl] -N- [tribenzyl-3,3-difluoro-2-oxo- Synthesis of 3- [N-[(N-ethylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

 The title compound was obtained as a pale-yellow powder (M3 mg, 7 mg) by the same reaction as in Example 2 using the title compound of Example).

Ή NR (500MHz. D SO-d6 + D ₂₀ ) o 7.38-7.00 (m. 9H), 7.36 (s. 1H).

4.41 (m, 1H). 4.38, 4.28 (ABq, J = 16. LHz, 2H), 3.77 (s, 2H), 3.) 3 (dd, J = 2.5.14.1 Hz), 3.10 -3.05 (m, 1H), 2.62 (dd, J-ll.3.) 4. I Hz), 2.2 (s, 3H), 0.99 (t, J = 7.2 Hz, 3H)

 ] R (Br) 3300. 3020, 1750, 1650, 1605, 1550-1520 cm—l

 MS (SI S (+). On glycerol) m / z 587, 569

Example i 7

 2- [5-benzyloxycarbonylamino-1.6-dihydro-2- (3-methylphenyl) -6-oxo-topyrimidinyl] -N- [1-benzyl-3,3-difluoro-2- Synthesis of oxo-3- [N-[(N.N-Jetylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

 The same reaction as in Example 3 was carried out using the compound obtained in Example 15 (3) to obtain 238 mg (40 mg) of the title compound as a pale yellow powder.

 lH NMR (500MHz. D S0-d6 + D20) δ 8.42 (s, III), 7.5-7.07 (m, MH), 5.19 (s. 2H), 4.36 (d, J = 5.5Hz, 2H) , 4.27 (dd, J = 2.4, 11.3Hz.) H), 4.01 (m, 2H), 3.30-3.24 (m, 4H), 3, 13 (dd.J = 2.4. 14.1Hz, 1H). 60 (dd, J = ll.3, 14.1Hz, 1H), 1.32 (s, 3H). 1.10 (t, J = 7.1Hz, 3H), 1.01 (t, J-7.1Hz) , 3H)

] R (KBr) 3280, 3020. 2980. 1690, 1660, 1640, 1510 cm— ¹

 MS (SIMS (+). On glycerol) m / z 749, 731

Example 18

2- [5-amino-1,6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidini Synthesis of [N] -N- [tribenzyl-3,3-difluoro-2-oxo-3- [N-[(Ν, Ν-getylcarbamoyl) methyl] -caproluvamoyl] propyl] acetamide

 The same reaction as in Example 1 was carried out using the compound shown in Example 17 to give 114 mg (83%) of the title compound as a pale yellow powder.

 1H N R (500MHZ. DMS0-d6 D20) 0 7.38-7.03 (m, 911), 7.35 (s. 1H).

4.35. 4.31 (ABq, J = 16.2Hz, 2H), 4.27 (m. 1H). 4.08-3.96 (m, 2H). 3.31-3.26 (m. 4H). 3.14 (dd, J = 2.4. H .1Hz.1H) .2.62 (dd.Jl I.1.M.Ilk, 111), .29 (s.3H), 1.12 (t, J-7.1Hz.3H), 1,04 (311, t. J- 7.] H z)

 | R (KBr) 4 0, 3320. 3250, 3020, 2950. 1750, 169Γ), 1650-1610. 1520 cm—l

 MS (SIMS (ten), on glycerol) m / z 597

Example i 9

 2- [5-benzyloxycaronylamino-1,6-dihydro-2-(:-methylphenyl) -6-oxo-1-pyrimidinyl] -N- [1-benzyl-3,3 -Synthesis of difluo mouth-2-oxo-3- [N- (l-rubamoylmethyl) l-rubamoyl] provir] acetamide

 By a reaction similar to that in Example 5 using the compound obtained in Example 5, 325 mg (59%) of a surface-active compound was obtained as a pale yellow powder.

 iH NMR (500 MHz.DMSO- + 0) δ 8.41 (s, 7.46-7.10 (m, 14

Η), 5.19 (s, 2Η), 4.37 (s, 2H), 4.28-4.22 On, 1H), 3.74 (m.2H), 3.1 1 (dd, J = 2.2, 14.3Hz.1H), 2.61 (dd , J-ll.5, 14.3Hz. IH). 2.30 (s, 3 H)

IR (KBr) 3290, 1645, 1600, 1510 cm- ¹

 MS (SIMS (ten), on glycerol) m / z 693, 675

Example 20

2- [5-amino-1,6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl] -N- [1-benzyl-3,3-difluoro-2_oxo- 3- [N- (forcerubamoylmethyl) Synthesis of Levamoyl] bropyr] acetamide

 The same reaction as in Example 2 was carried out using the title compound of Example 19 to obtain 133 mg (74 mg) of the title compound as a pale yellow powder.

H \ NMR (500MHz. DMS0-d ₆ + D20) δ 7.38-7.03 (m, 9H). 7.36 (s, 1H),

4.40 _: 4.25 On, 3H), 3.89-3.67 (m, 2 (1), 3.1 (dd, J = 2.6.14 OHz, 1H).

2.62 (dd, J = l 1.4, 14.0Hz.1H), 2.29 (s, 3H)

 IR (KBr) 3400. 3280, 1650, 1605, 1550 cm—】

 MS (SIMS (+), on glycerol) m / z 559, 541

Example 2 1

 2- [5-benzyloxycarbonylamino-1,6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl] [1-benzyl-3,3-difluoro-2- Synthesis of oxo-3-[N-[(hexahydrid j-1H-azepin-1-yl) carbonylmethyl] pothamamoyl] propyl] acetamide

 Using the compound obtained in Example 15- (3) and in the same reaction as in Example 3, 573 mg (73%) of the title compound was obtained as a pale yellow powder.

 iH NMR (300MHz, DMS0- + ϋ'0) o 8.42 (s, 1H), 7.45-7.07 (m.14H), 5.19 (s, 2H), 4.36 (s.2H), 4.28 (dd, J = 2.2. 10.8Hz, IH). 4.) 3.9 (m, 2H), 3.43-3.36 On, 4H). 3.14 (dd.J = 2.2. 14.0Hz. IH), 2.61 (dd , J = I0.8, 14.0Hz, IH), 2.31 (s, 3 [1], 1.67-1.47 (m, 8H)

 IR (KBr) 3290.3010, 2910, 1690, 1630.1505

 MS (S1MS (+), on glycerol) m / z 775. 757

Example 1 2

 2- [5-amino-1,6-dihydro-2- (3-methylphenyl) -6-oxo-]-pyrimidinyl] -N- [1-benzyl-3,3-difluoro- Synthesis of 2-oxo-3- [N-[(hexahydro-1H-azepine-]-yl) carbonylmethyl] pothamamoyl] propyl] acetamide

The title compound was obtained in the same manner as in Example 2 using the title compound of Example 21. 241 mg (69 mg) was obtained as a pale yellow powder.

 i NR (300MHz.DMSO-dg + D2 0) δ 7.36 (s, III), 7.36-7.03 (m, 9H) .4.33 (s, 2H), 4.28 (dd, J = l.9. 11.2Hz, 1H ), 4.03 (d, J = 6.7Hz, 2H),

3.42-3.37 (iri, 4H), 3.1 (dd, J = l.9, 14.0Hz, 110.2.63 (dd, J = ll.2.

4. OHz, 1H), 2.30 (s, 3H), 1.70-i.48 (m. 8H)

 IR (KBr) 345 3330, 3290, 3200, 3010, 2900, 1760.〗 705, 1645, 1625, 1615. 1580 cm-1

 MS (SIMS (+), on glycerol) m / z 623

Example 23

 2- [5-benzyloxycarbonylamino-], 6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl] [tribenzyl-3,3-difluoro-2- Synthesis of oxo-3-[[N-[(piperidin-1-yl) carbonylmethyl] caprubamoyl] propyl] acetamide

 The same reaction as in Example 3 was carried out using the compound obtained in Example 15- (3) to obtain 563 mg (73 mg) of a compound as a pale yellow powder.

lH NMR (300MHz, DMS0- d ₆ ten D 0) δ 8.42 (s, 111), 7.46-7.08 (m. 14 H). 5.19 (s, 2H). 4.36 (s, 2H), 4.27 (dd, J = 2.1, 10.8Hz, 1H), 4.09-3.94 (m.2H), 3.45-3.30 (m, 4H) .3.13 (dd, J = 2.1.1.9Hz, 1H), 2.61 (dd, J = I0., 13.9Hz, III), 2.31 (s, 3H), 1.60-1.20 (m. 6H)

 IR (KBr) 3250. 3010. 2900. 1695, 1640-1630, 1505 cm

 MS (SIMS (, on glycerol) m / z 761, 743

Example 2 4

 2- [5-amino-], 6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl: [tribenzyl-3,3-difluo □ -2-oxo -Synthesis of 3- [N-[(piberidine-tolyl) carbonylmethyl] caphambyl] propyl] acetamide

By the same reaction as in Example 2 using the title compound of Example 23, 324 mg (94%) of the title compound was obtained as a pale yellow powder. lH NR (300MHz, DMSO-dfi + D 2 0) ό 7.36 (s, 1H), 7.35-7.03 (m, 911), 4.33 Mr s. 2H). 4.28 (dd . J = l.9, 11.2Hz, 1H), 4.03 (d.J = 6.OHz, 211), 3.45-3.30 (m.4H), 3.H (dd, J = l.9, 14.OHz, 1H) .2.62 (dd, J = l 1.2.

14.0Hz, 1H), 2.29 (s. 311), 1.59-1.43 (m, 6H)

[R (KBr) 3320, 3030. 2920, 2850, 1750, 1720, 1705, 1640 cm " ¹

 MS (SIMS (+), on glycerol) m / z 609

Example 1

 2- [5-benzyloxycarbonylamino-i, 6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl]-[tribenzyl-3,3-difluoro- Synthesis of 2-oxo-3-[N-[(pyrrolidine-1-yl) carbonylmethyl] caprubamoyl] propyl] acetamide

 The title compound was obtained as a pale-yellow powder (553 mg, 73%) by the same reaction as in Example 3 using the compound obtained in Example 15- (3).

 iH NMR (300MHz, DMSO-dg + 020) δ 8.42 (s, 1Η), 7.46-7.08 (m, 14H), 5.19 (s.2H) .4.37 (s, 2H), 4.29 ( dd, J = 2.0. 10. Hz. IH). 3.6 (s, 2H), 3.38 (t, J = 6.7 Hz, 2H). 3.30 (t, J = 6.7 Hz, 2H), 3.1 ( dd.J = 2.0, 13.9Hz, IH) .2.61 (dd.J = 10.8, 13.9Hz, IH), 2.31 (s, 3H), 1.91-1.84 (m, 2H), 1.81-1.74 ( m, 2H)

 IB (KBr) 3250, 3010, 2940, 1640-1630.1505 curl

 MS (SIMS (+), on glycerol) m / z 741, 729

Example 26

 2- [5-amino-1.6-dihydro-2- (3-methylphenyl) 6-oxo-1-pyrimidinyl] -N-U-benzyl-3,3-difluoro-2-oxo-3- Synthesis of [N-[(pyrrolidine-1-yl) carbonylmethyl] caprubamoyl] propyl] acetamide

 The title compound of Example 25 was reacted in the same manner as in Example 2 to obtain 309 mg (88 mg) of the title compound as a pale yellow powder.

