KR100811865B1 - Pyrimidinone derivatives or pyridazinone derivatives for inhibition of factor viia activity - Google Patents

Abstract

A novel pyrimidinone based or pyridazinone based compound is provided to show excellent inhibitory activity on factor VIIa relating to blood coagulation mechanism. A compound having the inhibitory activity on factor VIIa is represented by the formula(I), wherein A is a group represented by the structural formula(1) or (2); R^1 is C6-10 aryl which may be substituted by at least one selected from the group consisting of nitro, amino, hydroxy, carboxy, and C2-7 alkylcarboxy and may include at least one hetero atom selected from the group N, O or S at an aromatic ring; R^2 is H, C1-6 alkyl, or a cyclic compound which is selected from the group consisting of phenyl, pyridine, pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isothiazole, pyridazine, pyrimidine, pyrazine, naphthalene, isoquinoline, benzofuran, benzothiophene and indole and may be substituted by one or two substitutent(s) selected from the group consisting of C1-4 alkyl, halogen, CN, OH, CF3, OR, CO2R and NHR(where R is C1-4 alkyl); each Q^1 and Q^2 is independently H or C1-6 alkyl; each m and n is independently an integer from 0 to 3; L is -(C=O)-,-CO2-,-CONH-,-CONR^4, -CH2-, -O-, -NR^4-, -N(R^4)(C=O)-, or -N(R^4)(SO2)-(where R^4 is C1-10 alkyl); and R^3 is amidino, guanidino, aminomethyl, amino, cyano, cyanomethyl, hydroxy, -OCH2CO2R^5, hydroxy methyl, or C6-10 aryl substituted by chloro(where R^5 is H, methyl, ethyl, or t-butyl). A pharmaceutical composition for preventing blood coagulation or treating thrombosis comprises the compound of the formula(1), a hydrate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an effective ingredient.

Description

Pyrimidinone derivatives or pyridazinone derivatives for inhibition of factor VIIa activity}

The present invention relates to a pyrimidinone-based or pyridazinone-based compound having a novel structure and a method for producing the same, and the present invention also provides a method for preventing blood clotting and various thrombosis containing a pyrimidinone-based or pyridazinone-based compound having a new structure as an active ingredient. It relates to a composition for treatment.

The blood clotting process involves many serine proteases and cofactors. The thrombus generation mechanism begins with the activation of factor VIIa (FVIIa) with tissue factor (TF) to form the TF.FVIIa complex. TF.FVIIa activates factors IX and X to make factor Xa (factor Xa, FXa), an important component of blood coagulation, and activated factor Xa converts prothrombin, the last stage of blood coagulation, to thrombin. The resulting thrombin activates platelets and converts fibrinogen to fibrin, which is crosslinked by polymerization and factor XIII to form insoluble clots. Thrombin also accelerates blood coagulation by activating factors V and VIII, which are involved in the blood coagulation process. Therefore, since thrombin inhibitors can inhibit platelet activity and prevent fibrin production, direct thrombin generation has been preceded by the development of thrombin inhibitors for preventing blood coagulation and treating various thrombosis. However, in the results of clinical trials, thrombin inhibitors effectively suppressed thrombin in blood but did not suppress thrombin generation reactions, and thus did not show sufficient antithrombotic effect. Therefore, excessive inhibitors should be administered for thrombin inhibition and many hemorrhagic effects have been reported.

In contrast to thrombin, factor Xa (FXa) does not affect platelet function and is specifically involved in blood coagulation, so there is less concern for side effects of bleeding than thrombin inhibitors. In addition, tissue factor / factor FVIIa (TF.FVIIa) complexes have recently become an alternative to the treatment of new thrombosis (Curr. Med. Chem., 2004, 11, 2535). Tissue factor / factor FVIIa (TF.FVIIa) complexes limit the initial blood coagulation mechanism since they are always present on the surface of vascular cell membranes. Thus, unlike the thrombin or factor Xa inhibitors, factor VIIa inhibitors act directly on the site of blood vessel damage and inhibit the foremost stage of the blood coagulation pathway, and thus do not affect physiological hemostatic action. In addition, factor VIIa is present at lower concentrations than thrombin or factor Xa, so treatment with low drug concentrations can significantly reduce the risk of bleeding side effects.

For this reason, the necessity of inhibitors of factor VIIa is gradually emerging, and researches on the development of inhibitors of factor VIIa are being conducted by leading research institutes.

PHA-927 compound (US 6664255B1; J. Med. Chem., 2003, 46, 4050), a pyrazinone derivative developed by Pharmacia corp., Exhibited an IC ₅₀ = 16 nM activity against the TF.FVIIa complex. It is known to show good selectivity for thrombin and Fxa.

PHA-927의 구조

Structure of PHA-927

Benzimidazole-structured FVIIa inhibitors (Bioorg. Med. Chem. Lett., 2006, 16, 2243), developed by Celera Genomics, introduced two carboxylic acid groups with high efficacy (Ki = 4 nM) and were used in rats. It has been announced that oral absorption is possible.

벤즈이미다졸 구조의 FVIIa 억제제

FVIIa inhibitors of benzimidazole structure

An object of the present invention is to provide a pyrimidinone-based or pyridazinone-based compound, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a blood clotting prevention or thrombosis containing a pyrimidinone-based or pyridazinone-based compound of the new structure, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. Another object is to provide a therapeutic pharmaceutical composition.

Under this technical background, the present inventors have made intensive studies to develop a new compound having excellent FVIIa inhibitory activity, and as a result, have found that the compound of formula (I) meets this purpose and have completed the present invention.

Accordingly, the subject of the present invention is a compound represented by the following general formula (I) having excellent inhibitory activity against FVIIa and physiologically acceptable salts thereof.

[Formula I]

또는

이고;A is

or

ego;

R ¹ is C ₆ to C ₁₀ unsubstituted or substituted with one or more substituents selected from nitro (-NO ₂ ), amino, hydroxy, carboxy (-CO ₂ H) or alkyl carboxy of C ₂ to C ₇ Aryl, wherein the aryl may include one or more heteroatoms selected from nitrogen, sulfur, or oxygen in the aromatic ring;

R ² is hydrogen, alkyl of C ₁ to C ₆ , or a cyclic compound, phenyl, pyridine, pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isoazole, pyridazine , Pyrimidine, pyrazine, naphthalene, quinoline, isoquinoline, benzofuran, benzothiophene or indole, the cyclic compound is C ₁ -C ₄ alkyl, halogen atom, -CN, -OH, -CF ₃ ,- Or may be substituted with one or two substituents independently selected from OR, -CO ₂ R or -NHR, wherein R of the substituents represents C ₁ -C ₄ alkyl;

Q ¹ and Q ² are independently hydrogen or alkyl of (C ₁ -C ₆ );

m and n are independently integers from 0 to 3;

L is-(C = O)-,-CO ₂ -,-CONH-,-CONR ⁴ , -CH _2- , -O-, -NR ^4- , -N (R ⁴ ) (C = O)-, Or -N (R ⁴ ) (SO ₂ )-, wherein R ⁴ is C ₁ -C ₁₀ alkyl;

R ³ is substituted by amidino, guanidino, aminomethyl, amino, cyano (-CN), cyanomethyl, hydroxy, -OCH ₂ CO ₂ R ⁵ , hydroxymethyl, chloro Selected from C ₆ to C ₁₀ aryl, R ⁵ is selected from hydrogen, methyl, ethyl or t-butyl, and the aryl is selected from nitrogen, sulfur or oxygen in the aromatic ring. It may include.

Unless stated otherwise, the term alkyl is preferably an acyclic saturated hydrocarbon moiety having 1 to 6 carbon atoms, which may be linear or branched, (C ₂ to C ₆ ) -alkenyl and (C ₂ to C ₆ ) Acyclic unsaturated hydrocarbon residues having 2 to 6 carbon atoms which may be linear or branched, such as alkynyl, and cyclic alkyl groups having 3 to 8 ring carbons.

Unless stated otherwise, an alkyl group is generally unsubstituted or substituted by one or more, for example 1 to 4, identical or different substituents, regardless of the particular substituents attached to the alkyl groups described in the definition of Formula (I). Can be substituted. Certain substituents present on the substituted alkyl moiety may be present at the desired position so long as the substitution does not lead to unstable molecules. Examples of specific kinds of substituents include halogen atoms, hydroxy, carboxy groups and the like.

Among the compounds of the formula (I) according to the invention, preferred compounds are

R ¹ is unsubstituted or substituted with one or more substituents selected from nitro (-NO ₂ ), amino, hydroxy, carboxy (-CO ₂ H) or alkyl carboxy of C ₂ to C ₇ C ₆ -C ₁₀ aryl, wherein the aryl is selected from phenyl, thiophene, pyridine, pyrazole, oxazole or aminothiazole;

R ² is selected from methyl, isopropyl, phenyl, pyridine, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole or isoazole;

Q ¹ and Q ² are independently hydrogen or alkyl of (C ₁ -C ₄ );

m and n are independently integers, 0, 1, 2,

L is -CO ₂ -,-CONH-,-CONR ⁴ , -N (R ⁴ ) (C = O)-, or -N (R ⁴ ) (SO ₂ )-, wherein R ⁴ is C ₁ -C ₁₀ alkyl;

R ³ is selected from amidino, aminomethyl, amino, cyano (-CN), cyanomethyl, hydroxy, -OCH ₂ CO ₂ R ⁵ , hydroxy methyl, aryl substituted chloro, and R ⁵ is selected from hydrogen, methyl, ethyl or t-butyl and the aryl of R ³ is selected from phenyl, thiophene, pyridine or indole.

Among the compounds of the formula (I) according to the invention, more preferred compounds are

R ¹ is C ₆ to C ₁₀ unsubstituted or substituted with one or more substituents selected from nitro (-NO ₂ ), amino, hydroxy, carboxy (-CO ₂ H) or alkyl carboxy of C ₂ to C ₇ Aryl, wherein the aryl is selected from phenyl, thiophene, pyridine or aminothiazole;

R ² is selected from methyl, isopropyl, phenyl, pyridine, thiophene, oxazole, pyrazole, or thiazole;

Q ¹ and Q ² are independently hydrogen, methyl;

L is -CONH-;

m and n are independently 0, 1, 2 as integers;

R ³ is selected from amidino, aminomethyl, amino, cyano (-CN), cyanomethyl, hydroxy, -OCH ₂ CO ₂ R ⁵ , hydroxy methyl, aryl substituted chloro, and R ⁵ is selected from hydrogen, methyl, ethyl or t-butyl and the aryl of R ³ is selected from phenyl, thiophene, or pyridine.

Representative compounds of the compounds of formula (I) include the following.

