WO2016019844A1 - Dabigatran cyclic ester derivative, and method for preparation and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to a dabigatran cyclic ester derivative, as represented by formula (I), and a stereoisomer or pharmaceutically acceptable salt thereof, as well as a use thereof in the preparation of a pharmaceutical used for prevention and treatment of a thromboembolic disorder; the structure is as represented by the formula (I), and the definitions of X₁, X₂, R¹, and R² are consistent with the description.

Description

Dabigatran group cycloester derivative, preparation method thereof and use thereof in pharmacy Technical field

The present invention relates to a dabigatran group-containing cyclic ester derivative, and a stereoisomer or pharmaceutically acceptable salt thereof, and use thereof in the preparation of a medicament for preventing and treating a thromboembolic disease.

Background technique

At present, cardiovascular disease is one of the main causes of death in humans. One of its main aspects is thrombosis, which is caused by a series of complex reactions. Blood coagulation is a protective mechanism of the organism whereby the defect of the vessel wall can be "sealed" quickly and reliably, thus avoiding blood loss or minimizing it. Maintaining normal hemostasis, ie hemorrhage and clotting balance, is regulated by a complex mechanism. Unregulated activation of the coagulation system or lack of inhibition of the activation process can lead to a variety of diseases and complications, such as venous thrombosis, deep vein thrombosis, pulmonary embolism, atherosclerosis, acute coronary syndrome, cerebrovascular disease and the like.

Oral anti-hemagglutination drugs that have been marketed mainly include direct thrombin inhibitors, factor Xa inhibitors, factor IX inhibitors, tissue factor inhibitors, and novel vitamin K antagonists. Among them, dabigatran etexilate is an oral, selective and highly potent thrombin inhibitor. It has been clinically proven to replace warfarin to prevent stroke and systemic embolism in patients with non-valvular atrial fibrillation and to replace enoxaparin sodium. The first choice for the prevention of venous thromboembolic events in patients undergoing major plastic surgery.

Dabigatran etexilate was marketed in 2008 and is used to prevent stroke or systemic embolism, deep vein thrombosis (DVT) or pulmonary vascular occlusion and its recurrence in patients with non-valvular atrial fibrillation. It is a double prodrug obtained by esterification of the free carboxyl group and the thiol group in the dabigatran group, which solves the problem that the insoluble thiol group can not be taken orally, and improves the oral bioavailability. . After oral administration of dabigatran etexilate, it is absorbed from the gastrointestinal tract and then rapidly converted into dabigatran in the body to exert an anticoagulant effect. However, the oral bioavailability of dabigatran diester is low, only 3 to 7%, so the higher dosage is medicinal and the side effects are increased.

There are many reports on the prodrugs of dabigatran. As disclosed in WO09837075 and WO2004014894, dabigatran and its analogs, as well as prodrugs thereof such as alkyl carboxylates, sulfonyl substituted carboxylic acid esters or sulfonylamino groups; CN102875533 and CN102838588 patents report Dabiga Group of ferulic acid or sulphate prodrugs, and has a certain anti-coagulant effect; CN200910211164, CN200910211165 and CN201210158600 and other patents disclose dabigatran carbonate, carboxylic acid ester and other prodrugs.

The object of the present invention is to solve the problem that dabigatran cannot be taken orally because of its strong alkalinity, and provide a novel and effective problem. Oral dabigatran prodrugs with good stability, solubility, bioavailability, and low dose, low toxic side effects or long-acting effects.

Summary of the invention

The present invention relates to a dabigatran group-based cyclic ester derivative, and stereoisomers thereof and a pharmaceutically acceptable salt thereof, and to use in the preparation of a medicament for preventing and treating a thromboembolic disease.

The present invention provides a compound of the formula (I), and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein:

X ₁ and X ₂ are each independently selected from O or S;

R ^{1 is} selected from a C _6-10 carbocyclic ring, and the carbocyclic ring is optionally further substituted with 0 to 4 R ^1a ;

R ^{1a is} independently selected from H, F, Cl, Br, I, CN, C _1-4 alkyl, C _1-4 alkoxy, -SC _1-4 alkyl or -(CH ₂ ) _n COO C _1-4 alkyl, said alkyl or alkoxy optionally further from 0 to 4 selected from H, F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy Substituted by a substituent;

R ^{2 is} selected from C _1-10 alkyl, and the alkyl group is optionally further substituted with from 0 to 12 R ^2a ;

R ^{2a is} independently selected from H, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 carbocyclic, said alkyl, alkoxy or carbon The ring is optionally further substituted with from 0 to 4 substituents selected from H, F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy;

n is selected from 0, 1, or 2.