_{iH NMR (300MHz. DMS0- d 6} + D 2 0) 5 7.36 (s, IH). 7.35-7.02 On, 9H), 4.33 (s, 2H), 4.28 (dd, J = l.9, 11.3Hz, 1H), 7 (m, 2H), 3.42-3.29 (m.H), 3.13 (dd.J = l.9, 13.9 Hz, 1H), 2.62 (dd. J = ll.3, 13.9Hz. 1 i!), 2.2 (s, 311) .1.93-1.76 (m, 41])

 IR (KBr) 3450, 3350, 3250, 3010. 1755. 1735, 1685, 1650. 1625. 1565. 1520 cm-1

 MS (SI MS (+), on glycerol) m / z 595

Example 2 7

 2- [5-benzyloxycarbonylamino-6-dihydro-2- (3-methylphenyl) -6-oxo-tripyrimidinyl] -N- [tribenzyl-3,3-difluoro-2- Synthesis of oxo-3-[Ν- [(morpholinyl) carbonylcarbonyl] caprolbamoyl] propyldiacetamide

 Using the compound obtained in Example 15-(: 3), the title compound was obtained as a pale-yellow powder (570 mg, 74%) by the same reaction as in Example 3.

 iH image (300MHz, DMS0-d6 + D20) δ 8.42 (s, 1H), 7.46-7.08 (m, 14H), 5.19 (s, 2H), 4.36 (s, 211), 4.28 (dd, J = 4.13-3.97 (m, 2H), 3.58-3.54 (m, 4H), 3.49-3.38 (m.4H), 3.13 (dd.J = 2.1, I.9Hz, 1H) ), 2.61 (dd, J = ll.0, 13.9Hz, 1H), 2.30 (s, 3H)

IR (KBr) 3280. 1650-1635, 1595 , 1505 cm one ¹

 MS (S1 S (+), on glycerol) m / z 763, 7 5

Example 18

 2- [5-amino-1.6-dihydro-2- (3-methylphenyl) -6-oxo-tripyrimidinyl] -N- [1-benzyl-3.3-difluoro-2-oxo-3- [ Synthesis of N-[(morpholine-]-yl) carbonylmethyl] caprubamoyl] propyl] acetamide

 The same reaction as in Example 2 was performed using the title compound of Example 27 to give the title compound (320 mg, 88%) as a pale-yellow powder.

iH NR (300MHz, DMS0-d 6 + D 2 0) <5 7.35 (s, IH), 7.29-7.02 (tn, 9H), 4.33 (s, 2H), 4.28 (dd, J = l.9. 11.3 Hz, IH), 4.12-3.95 (m, 2H), 3.61 -3.57 (m, 4H), 3.50-3.1 On.4H) .3.13 (dd, Jl.9, 14.lFlz, 1H) .2.62 (dd, J = ll.3, 14.1Hz, 1H). 2.29 (s, 3H)

 IR (KBr) 3320, 1750, 1675, 1660-1640, 1610, 1525 cm— 1

 MS (SIMS (+), on glycerol) m / z 629, 611

Example 19

 2-[5-benzyloxycarbonylamino-1, 6-dihydroxy ϋ-6-oxo-2-phenyl-1-pyrimidinyl] [tribenzyl-3,3-difluoro-2-oxo- 3- [Ν-

Synthesis of ジ ェ -Getylcarbamoyl) methyl] carbamoyl] propyl] acetamide

(1) The title compound of Reference Example 4 and the title compound of Reference Example 15 were reacted in the same manner as in Example 1 to give 2- [5-benzyloxycarbonylamino-], 6- Dihydro-6-agexo-2-phenyl-tripyrimidinyl] -Ν- [tribenzyl-3,3-difluoro-2--3-hydroxy-3- [Ν-[(Ν, Ν-getylcarbamoyl) 290 mg (79%) of [methyl] caprubayl] propyl] acetamide was obtained as a pale yellow solid.

 (2) 150 mg (58 mg) of the title compound was obtained as a pale yellow solid by the same reaction as in Example (2) using the above compound.

 】 1 Marauder (300MHz, DMS0-d6) <5 9.13 (t, J = 5.5Hz.11!), 8.93 (s.1H), 8.86 (d, J = 7.6Hz, 1H), 8.45 (s. 1H), 7.52-7.15 (m, 15H) .5.34 (s.2H) .5.00 (m.Ill), 4.46, 4.36 (ABq.J = lfi.7Hz.2H), 4.02 (br.2H), 3.33- 3.16 (m, 5H). 2.70 (dd. J = 9.8, 14.2Hz, 1H), 1.10 (then J = 7.1Hz, 3H), 1.00 (t, J = 7.1Hz, 3H)

IR (KBr) 3300, 1650, 1510 cm " ¹

Example 30

 2- [5-amino-1,6-dihydro-6-oxo-2-phenyl-1-pyrimidinyl] -N- [tribenzyl-3,3-difluoro-2-oxo-3- [ Synthesis of N-[(N, N-Jetylcarbamoyl) methyl] lubamoyl] bropyr] acetamide

By a reaction similar to that of Example 2 using the title compound of Example 29, 84 mg (80%) of the title compound was obtained as a pale yellow powder. iH NMR (300MHZ, DMSO-d ₆ ) δ 9.16 (br, 1H), 8.82 (d, J = 7.3IIz, 1H), 7.48-7.17 (m.11H), 5.17 (s, 1H), 5.15 ( s, III), 4.97 (m, 1H), 4.42, 4.33 (ABq, J-16.6Hz, 2H), 4.03 (br, 211), 3.39-3.23 (m, 4H), 3.18 (dd,

J-3.9, 14.2Hz, 1H), 2.73 (dd, J-9.8, 14.2Hz, 1H), 1.12 (t, J- 7.0Hz,

310. 1.01 (t, J = 7. OHz, 311)

 IR (Br) 3300, 1690, 1630

 MS (SIMSC +), on glycerol) m / z 583

Example 3 1

 2- [5-benzylaminequincarbonylamino-1,6-dihydro-2- (4-methylphenyl) -6-oxo-1-pyrimidinyl] -N-L1-benzyl-3,3-difluoro -2-oxo-3- [N-[(N, N-Jetylcarbamoyl) methyl] methyl rubamoyl! Provir] Synthesis of Acetamide

 (1) WSCI hydrochloride (1.10 g, 5.75 mmol) was added to a mixed solution of the compound obtained in Reference Example 15- (4) (564 mg, 1.15 nraol) in DMSO (10 ml) and toluene (10 ml). Then, acetic acid (0.190 ml, 2.30 mmol) was added dropwise under ice cooling, and the mixture was stirred at 0 "C for 40 minutes. After further stirring at room temperature for 3 hours, the reaction mixture was poured into 1M hydrochloric acid (50 ml). The mixture was extracted with ethyl acetate (50 ml x 2) The organic layer was extracted with water (50 ml), saturated aqueous sodium hydrogen carbonate solution (50 ml x 2), water (50 ml), and saturated sodium chloride. The extract was washed with an aqueous solution (50 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (7: 5, gel-form-ethyl acetate). 2- [4 (S) L (benzyloxycarbonyl) amino 2,2-difluoro-3--3-oxo-5-phenylpentanoylamino] acetyl The emission as a white solid, 485 mg (87%) was obtained.

 (2) "2- [4 (S) -Amino-2,2-difluoro-3-oxo-5-phenylpentanoylamino] acetyl by the same reaction as in Example 2 using the above compound 330 mg (86 mg) of getyl was obtained as a pale yellow powder.

(3) The same reaction as in Example 7 was carried out using the above compound and the title compound of Reference Example 5. Thus, 61 mg (16%) of the title compound was obtained as a pale yellow solid.

iH NB (300MHZ.DMS0-d ₆ ) δ 9.14 (br, 1H), 8.89 (s, 1H), 8.86 (d, J = 7.5Hz.1H), 8.3 (s.1H), 7.45-7.16 ( 14H), 5.18 (s.2H) .4.99 (m, 1H), 4.47, 4.35 (ABq, J = 16.6Hz, 2H), 4.03 (br.2H), 3.33-3.IB (m.

5H), 2.75-2.67 (m, 1H). 2.37 (s, 3H), 1.10 (t, J = 7.1Hz, 3H) .1.00 (t.J = 7.1Hz, 3H)

 IR (KBr) 3300. 1640, 1500 cm-l

Example 3 2

 2- [5-amino, 6-dihydro-2- (4-methylphenyl) -6-oxo-1-pyrimidinyl] -N- [1-benzyl-3,3-difluoro-2-oxo -3- Synthesis of [N-[(N.N-Jetylcarbamoyl) methyl] dirubamoyl] bropyr] acetamide

 The title compound of Example 31 was reacted in the same manner as in Example 2 to obtain 21 mg (51%) of the title compound as a pale yellow powder.

iH NMR (300 MHz. DMS0-d ₆ ) 5 9.10 (br,) H), 8.81 (d, J = 7.2 Hz, 1H), 7.35-7.15 On.] 0H), 5.12 (br, 2H), 4.98 (m 4.41, 4.32 (ABq.J = 16.6 Hz, 2H), 4.04 (br, 2H), 3.40-3.16 (m, 5H), 2.76-2.68 (m.IH), 2.35 (s.3H). , 1.17 (t, J = 6.9 Hz. 3H), 1.01 (t, J = 6.9 Hz. 3H)

 IR (KBr) 3300, 1640 cm-l

 MS (SIMS (+), on glycerol) m / z 597

Example 3 3

2- [5-benzyloxycarbonylamino-1.6-dihydro-6-oxo-2- (4-pyridyl) -1-pyrimidinyl] -Ν-Π-benzyl-3,, Ί-difluoro- Synthesis of 2-oxo-3-[[N-[(N, N-Jetylcarbamoyl) methyl] caprubamoyl] propyl] acetamide (1) Performed using the title compound of Reference Example 6 and the title compound of Reference Example 15. According to the same reaction as in Example (1), 2- [5 benzyloxycarbonylamino-6-dihydro-6-oxo-2- (4-pyridyl) -topyrimidinyl] -Ν- Π-Benzyl-3,3-difluor-2--2-hydroxy-3- [N-[(N, N-getylcarbamoyl) methyl] caprubamoyl] pro PC so-called 86

296 mg (81 mg) of [pyr] acetamide was obtained as a pale yellow solid.