N- (4-cyanobenzyl) -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] Acetamide;

N- [4- (hydroxycarbamimidoyl) -benzyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyri Midin-5-yl] -acetamide;

N- (4-carbamimidoylbenzyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl ] -Acetamide;

N- [4- (N-hydroxycarbamimidoyl) -benzyl] -2- [1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidine-5- General] -acetamide;

N- (4-cyanobenzyl) -2- (1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl) -acetamide;

N- (4-N-carbamimidoylbenzyl) -2- (1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl) -acetamide ;

N- [4-N- (hydroxycarbamimidoyl) -benzyl] -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl) -acet Amides;

N- (4-N-carbamimidoylbenzyl) -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl) -acetamide;

N- [3- (N-hydroxycarbamimidoyl) -benzyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro -Pyrimidin-5-yl] -acetamide;

N- [5- (N-hydroxycarbamimidoyl) -thiophen-2-ylmethyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo- 1,6-dihydro-pyrimidin-5-yl] -acetamide;

2- [4- (3-aminophenyl) -1-isobutyl-2-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl] -N- (3-carbamimidoylbenzyl) Acetamide;

2- [4- (3-aminophenyl) -1-isobutyl-1-ethyl-2-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl] -N- (4-carbam Imidoylbenzyl) -acetamide;

2- [4- (3-aminophenyl) -2-methyl-6-oxo-1- (2-pyridin-2-yl-ethyl) -1,6-dihydro-pyrimidin-5-yl] -N -(4-carbamimidoylbenzyl) -acetamide;

N- (5-chloro-2-hydroxymethylbenzyl) -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidine -5-yl] -acetamide;

N- (5-chloro-2-hydroxymethylbenzyl) -2- (1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl)- Acetamide;

N- (5-chloro-2-hydroxymethylbenzyl) -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl] -acetamide;

N- (5-chloro-2-cyanomethylbenzyl) -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl] -acetamide;

N- (5-chloro-2-hydroxybenzyl) -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydroxypyrimidine- 5-yl] -acetamide;

N- (5-chloro-2-hydroxybenzyl) -2- [1-isobutyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydroxy-pyrimidin-5-yl ] -Acetamide;

[4-Chloro-2-({2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl]- Acetylamino} -methyl) -phenoxy] -acetic acid ethyl ester;

[4-Chloro-2-({2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl]- Acetylamino} -methyl) -phenoxy] -acetic acid;

[2-({2- [4- (3-aminophenyl) -1-isobutyl-2-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetylamino} -4 -Chloro-phenoxy) -acetic acid;

N- (4-cyanobenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acetamide;

N- (4-carbamimidoylbenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acetamide;

N- (5-Chloro-2-hydroxymethylbenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acetamide;

N- (5-Chloro-2-cyanomethylbenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acetamide;

N- (4-carbamimidoylbenzyl) -2- [2- (4-methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2,3-dihydro-pyridazine-4- General] -acetamide;

2- [5- (3-aminophenyl) -2- (4-methoxybenzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -N- (4-carbamimidoylbenzyl ) -Acetamide;

N- (3-carbamimidoylbenzyl) -2- [2- (4-methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2,3-dihydro-pyridazine-4- General] -acetamide;

2- [5- (3-aminophenyl) -2- (4-methoxybenzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -N- (3-carbamimidoylbenzyl ) -Acetamide;

N- (5-Chloro-thiophen-2-ylmethyl) -2- [2- (4-methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2,3-dihydro- Pyridazin-4-yl] -acetamide;

2- [5- (3-aminophenyl) -2-ethyl-3-oxo-2,3-dihydro-pyridazin-4-yl] -N- (4-carbamimidoylbenzyl) -acetamide; And

2- [5- (3-aminophenyl) -2-phenethyl-3-oxo-2,3-dihydro-pyridazin-4-yl] -N- (4-carbamimidoylbenzyl) -acetamide.

The compounds of formula I according to the invention may also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and tartaric acid. Organic carbonic acid, such as formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid Acid addition salts formed by sulfonic acids and the like, and the like.

인 피리미디논계 화합물과 A가

인 피리다지논계 화합물로 구분할 수 있는데, 상기 피리다지논계 화합물은 하기 반응식 1에 도시한 바와 같은 역합성(retrosynthesis)과정을 통해서 제조할 수 있으며, 상기 피리미디논계 화합물은 하기 반응식 2 에 도시한 바와 같은 역합성과정을 거쳐서 제조할 수 있다. Compounds of formula I as defined above, depending on their structure, specifically

Phosphorus pyrimidinone compound and A

Phosphoryl pyridazinone-based compounds, which may be prepared by the reverse synthesis (retrosynthesis) process as shown in Scheme 1, the pyrimidinone-based compound is shown in Scheme 2 It can be prepared through the same reverse synthesis process.

[Scheme 1] Reverse synthesis of the compound of the pyridazinone skeleton

Compound [2] of the pyridazinone skeleton of the compound of formula (I) is synthesized through the usual amidation reaction of an organic carboxylic acid compound [3] and an amine [4], which is a compound [3] of compound [5] It can be prepared through a conventional hydrolysis reaction. Compound [5] can be synthesized through Suzuki coupling of ester compound [7] (R '= methyl, ethyl, tertiary butyl, benzyl) with organic boronic acid [6]. Compound [7] can be obtained by the alkaline reaction of compound [8] with compound [9] having a leaving group (LG). Compound [8] can be obtained by several units of commercially available compound [10]. Can be obtained through the operation process.

[Reaction Scheme 2] Reverse Synthesis of Compound of Pyrimidinone Skeleton

Compound [11] of the pyrimidinone skeleton in the compound of formula (I) is synthesized through a conventional amidation reaction of an organic carboxylic acid compound [12] and an amine [4], which is a compound [12] of compound [13] It may be prepared through a conventional hydrolysis reaction. Compound [13] can be obtained by alkaline reaction with compound [9] having a leaving group (LG), and compound [14] is β-chitoester [16] (R '= methyl, ethyl, 3 Tea butyl, benzyl) and amidine [15]. Compound [16] can be obtained by converting a commercially available organic acid chloride or its precursor organic acid into organic acid chloride through several unit operations.

In the above-described preparation method, known coupling reagents that can be used for the amination reaction include dicyclohexylcarbodiimide (DCC), 3-ethyl-3 '-(dimethylamino) -propylcarbodiimide (EDC), bis- (2-oxo-3-oxazolidinyl) -phosphinic chloride (BOP-Cl), diphenylphosphoryl azide (DPPA), isobutylchloroformate, O- (7-azabenzo Triazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) and the like can be mentioned, but are not limited to these.

Known reagents that can be used for the hydrolysis reaction in the above-described preparation method may mention hydroxides of alkali metals (lithium, sodium, potassium, cesium), tetrabutylammonium hydroxide, hydrochloric acid, trifluoroacetic acid and the like. May be, but is not limited to these.

After completion of the reaction according to the invention described above, the separation of the general mixture can be separated by conventional post-treatment methods such as tube chromatography, recrystallization, HPLC.

The compounds of formula (I) according to the invention are FVIIa inhibitors with new structures and excellent potency. Accordingly, the present invention provides a pharmaceutical composition for the prevention of blood clotting or for the treatment of thrombosis, containing as an active ingredient a compound of formula (I), another suitable derivative thereof (such as a prodrug) or a pharmaceutically acceptable salt thereof. The compound of formula (I) encompasses all stereoisomers, optical isomers and racemates thereof, as well as mixtures comprising different enantiomers in different proportions, when isomers and enantiomers are present, solvates and It also covers hydrates.

Preferred activities of the compounds of formula (I) of the present invention have a Ki for TF / FVIIa inhibition measured by assay methods known in the art of 10 uM or less, particularly preferably 1 uM or less.

When the compound of the present invention is to be clinically administered to obtain the desired antithrombotic effect, the active compound of formula (I) may be administered simultaneously with at least one component selected from thrombolytics and platelet inhibitors. Thrombolytic agents that can be administered in combination with the compounds of the present invention in this manner include T-PA, urokinase, Streptokinase, and the like, and platelet activity inhibitors include aspirin, Ticlopidin, Clopidogrel, 7E3 monoantibodies, and the like.

However, the compound-containing preparation according to the present invention for the purpose of treating and preventing thrombus is not limited to the above-mentioned one, and any agent useful for the treatment and prevention of thrombus may be included.

Any one selected from a compound of formula (I), a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient in the pharmaceutical composition for preventing blood clotting or treating thrombosis according to the present invention. The above-mentioned effective amount can be prepared by combining with a pharmaceutically acceptable carrier. Pharmaceutical compositions also include fillers, disintegrants, binders, suspending agents, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, dyes, fragrances, fragrances, thickeners, diluents, buffers, solubilizers, to obtain sustained release effects. Auxiliary materials such as reagents, salts for changing the osmotic pressure, coating agents, antioxidants may be further included.

The active ingredient according to the present invention may vary depending on the specific compound, the method of administration, the subject to be treated, and the disease to be treated, as well as the dosage of the pharmaceutical composition for preventing blood clotting or thrombosis used to achieve a therapeutic effect according to the present invention. Usually 0.01 mg / Kg to 1 mg / based on one or more compounds of Formula I and / or physiologically acceptable salts thereof, prodrugs thereof, solvates, hydrates thereof, or isomers thereof It is about Kg, and may be administered once or several times a day, and the dosage may be variously adjusted according to the weight, age, sex, health condition, diet, time of administration, administration method, excretion rate, and severity of disease. The method of administration is in the form of pills, capsules, granules, powders, solutions and suppositories that can be administered anal orally or parenterally (eg intravenously). Intracutaneous, intraperitoneal, topical or visual route).

Hereinafter, the present invention will be described in more detail by the following Preparation Examples and Examples. However, these preparation examples and examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited thereto.

Reagents frequently used in the following Preparation Examples and Examples may be abbreviated as follows.

PMB: Paramethoxybenzyl Et: Ethyl

Me: Methyl DMSO: Dimethyl Sulfoxide

CAN: Cerium ammonium nitrate tBu: t-butyl (tertiary butyl)

AcOH: acetic acid BOC (Boc): t-butyloxycarbonyl

CBZ (Cbz): benzyloxycarbonyl DCM: dichloromethane

DMF: Dimethylformamide THF: Tetrahydrofuran

TEA: triethylamine DIPEA: diisopropylethylamine

EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

HOBt: Hydroxybenzotriazole MeOH: Methanol

EtOH: Ethanol

Preparation Example 1 Preparation of (5-Chloro-3-oxo-2,3-dihydro-pyridazin-4-yl) -acetic acid ethyl ester

Producing a pyridazin-3-one - prepared in Example 1-1), 4,5-dichloro-2- (4-methoxybenzyl) -2 H

Sodium hydride (60%, 10.2 g, 255 mmol) was suspended in dimethylformamide (100 mL), followed by 4,5-dichloro-3-hydroxypyridazine (35.0 g, 212 mmol) at 0 ° C. Put and stirred for 10 minutes. 4-methoxybenzyl chloride (34.5 mL, 255 mmol) was added slowly, and the temperature was raised to room temperature and stirred for 3 hours. The reaction solution was poured into saturated ammonium chloride solution (500 mL), extracted with ethyl acetate (200 mL x 2), and then the organic layer was washed with water (100 mL x 2) and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, passed through silica gel (depth 10 cm x 12 cm in diameter) with dichloromethane / n-hexane (1: 1, 1 L), concentrated and recrystallized from n-hexane (500 mL) to give the title compound. (49.8 g, 82%) was obtained as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.73 (s, 1H), 7.37 (d, 2H, J = 8.8 Hz), 6.82 (d, 2H, J = 8.8 Hz), 5.23 (s, 2H), 3.75 (s, 3 H).