A preferred embodiment of the invention, a compound of the formula (I), and a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein:

R ^{1 is} selected from substituted or unsubstituted phenyl, benzocyclopentyl or naphthyl, and when substituted, is optionally further substituted with from 0 to 4 R ^1a ;

R ^{2 is} selected from C _1-8 alkyl groups, and the alkyl group is optionally further substituted with from 0 to 12 R ^2a .

A preferred embodiment of the invention, a compound of the formula (I), and a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein:

R ^{1 is} selected from a C _6-10 carbocyclic ring, preferably a substituted or unsubstituted phenyl group, a benzocyclopentyl group or a naphthyl group, and the carbocyclic, phenyl, benzocyclopentyl or naphthyl group is optionally further 0 to 4 R ^1a substituted;

R ^{1a is} independently selected from the group consisting of H, F, Cl, Br, CN, CF ₃ , -CHF ₂ , -SCH ₃ , -OCF ₃ , -OCHF ₂ , methyl, ethyl, isopropyl, methoxy, Ethoxy, isopropoxy, -COOCH ₂ CH ₃ or -CH ₂ COOCH ₃ ;

R ^{2 is} selected from C _1-10 alkyl, preferably C _1-8 alkyl, and the alkyl group is optionally further substituted with from 0 to 12 R ^2a ;

R ^{2a is} independently selected from H, F, Cl, Br, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl.

A preferred embodiment of the invention, a compound of the formula (I), and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:

Preferred according to the invention, the compound according to the invention, and the stereoisomers and pharmaceutically acceptable salts thereof, wherein the salt is selected from the group consisting of hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, Acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylic acid Salt, glucuronide, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonic acid Salt, mesylate, ethanesulfonate, triflate, ferulic acid or a combination thereof.

The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

The invention further provides the use of a compound of any of the foregoing, and a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with a thrombin inhibitor.

The present invention also provides the use of a pharmaceutical composition as described above for the preparation of a medicament for treating a disease associated with thrombin inhibitors.

In a preferred embodiment of the invention, the thrombin-related disease is selected from a thromboembolic disorder.

In a preferred embodiment of the invention, the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolization.

The present invention further provides a method of treating a disease associated with a thrombin inhibitor, wherein the method comprises administering a compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, or the present invention Compositions.

In a preferred embodiment of the invention, the thrombin-related disease is selected from a thromboembolic disorder.

In a preferred embodiment of the invention, the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolization.

Specific synthesis method of the invention

method one:

X ₂ is O; R ² is n-hexyl;

R ¹ and X _{1 are} identical to the definitions of the above formula (I).

Method Two:

Wherein X ₁ and X ₂ are each independently selected from O or S;

R ^{1 is} selected from a C _6-10 carbocyclic ring, and the carbocyclic ring is optionally further substituted with 0 to 4 R ^1a ;

R ^{1a is} independently selected from H, F, Cl, Br, I, CN, C _1-4 alkyl, C _1-4 alkoxy, -SC _1-4 alkyl or -(CH ₂ ) _n COO C _1-4 alkyl, said alkyl or alkoxy optionally further from 0 to 4 selected from H, F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy Substituted by a substituent;

R ^{2 is} selected from C _1-10 alkyl, and the alkyl group is optionally further substituted with from 0 to 12 R ^2a ;

R ^{2a is} independently selected from H, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 carbocyclic, said alkyl, alkoxy or carbon The ring is optionally further substituted with from 0 to 4 substituents selected from H, F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy;

n is selected from 0, 1, or 2.

detailed description

The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), The internal standard is tetramethylsilane (TMS).

The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18100 x 4.6 mm).

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.

The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.

Intermediate 1

3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl)amino]propyl Acid (intermediate 1)

3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid

First step: 3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl Amino]propionic acid (intermediate 1)

3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid

3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Ethyl propionate (1a) (63 g, 100 mmol) was added to a mixed solvent of ethanol (600 mL) and water (300 mL), and sodium hydroxide (8 g, 200 mmol) was added thereto, and the mixture was stirred at room temperature for half an hour until the reaction liquid was clarified. Concentrate the reaction solution, steam off most of the ethanol, add water (200 mL), adjust the pH to 4-5 with 10% aqueous citric acid solution, precipitate a large amount of viscous solids, filter, transfer the solid into the reaction flask, add methanol (300 mL), heating until the solid is dissolved, stirring is continued until the solid is in the form of a granule, which is cooled to 0 ° C, and more product is precipitated, filtered and dried to give the title compound 3-[[2-[[4-[N] `-Hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid (Intermediate 1) (50 g, yield 83 %).