 (2) Using the above compound and performing the same reaction as in Example 1- (2), 125 mg (46%) of the title compound was obtained as a pale yellow solid.

Hi Sat (300MHz, DMS0-d ₆ ) δ 9.13 (t, J = 5.2Hz, 1H) .9.03 (s, 1H), 8.1 (d.J = 7.8Hz, IH). 8.65 (d, J = 6.0Hz, 2H), 8.48 (s, 1H), 7.55-7.15 (m, 12H), 5.19 (s, 2H), 5.00 On, 1H), 4.46, 4.36 (ABq.J = 16.8l! z. 2H),

4.02 (br, 2H), 3.31-3.16 (m, 5H), 2.70 (dd, J = 10.0, 14.2Hz, 1H), 1.10 (t, J = 7.0Hz, 3H), 1.00 (t, J = 7,0Hz, 3H)

 IR (KBr) 3300, 1650, 1510 cm—i

Example 3 4

 2- [5-amino-1.6-dihydro-6-oxo-2- (4-pyridyl) -topyrimidinyl] -N- [1-benzyl-3.3-difluoro-2-oxo--3- [N Synthesis of-[(N, N-Jetylcarbamoyl) methyl] lubamoyl] propyl] acetamide

 By a reaction similar to that of Example 2 using the title compound of Example 33, 70 mg (82%) of the title compound was obtained as a pale yellow powder.

 IH NMR (300MHZ, D SO-dg) δ 9.16 (br, 1H), 8.89 (d, J = 5.Hz, 111) .8.58 (d, J = 5.9Hz, 2H), 7.35-7.09 (m, 8H ), 5.35 (s.IH), 5.33 (s, 111),

4.99 (m.IH). 4.45, 4.35 (ABq, J = 16.7Hz, 2H). 4.03 (br,, 3.33-3.23 (m, 4H), 3.18 (dd, J = 3.4, 14.3Hz. 1H), 2.70 (dd, J = 9.9, 14.3Hz, 1H), 1.12 (t, J = 7.0Hz. 3H). 1.01 (t, J = 7.0Hz: 3H)

IR (KBr) 3300, 1640 cm— ¹

 MS (SIMS (+), on glycerol) m / z 584

Example 3 5

 2- [5-benzyloxycarbonylamino-1,6-dihydro-2- (4-methoxyphenyl) -6-oxo-1-pyrimidinyl] -N- [tribenzyl-3,3 -Gifolo-2-oxo-

Synthesis of 3-[N-[(N, N-Jetylcarbamoyl) methyl] caphambyl] propyl] acetamide () Example using the compound of Reference Example 7 and the title compound of Reference Example 15)-2- [5-benzyloxycarbonylamino-1.6-dihydro- 2- (4-Methoxyphenyl) -6-oxo-tripyrimidinyl] -N- [tribenzyl-3,3-difluoro-2-hydroxy-: tri [N-[(N, N-Jetylcarbamoyl) Methyl] -lvamoyl] propyl] acetamide was obtained as a pale yellow solid suspension: mg (90%).

 (2) The title compound was obtained as a pale yellow solid (106 mg, 33 mg) by the same reaction as in Example (2) using the above compound.

 Ή NMR (300MHz, DMS0-d6) δ 9.14 (t, J = 5.4Hz, 1H). 8.89 (d, J = B.OH z, 1H) .8.88 (s.1H). 8.42 (s, 1H), 7.45-7.18 (m, 12H), 6.4 (d, J = 8.8 Hz, 2H), 5.18 (s, 2H), 5.01 (m, 1H), 4.49, 4.38 (ABq, J = 16.5Hz, 2H).

4.01 (br, 2H), 3.82 (s.311), 3.31-3.16 (m, 5H), 2.72 (dd, J = 9.9, 14.3Hz.111). 1.10 (t, J = 7.1Hz, 3H), 1.00 (t, J = 7.lHz, 3H)

[R (KBr) 3300, 1690, 1640. 1500 cm— ¹

Example 3 6

 2- [5-amino-1,6-dihydro_2- (4-methoxyphenyl) -6-year-old oxo-tripyrimidinyl] -N- [tribenzyl-3,3-difluoro mouth- Synthesis of 2-oxo- [3- [Ν '-[(N-Jetylcalbamoyl) methyl] -lubamoyl] brovir] acetamide

 The title compound was obtained as a pale yellow powder by the same reaction as in Example 35 using the title compound of Example 35 as a pale yellow powder (55 mg, 77%).

 H NMR (300MHz, DMSO-de) δ 9.17 (br, 1H), 8.84 (d, J = 5.8Hz.1H), 7.32-7.19 (m, 8H), 6.89 (d, J = 8.7Hz, 2 \ \), 5.11 (s. 1H) .5.09 (s, 1H),

5.00 (m, 1H), 4.4:!. 4.34 (ABq, J = 16.5Hz, 2H). 4.04 (br, 2W), 3.80 (s, 3H), 3.33-3.1 (m, 5H), 2.71 (dd, J = 3.1. 14.1Hz. 1H), 1.11 (t. J = 7.1Hz, 3H), 1.00 (t, J = 7.1Hz, 3H)

IR (KBr) 3300, 1790, 1630, 1510 cm- ¹

 MS (SIMS (+), on glycerol) m / z 613

Example 3 7 2-L5-benzyloquincarbonylamino-2- (4-chlorophenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl] -N- [1-benzyl-3,3 -Difluoro-2-oxo-3-! N-((N-Getylcarbamoyl) methyl) Synthesis of Rivalmoyl] propyl] acetamide

 (1) Using the title compound of Reference Example 8 and the title compound of Reference Example 15, 2- [5-benzyloxycarbonylamino-2--2-chlorophenyl) was obtained in the same reaction as in Example 1- (1). -1,6-dihydroxy-6-age-oxo-1-pyrimidinyl ''-N- [l-benzyl-3,3-difluoro-2--2-hydroxy-3- [N-i (N, N- Getylcarbamoyl) methyl] carbamoyl] propyl :! 318 mg (83 mg) of acetamide was obtained as a pale yellow solid ,:

 (2) 142 mg (49 mg) of the title compound was obtained as a pale yellow solid by the same reaction as in Example 1- (2) using the above compound.

111 NMR (300 MHz, DMS0-d ₆ ) δ 9.14 (t, J--5.4 Hz,〗 Η), 8.95 (s, 1Η), 8.89 (d, J = 7.7 Hz, 1H), 8.45 (s, 1H), 7.49-7.15 (m, 14H), 5.19 (s, 2H), 5.00 (m, 1H), 4.47, 4.33 (ABq,

211), 4.03 (br, 2H), 3.31-3.20

(m, 4H), 3, 18 (dd, J = 3.7, 14.2Hz, 1H), 2.71 (dd, J = 9.9, 14.1Hz, 1H),

1.10 (t, J-7.0Hz, 3H), 1.00 (t, J-7. OHz, 3H)

IR (Br) 3300, 1690, 1640, 1510 cm— ¹

 MS (SIMS (ten), on glycerol) m / z 628

Example 3 8

 2-5-Amino-2- (4-chlorophenol) -1,6-dihydro-6-oxo-1-pyrimidinyl] -N- "1-benzyl-3,3- Synthesis of difluoro-2-oxo-3-iN-L (N, N-getylcarbamoyl) methyl] pyrubamoyl] propyl] acetamide

To a solution of the title compound of Example 37 (116 mg, 0.155 mraol) in dichloromethane (4 ml) was added anisol (0.050 ml). After cooling with ice, trifluoromethansulfonic acid (0.082 πι1, 0.930 mmol) was added, and the mixture was stirred at room temperature. For 30 minutes. The reaction mixture was ice-cooled, an aqueous sodium hydrogencarbonate solution (5 ml) was added, and the mixture was stirred for 10 minutes. The mixture was poured into saturated aqueous sodium hydrogen carbonate (30 ml) and extracted with ethyl acetate (30 ml x 2). Was. The organic layer was washed with a saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15: 1, chloroform-methanol) to give 57 mg (B05O) of the title compound as a white powder.

^] H NMR (300MHz, DMSO-dg) δ 9.16 (br, 1Η), 8.84 (d, J = 7.3Hz.1H7.3-7.17 (m.9H), 5.22 (s, 1H), 5.20 (s, III), 4.98 (m, IH), 4.43, 4.31 (ABq, J = 16.7Hz, 2H), 4.04 (br, 2H), 3.33-3.15 (m.5H), 2.72 (dd, J = 9.8, 14.1Hz. 1H), 1.12 (t, J = 6.9Hz, 3H), 1.01 (t, J = 6.9Hz, H)

IH (KBr) 3250, 1630 cm— ¹

 MS (SI S (+). On glycerol) m / z 617

Example 3 9

 2- [5-benzyloxycarbonylamino-1, 6-dihydro □ -2- (4-nitrophenyl) -6-oxo-1-pyrimidinyl] -N- [tribenzyl-3,3- Synthesis of difluoro-2-oxo-3- [N-[(Ν · N-Jetylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

 (1) Using the title compound of Reference Example 9 and the title compound of Reference Example 15, a reaction similar to that of Example 1- (1) was carried out to give 2- [5-benzyloxycarbonylamino-1,6-dihydric acid. Dro-2- (4-nitrophenyl) -6-oxo-1-pyrimidinyl] -N- [1-benzyl-3,3-difluoro mouth-2-hydroquinine-3- [NN-Jetylcarbamoyl ) 576 mg (84 mg) of methyl] carbamoy] propyl] acetamide was obtained as a pale yellow solid.