Preparation Example 1-2 Preparation of 2- [5-chloro-2- (4-methoxybenzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -malonic acid diethyl ester

Diethyl malonate (68.0 mL, 447 mmol) was dissolved in diisopropyl ether (800 mL), and sodium ethoxide (30.4 g, 447 mmol) was added at 0 ° C. and stirred at room temperature for 30 minutes. Compound (51.0 g, 179 mmol) obtained in Preparation Example 1-1) was added dropwise and stirred under reflux for 3 hours. The reaction solution was cooled to room temperature, poured into 1 N aqueous hydrochloric acid solution (500 mL), and the organic layer was separated. The mixture was extracted with an aqueous layer with ethyl acetate (200 mL), and the organic layers were collected, washed again with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the reaction mixture was concentrated under reduced pressure and subjected to column chromatography (n-hexane / ethyl acetate, 4/1 → 1/1) to give the title compound and the isomer (= 2- [5-chloro-1- (4-methoxybenzyl) 6-oxo-1,6-dihydro-pyridazin-4-yl] -malonic acid diethyl ester) was obtained. Recrystallization from diethyl ether (300 mL) gave the title compound (27.0 g, 36.9%) as a white solid, which gave a mixture of the title compound and the isomer (39.0 g, 3: 7).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.75 (s, 1H), 7.36 (d, 2H, J = 8.4 Hz), 6.85 (d, 2H, J = 8.4 Hz), 5.23 (s, 2H), 5.06 (s, 1 H), 4.25 (q, 2 H, J = 7.2 Hz), 3.78 (s, 3H), 1.23 (t, 3H, J = 7.2 Hz).

Preparation Example 1-3) Preparation of [5-Chloro-2- (4-methoxybenzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -acetic acid ethyl ester

The compound (27.0 g, 66.0 mmol) obtained in Preparation Example 1-2) was dissolved in dimethyl sulfoxide (150 mL), followed by addition of water (5 mL), followed by heating to 135 ° C., and stirring for 2 hours. The reaction solution was cooled, and water (300 mL) was added thereto, followed by extraction with ethyl acetate (150 mL x 2). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, column chromatography (n-hexane / ethyl acetate, 4/1-> 2/1) was carried out to obtain the title compound (22.1 g, 99%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.75 (s, 1H), 7.37 (d, 2H, J = 8.4 Hz), 6.85 (d, 2H, J = 8.4 Hz), 5.23 (s, 2H), 4.18 (q, 2H, J = 7.2 Hz), 3.78 (s, 3H), 3.75 (s, 2H), 1.25 (t, 3H, J = 7.2 Hz).

Preparation Example 1-4) Preparation of (5-chloro-3-oxo-2,3-dihydro-pyridazin-4-yl) -acetic acid ethyl ester

Compound (12.0 g, 35.6 mmol) obtained in Preparation Example 1-3) was dissolved in acetonitrile (200 mL) and water (50 mL), and then ammonium cerium nitrate (78. 1 g, 142 mmol) was added thereto, and room temperature. Stirred for 5 hours. The solvent was concentrated under reduced pressure, saturated brine (100 mL) was added, and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated sodium bicarbonate (100 mL) and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, column chromatography (n-hexane / ethyl acetate, 4/1-> 1/1) was carried out to obtain the title compound (7.31 g, 95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.6 (br s, 1H), 7.81 (s, 1H), 4.20 (q, 2H, J = 7.2 Hz), 3.78 (s, 3H), 1.28 (t, 3H, J = 7.2 Hz).

[Production Example 2]

Preparation Example 2-1 Preparation of [2-Methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid t-butyl ester

Preparation Example 2-1-1) Preparation of 3- (3-nitrophenyl) -3-oxo-propionic acid ethyl ester

Suspend ethyl potassium malonate (21.4 g, 126 mmol) in acetonitrile (150 mL) and add triethylamine (18.3 mL, 132 mmol) and anhydrous magnesium chloride (14.2 g, 149 mmol) at 0 ° C. It stirred at room temperature and nitrogen atmosphere for 150 minutes. 3-nitrobenzoyl chloride (11.1 g, 59.8 mmol) was slowly added thereto, followed by stirring at room temperature for 16 hours. The reaction solvent was concentrated under reduced pressure, 1N aqueous hydrochloric acid solution (100 mL) was added, followed by extraction with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (100 mL) and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, column chromatography (n-hexane / ethyl acetate, 4/1) was carried out to obtain the title compound (14.1 g, 95%) as a pale yellow solid.

Preparation Example 2-1-2) Synthesis of 2- (3-nitrobenzoyl) -succinic acid 4-t-butyl ester 1-ethyl ester

Sodium hydride (60%, 1.21 g, 50.6 mmol) was suspended in dimethylformamide (100 mL), followed by compound (10.0 g, 42.2 mmol) and bromo obtained at Preparation Example 2-1-1 at 0 ° C. After t-butyl acetate was added sequentially, the temperature was raised to room temperature, and the mixture was stirred for 8 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (100 mL) was added followed by extraction with diethylether (100 mL x 2). The combined organic layers were washed with water (100 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, column chromatography (n-hexane / ethyl acetate, 4/1) was carried out to obtain the title compound (13.5 g, 91%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.91 (s, 1H), 8.49-8.43 (m, 1H), 8.40-8.35 (m, 1H), 7.72 (t, 1H, J = 8 Hz), 4.83 (dd, 1H, J = 9.2 Hz, 5.6 Hz), 4.16 (q, 2H, J = 7.2 Hz), 3.17 (dd, 1H, J = 9.2 Hz, 13.2 Hz), 2.98 (dd, J = 13.2 Hz, 5.6 Hz), 1.41 (s, 9H), 1.18 (t, 3H, J = 7.2 Hz).

Preparation Example 2-1-3) Preparation of [2-Methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid t-butyl ester

Sodium (1.32 g, 57.4 mmol) was dissolved in ethanol (80 mL) at 0 ° C., and hydrochloride (5.41 g, 57.4 mmol) of acetamidine was added, and the compound obtained in Preparation Example 2-2 (4.02 g, 11.4 mmol) was added. ) Was dissolved in ethanol (20 mL) and slowly added dropwise. The reaction temperature was raised to 40 ° C and stirred for 16 hours. The reaction solvent was concentrated under reduced pressure, 1N aqueous hydrochloric acid solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure and recrystallized from diethyl ether (100 mL) to obtain the title compound (2.85 g, 72%) as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 13.0 (br s, 1H), 8.46 (t, 1H, J = 2 Hz), 8.31 (ddd, 1H, J = 8 Hz, 2 Hz, 1.2 Hz), 7.91 (dt, J = 8 Hz, 1.2 Hz), 7.65 (t, 1H, J = 8 Hz), 3.45 (s, 2H), 2.54 (s, 3H), 1.48 (s, 9H).

Preparation Example 2-2 Preparation of [4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid t-butyl ester

The title compound was prepared in the same manner as in Preparation Example 2-1, except that formamidine was used instead of acetamidine.

Preparation Example 2-3 Preparation of [2-Methyl-4-phenyl-6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid t-butyl ester

The title compound was prepared in the same manner as in Preparation Example 2-1, except that benzoyl chloride was used instead of 3-nitrobenzoyl chloride.

Preparation Example 2-4 Preparation of [4-phenyl-6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid t-butyl ester

The title compound was prepared in the same manner as in Preparation Example 2-1, except that formamidine and benzoyl chloride were used instead of acetamidine and 3-nitrobenzoyl chloride.

[Production Example 3]

Preparation Example 3-1) [1-Isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid t-butyl ester Manufacture

The compound obtained in Preparation Example 2-1 (2.85 g, 8.25 mmol) was dissolved in dimethylformamide (30 mL), and cesium carbonate (4.03 g, 12.4 mmol) and isobutyl bromide (1.79 mL, 16.5 mmol) were added dropwise. Stir at 50 ° C. for 16 h. The reaction solution was added to saturated aqueous ammonium chloride solution (50 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and subjected to column chromatography (n-hexane / ethyl acetate, 6/1 → 3/1) to give a title compound ( 1.15 g, 35%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.47 (br s, 1H), 8.32-8.25 (m, 1H), 7.91 (dd, 1H, J = 8 Hz, 1.2 Hz), 7.64 (t, 1H, J = 8 Hz), 3.93 (d, 2H, J = 7.6 Hz), 3.42 (s, 2H), 2.61 (s, 3H), 2.28-2.17 (m, 1H), 1.46 (s, 9H), 1.01 ( d, 6H, J = 6.8 Hz).

Preparation Example 3-2) Preparation of [1-isobutyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-5-yl) -acetic acid t-butyl ester

The title compound was prepared in the same manner as in Preparation Example 3-1, except that the compound obtained in Preparation Example 2-2 was used.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 8.30 (d, 1H, J = 8.0 Hz), 8.07 (s, 1H), 7.92 (d, 1H, J = 8.0 Hz), 7.64 (t, 1H, J = 8.0 Hz), 3.79 (d, 2H, J = 7.4 Hz), 3.46 (s, 2H), 2.25-2.17 (m, 1H), 1.48 (s, 9H), 0.95 (d, 6H, J = 7.4 Hz).