LCMS m/z = 600.2 [M + 1].

^{1 H NMR (400MHz, DMSO)} : δ8.38 (d, 1H), 7.79 (d, 2H), 7.56 (m 1H), 7.48 (s, 1H), 7.39 (d, 1H), 7.14 (m2H), 6.95(d,2H), 6.77(d,2H), 4.60(d,2H), 4.18(t,2H),3.99(t,2H),3.77(s,3H),2.68-2.58(m,3H) , 1.58 (dd, 2H), 1.29 (d, 6H), 0.87 (t, 3H).

Example 1

3-(2-((4-(N'-((hexyloxy)))carbonyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H -Benzo[d]imidazol-5-carboxamido)propionic acid 2-methoxyphenyl ester (Compound 1)

2-methoxyphenyl 3-(2-((((((())))))))))))))) d]imidazole-5-carboxamido)propanoate

3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propionic acid (intermediate 1) (3 g, 5 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 mL), and 2-methoxyphenol (1A) (0.93 g, 7.5 mmol), 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.5 mmol), 4-dimethylaminopyridine (0.37 g, 3 mmol). Concentrate directly with an oil pump, and the residue was purified by silica gel column chromatography (ethyl acetate: methylene chloride (v/v) = 1:1 to 2:1), then dissolved in dichloromethane (50 mL) with 10% The sodium dihydrogen phosphate solution (100 mL) was washed, dried over anhydrous sodium sulfate, and then evaporated. (2-((4-(N'-((hexyloxy))carbonyl)methyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzene And [d]imidazole-5-carboxamido)propanoic acid 2-methoxyphenyl ester (Compound 1), white solid (2.0 g, yield 57%).

LCMS m/z = 706.3 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (dd, 1H), 7.73 (dd, 3H), 7.37-7.29 (m, 2H), 7.20-7.14 (m, 1H), 7.09 (d, 1H), 7.04–6.96 (m, 2H), 6.96–6.89 (m, 2H), 6.77 (d, 1H), 6.66 (d, 2H), 5.33 (t, 1H), 4.55 (t, 2H), 4.46 (d, 2H), 4.14 (t, 2H), 3.80 (s, 3H), 3.68 (s, 3H), 3.11 (t, 2H), 1.78 - 1.66 (m, 2H), 1.46 - 1.35 (m, 2H), 1.35 – 1.23 (m, 4H), 0.89 (t, 3H).

Preparation of Compound 1 Mesylate:

The starting material is 3-(2-(((4-(N'-((hexyloxy))carbonyl)) phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl) -1H-benzo[d]imidazol-5-carboxamido)propanoic acid 2-methoxyphenyl ester (Compound 1) (0.3 g, 0.42 mmol) was dissolved in acetone (10 mL). A solution of mg (0.42 mmol) in acetone (1 mL) was stirred at room temperature for 1 hour. The solid was filtered to give Compound 1 methanesulfonate as a pale yellow solid (250 mg, yield 74.18%).

LCMS m/z = 706.3 [M + 1].

^{1 H NMR (400MHz, DMSO)} δ11.86 (s, 1H), 10.62 (s, 1H), 10.01 (s, 1H), 8.43 (dd, 1H), 7.66 (d, 2H), 7.59 (ddd, 2H ), 7.51 (d, 1H), 7.44 (d, 1H), 7.27 - 7.18 (m, 2H), 7.18 - 7.09 (m, 2H), 7.06 (dd, 1H), 7.01 - 6.92 (m, 2H), 6.88(d,2H), 4.70(d,2H), 4.34(t,2H), 4.26(t,2H), 3.79(s,3H),3.75(s,3H),2.98(t,2H),2.30 (s, 3H), 1.67 (dd, 2H), 1.38 (dd, 2H), 1.35 - 1.21 (m, 4H), 0.89 (t, 3H).

Preparation of Compound 1 Sulfonic Acid Salt:

The starting material is 3-(2-(((4-(N'-((hexyloxy))carbonyl)) phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl) -1H-benzo[d]imidazol-5-carboxamido)propanoic acid 2-methoxyphenyl ester (Compound 1) (0.3 g, 0.42 mmol) was dissolved in acetone (15 mL) and concentrated sulfuric acid (42.2 mg) A solution of 0.42 mmol) in acetone (1 mL) was stirred at room temperature for 1 hour. The solid was filtered to give the compound 1 sulfonate as a white solid (50 mg, yield 14.79%).

LCMS m/z = 706.3 [M + 1].