 (2) Using the above compound and performing the same reaction as in Example 1- (2), 376 mg (65%) of the title compound was obtained as a pale yellow solid.

 lH NMR (300 MHz, DMS0-d6) δ 9.13 (t.J-6.1 Hz, IH), 9.03 (br.IH), 8.89 (d, J = 7.8 Hz, IH), 8.48 (s, IH), 8.24 ( d, J = 8.8IIz, 2H), 7.66 (d, J = 8.8Hz, 2H), 7.46-7.14 (m.10H), 5.19 (s, 2H), 5.00 (m.IH), 4.50, 4.33 (ABq / J = 16.7Hz, 2H) .4.02 (br, 2H), 3.30-3.15 (m.5H), 2.70 (dd, J = 11, 13.3Hz.IH). 1.10 (t, J = 7.0Hz, 3H), 0.99 (t, J = 7.0Hz, 3H)

SO JR (KBr) 3300, 1640, 1510 cm—J

Example 4

 2- [5-amino-1,6-dihydro-2- (4-nitrophenyl) .- 6-oxo-tripyrimidinyl] -N- [tribenzyl-3,3-difluoro-2 -Synthesis of oxo 3- [NN-Jetylcarbamoyl) methyl] carbamoyl] propyl] acetamide

 The title compound was obtained as a pale yellow solid by the same reaction as in Example 39 using the title compound of Example 39 to give 93 mg (fi3%).

 11 N'MR (300 MHz, DMSO-de) δ 9.17 (t, J = 5.6 Hz, 1H), 8.88 (d.J = 7.6 Hz, 1H). 8.19 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.7Hz.210, 7.34 (s,) H), 7.26-7.10 (m, 5H) .5.38 (s, 1H), 5.36 (s.1H), 4.99 (m, 3H), 4.48 , 4.33 (ABq, J = 16.7Hz, 2H) .4.03 (br, 2H), 3.40-3.15 (m, 5H), 2.70 (dd, J = 10.1, 14.1Hz.1H), 1.11 (t, J = 6.9Hz. 3H), 1.00 (t, J = 6.9Hz, 3H)

 IR (KBr) 3300, 1690, 1650 cm ~ ^

 MS (SIMS (+). On glycerol) m / z 628

Example 4 1

 2-[“hiro amino-2- (4 amino-phenyl) -1,6-dihydro-6-oxo-tripyrimidinyl] -N- [1-benzyl-3,3-difluoro-2-oxo -Synthesis of 3- [N-[(N, N-Jetylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

 The same reaction as in Example 2 was carried out using the title compound of Example 39 to obtain 67 mg (45 mg) of the title compound as a pale yellow powder.

 111 NMR (300MHz, DMSO-de) δ 9.I8 (t, J = 5.6Hz.1H), 8.84 (d, J = 7.z, 1H), 7.33 On, 5H), 6.98 (d, J = 8 Hz, 2H), 6.51 (d, J = 8.4Hz, 2H), 5.49 (s.IH), 5.47 (s, HI), 4.98 (br.3H), 4.45, 4.37 (ABq, J = 16.4Hz,

2H), 4.04 (br, 2H), 3.34-3.18 (m, 5H), 2.75 (dd, J = 10.0, 14.3Hz, IH),

1.12 (t, J = 7.0Hz. 3H) .1.01 (t, J = 7.0Hz, 3H)

IR (KBr) 3300, 1690, 1630, 1510 cm ^-1

MS (SIMS Hi), on glycerol) m / z 598 Example 4 2

 2- [5-benzyloxycarbonylamino-2- (3-fluorophenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl] -N- [1-benzyl-3 , 3- difluoro- 2-oxo-

3-Synthesis of [N-[(N, N-Jetylcarbamoyl) methyl I-caprolumyl] propyl] acetamide

 (1) Using the title compound of Reference Example 10 and the title compound of Reference Example 15, the same reaction as in Example 1- (1) was carried out to give 2-benzyloxycarbonylamino-2- (3-fluorophenic acid). )-1, 6-dihydroxy-6-oxo-tripyrimidinyl] -N- [1-benzyl-3,3-difluoro-2-hydroxy-3- [N-[(N, N- 1.49 g (79) of tylcarbamoyl) methyl] carbamoyl] propyl] acetamide was obtained as a pale yellow solid.

 (2) WSCI hydrochloride (1.91 g, 9.95 mmol) was added to a mixed solution of the above compound (1.47 g, 1.99 mmol) in DMS0U (7 ml) and toluene (Π ml). , 3.98 Dimol) and stirred at room temperature for 3 hours. The reaction mixture was poured into 1M hydrochloric acid (200 ml) and extracted with ethyl acetate (150 ml × 2). The organic layer was washed with water (200 ral), saturated aqueous sodium bicarbonate solution (200 ral), water (200 ml) and saturated aqueous sodium chloride solution (200 ml), and dried over anhydrous magnesium sulfate. . After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (1: 1, chloroform-ethyl acetate) to obtain 1.18 g (80¾) of the title compound as a white solid. .

_{iH NMR (300MHZ, DMSO- d 6} ) (5 9.13 (t, J-5.3Hz, 1H), 8.99 (s, 1H), 8.88 (d, J = 7.7Hz, IH), 8.45 (s, 1H), 7.50-7.14 (m, 14H), 5.19 Cs, 2 H), 4.96 (m, III), 4.49, 4.37 (ABq, J = 16.7 Hz, 211), 4.02 (m, 2H), 3.28 (q, J- 8.0Hz, 411), 3.18 (dd, J- 14.4, 3.8IIz, IH), 2.69 (dd, J-14, 9.9IIz, IH), 1.10 (t, J = 7.1Hz, 3H), 1.00 (t, J— 7.1Hz, 3H)

IR (KBr) 3300, 1650, 1520 cm— ¹

Example 4 3

2- [5-amino-2- (3-fluorophenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl] -N-[:!-Benzyl-3,3- Difluoro-2-oxo-3- [N-[(N, N-Jeticalcal Synthesis of Bamoyl) Methyl] L-Bamoyl] Buguchi Pill] Acetamide

 By the same reaction as in Example 8) using the title compound of Example 42, 724 mg (77%) of the title compound was obtained as a white solid.

^] H NMR (300 MHz. DMS0-d6) δ 9.15 (t, J = 5.8 Hz, 1H), 8.85 (d, J = 7.6 Hz.1H), 7.41-7.12 (m.J OH), 5.25 (s, 21.1 ), 4.95 (m, 1H), 4.45, 4.35 (ADq, J = 16.3Hz, 211), 4.03 (d.J = 5.7Hz, 1H). 3.24 (q.J = 7.lHz.4H), 3. ! 8 (dd, J = 14.4, 3.9Hz. 1H), 2.7! (Dd, J-14.3, 9.9Hz, 1H). 1.12 (t, J -7.0Hz, 3H). 1.01 (t. J = 7. lllz, 3H).

IR (KBr) 3350. 1760, 1690. 1650, 1630 cm- ¹

 MS (SIMS (+), on glycerol) m / z 601

Example 4 4

 2- [5-benzyloxycarbonyl-2-amino (2-chloro-3-phenyl)-1, (5-dihydro-6-oxo-1-pyrimidinyl] -N- [1-benzyl-3 Of 3,3-Difluoro-2-oxo-3-[N-[(N.N-Jetylcarbamoyl) methyl] -caproluvamoyl] propyl diacetamide

 (1) Using the title compound of Reference Example 11 and the title compound of Reference Example 15, the same reaction as in Example (1) was carried out to give 2- [5-benzyloxycarbonylamino-2- (3- -Chlorophenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl] [1-benzyl -3.3-difluoro-2--2-hydroxy-3--3- [N-[(Ν, Ν-jeti 1.51 g (78%) of rucarbamoyl) methyl] carbamoyl] propyl] acetamide was obtained as a pale yellow solid.

 (2) Using the above compound and performing the same reaction as in Example 42- (2), 1.09 g (74%) of the title compound was obtained as a white powder.

 iH NMR (300MHz, DMS0-d6) δ 9.12 (t, J = 5.IHz.1H), 8.99 (s, 1H), 8.89 (d, J = 7.7Hz, 1H), 8.45 (s, 111), 7.62 -7.13 (m, 14H), 5.19 (s, 211),

4.97 (m, 1H), 4.50, 4.37 (ABq, J = 16.5Hz.2H), 4.02 (br, 2H), 3.26 (q.J = 7.4Hz, 4H), 3.17 (dd, J = 14.2.3.8Hz , 1H), 2.70 (dd, J = 14.2, 9.7Hz, IH). 1.10 (t, J = 7.1Hz.3H) .1.00 (t, J = 7.lHz.3H) iR (Br) 3300. 1650, 1510 cm— ¹

Example 4 5

 2- [5-amino-2- (3-chlorophenyl)-], 6-dihydro-6-oxo-tripyrimidinyl] -N- [tribenzyl-3,: tridifluoro- Synthesis of 2-oxo-3- [N-[(N, N-Jetylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

 The same reaction as in Example 38 was carried out using the title compound of Example 42 to obtain 700 mg (82%) of the title compound as a white solid.

 lH NMR (300MHz, DMSO-d ^) δ 9.14 (t, J = 5.6Hz, 1H), 8.85 (d, J = 7.6Hz. lH), 7.54-7.15 (m.plot), 5.25 (s, 2H) , 4.95 (m, 1H). 4.45, 4.35 (ABq. J = 16.6Hz, 2H), 4.03 (d, J = 5.5Hz, 2H). 3.27 (η, J = 7.3Hz, 411), 3.17 ( dd, J = 14.0, 4.0Hz.IH) .2.71 (dd, J = 14.2.9.7Hz, IH), 1.12 (t.J = 7.0Hz, 3H), 1.01 (t, J = 7.1Hz. 311)

IR (KBr) 3350, 1760, 1690. 1650, 1630 cm ^_ l

 MS (SIMS (+), on glycerol) m / z 617

Example 4 6

 2- [5-benzyloxycarbonylamino-1,6-dihydro-2- (3-methoxyphenyl) -6-oxo-topyrimidinyl] -N- [tribenzyl-3,3-difluoro -2-oxo-

Synthesis of 3- [N-[(N, N-Jetylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

 (I) Using the title compound of Reference Example 12 and the title compound of Reference Example 15, the same reaction as in Example (1) was carried out to give 2- [5-benzyloxycarbonylamino-1,6-dihydroxy. -2-(3-Methoxyfurnyl) -6-oxo-tripyrimidinyl] -N-[]-benzyl-3,3-difluoro-2- 2-hydroxy-3- [N-[(Ν, Ν -Jetylcarbamoyl) methyl] potambamoyl] propyl] acetamide was obtained as a pale yellow solid in the amount of 1-67 g (875).