Preparation Example 3-3) (1-Isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-5-yl) -acetic acid t-butyl ester

The title compound was prepared in the same manner as in Preparation Example 3-1, except for using the compound obtained in Preparation Example 2-3.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.53-7.50 (m, 2H), 7.43-7.41 (m, 3H), 3.91 (d, 2H, J = 7.2 Hz), 3.43 (s, 3H), 2.30- 2.10 (m, 1H), 1.44 (s, 9H), 1.00 (d, 6H, J = 6.4 Hz)

Preparation Example 3-4) (1-Isobutyl-6-oxo-4-phenyl-1,6-dihydro-5-yl) -acetic acid t-butyl ester

The title compound was prepared in the same manner as in Preparation Example 3-1, except for using the compound obtained in Preparation Example 2-4.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.43-7.40 (m, 2H), 7.33-7.29 (m, 3H), 3.65 (d, 2H, J = 8.0 Hz), 3.38 ( s, 2H), 2.14-2.05 (m, 1H), 1.33 (s, 9H), 0.86 (d, 6H, J = 6.4 Hz)

Preparation Example 3-5) [1-Ethyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid ethyl ester

The title compound was prepared in the same manner as in Preparation Example 3-1, except that ethyl bromide was used instead of isobutyl bromide.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (s, 1H), 8.28 (d, 1H, J = 8.4 Hz), 7.88 (d, 1H, J = 7.6 Hz), 7.63 (t, 1H, J = 8.4 Hz), 4.21-4.13 (m, 4H), 3.48 (s, 2H), 2.64 (s, 3H), 1.39 (t, 3H, J = 7.2 Hz), 1.28 (t, 3H, J = 7.2 Hz)

Production Example 4 [2-Methyl-4- (3-nitrophenyl) -6-oxo-1- (2-pyridin-2-yl-ethyl) -1,6-dihydro-pyrimidine-5- Sun] -ethyl acetate

[2-Methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid ethyl ester (preparation 2-1 compound) (252 mg, 0.79 mmol) was dissolved in toluene (3 mL), and 2-vinylpyridine (0.26 mL, 2.38 mmol) was added dropwise and refluxed and stirred for 8 hours. 2-vinylpyridine (0.26 mL, 2.38 mmol) was added dropwise to the reaction solution, which was further refluxed and stirred for 8 hours. The reaction solution was concentrated and subjected to column chromatography (n-hexane / ethyl acetate, 1/2 → ethyl acetate / methanol, 20/1) to give the title compound (240 mg, 72%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.58 (d, 1H, J = 5.6 Hz, 2.0 Hz), 8.44 (s, 1H), 8.29 (d, 1H, J = 8.0 Hz), 7.89 (d, 1H , J = 7.6 Hz), 7.63 (t, 2H, J = 8.0 Hz), 7.21-7.18 (m, 2H), 4.56 (t, 2H, J = 7.6 Hz), 4.22 (q, 2H, J = 7.2 Hz ), 3.51 (s, 2H), 3.26 (t, 2H, J = 7.6 Hz), 2.51 (s, 3H), 1.29 (t, 3H, J = 7.6 Hz)

Production Example 5

Preparation Example 5-1) [5- (3-Nitrophenyl) -3-oxo-2-phenethyl-2,3-dihydro-pyridazin-4-yl] -ethyl acetate

Preparation Example 5-1-1)

The compound obtained in Preparation Example 1 (3.0 g, 13.8 mmol) was dissolved in dimethylformamide (40 mL), and cesium carbonate (6.77 g, 20.8 mmol) and 2-bromoethylbenzene (2.83 mL, 20.8 mmol) were added dropwise. And stirred at room temperature for 4 hours. The reaction solution was added to 1 N aqueous hydrochloric acid solution (80 mL) and then extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure and subjected to column chromatography (n-hexane / ethyl acetate, 6/1 → 4/1) to give the title compound (3.86). g, 87%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.73 (s, 1H), 7.33-7.26 (m, 2H), 7.26-7.20 (m, 3H), 4.36 (t, 2H, J = 8 Hz), 4.20 (q, 2H, J = 7.2 Hz), 3.78 (s, 2H), 3.09 (t, 2H, J = 8 Hz), 1.28 (t, 2H, J = 7.2 Hz).

Preparation Example 5-1-2) Preparation of [5- (3-nitrophenyl) -3-oxo-2-phenethyl-2,3-dihydro-pyridazin-4-yl] -acetic acid ethyl ester

The compound obtained in Preparation Example 5-1-1 (505 mg, 1.57 mmol) was dissolved in 1,4-dioxane (20 mL), and then 2-nitrophenylboronic acid (394 mg, 2.36 mmol) and carbonic acid under nitrogen atmosphere. Cesium (2.05 g, 6.29 mmol) and tetrakistriphenylphosphine palladium (182 mg, 0.16 mmol) were added thereto, and the mixture was heated and stirred at 80 ° C. for 16 hours. The reaction solution was cooled, water (30 mL) was added, and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, column chromatography (n-hexane / ethyl acetate, 4/1-> 2/1) was carried out to obtain the title compound (332 mg, 52%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, 1H, J = 7.6 Hz), 8.24 (s, 1H), 7.71-7.64 (m, 3H), 7.30-7.20 (m, 5H), 4.18 ( t, 2H, J = 8.0 Hz), 4.17 (q, 2H, J = 6.8 Hz), 3.49 (s, 2H), 3.12 (t, 3H, J = 8.0 Hz), 1.24 (t, 3H, J = 6.8 Hz).

Preparation Example 5-2) Preparation of (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acetic acid ethyl ester

The title compound was prepared in the same manner as in Preparation Example 5-1, except for using isopropyl bromide instead of 2-bromoethylbenzene and phenylboronic acid instead of 2-nitrophenylboronic acid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.76 (s, 1H), 7.50-7.35 (m, 5H), 4.17 (q, 2H, J = 6.0 Hz), 4.03 (d, 2H, J = 7.2 Hz) , 3.56 (s, 2H), 2.35-2.27 (m, 1H), 1.24 (t, 3H, J = 7.2 Hz), 0.97 (d, 6H, J = 6.0 Hz).

Preparation Example 5-3) [2- (4-methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -acetic acid ethyl ester Produce

The title compound was prepared in the same manner as in Preparation Example 5-1 except for using 4-methoxy-bromomethylbenzene instead of 2-bromoethylbenzene.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.32 (d, 1H, J = 7.2 Hz), 8.24 (s, 1H), 7.74-7.66 (m, 3H), 7.46 (d, 2H, J = 8.4 Hz) , 6.87 (d, 2H, J = 8.4 Hz), 5.23 (s, 2H), 4.18 (q, 2H, J = 7.2 Hz), 3.79 (s, 3H), 3.51 (s, 2H), 1.25 (t, 3H, J = 7.2 Hz).

Preparation Example 5-4) Preparation of [2-ethyl-5- (3-nitrophenyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -acetic acid ethyl ester

The title compound was prepared in the same manner as in Preparation Example 5-1, except for using ethyl bromide instead of 2-bromoethylbenzene.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, 1H, J = 6.4 Hz), 8.23 (s, 1H), 7.72-7.64 (m, 3H), 4.22 (q, 2H, J = 7.2 Hz) , 4.13 (q, 2H, J = 5.6 Hz), 3.48 (s, 2H), 1.38 (t, 3H, J = 7.2 Hz), 1.21 (t, 3H, J = 5.6 Hz).

Example 1

Example 1-1) N- (4-carbamimidoylbenzyl] -2- [1-isobutyl-2-methyl-4- (3-aminophenyl) -6-oxo-1,6-dihydro-pyri Acetate of midin-5-yl] -acetamide

Example 1-1-1) N- (4-cyanobenzyl) -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro Preparation of -pyrimidin-5-yl] -acetamide

The compound (1.15 g, 2.86 mmol) obtained in Preparation Example 3-1 was dissolved in dichloromethane (5 mL) and hydrochloric acid (4 N 1,4-dioxane solution, 10 mL) was added. Stir for hours. Concentrate the solvent under reduced pressure to [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid (980 mg, 99 %) Was obtained.

[1-Isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid (490 mg, 1.42 mmol) obtained above Dissolved in dimethylformamide (5 mL), 4- (aminomethyl) benzonitrile hydrochloride (263 mg, 1.56 mmol), N, N-diisopropylethylamine (0.74 mL, 4.26 mmol), 1-hydroxy Benzotriazole hydrate (109 mg, 0.71 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (408 mg, 2.13 mmol) were added sequentially, followed by stirring at room temperature and nitrogen atmosphere for 5 hours. It was. The reaction solution was added to saturated aqueous ammonium chloride solution (30 mL) and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated sodium hydrogen carbonate (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and subjected to column chromatography (n-hexane / ethyl acetate, 1/2) to give the title compound (570 mg). , 87%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.72 (br s, 1H), 8.39-8.35 (m, 1H), 8.33-8.29 (m, 1H), 7.70-7.76 (m, 1H), 7.68 (t , 1H, J = 8 Hz), 7.60 (d, 2H, J = 8 Hz), 7.40 (d, 2H, J = 8 Hz), 4.51 (d, 2H, J = 6 Hz), 3.95 (d, 2H , J = 7.2 Hz), 3.45 (s, 2H), 2.66 (s, 3H), 2.12-2.05 (m, 1H), 0.99 (d, 6H, J = 6.4 Hz).

Example 1-1-2) N- [4- (hydroxycarbamimidoyl) -benzyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo- Preparation of 1,6-dihydro-pyrimidin-5-yl] -acetamide

Compound (545 mg, 1.19 mmol) obtained in Example 1-1-1 was dissolved in ethanol / water (4/1, 15 mL), sodium carbonate (189 mg, 1.78 mmol) and hydroxylamine hydrochloride (247 mg, 3.55 mmol) ) Was added and stirred under reflux for 8 hours. The reaction solvent was concentrated under reduced pressure, saturated brine (20 mL) was added, and extracted with ethyl acetate (30 mL x 2). After drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure, and recrystallization in diethyl ether (50 mL) to give the title compound (543 mg, 93%) as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.71 (t, 1H, J = 2 Hz), 8.45-8.41 (m, 1H), 8.32-8.28 (m, 1H), 8.03 (t, 1H, J = 6 Hz), 7.67 (t, 1H, J = 8 Hz), 7.46 (d, 2H, J = 8.4 Hz), 7.19 (d, 2H, J = 8.4 Hz), 4.93 (br s, 2H), 4.44 ( d, 2H, J = 5.6 Hz), 3.94 (d, 2H, J = 7.2 Hz), 3.49 (s, 2H), 2.64 (s, 3H), 2.23-2.12 (m, 1H), 0.99 (d, 6H , J = 6.4 Hz).

Example 1-1-3) N- (4-carbamimidoylbenzyl] -2- [1-isobutyl-2-methyl-4- (3-aminophenyl) -6-oxo-1,6-dihydro Preparation of Acetate of Pyrimidin-5-yl-acetamide

The compound obtained in Example 1-1-2 (320 mg, 0.65 mmol) was dissolved in methanol (20 mL), acetic acid (74 mL, 1.30 mmol) and palladium / charcoal (69 mg, 0.065 mmol) were added. Stir under balloon for 16 hours. The reaction solution was filtered through celite, and the filtrates were concentrated under reduced pressure. Recrystallization in diethylether (50 mL) gave the acetate of the title compound (261 mg, 90%) as a white solid.

¹ H-NMR (400 MHz, CD ₃ OD) δ 7.72 (d, 2H, J = 8.4 Hz), 7.50 (d, 2H, J = 8.4 Hz), 7.13 (t, 1H, J = 6 Hz), 6.84 -6.81 (m, 1H), 6.79-6.73 (m, 2H), 4.45 (s, 2H), 3.94 (d, 2H, J = 8 Hz), 3.46 (s, 2H), 2.58 (s, 3H), 2.22-2.12 (m, 1 H), 0.96 (d, 6H, J = 6.8 Hz). MS m / z 447 [M +1] ⁺

Example 1-2) N- [4- (N-hydroxycarbamimidoyl) -benzyl] -2- [1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro Preparation of -pyrimidin-5-yl] -acetamide

The title compound was prepared in the same manner as described in Example 1-1-1 to Example 1-1-2, using the compound of Preparation Example 3-3 instead of the compound of Preparation Example 3-1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, 2H, J = 7.6 Hz), 7.50-7.44 (m, 5H), 7.23 (d, 2H, J = 6.9 Hz), 4.83 (brS, 2H ), 4.45 (d, 2H, J = 5.2 Hz), 3.92 (d, 2H, J = 6.8 Hz), 3.5 (s, 2H), 2.63 (s, 3H), 2.14-2.21 (m, 1H), 0.98 (d, 6H, J = 6.6 Hz).