¹ H NMR (400 MHz, DMSO) δ 11.86 (s, 1H), 10.61 (s, 1H), 10.00 (s, 1H), 8.43 (dd, 1H), 7.66 (d, 2H), 7.64 - 7.54 (m) , 2H), 7.52 (d, 1H), 7.44 (d, 1H), 7.27 - 7.18 (m, 2H), 7.14 (ddd, 2H), 7.06 (dd, 1H), 7.01 - 6.91 (m, 2H), 6.89 (s, 2H), 4.71 (s, 2H), 4.34 (t, 2H), 4.26 (t, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 2.98 (t, 2H), 2.09 (s, 1H), 1.75 - 1.61 (m, 2H), 1.47 - 1.34 (m, 2H), 1.30 (dd, 4H), 0.89 (t, 3H).

Preparation of Compound 1 Hydrochloride:

3-(2-(((4-(N'-((hexyloxy))carbonyl)) phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)- 1H-Benzo[d]imidazol-5-carboxamido)propanoic acid 2-methoxyphenyl ester (Compound 1) (0.3 g, 1.4 mmol) was dissolved in acetone (30 mL). The gas was reacted at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give (yield: 20%).

LCMS m/z = 706.3 [M + 1].

^{1 H NMR (400MHz, DMSO)} δ11.99 (s, 1H), 11.11 (s, 1H), 10.10 (s, 1H), 8.41 (dd, 1H), 7.83 (d, 1H), 7.76 (s, 1H ), 7.73 (d, 2H), 7.67 (td, 1H), 7.41 (dd, 1H), 7.26 - 7.08 (m, 4H), 7.05 (dd, 1H), 6.99 (d, 2H), 6.94 (td, 1H), 5.04 (s, 2H), 4.33 (t, 2H), 4.27 (t, 2H), 4.00 (s, 3H), 3.74 (s, 3H), 3.00 (t, 2H), 2.09 (d, 2H) ), 1.74 - 1.60 (m, 2H), 1.37 (dd, 2H), 1.30 (dd, 4H), 0.88 (t, 3H).

Example 2

(5-fluoro-2-methoxyphenyl)3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5- Carbonyl]-(2-pyridyl)amino]propionate (Compound 2)

(5-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propanoate

See Method 1 for the preparation method.

LCMS m/z = 724.32 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (dd, 1H), 7.76 (s, 1H), 7.74 (d, 2H), 7.33 (ddd, 2H), 7.11 (d, 1H), 7.03-6.96 ( m,1H), 6.90–6.85 (m, 2H), 6.82 (dd, 1H), 6.75 (d, 1H), 6.68 (d, 2H), 5.34 (s, 1H), 4.55 (t, 2H), 4.49 (d, 2H), 4.14 (t, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 3.10 (t, 2H), 1.76 - 1.66 (m, 2H), 1.40 (dd, 2H), 1.35–1.27 (m, 4H), 0.89 (dd, 3H).

Example 3

(2-methoxyphenyl)3-[[2-[[4-[N`-heptyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-( 2-pyridyl)amino]propionate (compound 3)

(2-methoxyphenyl)3-[[2-[[4-[(E)-N`-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

First step: 3-[[2-[[4-[N`-heptyloxycarbonylmethylhydrazine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) Amino]ethyl propionate (3B)

Ethyl 3-[[2-[[4-[N`-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimida Zole-5-carbonyl]-(2-pyridyl)amino]propanoate

N,N'-carbonyldiimidazole (0.63 g, 3.87 mmol) was added to 10 mL of tetrahydrofuran of n-heptanol (0.415 g, 3.58 mmol) at room temperature, and the mixture was stirred at room temperature for 30 min. Ethyl 3-[[2-[(4-carboxanilide)methyl]-1 methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propionate p-toluenesulfonic acid To the salt (3A) (2 g, 2.98 mmol), acetone (60 mL), water (30 mL), and potassium carbonate (1.23 g, 8.94 mmol) were added, and the mixture was stirred, and the reaction mixture 1 was added thereto, and the mixture was reacted at room temperature for 5 hours. After that, water (100 mL) was added, and the mixture was extracted with ethyl acetate (150 mL), and the organic layer was combined. The organic layer was washed with water (100 mL×2). [[2-[[4-[N`-heptyloxycarbonyl] aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid ethyl ester (3B), white solid (1.3 g, yield 56.76%).

LCMS m/z = 642.33 [M + 1].