 (2) By the same reaction as in Example 42- (2) using the above compound, 1.43 g (86%) of the title compound was obtained as a white powder.

IH NMR (300MHz, DMS0-dg) δ 9.14 (t, J = 5.5Hz, 1H), 8.94 (s. IH). 8.86 (d, J = 7.5Hz, 1H), 8.44 (s, 1H) .7.46-6.85 (m, 14H), 5.19 (s, 2H), 4.98 (m.1H), 4.48, 4.36 (ADn, J = I6.3Hz, 2H) .4.02 (br.2H), 3.71 (s, 3iJ), 3.26 (q, J = 7.2Hz.4H), 3.18 (dd, J = 14.3, 3.7Hz.Ill), 2.70 ( dd.J = .3, 9.7Hz.1H), 1.10 (t.J = 7.1Hz, 3H), L00 (t.J- 7.1Hz.3H)

IR (Br) 3300, 1650, 1510 cm- ¹

Example 4 7

 2- [5-Amino-]. 6-dihydro-2- (3-methoxyphenyl) -6-oxo-tripyrimidinyl] ^-zinyl-: 3,3-difluoro-2-oxo -Synthesis of 3- [N-[(Ν, Ν-Jeticalcalbamoyl) methyl] dirubamoyl] propyl] acetamide

 The same procedures as in Example 38 were carried out except for using the title compound of Example 46, to give 770 mg (71%) of the title compound as a white solid.

 iH NMR (300MHz, DMSO-d6) δ 9.17 (t, J = 5.7Hz, 1H), 8.82 (d, J = 7.Hz.1H) .7.1,) H), 7.28-7.15 On, 6H) , 7.01 (dd.J = 8.0, 2.4Hz, 1H), 9 "t.J-2.3Hz.1H), 6.86 (d.J = 7.6Hz, 1H), 5.18 (s.2H), 4.7 On ,

4.43, 4.33 (ABq, J = 16.5Hz, 2H), 4.03 (br, 2H), 3.70 (s.3H), 3.27 (q, J = 7.0Hz, 4H), 3.17 (dd, J = 14.1, 3.5Hz, H) .2.72 (dd.J = 14.2,

9.6Hz. IH), 1.12 (t, J = 7.0Hz, 3H), 1.01 (t. J = 7. IHz, 3H)

 IR (KBr) 3350, 1760. 1690. 1650. 1630 cm—1

 MS (SIMS (+), on glycerol) m / z 613

Example 4 8

 2- [5-Benzyloxycarbonylamino-1,6-dihydro-2- (3-ditrophenyl) -6-oxo-1-pyrimidinyl] -N- [l-benzyl-3,3 -Difluo mouth-2-Synthetic oxo-3- Synthesis of [N-[(N-Jetylcarbamoyl) methyl] caprolbumoyl] propyl] acetamide

(1) Using the title compound of Reference Example 13 and the title compound of Reference Example 15, the same reaction as in Example〗-(1) was carried out to give 2- [5-benzyloxycarbonylcarbonyl-1,6-dihydrogen. Doro- 99/32459

 PCT / JP98 / 05786

2- (3-nitrophenyl) -6-oxo-1-pyrimidinyl] -N- [tribenzyl-3,3-difluoro-2-hydroxy-3--3-[, N _ [(N, N-ethylcarbamoyl ) 2.54 g (87¾) of methyl] carbamoyl] α-pyr] acetamide was obtained as a white solid solution.

 (2) Using the above compound and performing the same reaction as in Example 42- (2), 2.13 g (85%) of the title compound was obtained as a white powder.

 iH NR (300MHz.DMSO-dg) δ 9.11 (t, J = 5.5Hz, 1H), 9.03 (s, HI). 8.88 (d. J = 7.7Hz, 111). 8.48 (s, 1H), 8.36 ( d, J = 8.2Hz, 1H), 8.31 (s, 1H), 7.82 (d, J-7.8Hz, 1H), 7.70 (t, J = 8.0Hz.1H), 7.47-7.07 (m. 10H) , 5.20 (s, 2H), 4.95 (m, 1H), 4.55, 4.39 (ABq, J = 16.6Hz, ZH), 3.99 (br, 2H), 3.26 (q, J = 7.6Hz, 4H). dd, J = 14.3. 3.7Hz, 1H), 2.66 (dd, J = 14.2, 9.9Hz,] H), 1.10 (t, J = 7.1Hz, 3H) .1.00 (t, J = 7. OHz, 3 H)

 IR (KBr) 3400, 1660, 1520 cm— 1

Example 4 9

 2- [5-amino-1,6-dihydro-2- (3-nitrophenyl) -6-oxo-1-pyrimidinyl] -N- [1-benzyl-3,3-difluoro-2- SYNTHESIS-Synthesis of 3- [N-[(N, N-Jetylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

 By a reaction similar to that of Example 38 using the title compound of Example 48, 700 mg (85%) of the title compound was obtained as a white solid.

 h] NMR (300 MHz, D S0-d6) δ 9.13 (t, J = 5.2 Hz, 1H). 8.85 (d, J = 7.7 Hz, 1H). 8.29 (d. J = 7.9 Hz, 1H). 8.23 ( s, 1H), 7.75 (d, J = 7.9Hz, 1H), 7.64 (t.J = 7.9Hz.1H), 7.33 (s, 1H), 7.24-7.09 n, 5H), 5.33 (s.2H) .

4.94 (m, 1H). 4.51, 4.36 (ABq.J = 16.5H, 2H), 4.01 (br.2H), 3.26 (q,

J-7.0Hz, 4H). 3.16 (dd, J = 14.3.3.9Hz, 1H), 2.67 (dd.J = 14.2, 9.8Hz.

1H), 1.11 (t, J = 7.1Hz, 3H), 1.01 (t, J = 7.lliz, 3H)

 IR (KBr) 3300, 1760. 1690, 1650, 620, 1530 cm'l

MS (SIMS (10). On glycerol) m / z 628 Example 5 0

 2- [5-amino-2- (3-aminophenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl] [1-benzyl-3,3-difluoro- Synthesis of 2-oxo-3- [N-[(N-Jetylcarbamoyl) methyl] dirubamoyl] propyl] acetamide

 Using the title compound of Example 48 and performing the same reaction as in Example 2, 680 mg (86 μl) of the title compound was obtained as a white solid.

^] H NMR (300MHz. DMSO-dfi) δ 9.16 (t, J = 5.1Hz, 1H), 8.78 (d, J = 7. \ Hz, 1H), 7.30-7.17 (m, 6H), 6.97 (t, J = 7.8Hz, 1H), 6.63 (d, J = 7.7Hz ₍ 111), 6.55 (s, 1H). 6.38 (d, J = 7.5Hz, 1H), 5.23 (s, 2H) .5.09 (s, 211),

4.97 (m, 1H), 4.44, 4.36 (ABq, J = 16.5Hz, 2H) .4.03 (br, 2H). 3.27 (q,

J = 7. LHz.4H), 3.18 (dd, J = 14.1, 3.811 z, H). 2.76 (dd, J = 14.2.9.4Hz.

1H), 1.11 (t, J = 7.0Hz, 3H), 1.01 (t, J = 7.1Hz, 3H)

 IR (KBr) 3350, 1760. 1690, 1630 cm— 1

 MS (S1MS (+). On glycerol) m / z 598

Example 5 I

 2- [5-benzyloxycarbonylamino-1, 6-dihydro-2- (3-methylphenyl) -6-s-oxopyrimidinyl] -N- [1-benzyl-3,3-difluoro Mouth-2-oxo-3--3- [N- [2- (N, N-Jetylcarbamoyl) ethyl] lubamoyl] propyl] Acetone Synthesis

 (1) Using the title compound of Reference Example 2 and the title compound of Reference Example 16, the same reaction as in Example 1- () was performed to give 2- [5-benzyloxycarbonylamino-1,6- -Dihydroxy-2- (3-methylphenyl) -6-oxo-pyrimidinyl]-N- [1-benzyl-3,3-difluoro-2--2-hydroxy-3- [N- [2 -584 mg (78 mg) of-(N-getylcarbamoyl) ethyl] lvamoyl] propyl] acetamide was obtained as a pale yellow solid.

 (2) Using the above compound and performing the same reaction as in Example 1- (2), 524 mg (92 mg) of the title compound was obtained as a pale yellow powder.

Ui NMR (500 MHz, D S0-d ₆ + D ₂₀ ) δ 8.38 (s, 1H), 7.40-7.01 (m, 14 H) .5.1 (s, 2H), 4.35, 4.26 (ABq, J- 16.3Hz, 2H), 4.24 (dd, J = ll.1. 2.0Hz. 1H) .3.34-3.26 (m, 2H), 3.20 -3.10 (m, 4H), 3.07 (dd, J = 2.0, 1

3.84, dd, J = 1L 1, 13.8Hz, 1H), 2.50-2.40 (m, 2H). 2.26 (s, 3H), 0.98 (t.J = 7.1Hz, 3H) .0.94 (t. J = 7.1Hz, 3H)

 IR (KBr) 3350, 3050, 2030. 1660-1640, 1505 cm-1

Example 5 2

 2- [5-amino-1,6-dihydro-2- (3-methylphenyl) -6-oxo-topyrimidinyl] -N- [1-benzyl-3,3-difluoro mouth -Synthesis of 2-oxo- 3- [N- [2- (N, N-Jetylcarbamoyl) ethyl] lubamoyl] propyl] acetamide

 By the same reaction as in Example 38 using the title compound of Example 51, 253 mg (78%) of the title compound was obtained as a white solid.

1 (1 MR (500MHz, DMS0-d ₆ + D ₂₀ ) δ 7.32 (s, 1H), 7.32-6.97 (m, 9H),

4.32. 4.23 (ABq, J-16.1Hz.2H), 4.21 (dd.J = 2.1, 11.3Hz, 1H) .3.37-3.28 (m, 2H), 3.23-3.12 (m, 4H) .3.08 ( dd.J = 2.1, 14.1Hz.1H) .2.56 (dd.