Example 1-3) N- (4-Cyanobenzyl) -2- (1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl) Acetamide

The title compound was prepared in the same manner as described in Example 1-1-1 using the compound of Preparation Example 3-4 instead of the compound of Preparation Example 3-1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.84 (dd, 2H, J = 2 Hz, 8.4 Hz), 7.69 (t, 1H, J = 8 Hz), 7.60 (d, 2H, J = 8.4 Hz), 7.52-7.45 (m, 3H), 7.39 (d, 2H, J = 8.4 Hz), 4.51 (d, 2H, J = 6 Hz), 3.79 (d, 2H, J = 7.2 Hz), 3.53 (s, 2H), 2.18-2.10 (m, 1H), 0.99 (d, 6H, J = 6.4 Hz).

Example 1-4) N- (4-N-carbamimidoylbenzyl) -2- (1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidine-5 -Yl) -acetamide; Acetate

The title compound was prepared in the same manner as described in Example 1-1, using the compound of Preparation Example 3-3 instead of the compound of Preparation Example 3-1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (t, 1H, J = 6 Hz), 7.73 (d, 2H, J = 7.2 Hz), 7.60-7.58 (m, 2H), 7.46-7.42 (m, 5H), 4.34 (dd, 2H, J = 14 Hz, 6 Hz), 3.89 (d, 2H, J = 7.6 Hz), 3.34 (s, 2H), 2.57 (s, 3H), 2.08-2.15 (m, 1 H), 1.73 (s, 3 H), 0.92 (d, 6H, J = 6.8 Hz).

Example 1-5) N- [4-N- (hydroxycarbamimidoyl) -benzyl] -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidine- 5-day) -acetamide

The title compound was prepared in the same manner as described in Example 1-1-1 to Example 1-1-2, using the compound of Preparation Example 3-4 instead of the compound of Preparation Example 3-1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (br s, 1H), 8.47-8.41 (m, 1H), 8.41 (s, 1H), 7.57-7.52 (m, 3H), 7.40 (m , 3H), 7.18 (d, 2H, J = 7.2 Hz), 5.74 (s, 2H), 4.27 (d, 2H, J = 6.4 Hz), 3.71 (d, 2H, J = 7.2 Hz), 3.36 (s , 2H), 2.06-1.99 (m, 1H), 0.84 (d, 6H, J = 6.4 Hz).

Example 1-6) N- (4-N-carbamimidoylbenzyl) -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl)- Acetamide; Acetate

The title compound was prepared in the same manner as described in Example 1-1, using the compound of Preparation Example 3-4 instead of the compound of Preparation Example 3-1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (t, 1H, J = 6 Hz), 8.48 (s, 1H), 7.76 (d, 2H, J = 8.4 Hz), 7.61-7.59 (m , 2H), 7.48-7.42 (m, 5H), 4.37 (d, 2H, J = 5.6 Hz), 3.78 (d, 2H, J = 6.8 Hz), 3.36 (s, 2H), 2.20-2.10 (m, 1H), 1.75 (s, 3H), 0.90 (d, 6H, J = 6.8 Hz).

Example 1-7) N- [3- (N-hydroxycarbamimidoyl) -benzyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo- 1,6-dihydro-pyrimidin-5-yl] -acetamide

Examples 1-1-1 to 1-1 except for using 3- (aminomethyl) benzonitrile hydrochloride instead of 4- (aminomethyl) benzonitrile hydrochloride in Example 1-1-1 Proceeded in the same manner as described in -2, the title compound was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.68 (t, 1H, J = 4 Hz) 8.35 (d, 1H, J = 7.6 Hz), 8.34-8.26 (m, 2H), 7.66 (t, 1H, J = 8 Hz), 7.56-7.46 (m, 3H), 7.31 (d, 1H, J = 4.4 Hz), 5.05 (br s, 2H), 4.47 (d, 2H, J = 6 Hz), 3.91 (d , 2H, J = 7.2 Hz), 3.46 (s, 2H), 2.65 (s, 3H), 2.17-2.10 (m, 1H), 0.97 (d, 6H, J = 6.4 Hz).

Example 1-8) N- [5- (N-hydroxycarbamimidoyl) -thiophen-2-ylmethyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl ) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetamide

Use of 5- (aminomethyl) thiophene-2-carbonitrile (5- (aminomethyl) thiophene-2-carbonitrile) hydrochloride in place of 4- (aminomethyl) benzonitrile hydrochloride in Example 1-1-1 Except for the same procedure as described in Example 1-1-1 to Example 1-1-2, the title compound was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.70-8.66 (m, 1H) 8.38-8.30 (m, 1H), 8.30-8.27 (m, 1H), 7.88 (t, 1H, J = 5.2 Hz), 7.70-7.64 (m, 1H), 7.38 (d, 1H, J = 4 Hz), 7.05 (d, 1H, J = 4 Hz), 4.82 (br s, 2H), 4.55 (d, 2H, J = 6 Hz), 3.97-3.89 (m, 2H), 3.43 (s, 2H), 2.64 (s, 3H), 2.22-2.12 (m, 1H), 0.99 (d, 6H, J = 6.8 Hz).

Example 1-9) 2- [4- (3-aminophenyl) -1-isobutyl-2-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl]-{5- ( N-carbamimidoyl) -thiophen-2-ylmethyl} -acetamide; Acetate

Use of 5- (aminomethyl) thiophene-2-carbonitrile (5- (aminomethyl) thiophene-2-carbonitrile) hydrochloride in place of 4- (aminomethyl) benzonitrile hydrochloride in Example 1-1-1 Except for the same procedure as described in Example 1-1, the title compound was prepared.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (t, 1H, J = 6 Hz), 7.55 (d, 1H, J = 4 Hz), 7.05 (t, 1H, J = 8 Hz), 6.94 (d, 1H, J = 4 Hz), 6.72 (s, 1H), 6.65 (d, 1H, J = 7.2 Hz), 6.60 (dd, 1H, J = 2 Hz, 7.2 Hz) 5.14 (s, 2H ), 4.34 (d, 2H, J = 5.6 Hz), 3.85 (d, 2H, J = 7.6 Hz), 2.53 (s, 3H), 2.13-2.04 (m, 1H), 0.87 (d, 6H, J = 6.8 Hz)

Example 1-10) 2- [4- (3-aminophenyl) -1-ethyl-2-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl] -N- (4- Carbamimidoylbenzyl) -acetamide

The title compound was prepared in the same manner as described in Example 1-1, using the compound of Preparation Example 3-5 in place of the compound of Preparation Example 3-1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (t, 1H, J = 6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H, J = 8 Hz), 7.04 (t, 1H, J = 8 Hz), 6.72 (s, 1H), 6.65 (d, 1H, J = 7.6 Hz), 6.61 (dd, 1H, J = 2 Hz, 7.6 Hz) 5.16 (s, 2H ), 4.31 (d, 2H, J = 5.6 Hz), 4.03 (q, 2H, J = 7.2 Hz), 2.56 (s, 3H), 1.25 (t, 3H, J = 7.2 Hz)

Example 1-11) 2- [4- (3-Aminophenyl) -2-methyl-6-oxo-1- (2-pyridin-2-yl-ethyl) -1,6-dihydro-pyrimidine- 5-yl] -N- (4-carbamimidoylbenzyl) -acetamide

The title compound was prepared in the same manner as described in Example 1-1, using the compound of Preparation Example 4 instead of the compound of Preparation Example 3-1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (dd, 1H, J = 1.2 Hz, 4.4 Hz), 8.44 (t, 1H, J = 6 Hz), 7.82 (d, 1H, J = 8.4 Hz), 7.74 (d, 2H, J = 7.6 Hz), 7.39 (d, 1H, J = 8.4 Hz), 7.35-7.27 (m, 3H), 7.05 (td, 1H, J = 3.6 Hz, 7.6 Hz) , 6.73 (s, 1H), 6.66 (d, 1H, J = 6.8 Hz), 6.62 (dd, 1H, J = 1.6 Hz, 8 Hz), 5.19 (s, 2H), 4.36-4.31 (m, 4H) , 3.36 (s, 2H), 3.14 (t, 2H, J = 8 Hz), 2.53 (s, 3H).

Example 1-12) N- (4-Cyanobenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acetamide

The title compound was prepared in the same manner as described in Example 1-1-1 using the compound of Preparation Example 5-2 instead of the compound of Preparation Example 3-1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.06 (br s, 1H), 7.89 (s, 1H), 7.60 (m, 4H), 7.53-7.51 (m, 3H), 7.37 (d, 2H, J = 7.6 Hz), 4.49 (s, 2H), 4.06 (d, 2H, J = 7.6 Hz), 3.54 (s, 2H), 2.35-2.22 (m, 1H), 0.97 (d, 6H, J = 6.4 Hz ).

Example 1-13) N- (4-carbamimidoylbenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acet Amides; Acetate

The title compound was prepared in the same manner as described in Example 1-1, using the compound of Preparation Example 5-2 instead of the compound of Preparation Example 3-1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (t, 1H, J = 5.6 Hz), 7.93 (s, 1H), 7.73 (d, 2H, J = 8.4 Hz), 7.52 (br s, 5H), 7.41 (d, 2H, J = 8.4 Hz), 4.35 (d, 2H, J = 6.0 Hz), 3.95 (d, 2H, J = 7.2 Hz), 3.41 (s, 4H), 2.25-2.15 ( m, 1H), 1.69 (s, 3H), 0.92 (d, 6H, J = 6.8 Hz).

Example 1-14) N- (4-carbamimidoylbenzyl) -2- [2- (4-methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2,3-dihydro -Pyridazin-4-yl] -acetamide

[2- (4-Methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -acetic acid ethyl ester (Preparation Example 5-3 compound ) (200 mg, 0.47 mmol) was dissolved in tetrahydrofuran / distilled water (3/1, 8 mL), and lithium hydroxide hydrate (60 mg, 1.43 mmol) was added thereto, followed by stirring at room temperature for 16 hours. Benzyl amino [4- (aminomethyl) phenyl] methylenecarbamate (180 mg, 0.57 mmol) was added to the reaction solution, and the mixture was neutralized with 2N aqueous hydrochloric acid. 1-hydroxybenzotriazole hydrate (110 mg, 0.71 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (140 mg, 0.71 mmol) were added sequentially, followed by normal temperature and nitrogen atmosphere. Stir for 5 hours. The reaction solution was added to saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated sodium hydrogen carbonate (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and subjected to column chromatography (n-hexane / ethyl acetate, 1/2) to obtain a white solid (180). mg, 60%).