J = ll.3, 14.1Hz, 1H) .2.51-2.42 (m.2H), 2.24 (s, 3H) .1.01 (t, J = 7.1 Hz, 3H), 0.9fi (t, J = 7.1Hz, 3H)

1R (KBr) 3300, 3080. 2960. 1750. 1660, 1600, 1520 cm— ¹

 MS (SIMS (10). On glycerol) m / z 629, 611

Example 5 3

 2- [5-benzyloxycarbonylamino-1, 6-dihydro 2- (3-methylphenyl) -6-oxo- 1-pyrimidinyl] -N- [l-benzyl-3,3-difluoro- Synthesis of 2-oxo-3- [N- [3- (N, N-Jetylcarbamoyl) propyl] dirubamoyl] propyl] acetamide

 (1) Using the compound obtained in Reference Example 14_ (3), a reaction similar to that of Example 2 was performed to obtain 4 (S) -amino-2-2.2-fluoro-3-hydroxy-5-phenylpentanoic acid. 3.17 g (84½) of ethyl was obtained as a white powder.

(2) The same reaction as in Example 1- (1) was carried out using the above compound and the compound of Reference Example 2. 2-L5-benzyloquincarbonylamino-1,6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl N-U-benzyl-3,3-difluoro- 2.39 g (90%) of 2-hydroxy-3-ethoxycarbonylpropyl] acetamide was obtained as a white solid.

 (3) To a solution of 3.33 g (5.14 mmol) of the above compound in THF (15 ml) was added a 1 M aqueous sodium hydroxide solution (5.1 ml), and the mixture was stirred for 90 minutes. The reaction mixture was concentrated under reduced pressure to give 2--benzyloxycarbonylamino-1,6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl] -N- [1 -Benzyl-3,3-difluoro-2-hydroxy-3-carboquinpropyl :! 3.00 g (91%) of acetamido sodium salt was obtained as a white powder,

(4) L4- (tert-Butoxycarbonylamino) butyryl] ethylamine by the same reaction as in Example 1- (1) using 4- (tert-butoxycarbonylamino) butyric acid and getylamine. 3.74 g (98 kg) were obtained.

 (5) Using the above compound and performing the same reaction as in Example 1- (3), 2.26 g (quant.) Of (4-aminobutyryl) getylamine hydrochloride as white amorphous was obtained.

(6) Using the compound obtained in (3) and the above compound, the same reaction as in Example 1- (1) was carried out to give 2- [5-benzyloxycarbonylamino-1,6-dihydroxy. -2- (3-methylphenyl) -6-oxo-1-pyrimidinyl] -benzyl-3,3-difluoro-2- 2-hydroxy-3- [N- [3- (Ν, Ν-je 134 rag (23¾ί) of tylcarbamoyl) propyl “pyrumomoyl” propyl] acetamide was obtained as a white solid.

 (7) 81 mg (69%) of the title compound was obtained as a pale yellow powder by a reaction similar to that of Example 1- (2) using the above compound.

III NM (300MHz, D S0-d ₆ ) δ 9.18 (t, J-5.Hz, 3D), 8.92 (s, HI), 8.84 (d, J-7.4Hz, 111), 8.43 (s, 1H) , 7.45-7.15 (ra, 1410, 5.18 (s, 2H),

4.97 (m, 111), 4.42 (s, 2H), 3.26-3.12 (m, 711), 2.70 (dd, J-9.6, 14.21Iz, 1U), 2.31 (s, 3H), 2.27 (t, J -7.2Hz, 2H), 1.69 (quint, J-7.0Hz,

211), 1.05 (t, J-7.1Hz, 310, 0.98 (t, J = 7.0Hz, 310

IR (KBr) 3300, 1650, 1510 cm— ¹ Example 5 4

 2-C5-Amino-1,6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl] -N- 1-benzyl-3,3-difluoro-2-oxo -Synthesis of 3- [N [3- (N, N-Jetylcarbamoyl) propyl] -lubamoyl] propyl] acetamide

 By a reaction similar to that of Example 2 using the title compound of Example 53, 30 mg (49¾i) of the title compound was obtained as a white solid.

lH NMR (300 MHz, DMS0-d ₆ ) δ 9.18 (br, 1Η), 8.78 (d, J = 7.1 Hz, 1H), 7.33-7.09 (m, 10H), 5.12 (s, 2H), 4.96 (tn, 111), 4.38 (s, 211), 3.31-3.12 (m, 7H), 2.71 (dd, J-9.4, 13.9Hz, 1H), 2.35-2.24 (m, 5H), 1.70 (qu int, J = 7.0Hz, 2H), 1.06 (t, J = 7.0Hz, 3H), 0.99 (t, J-7.0Hz, 3H)

IR (KBr) 3300, 1690, 1660, 1610 cm— 1

 MS (SI SC, on glycerol) m / z 625

Example 5 5

 2- [5-Acetylamino-1,6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl] -N- [1-benzyl-3.3-difluoro mouth-2-oxo -3- [N- “3- (N, N-Jethylcarbamoyl) methyl] dirubamoyl] Synthesis of propyl and acetamide

 To a solution of the title compound of Example 18 (30.0 mg, 0.0503 nunol) in THF (3 ml) was added sodium carbonate (13.8 mg, 0.131 mmol) and acetyl chloride (5.13 mg. 0.0654 mmol), and the mixture was stirred at room temperature for 18 hours. . The reaction mixture was diluted with ethyl acetate (40 ml) and washed sequentially with 1M hydrochloric acid (10 ml x 3), saturated aqueous sodium hydrogen carbonate (10 ml x 2), and saturated aqueous sodium chloride (10 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate-getyl ether-hexane (1: 2: 5) and collected by filtration to obtain 28.0 mg (87%) of the title compound as a colorless powder.

 mp 97.0-98.0 ° C

111 NMR (500MHz, D S0-d ₆ ID ₂₀ ) δ 8.73 (s, 1H), 7.36-7.06 (m, 9H), 4.41, .35 (ABq.J- 16.3Hz, 2H). 111), 4.05 Cm, 2H), 3.29 (m, 4H), 3.13 (dd, J-2.7, 14.0Hz, 1H), 2.61 (dd, J 11.0, 14.0Hz, III), 2. JP98 / 05786

31 (s,: Ml), .16 (s, 3H), 1.12 (t, J-7. Lllz, 31]), 1.04 (L, J-7. Ulz, 3H)

 IR (KBr) 3380, 1750, 1690, 1640, 1515 cm "J

 MS (SIMS Hi), on glycerol) m / z 657, 639

 The following compounds were synthesized in the same manner as in the above examples.

Example 5 6

 2- [5-benzyloxycarbonylamino-2- (3-fluorophenyl) -1,6-dihydro □ -6-oxo-1-pyrimidinyl] [tribenzyl-3,3-difluoro- 2-oxo-3-[N-[(hexahydro-1H-azepine-tolyl) carbonylmethyl] caphambyl] provir] acetamide

White solid

 ! HR (300MHZ. DMS0 d6) δ 9.14 (t. J = 5.2Hz, 1H), 8.98 (s.] H), 8.8 (d. J = 7.4Hz, 111), 8.45 s,] H) 7.50-7.15 (m, 14H), 5.19 (s.2H).

4.96 (m, 1H). 4.58, 4.37 (Abq, J = 16.5 Hz. 2H) .4.03 (m, 2H), 3.40 (m, 4H). 3.18 (dd.J = 14, 1, 3.7Hz. 1H) , 2.70 (dd, J = 14.1, .9Hz, 1H),

I.67 (m. 2H), 1.56 (m, 2H), 1.47 (m, 4H)

Example 5 7

 2- [5-amino-2- (3-fluorophenyl) -1.6-dihydro-6-oxo-1-pyrimidinyl] -N- [1-benzyl-3,3-difluoro □ -2 -Oxo-3- [N-[(hexahydro-] H-azebin-1-yl) carbonylmethyl] pothambamoyl] propyl] acetamide White solid

mp 165-166 ° C (form hexane)

iH NMR (300 MHz, DMS0-d ₆ ) δ 9.16 (t, J = 5.5 Hz, 1H), 8.85 (d.J = 7.6 Hz, 1H) .7.46-7.08 (m, 10H), 5.25 (s.2H ), 4.95 (m, 1H). 4.45. 4.35 (Abq, J = 16.5 Hz, 2H), 4.04 (m. 2H), 3.44 (m, H), 3.18 (dd, J = 14.2, 3.7 Hz, 1H) ), 2.71 (dd, J = 13.2, 9.8Hz, 111), L 66 (m, 2H), 1.8 (m, 2H), 1.48 (m. 4H) IR (Br) 3468, 3358. 3294. 3034, 2932. 1754. 1696, 1646, 1631, 1585 cm "t

 MS (ESI) m / z 627

Example 5 8

 2- [5-benzyloxycarbonylamino-2- (3-chlorophenyl) -1.6-dihydro-6-oxo-tripyrimidinyl] [1-benzyl-3,3-difluoro □-2- Oxo-3-[N-[(hexahydro-IH-azepin-1-yl) carbonylmethyl] pothamb] yl] propyl] acetamide

White solid

 111 NM (300MHz, D SO-dg) δ 9.13 (t, J = 5.6Hz, 111), 8.98 (s.) H) .8.99 (d, J = 7.5Hz, 1H) .8.5 (s. 1H). 7.65-7.05 (m. 14H), 5.19 (s, 2H),

4.96 (m.1H). 4.49, 4.36 (Abq.J-16.8Hz, 211), 4.03 (m, 2H), 3.40 (m.

411), 3.17 (dd, J = 14.0, 4.0Hz, 1H) .2.70 (dd, J = 14.2, 9.7l! Z.1H) .1.67 (m, 2H), 1.56 (m, 2H) , 1.47 (m, 4H)

IR (KBr) 3391, 3064, 2933, 1703. 1656, 1518 cm— 1

MS (ESI) m / z 777

Example 5 9

 2- [5-amino-2- (3-chlorohydrinyl) -1, 6-dihydro-6-oxo-tripyrimidinyl] [tribenzyl-3,3-difluorin-2- Oxo-3-[[N-[(hexahydro-11-tazepine-tolyl) carbonylmethyl] pothambamoyl] propyl] acetamide White solid

Immediately 172.5-174 t

IH NMR (300MHz, DMSO-dft) <5 9.15 (t, J = 5.6Hz.1H), 8.85 (d, J = 7.6Hz, 1H), 7.57-7.32 (m, 3H), 7.31 (s, 1H), 7.29-7.10 (m, 6H), 5.26 (br s, 2H). 4.96 (tn, 1H), 4.45, 4.34 (Abq, J = 16.7Hz, 2H), 4.04 ( d, J = 5.6 Hz, 2H), 3.41 (m, 4H), 3.17 (dd, J = 14.2, 3.9 Hz, IH), 2.71 (dd.J = 14.2, 9.7 Hz, IH), 1.68 On, 2H), 1.58 (m. 2H), 1.48 On, 4H) [R (Br) 3443, 3341. 3309, 3032. 2931. 1761. 1698, 1648 cm ^-1

MS (ESI) m / z B43

Example 6 0

 2- [5-benzyloxycarbonylamino-2- (4-fluorophenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl] -N- [l-benzyl-3,3 -Difluoro-2-oxo-3-[N-[(hexahydro-1H-azepin-1-yl) carbonylmethyl] carbonyla] propyl] acetamide

White fixed holiday

mp 108-113 "C (ethyl acetate-hexane)

] _{H NMR (300MHz. DMSO- d 6} ) <5 9.15 (t, J = 5.6Hz, 1H), 8.95 (s, 1H). 8. 88 (d, J = 7.7Hz, 1H), 8.44 (s. 1H), 7.49-7.11 (m, 1 H), 5.19 (s, 2H),

4.99 (m, 1H), 4.47, 4.35 (Abq, J = 16.7Hz.2H), 4.04 (d, J = 5.4H?., 2H),

, 1.0 On, 4H), 3.18 (dd.J = 14.2. 3.6Hz, 1H), 2.70 (dd, J = 14.2, 9.9Hz,

1H). 1.66 (m, 2H), 1.56 (m, 2H), 1.7 (m, 4H)

1R (KBr) 3291, 3064, 2932, 1703, 1651, 1607, 1526, 1504 cm-1

MS (ESI) m / z 761

Example 6 I

 2- [5-amino-2- (4-fluorophenyl) -1,6-dihydro-fi-oxo-1-pyrimidinyl] -N-Π-benzyl-3.3-difluoro-2- Oxo-3- [N-[(hexahydro-1H-azepin-1-yl) kyrponylmethyl] pyrubamoyl] propyl] acetamid White solid

mp 130-155 ° C (ethyl acetate-hexane)

 H thigh (300MHz, DMS0-d6) δ 9: 17 (t, J = 5. HHz, 1H), 8.84 (d, J-7.6Hz, 1H), 7.40-7.10 (m, 10H). 5.19 ( brs, 2H), 4.98 (m, 1H), 4.43, 4.32

(Abq.J = 16.6Hz.2H) .4.05 (d, J = 5.5Hz, 2H), 3.41 (m, 4H), 3.18 (dd.

J-14.2. 3.7Hz, 1H), 2.71 (dd, J = 14.2, 9.9Hz, 1H), 1.68 (m, 2H), 1.58 (m, 2H), 1.47 (m. 4H) 1R (Br) 3351, 3058, 2931, 1756, 1700, 1650, 1611. 1535, 1509 cm— 1 MS (ESI) m / z 627

Example 6 2

 2- [Γ) benzyloxyamino-2- (3-full-form phenyl) -1,6-dihydro-6-oxo-1-pyrimidinyl] -Ν- -benzyl-3,3 -Difluoro-2-oxo- -3-[Ν-[(pyrrolidine-:!-Yl) carbonylmethyl] dirubamoyl] propyl]

White solid

mp 1 5-131

 lH face (300MHz, DMS0-d6) δ 9.18 (brs, 1H), 8.99 (brs, 1H), 8.95-8.80 (m. 1H). 8.45 (s, 1H). 7.50-7.00 (m, 14H) , 5.19 (s, 2H) .5.00-4.8 5 (m, 1H), 4.60-4.16 (m, 2H), 3.50-3.00 (m, 5H), 2.80-2.50 (m, 1H), 2.00-1.62 (m . 4H)

IR (KBr) 3300, 1640. 1520 cm- ¹

Example 6 3

 2- [5-amino-2- (3-fluorophenyl) -1,6-dihydro-6-age-oxo-pyrimidinyl] -N-Π-benzyl-3,3-difluoro -2-oxo- 3- [N-[(pyrrolidine-tolyl) carbonylmethyl] caprolbumoyl] propyl] acetamide

White solid

mp 206-209 ° C

iH (300MHz, D S0-d ₆ ) δ 9.20 (t, J = 5.5Hz, 1H), 8.88 (d, J = 7.6H z, 1H), 7.50-7.00 (m, 10H), 5.35-5.10 ( m, 2H), 5.00-4.83 (m, Hi), 4.56-3.70 (m, 4H), 3.52-3.00 (m, 5H) .2.81-2.54 (m, 1H), 2.00-1.70 (m,

4H)

IR (KBr) 3350, 1640 cm— ¹

Example 6 4

2- [5-benzyloxycarbonylamino-2- (3-chlorophenyl) -1,6-dihydro -6-oxo-Tripyrimidinyl] -N- -Benzyl-3,3-difluoro-2-oxo-3--3- [N-[(pyrrolidin-1-yl) carbonylmethyl] dirubamoyl] propyl] acetami Do

White fixed holiday

m 113-115.5 "C

iH NMR (300MHZ. DMS0-d ₆ ) δ 9.17 (t. J = 5.7 Hz,〗 H), 9.00 (s. 1H) .8.1 (d. J = 7.7 Hz, 1H), 8 .5 (s, 1H), 7.65-7.05 (m, 14H), 5.19 (s, 2H), 4.95 (m, 1H). 4.49. 4.37 (Abq, J = 16.7Hz, 2H), 3.96 (m .2 (H) .3.0 (t, J = 6.7Hz.2H). 3.28 (t, J = 6.8Hz, 211) .3.18 (dd, J = I4.2, 3.9Hz, 1H),

2.7] (dd.J-14.2, 9.7IIz, 1H), 1.87 (m, 2H), I.75 (m, 2H)

IR (KBr) 3292, 3034, 1704, 1640. 1518 cm one ¹

 MS (ESI) m / z 749

Example 6 5

 2- [5-amino-2- (3-chlorophenyl) -1,6-dihydro 6-oxo-tripyrimidinyl] -Ν- [tribenzyl-3,3-difluoro-2 -Oxo-3- [Ν-[(pyrrolidine-tolyl) carbonylmethyl] rubamoyl propyl] acetamide

White solid

mp 191-193 "C

 iH NMR (300MHz, DMS0-d6) δ 9.19 (t, J = 5.6Hz.1H), 8.89 (d, J = 7.611z, 1H), 7.58-7.08 (m, 10H) .5.26 (brs.2H ), 4.95 (m, 1H), 4.45, 4.34

(Abq, J = 16.7Hz, 2H). 3.97 (m, 2H), 3.41 (t, J = 6.7Hz, 2H). 3.29 (t.J = 6.8Hz, 2H), 3.18 (dd. 14.1, 3.9Hz, 1H), 2.72 (dd, J = 14.2.i), 7Hz.

 1.88 On, 2H), 1.76 (m, 2H)

 IR (KBr) 3452, 3351, 3283. 3042. 1755, 1699, 1635. 1586, 1570, 1525

MS (ESI) m / z 615

Example 6 6 2- [5-benzyloxycarbonylamino-2- (4-fluorophenyl) -shi 6-dihydro-6-oxo-tripyrimidinyl] -N- [tribenzyl-3,3-difluoro -2-oxo-3-[N-[(pyrrolidin-1-yl) carbonylmethyl] caphambyl] bropyr] acetamide

White solid

m 127-137 "C (ethyl acetate-hexane)

 Ή NM (300MHz. DMSO-dg) δ 9.】 9 (t, J-5.6Hz, lf】), 8.96 (s.〗 H) .8.91 (d, J = 7.7Hz.1H), 8.44 ( s, 1H), 7.48-7.12 (m. 14H). 5.19 (s, 2H).

4.98 (m.1H), 4.47, 4.35 (Abq.J = 16.6Hz, 211), 3.96 (d.J-5.2Hz, 2H).

3.40 (t, J = 6.8Hz, 211), 3.28 (t, J = 6.7Hz, 2H), 3.19 (dd.J = 14.2. 3.7Hz, 1H), 2.71 (dd, J = 14.2, 9.9Hz , IH), 1.88 (m, 2H). 1.75 (m, 2H) IR (KBr) 3392, 3289. 3033, 2974, 1752. 1706. 1640. 1607, 1527, 1504 cm—]

 MS (ESI) m / z 733

Example 6 7

 2-[")-amino-2- (4-fluorophenyl) -1,6-dihydro-6-oxo-]-pyrimidinyl] -N- N-benzyl-3,3-difluoro-2 -Oxo-3- [N-[(pyrrolidine-1-yl) carbonylmethyl] caprubamoyl] bropyr] acetamide

White solid

mp 224-225 ° C

iH 麵 (300 MHz. l) S0-d ₆ ) δ 9.21 (t.J = 5.5 Hz, 1H), 8.88 (d, J = 7.71.1 z, IH), 7.40-7.10 (m. 10H 5.20 (brs. 211) ..97 (m.IH), 4.42. 4.32

(Abq, J = 16.6Hz, 2H), 3.98 (d, J = 5.4Hz.2H), 3.41 (t, J = 6.7Hz, 2H). 3.29 (t, J = 6.6Hz, 2H). (dd, J = 14.2.3.9Hz, IH), 2.72 (dd, J-14.2, 9.9Hz, IH), 1.88 (m. 2H), 1.76 On, 2H)

IR (KBr) 3458, 3351, 3284. 3043, 1754, 1697,] 631, 1615. 1579. 1 08 cm -1 S (ESI) m / z 599 one

The compounds obtained in the above Examples are shown in Tables ¹ , ² , ³ , 4 and 5. Note in the table, _{M e} is methyl, the E t is Echiru shows C bz Habe Nji Ruo alkoxycarbonyl.

table 1

CH ₂ NH ₂

14 HN Table 2

9 9

19 Cbz N CH ₄ NH ₂众 H _3-

 23 bz N

H ₂

 26 H N C

Cbz N CH _Z

 27-N 0

 \ f

CH ₂

28 HNJ ₃ -N p 001

¾3N-N zqo

¾3N ^¾ HO NH it

¾3 ^e HO-NH

C

 ¾N N H ε

¾ ^z O-σ N ZQO εε '

¾N ^z HO N. H ζζ

¾ ^s HO-N zqo ΐ-ε

¾N ^z HO NH οε

¾N ² HO N

 Z W

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£ S0 / 86df / XDd 6SW £ / 66 OM Experimental Example I: Inhibitory activity of the compound of the present invention on human cardiac chimase

 The inhibitory activity of the compound (I) of the present invention was measured as the inhibitory activity on the amidase activity of human cardiac chimase, and its effectiveness was evaluated as follows.