The compound obtained above (70 mg, 0.10 mmol) was dissolved in methanol / distilled water (4/1, 5 mL), and lithium hydroxide hydrate (66 mg, 0.65 mmol) was added thereto, followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, recrystallized with diethyl ether (20 mL), and the obtained white solid was washed with water (20 mL) and dried to obtain the title compound (44 mg, 83%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (t, 1H, J = 5.6 Hz), 8.45 (s, 1H). 8.34 (d, 1H, J = 8.0 Hz), 8.01 (s, 1H), 7.98 (d, 1H, J = 8.4 Hz), 7.83-7.78 (m, 2H), 7.72 (d, 1H, J = 8.4 Hz ), 7.40 (d, 1H, J = 8.0 Hz), 7.36-7.31 (m, 3H), 6.91 (d, 2H, J = 8.8 Hz), 5.25 (s, 2H), 4.31 (d, 2H, J = 5.6 Hz), 3.73 (s, 3H), 3.40 (s, 2H).

Example 1-15) 2- [5- (3-aminophenyl) -2- (4-methoxybenzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -N- ( 4-carbamimidoylbenzyl) -acetamide; Hydrochloride

The title compound was prepared in the same manner as described in Example 1-1-3 except for using the compound of Preparation Example 5-3 instead of the compound of Preparation Example 3-1 and using hydrochloric acid instead of acetic acid. It was.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 9.08 (s, 1H), 8.68 (t, 1H, J = 5.6 Hz), 7.89 (d, 1H, J = 4.0 Hz ), 7.84 (d, 1H, J = 8.4 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.49 (d, 1H, J = 8.4 Hz), 7.45 (s, 1H), 7.35 (d, 1H , J = 8.4 Hz), 7.34 (d, 2H, J = 8.2 Hz), 7.23 (s, 2H), 6.90 (d, 2H, J = 8.2 Hz), 5.23 (s, 2H), 4.34 (d, 2H , J = 5.6 Hz), 3.88 (s, 3H), 3.43 (d, 2H, J = 9.2 Hz).

Example 1-16) N- (3-carbamimidoylbenzyl) -2- [2- (4-methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2,3-dihydro -Pyridazin-4-yl] -acetamide; Hydrochloride

Example 1-14 except for using benzyl amino [3- (aminomethyl) phenyl] -methylenecarbamate instead of benzyl amino [4- (aminomethyl) phenyl] -methylenecarbamate Proceed in the same manner as described in the above to prepare the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 8.43 (t, 1H, J = 5.6 Hz), 8.34-8.33 (m, 1H), 8.03-7.97 (m, 2H) , 7.82-7.74 (m, 3H), 7.62-7.37 (m, 3H), 7.33 (d, 2H, J = 8.0 Hz), 6.90 (d, 2H, J = 8.0 Hz), 5.24 (s, 2H), 4.31 (d, 2H, J = 6.0 Hz), 3.73 (s, 3H), 3.42 (s, 2H).

Example 1-17) 2- [5- (3-aminophenyl) -2- (4-methoxybenzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -N- ( 3-carbamimidoylbenzyl) -acetamide; Hydrochloride

3- (aminomethyl) benzonitrile hydrochloride instead of 4- (aminomethyl) benzonitrile hydrochloride, using the compound of Preparation Example 5-3 instead of the compound of Preparation Example 3-1 in Example 1-1-1 In Example 1-1-3, the title compound was prepared in the same manner as in Example 1-1 except for using hydrochloric acid instead of acetic acid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (t, 1H, J = 5.6 Hz), 7.97 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.75 (d , 1H, J = 6.8 Hz), 7.45-7.39 (m, 2H), 7.31 (d, 2H, J = 8.2 Hz), 7.21 (s, 1H), 6.89 (d, 2H, J = 8.2 Hz), 6.78 (s, 2H), 5.21 (s, 2H), 4.32 (d, 2H, J = 5.6 Hz), 3.72 (s, 3H), 3.41 (s, 2H).

Example 1-18) 2- [5- (3-aminophenyl) -2-ethyl-3-oxo-2,3-dihydro-pyridazin-4-yl] -N- (4-carbamimidoylbenzyl Acetamide

The title compound was prepared in the same manner as in Example 1-1 except for using the compound of Preparation Example 5-3 instead of the compound of Preparation Example 3-1 in Example 1-1-1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 8.50 (t, 1H, J = 5.6 Hz), 7.84 (s, 1H), 7.71 (d, 2H, J = 8 Hz), 7.30 (d, 2H, J = 8 Hz), 7.11 (t, 1H, J = 8 Hz), 6.65 (d, 1H, J = 8 Hz), 6.59 (s, 1H), 6.58 (d, 1H, J = 8 Hz), 5.29 (s, 2H), 4.31 (s, 2H), 4.13 (q, 2H, J = 7.4 Hz), 3.41 (s, 2H), 1.30 (t, 3H, J = 7.4 Hz).

Example 1-19) 2- [5- (3-aminophenyl) -2-phenethyl-3-oxo-2,3-dihydro-pyridazin-4-yl] -N- (4-carbamimidoyl Benzyl) -acetamide

The title compound was prepared in the same manner as in Example 1-1 except for using the compound of Preparation Example 5-1 instead of the compound of Preparation Example 3-1 in Example 1-1-1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 8.56 (t, 1H, J = 5.6 Hz), 7.85 (s, 1H), 7.74 (d, 2H, J = 8 Hz), 7.39 (d, 2H, J = 8 Hz), 7.35-7.20 (m, 5H), 7.12 (t, 1H, J = 7.6 Hz), 6.66 (d, 1H, J = 7.6 Hz), 6.59 (s, 1H), 6.58 (d, 1H, J = 7.2 Hz), 5.31 (br s, 2H), 4.35 (d, 2H, J = 5.6 Hz), 4.32 (t, 2H, J = 7.6 Hz), 3.43 (s, 2H), 3.06 (t , 2H, J = 7.6 Hz).

Example 2

Example 2-1) N- (5-chloro-2-hydroxymethylbenzyl) -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6 -Dihydro-pyrimidin-5-yl] -acetamide

[1-Isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetic acid (490 mg, 1.42 mmol) After dissolving in formamide (5 mL) (2-aminomethyl-4-chlorophenyl) -methanol (268 mg, 1.56 mmol), N, N-diisopropylethylamine (0.74 mL, 2.84 mmol), 1-hydro Roxybenzotriazole hydrate (109 mg, 0.71 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (408 mg, 2.13 mmol) were added sequentially, followed by room temperature and nitrogen atmosphere for 5 hours. Stirred. The reaction solution was added to saturated aqueous ammonium chloride solution (30 mL) and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated sodium hydrogen carbonate (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and subjected to column chromatography (n-hexane / ethyl acetate, 1/4) to give the title compound (532 mg). , 75%) was obtained as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.66 (br s, 1H), 8.35-8.27 (m, 2H), 7.69-7.59 (m, 2H), 7.32-7.21 (m, 3H), 4.68 (d , 2H, J = 5.6 Hz), 4.48 (d, 2H, J = 6 Hz), 3.92 (d, 2H, J = 7.6 Hz), 3.52 (t, 1H, J = 5.6 Hz), 3.38 (s, 2H ), 2.63 (s, 3H), 2.20-2.09 (m, 1H), 0.98 (d, 6H, J = 6.8 Hz).

The following compounds were synthesized in a similar manner to the above.

Example 2-2) N- (5-Chloro-2-hydroxymethylbenzyl) -2- (1-isobutyl-2-methyl-6-oxo- 4-phenyl-1,6-dihydro-pyrimidine -5-day) -acetamide

Preparation Example 3-1 The title compound was prepared in the same manner as in Example 2-1 except for using the compound of Preparation Example 3-3 instead of the compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.74 (dd, 2H, J = 2 Hz, 8.4 Hz), 7.59 (t, 1H, J = 8 Hz), 7.48-7.40 (m, 3H), 7.29 (d , 1H, J = 8 Hz), 7.28 (d, 1H, J = 2 Hz), 7.23 (dd, 1H, J = 2 Hz, 8 Hz), 4.68 (s, 2H), 4.47 (d, 2H, J = 6 Hz), 3.91 (d, 2H, J = 7.2 Hz), 3.41 (s, 2H), 2.61 (s, 3H), 2.17-2.12 (m, 1H), 0.97 (d, 6H, J = 6.6 Hz ).

Example 2-3) N- (5-chloro-2-hydroxymethylbenzyl) -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl Acetamide

Preparation Example 3-1 The title compound was prepared in the same manner as in Example 2-1 except for using the compound of Preparation Example 3-4 instead of the compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.78 (m, 2H), 7.56 (t, 1H, J = 8 Hz), 7.48-7.45 (m, 3H), 7.31-7.22 ( m, 3H), 4.68 (d, 2H, J = 5.6 Hz), 4.48 (d, 2H, J = 6 Hz), 3.77 (d, 2H, J = 7.2 Hz), 3.59 (t, 1H, J = 6 Hz) 3.46 (s, 3H) 2.17-2.10 (m, 1H), 0.98 (d, 6H, J = 6.4 Hz).

Example 2-4) N- (5-Chloro-2-cyanomethylbenzyl) -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl Acetamide

Preparation Example 3-1 A compound of Preparation Example 3-4 was used instead of the compound, and 2- (2-aminomethyl-4-chlorophenyl) acetonitrile instead of (2-aminomethyl-4-chlorophenyl) -methanol Except for using the title compound was prepared in the same manner as in Example 2-1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.78 (dd, 2H, J = 1.8 Hz, 6.8 Hz), 7.56 (t, 1H, J = 5.2 Hz), 7.52-7.43 (m , 3H), 7.34-7.28 (m, 2H), 7.24 (dd, 1H, J = 2 Hz, 7.6 Hz), 4.68 (d, 2H, J = 5.2 Hz), 4.49 (d, 2H, J = 6 Hz ), 3.77 (d, 2H, J = 7.6 Hz), 3.46 (s, 2H), 2.18-2.10 (m, 1H), 0.99 (d, 6H, J = 6.4 Hz).

Example 2-5) N- (5-chloro-2-hydroxybenzyl) -2- [1-isobutyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydroxypyri Midin-5-yl] -acetamide

Preparation Example 3-1 The title compound was prepared in the same manner as in Example 2-1 except for using the compound of Preparation Example 3-2 instead of the compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.70 (s, 1H), 8.36 (d, 1H, J = 7.6 Hz), 8.31 (d, 1H, J = 8.2 Hz), 8.10 (s, 1H), 7.67 (t, 1H, J = 8.2 Hz), 7.57 (s, 1H), 7.31-7.22 (m, 3H), 4.69 (d, 2H, J = 6.0 Hz), 4.49 (d, 2H, J = 6.0 Hz ), 3.79 (d, 2H, J = 7.2 Hz), 3.42 (s, 2H), 3.37 (t, 1H, J = 6.0 Hz), 2.17-2.12 (m, 1H), 0.98 (d, 6H, J = 6.8 Hz).