 Specified concentration series for 5 nM chimase in the presence of the synthetic substrate succinyl-aralanyl-aralanyl-prolyl-phenylalanine-P-nitroanilide at a final concentration of 2.5 mM Series (X1, X10, <X100 The inhibitory activity was quantified by the change in the residual activity fraction of the compound of the present invention (double equivalent). Inhibition potency was analyzed by least squares regression of Easson-Stedman plots (Pro Roy. Soc. B. 1936, 121. pl41) using a bimolecular equilibrium reaction linearization equation. The inhibitory activity was evaluated based on the apparent inhibition constant (Kiapp) obtained by this analysis and the inhibition constant (Ki) calculated from the final concentration of the reaction solution substrate and the Km value separately determined. The initial rate of the enzymatic reaction is determined spectrophotometrically by increasing the absorbance at 405 nm by subtracting the absorbance at 650 nm light from the amount of p-ditroaniline produced by hydrolysis of the substrate. did. The chimase inhibitory activity of the compound of the present invention is calculated as the fraction of the activity remaining in the presence of the inhibitor relative to the enzyme activity in the absence of the inhibitor, and is measured below the initial rate guaranteed absorbance at the substrate concentration used for the enzyme. After capturing the values, analysis was performed.

 The composition of the reaction solution was the compound of the present invention dissolved in 10 μl dimethyl sulfoxide (DMS0) at a concentration of 20 / il in 140 μl of a buffer solution (pH 7.5) of Tris-HC1 (100 m) -KCI (2). , The substrate dissolved in DMS◦, and 20 l of chimase were added to a total volume of 200/1.

 From the absorbance immediately after addition of the enzyme, the increase in absorbance was recorded as a progressive curve at exactly equal time intervals.

Based on the above data, if necessary, determine the residual activity of the sample with the inhibitor added to the control without the inhibitor based on the difference between the absorbance at the end of the reaction and the absorbance immediately after the addition, and perform the analysis. Calculate the reaction rates of the control and inhibitor-added samples with a time step width (≥20 minutes), shift the rate calculation every 1ϋ to 30 minutes, and calculate the reaction rates from each reaction rate averaged over the entire reaction time. , The same method for quantifying the residual activity fraction The inhibitory activity was analyzed by the method.

 In addition, the inhibitory activity against human leukocyte elastase was measured by using N-methoxysuccinyl-aralanyl-aralanyl-prolyl-valin-p-nitroanilide as a substrate and using 20 tnM CaCl2 and 0.1 0.1 0.1M Tris-HCl (pH 8.0) containing Twecn 80 was used, and the other composition was the same as above.

Examples 1 1, 16, 17, 18, 19, 22, 25, 44, 42, 43, 44, 45, 46, 48, 55, and 59 are obtained. Table 7 shows the results of the human cardiac chimase inhibitory activity test for the obtained compound together with the results of the comparative compound shown in Table 6.

 z M R5 R Comparative compound 1 *

Comparative compound 2 "H

 *: Compound of Example 90 of W096 / 33974

U: Compound of Example 91 of 096/33974

5786

Table 7

On the other hand, compounds of any inhibitory activity against human leukocyte elastase Ichize also was> I 0 ⁵ M. 8/05786

From the above results, it can be seen that the compound (ί) of the present invention does not inhibit human leukocyte elastase at all and strongly inhibits human cardiac chimase.

Experimental Example 2: Changes in plasma concentration after oral administration of rat

 Using an SD male rat, under fasting conditions, the compound obtained in Example 18 was orally administered at a dose of 〖Omg / kg and administered for 10 and 30 minutes and I, 1, 3, and 6 hours after administration. Blood was collected at the point. Pretreatment of plasma was performed by a general solid-phase extraction method, and the obtained sample was analyzed by HP-C using a DS column (solvent: acetonitrile / The reaction was carried out using a dihydrogen oxygen solution (aqueous aqueous solution).

 The results are shown in FIG.

 As is evident from Fig. I, the compound of the present invention showed the maximum concentration at about 30 minutes after administration, and after this, the plasma concentration decreased over 2 hours after administration, and then disappeared moderately over 6 hours after administration. Was. The half-life during the period of this mild disappearance was more than 10 hours. On the other hand, with respect to Comparative Compound 1, after 3 hours, the unchanged rest in plasma was below the detection limit.

Experimental Example 3: Changes in plasma concentration after oral administration of dog

 Using a male beagle dog, the compound obtained in Example 45 was orally administered at a ffl amount of 1 OmgZkg under fasting conditions, and blood was collected at 30 minutes and at i, 2, 4, and 7 hours after the administration. The pretreatment of the plasma was performed by a general solid phase extraction method, and the analysis of the obtained sample was performed by HPLC using an ODS column (solvent: acetonitrile / hydrogen potassium dihydrogen phosphate). Aqueous solution).

 The result is shown in figure 2. As is evident from FIG. 2, the compound of the present invention showed the maximum concentration (6.9 gZml) about 2 hours after administration, and the plasma concentration decreased relatively rapidly over the next 7 hours after administration. No change was detected at 7 hours.

Formulation Example 1: Tablet

 (1) Compound of the present invention (I) 1 Omg

(2) Fine particles for direct hit No.209 (Fuji Chemical Co., Ltd.) 46 mg Magnesium aluminate metasilicate 20% Tropical starch 30%

 Lactose 5 0%

 (3) Microcrystalline cellulose 24.0 mg

 () CarboxymethylcelluloseCalcium 4-0 mg

 (5) Magnesium stearate 0.4 mg

 (1), (3) and (4) are all passed through a 10 () 0 mesh sieve in advance. These (1), (3), (4) and (2) were each dried to reduce the water content to a certain level, and then mixed at the above weight ratio using a mixer. (5) is added to the mixed powder of uniform quality and mixed for a short time (30 seconds), and the mixed powder is tabletted (punch: 6.3 mm0, 6.0 mmR) to obtain .1 tablet 8 5 mg tablets were obtained.

 The tablet may be coated with a commonly used gastrosoluble film coating (eg, polyvinyl acetal getylamino acetate) or an edible colorant, if necessary.

Formulation Example 2: Capsule

 (1) Compound of the present invention (I) 50 g

 (2) Lactose 9 3 5 g

 (3) Magnesium stearate 15 g

 After weighing each of the above components, they were mixed uniformly, and the mixed powder was filled into hard gelatin capsules at 200 mg each.

Production Example 3: Injection

 (1) 5 mg of the hydrochloride of the compound (I) of the present invention

 (2) Sucrose I 0 0 mg

 (3) Saline 〖0 m 1

After filtering the above mixture with a membrane filter, sterilization filtration is performed again, and the filtrate is aseptically dispensed into vials, filled with nitrogen gas, sealed, and sealed with an intravenous injection agent. did. Industrial applicability

 INDUSTRIAL APPLICABILITY The heterocyclic amide compound of the present invention and a pharmacologically acceptable salt thereof have excellent chymase group inhibitory activity against mammals including human, and can be administered orally and parenterally. . Therefore, it is useful as a chimase inhibitor and is useful for the prevention and treatment of various diseases caused by chimase, including various diseases caused by angiotensin II. This application is based on Japanese Patent Application No. 3535572 filed in Japan and its contents are incorporated in full herein.

Claims

The scope of the claims

 1. Formula (I)

[Wherein, R is a hydrogen atom, alkyl, — CH0, -C 0 NH2, -COR ¹ , — C

◦ OR ^1, one CONHORl, one CONHR ^1, - CONRl R) ,, one C_〇_NH ^{S 02 R 1, -C 0 SR} 1, -C0C0R2, - C 0 C 00 R2, - C 0 HC

◦ OR ² , -C 0 C 0 NR ³ , 1 C SXRl, -SO 2 WRl, -SO 2 N Rl Rl 'or 1 SO2 E (where Rl and Rl' may be the same or different, Independently represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl, and R ² , R ³ , and R 4 may be the same or different Each independently represents a hydrogen atom, alkyl or arylalkyl; one NR ³ R4 may together represent a heterocycle; X represents a single bond, one NH—, — 0— or one S— , W represents a single bond, —NH—, —NHC0—, one NHC00— or one NHC0NH—, and E represents a hydroxyl group or an amino).

R5, R6, or _R 7 is was or hydrogen atoms may independently be the same or different represent an alkyl, or R ^5, R ^fi, 1 Tsu of R ⁷ Ariru, Ari Ruarukiru, § reel alkenyl Represents a heteroaryl, a heteroarylalkyl or a heteroarylalkenyl, and the rest represents a hydrogen atom;

M represents a carbon atom or a nitrogen atom. However, when M is a nitrogen atom, Ft ⁶ does not exist. Absent,

 Y represents cycloalkyl, aryl or heteroaryl,

R8 represents a hydrogen atom, alkyl or arylalkyl;

R9 and R10 may be the same or different and each independently represents a hydrogen atom, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroaryl Monoalkyl or heteroarylalkenyl, and NNR9R10 may be taken together to indicate a heterocycle;

Z is the equation (i)

One (0

(Wherein, RLL, Rl2 are the same or different and are well each independently a hydrogen atom, an alkyl, § reel alkyl or to indicate the heteroarylalkyl and R ¹¹ and Rl2 is - carbons turned cord 2 May represent a methylene chain of up to 6, m represents an integer of 1 to 6), formula (ii)

{Wherein Q represents 10—, 1—, a direct bond or a formula: NR13— (wherein R ¹³ represents a hydrogen atom, alkyl or arylalkyl), and P and r are the same or Which may be different and each independently represents an integer of 0 to 3) or a formula (ii i) (CH ₂ ) _p- ~ (V— Q— (CH ₂ ) _r — (Hi)

(Wherein, s and!; Represent an integer such that their sum is 1 to 6, and Q, p and r are as defined above).

n represents 0 or 1.

Of the above groups, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, heterocyclylalkyl are II-substituted groups, respectively. May be included)

Or a pharmacologically acceptable salt thereof.

 1. In the formula (I), Y is;! 2. The heterocyclic amide compound according to claim 1, which is an aryl which may have a substituent, or a pharmacologically acceptable salt thereof.

 3. The heterocyclic amide compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein Z in the formula (I) is a group represented by the formula (i).

4. In formula (I), one of R ⁵ , R ⁶ , and R ⁷ may have a substituent, and the rest is a hydrogen atom. However, when M is a nitrogen atom, R ⁶ does not exist. 4. The heterocyclic amide compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, which is a compound thereof.

 5. A pharmaceutical composition comprising the heterocyclic amide compound according to any one of claims I to 4, or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.

 6. The pharmaceutical composition according to claim 5, which is a chymase inhibitor.