Example 2-6) N- (5-chloro-2-hydroxybenzyl) -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6- Dihydroxypyrimidin-5-yl] -acetamide

The title compound was prepared in the same manner as in Example 2-1 except for using 2- (aminomethyl) -4-chlorophenol instead of (2-aminomethyl-4-chlorophenyl) -methanol.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.43 (s, 1H), 8.63 (s, 1H), 8.32-8.27 (m, 2H), 8.25 (d, 1H, J = 8 Hz), 7.69 (t, 1H, J = 8 Hz), 7.13 (dd, 1H, J = 2.4 Hz, 8.4 Hz) 7.05 (d, 1H, J = 2.4 Hz), 6.85 (d, 1H, J = 8.8 Hz), 4.26 (d, 2H, J = 6.4 Hz), 3.94 (d, 1H, J = 7.2 Hz) 3.42 (s, 2H), 2.63 (s, 3H) 2.13-2.08 (m, 1H), 0.96 (d, 6H, J = 6.8 Hz).

Example 2-7) N- (5-chloro-2-hydroxymethylbenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl Acetamide

Preparation 3-1 The title compound was prepared in the same manner as in Example 2-1 except for using the compound of Preparation Example 5-2 instead of the compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.60-7.57 (m, 2H), 7.53-7.48 (m, 3H), 4.68 (d, 2H, J = 6.0 Hz), 4.47 (d, 2H, J = 5.6 Hz), 4.04 (d, 2H, J = 7.6 Hz), 3.69 (t, 1H, J = 6.0 Hz), 3.47 (s, 2H), 2.29-2.22 (m, 1H) , 0.96 (d, 6H, J = 6.4 Hz).

Example 2-8) N- (5-chloro-2-cyanomethylbenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl Acetamide

Preparation Example 3-1 A compound of Preparation Example 5-2 was used instead of the compound, and 2- (2-aminomethyl-4-chlorophenyl) acetonitrile instead of (2-aminomethyl-4-chlorophenyl) -methanol Except for using the title compound was prepared in the same manner as in Example 2-1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.87 (s, 1H), 7.59-7.49 (m, 4H), 7.38-7.28 (m, 4H), 4.40 (d, 2H, J = 6.0 Hz), 4.06 (d, 2H, J = 7.6 Hz), 3.81 (s, 2H), 3.52 (s, 2H), 2.28-2.23 (m, 1H), 0.96 (d, 6H, J = 6.4 Hz).

Example 2-9) N- (5-Chloro-2-hydroxymethyl-benzyl) -2- [5- (3-nitrophenyl) -3-oxo- 2-phenethyl-2,3-dihydro -Pyridazin-4-yl] -acetamide

Preparation Example 3-1 The title compound was prepared in the same manner as in Example 2-1 except for using the compound of Preparation Example 5-1 instead of the compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.31 (d, 1H, J = 8 Hz), 8.08 (d, 1H, J = 8 Hz), 7.83 (s, 1H), 7.69 (t, 2H, J = 7.6 Hz), 7.31-7.17 (m, 8H), 4.65 (s, 2H), 4.47-4.40 (m, 4H), 3.38 (s, 2H), 3.08 (t, 2H, J = 7.6 Hz).

Example 2-10) N- (5-Chloro-thiophen-2-ylmethyl) -2- [2- (4-methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2 , 3-dihydro-pyridazin-4-yl] -acetamide

Preparation Example 3-1 A compound of Preparation Example 5-3 was used instead of the compound, and (5-chlorothiophen-2-yl) methanamine ((5) was used instead of (2-aminomethyl-4-chlorophenyl) -methanol. The title compound was prepared in the same manner as in Example 2-1, except that -chlorothiophen-2-yl) methanamine) was used.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (t, 1H, J = 5.6 Hz), 8.43 (s, 1H), 8.35-8.33 (m, 1H), 8.02 (s, 1H), 7.98 -7.96 (m, 1H), 7.81-7.77 (m, 1H), 7.35 (d, 2H, J = 8.4 Hz), 6.94-6.92 (m, 3H), 6.83 (s, 1H), 5.25 (s, 2H ), 4.32 (s, 2H), 3.75 (s, 3H), 3.39 (s, 2H).

Example 2-11) N- (5-Chlorothiophen-2-ylmethyl) -2- [5- (3-nitrophenyl) -3-oxo-2-phenethyl-2,3-dihydro- Pyridazin-4-yl] -acetamide

Preparation Example 3-1 A compound of Preparation Example 5-1 was used instead of the compound, and (5-chlorothiophen-2-yl) methanamine ((5) was used instead of (2-aminomethyl-4-chlorophenyl) -methanol. The title compound was prepared in the same manner as in Example 2-1, except that -chlorothiophen-2-yl) methanamine) was used.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.33 (d, 1H, J = 8 Hz), 8.10 (d, 1H, J = 8 Hz), 7.82 (s, 1H), 7.36 (t, 2H, J = 8 Hz), 7.30-7.22 (m, 5H), 6.71-6.68 (m, 2H), 4.46-4.42 (m, 4H), 3.41 (s, 2H), 3.10 (t, 2H , J = 7.6 Hz).

[Example 3] [2-({2- [4- (3-aminophenyl) -1-isobutyl-2-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl]- Preparation of Acetylamino} -4-chloro-phenoxy) -acetic acid

Example 3-1) [4-Chloro-2-({2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo_1,6-dihydro-pyrimidine -5-yl] -acetylamino} -methyl) -phenoxy] -acetic acid ethyl ester

The compound obtained in Example 2-6 (94 mg, 0.19 mmol) was dissolved in dimethylformamide (5 mL), followed by potassium carbonate (40 mg, 0.29 mmol) and 2-bromoethyl acetate (0.032 mL, 0.29 mmol) Was added dropwise and stirred at room temperature for 12 hours. The reaction solution was added to saturated aqueous ammonium chloride solution (20 mL) and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and recrystallized from diethyl ether (30 mL) to obtain the title compound (105 mg, 95%) as an off-white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.62 (t, 1H, J = 1.6 Hz), 8.33 (d, 1H, 6.8 Hz), 8.25 (d, 1H, J = 8.4 Hz), 7.62 (m, 2H ), 7.24 (d, 1H, J = 2.8 Hz), 7.16 (dd, 1H, J = 2.4 Hz, 8.4 Hz), 6.67 (d, 1H, J = 8.8 Hz), 4.68 (s, 2H), 4.47 ( d, 2H, J = 6 Hz), 4.24 (q, 2H, J = 7.2 Hz), 3.90 (d, 2H, J = 7.2 Hz), 3.42 (s, 2H), 2.62 (s, 3H), 2.21- 2.10 (m, 1 H), 1.29 (t, 3 H, J = 7.2 Hz), 0.97 (d, 6H, J = 6.8 Hz).

Example 3-2) [4-Chloro-2-({-[1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidine- 5-yl] -acetylamino} -methyl) -phenoxy] -acetic acid

The compound obtained in Example 3-1 (100 mg, 0.18 mmol) was dissolved in tetrahydrofuran / water (2/1, 6 mL), and lithium hydroxide hydrate (22 mg, 0.52 mmol) was added thereto, followed by stirring at room temperature for 1 hour. It was. The reaction solution was adjusted to pH 5 with 1 N aqueous hydrochloric acid solution and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized from diethyl ether (30 mL) to obtain the title compound (93 mg, 98%) as an off-white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (t, 1H, J = 6 Hz), 8.51 (t, 1H, J = 2 Hz), 8.31 (dd, 1H, J = 2.4 Hz, 8.4 Hz ) 8.11 (d, 1H, J = 7.6 Hz), 7.56 (t, 1H, J = 8 Hz), 7.33 (d, 1H, J = 2.4 Hz), 7.22 (dd, 1H, J = 2.4 Hz, 8.4 Hz ), 6.88 (d, 1H, J = 8.8 Hz), 4.72 (s, 2H), 4.27 (d, 2H, J = 5.6 Hz), 3.92 (d, 2H, J = 7.2 Hz), 3.36 (s, 2H ), 2.59 (s, 3H) 2.19-2.15 (m, 1H), 0.92 (d, 6H, J = 6.4 Hz).

Example 3-3) [2-({2- [4- (3-aminophenyl) -1-isobutyl-2-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl] -Acetylamino} -4-chloro-phenoxy) -acetic acid

The compound (90 mg, 0.17 mmol) obtained in Example 3-2 was dissolved in methanol (20 mL), palladium / charcoal (10 wt%, 50 mg) was added thereto, and stirred at room temperature and under a hydrogen balloon for 1 hour. The reaction solution was filtered through celite, and the filtrates were concentrated under reduced pressure. Recrystallization in diethylether (20 mL) gave the title compound (40 mg, 47%) as a white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (t, 1H, 6 Hz), 7.39-7.12 (m, 5H), 6.92-6.85 (m, 2H), 4.72 (s, 2H), 4.29 ( d, 2H, J = 6 Hz), 3.89 (d, 2H, J = 7.6 Hz), 3.34 (s, 2H), 2.58 (s, 3H) 2.15-2.08 (m, 1H), 0.92 (d, 6H, J = 6.8 Hz).

Test Example Analysis of Factor VIIa / Tissue Factor (FVIIa / TF) Inhibitory Ability

1) Reagent and Material

Factor Vlla / tissue factor (TFVIIa / TF) chromogenic substrate necessary for measuring the activity (chromogenic substrate) is S-2765 (N-α- ZD-Arg-Gly-Arg-pNA. 2HCl) is purchased from chromotherapy Xenix (Chromogenics) Was used. FVIIa, FX were purchased from Enzyme Research Laboratories. As a tissue factor (TF) source, Neo-Plastine (STA-Neoplastine) purchased from DiagnoStago was used. All reagents used for activity measurement were reagent grade. 96-well microtiter plates were purchased from Costar.

2) Factor VIIa / Tissue Factor (FVIIa / TF) Inhibitory Activity

The inhibitory capacity for FVIIa / TF activity of the compounds according to the invention was measured as described below. FVIIa / TF activity was used to measure the activity of the above-described chromogenic substrate of Factor FXa generated from Factor FX used as the substrate (JBC (2001) 276 (31) 29195-29199; Which is incorporated herein by reference]. In a 96-well plate, 0.2 uM FX solution dissolved in 60 mM Tris buffer (pH 7.4) containing 180 mM NaCl, 0.12% BSA (Bovine Syrum Albumin, Bovine Serum), 6 mM CaCl ₂ . 50 uL each was added, and as an inhibitor solution, the inhibitor compound according to the present invention was dissolved in dimethyl sulfoxide (DMSO) to 10 mM and diluted with tertiary distilled water to a solution of 7.8-500 uM (final 10% DMSO solution). ) And added 10 uL.

20 uL of 0.1 mg / mL neoplastin solution dissolved in 50 mM Tris buffer solution (pH 7.4) containing 150 mM NaCl, 0.1% BSA, 5 mM CaCl ₂ was added and the reaction was carried out in a concentration of 5 nM in the same buffer. 20 uL of FVIIa dissolved in each were added. The reaction was carried out at 37 ° C. for 20 minutes. At room temperature, 100 mM of 250 mM Tris buffer (pH 7.8) containing 30 mM EDTA, 375 mM NaCl, 2.5% PEG8000 (polyethylene glycol, molecular weight about 8,000) was added to stop the factor FVIIa activity and 1.5 mM in tertiary distilled water. 50 uL of S-2765 solution dissolved at the concentration was added. Kinetic analysis of this reaction was carried out for 2 minutes at 37 ° C. with a kinetics plate reader (Molecular Devices, Spectramax 190). The amount of para-nitroanilide produced by the reaction for 2 minutes after the addition of the S-2765 chromogenic substrate was monitored by a change in absorbance at 405 nm.

3) Analysis of Experiment Results

In order to determine the inhibitory capacity of the compound of formula (I) against factor VIIa, the concentration of the compound of formula (I) that inhibits the enzyme activity by 50%, i.e., the IC ₅₀ value (which is related to the inhibition constant Ki), can be evaluated. . After plotting the logarithm of the relative rate of hydrolysis (compared to the uninhibited control) versus the concentration of the compound of formula I, the concentration of the inhibitor that reduced the rate of substrate hydrolysis by 50% was determined by linear regression analysis. When calculating the suppression constant Ki, the IC ₅₀ value is calculated using the equation Ki = IC ₅₀ / {1+ (substrate concentration / Km)}, where Km is the Michaelis-Menten constant [Ref. Chen and Prusoff, Biochem. Pharmacol., 1973, 22, 3099-3108; Which is incorporated herein by reference] for correction to competition with the substrate.

As shown in Table 1 below, the inhibition constant Ki (TF / FVIIa)) was obtained.

TABLE 1 Inhibitory ability of selected inhibitors to the TF / FVIIa complex

As a result of measuring the inhibitory ability of the compound of formula (I) according to the present invention against factor VIIa, it can be seen that Ki <7 uM has an excellent inhibitory ability against the TF / FVIIa complex.

The pyrimidinone-based or pyridazinone-based compounds of formula (I) according to the invention have very good inhibitory activity against factor VIIa (FVIIa), which is associated with blood coagulation mechanisms.

Claims (5)

The compounds of formula (I), their hydrates, their isomers or their pharmaceutically acceptable salts. [Formula I]

In the above formula A is

or

ego; R ¹ is C ₆ to C ₁₀ unsubstituted or substituted with one or more substituents selected from nitro (-NO ₂ ), amino, hydroxy, carboxy (-CO ₂ H) or alkyl carboxy of C ₂ to C ₇ Aryl, wherein the aryl may include one or more heteroatoms selected from nitrogen, sulfur, or oxygen in the aromatic ring; R ² is hydrogen, alkyl of C ₁ to C ₆ , or a cyclic compound, phenyl, pyridine, pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole, isoazole, pyridazine , Pyrimidine, pyrazine, naphthalene, quinoline, isoquinoline, benzofuran, benzothiophene or indole, the cyclic compound is C ₁ -C ₄ alkyl, halogen atom, -CN, -OH, -CF ₃ ,- Or may be substituted with one or two substituents independently selected from OR, -CO ₂ R or -NHR, wherein R of the substituents represents C ₁ -C ₄ alkyl; Q ¹ and Q ² are independently hydrogen or alkyl of (C ₁ -C ₆ ); m and n are independently integers from 0 to 3; L is-(C = O)-,-CO ₂ -,-CONH-,-CONR ⁴ , -CH _2- , -O-, -NR ^4- , -N (R ⁴ ) (C = O)-, Or -N (R ⁴ ) (SO ₂ )-, wherein R ⁴ is C ₁ -C ₁₀ alkyl; R ³ is substituted by amidino, guanidino, aminomethyl, amino, cyano (-CN), cyanomethyl, hydroxy, -OCH ₂ CO ₂ R ⁵ , hydroxymethyl, chloro Selected from C ₆ to C ₁₀ aryl, R ⁵ is selected from hydrogen, methyl, ethyl or t-butyl, and the aryl is selected from nitrogen, sulfur or oxygen in the aromatic ring. It may include. The method of claim 1, R ¹ is C ₆ to C ₁₀ unsubstituted or substituted with one or more substituents selected from nitro (-NO ₂ ), amino, hydroxy, carboxy (-CO ₂ H) or alkyl carboxy of C ₂ to C ₇ Aryl, wherein the aryl is selected from phenyl, thiophene, pyridine, pyrazole, oxazole or aminothiazole; R ² is selected from methyl, isopropyl, phenyl, pyridine, thiophene, oxazole, isoxazole, imidazole, pyrazole, thiazole or isoazole; Q ¹ and Q ² are independently hydrogen or alkyl of (C ₁ -C ₄ ); m and n are independently integers, 0, 1, 2, L is -CO ₂ -,-CONH-,-CONR ⁴ , -N (R ⁴ ) (C = O)-, or -N (R ⁴ ) (SO ₂ )-, wherein R ⁴ is C ₁ -C ₁₀ alkyl; R ³ is selected from amidino, aminomethyl, amino, cyano (-CN), cyanomethyl, hydroxy, -OCH ₂ CO ₂ R ⁵ , hydroxy methyl, aryl substituted chloro, and R ⁵ is selected from hydrogen, methyl, ethyl or t-butyl and the aryl of R ³ is selected from phenyl, thiophene, pyridine or indole, a hydrate thereof, an isomer thereof or a pharmaceutical thereof Acceptable salts. The method of claim 2, R ¹ is C ₆ to C ₁₀ unsubstituted or substituted with one or more substituents selected from nitro (-NO ₂ ), amino, hydroxy, carboxy (-CO ₂ H) or alkyl carboxy of C ₂ to C ₇ Aryl, wherein the aryl is selected from phenyl, thiophene, pyridine or aminothiazole; R ² is selected from methyl, isopropyl, phenyl, pyridine, thiophene, oxazole, pyrazole, or thiazole; Q ¹ and Q ² are independently hydrogen or methyl; L is -CONH-; R ³ is selected from amidino, aminomethyl, amino, cyano (-CN), cyanomethyl, hydroxy, -OCH ₂ CO ₂ R ⁵ , hydroxy methyl, aryl substituted chloro, and R ⁵ is selected from hydrogen, methyl, ethyl or t-butyl and the aryl of R ³ is selected from phenyl, thiophene, or pyridine, a hydrate thereof, an isomer thereof or a pharmaceutically thereof Acceptable salts. The method of claim 3, wherein Compound of Formula (I) N- (4-cyanobenzyl) -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl] Acetamide; N- [4- (hydroxycarbamimidoyl) -benzyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyri Midin-5-yl] -acetamide; N- (4-carbamimidoylbenzyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl ] -Acetamide; N- [4- (N-hydroxycarbamimidoyl) -benzyl] -2- [1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidine-5- General] -acetamide; N- (4-Cyanobenzyl) -2- (1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl) -acetamide; N- (4-N-carbamimidoylbenzyl) -2- (1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl) -acetamide ; N- [4-N- (hydroxycarbamimidoyl) -benzyl] -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl) -acet Amides; N- (4-N-carbamimidoylbenzyl) -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl) -acetamide; N- [3- (N-hydroxycarbamimidoyl) -benzyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro -Pyrimidin-5-yl] -acetamide; N- [5- (N-hydroxycarbamimidoyl) -thiophen-2-ylmethyl] -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo- 1,6-dihydro-pyrimidin-5-yl] -acetamide; 2- [4- (3-aminophenyl) -1-isobutyl-2-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl] -N- (3-carbamimidoylbenzyl) Acetamide; 2- [4- (3-aminophenyl) -1-isobutyl-1-ethyl-2-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl] -N- (4-carbam Imidoylbenzyl) -acetamide; 2- [4- (3-aminophenyl) -2-methyl-6-oxo-1- (2-pyridin-2-yl-ethyl) -1,6-dihydro-pyrimidin-5-yl] -N -(4-carbamimidoylbenzyl) -acetamide; N- (5-chloro-2-hydroxymethylbenzyl) -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidine -5-yl] -acetamide; N- (5-chloro-2-hydroxymethylbenzyl) -2- (1-isobutyl-2-methyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl)- Acetamide; N- (5-chloro-2-hydroxymethylbenzyl) -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl] -acetamide; N- (5-chloro-2-cyanomethylbenzyl) -2- (1-isobutyl-6-oxo-4-phenyl-1,6-dihydro-pyrimidin-5-yl] -acetamide; N- (5-chloro-2-hydroxybenzyl) -2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydroxypyrimidine- 5-yl] -acetamide; N- (5-chloro-2-hydroxybenzyl) -2- [1-isobutyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydroxy-pyrimidin-5-yl ] -Acetamide; [4-Chloro-2-({2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl]- Acetylamino} -methyl) -phenoxy] -acetic acid ethyl ester; [4-Chloro-2-({2- [1-isobutyl-2-methyl-4- (3-nitrophenyl) -6-oxo-1,6-dihydro-pyrimidin-5-yl]- Acetylamino} -methyl) -phenoxy] -acetic acid; [2-({2- [4- (3-aminophenyl) -1-isobutyl-2-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl] -acetylamino} -4 -Chloro-phenoxy) -acetic acid; N- (4-cyanobenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acetamide; N- (4-carbamimidoylbenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acetamide; N- (5-chloro-2-hydroxymethylbenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acetamide; N- (5-Chloro-2-cyanomethylbenzyl) -2- (2-isobutyl-3-oxo-5-phenyl-2,3-dihydro-pyridazin-4-yl) -acetamide; N- (4-carbamimidoylbenzyl) -2- [2- (4-methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2,3-dihydro-pyridazine-4- General] -acetamide; 2- [5- (3-aminophenyl) -2- (4-methoxybenzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -N- (4-carbamimidoylbenzyl ) -Acetamide; N- (3-carbamimidoylbenzyl) -2- [2- (4-methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2,3-dihydro-pyridazine-4- General] -acetamide; 2- [5- (3-aminophenyl) -2- (4-methoxybenzyl) -3-oxo-2,3-dihydro-pyridazin-4-yl] -N- (3-carbamimidoylbenzyl ) -Acetamide; N- (5-Chloro-thiophen-2-ylmethyl) -2- [2- (4-methoxybenzyl) -5- (3-nitrophenyl) -3-oxo-2,3-dihydro- Pyridazin-4-yl] -acetamide; 2- [5- (3-aminophenyl) -2-ethyl-3-oxo-2,3-dihydro-pyridazin-4-yl] -N- (4-carbamimidoylbenzyl) -acetamide; And 2- [5- (3-aminophenyl) -2-phenethyl-3-oxo-2,3-dihydro-pyridazin-4-yl] -N- (4-carbamimidoylbenzyl) -acetamide A compound of formula (I), a hydrate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of: A pharmaceutical composition for preventing blood clotting or treating thrombosis, comprising as an active ingredient a compound of formula (I), a hydrate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.