Second step: 3-[[2-[[4-[N`-heptyloxycarbonylmethylhydrazine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) Amino]propionic acid (3C)

3-[[2-[[4-[N`-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid

3-[[2-[[4-[N`-heptyloxycarbonylmethylhydrazine]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl)amino group at room temperature To a solution of ethyl propionate (3B) (1.3, 2.03 mmol) in ethanol (15 mL), a solution of sodium hydroxide (162 mg, 4.06 mmol) in water (7.5 mL) was added. Thereafter, the ethanol was depressurized, and the reaction solution was adjusted to pH 4 to 5 with an aqueous solution of citric acid to precipitate a large amount of solid. The solid was filtered, and the solid was added to acetonitrile (20 mL) and stirred for 10 minutes, and the solid was filtered again, and the solvent was removed under reduced pressure. That is, the product white solid 3-[[2-[[4-[N`-heptyloxycarbonylcarboxamidine] phenylamine]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl Amino]propionic acid (3C) (1.0 g, yield 80.64%).

LCMS m/z = 614.32 [M + 1].

The third step: (2-methoxyphenyl)3-[[2-[[4-[N`-heptyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5- Carbonyl]-(2-pyridyl)amino]propionate (Compound 3)

(2-methoxyphenyl)3-[[2-[[4-[(E)-N`-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

3-[[2-[[4-[N`-heptyloxycarbonylmethylhydrazine]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl)amino group at room temperature Add guaiacol (0.3 g, 2.4 mmol), 1-ethyl-(3-di) to a solution of propionic acid (3C) (1.0 g, 1.63 mmol) in N,N-dimethylformamide (15 mL) Methylaminopropyl)carbodiimide hydrochloride (0.4 g, 2.08 mmol) and 4-dimethylaminopyridine (122 mg, 1 mmol) were reacted at room temperature for 15 hours. Water (30 mL) was added to the reaction mixture, and the mixture was evaporated. Separation and purification (dichloromethane:methanol (v/v) = 50:1 to 30:1) gave the title compound (2-methoxyphenyl) 3-[[2-[[4-[N `-Heptyloxycarbonylmethylhydrazine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propionate (Compound 3) (0.41 g, yield 35.04 %).

LCMS m/z = 720.34 [M + 1].

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (dd, 1H), 7.78 - 7.67 (m, 3H), 7.37 - 7.27 (m, 2H), 7.21 - 7.13 (m, 1H), 7.08 (d, 1H) ), 7.04–6.97 (m, 2H), 6.97–6.88 (m, 2H), 6.77 (d, 1H), 6.66 (d, 2H), 5.34 (s, 1H), 4.55 (t, 2H), 4.46 ( d, 2H), 4.13 (t, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 3.10 (t, 2H), 1.71 (dd, 2H), 1.39 (dd, 2H), 1.35 - 1.24 (m, 6H), 0.88 (t, 3H).

Example 4

(2-methoxyphenyl)3-[[2-[[4-[N`-(cyclopentylmethoxycarbonyl)methylindenyl]phenylamino]methyl]-1-methyl-benzimidazole -5-carbonyl]-(2-pyridyl)amino]propionate (Compound 4)

(2-methoxyphenyl)3-[[2-[[4-[(E)-N`-(cyclopentylmethoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino Propanoate

See Example 3 for the preparation method.

LCMS m/z = 704.31 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (d, 1H), 7.76-7.65 (m, 3H), 7.37-7.27 (m, 2H), 7.17 (t, 1H), 7.07 (d, 1H), 7.04–6.96 (m, 2H), 6.92 (dd, 2H), 6.76 (d, 1H), 6.64 (d, 2H), 5.42 (s, 1H), 4.54 (t, 2H), 4.45 (d, 2H) , 4.03 (d, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 3.10 (t, 2H), 2.35 - 2.25 (m, 1H), 1.80 (d, 2H), 1.58 (ddd, 4H) ), 1.35–1.19 (m, 2H).

Example 5

(2-methoxy-4-methyl-phenyl)3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5 -carbonyl]-(2-pyridyl)amino]propionate (Compound 5)

(2-methoxy-4-methyl-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propanoate

See Method 1 for the preparation method.

LCMS m/z = 720.34 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.45-8.39 (m, 1H), 7.72 (dd, 3H), 7.36-7.31 (m, 1H), 7.29 (dd, 1H), 7.07 (d, 1H), 6.99 (ddd, 1H), 6.88 (d, 1H), 6.79 - 6.68 (m, 3H), 6.65 (d, 2H), 5.34 (d, 1H), 4.53 (t, 2H), 4.44 (d, 2H) , 4.13 (t, 2H), 3.77 (s, 3H), 3.67 (s, 3H), 3.08 (t, 2H), 2.32 (s, 3H), 1.71 (dd, 2H), 1.46 - 1.36 (m, 2H) ), 1.34–1.28 (m, 4H), 0.89 (dd, 3H).

Example 6

o-Tolyl 3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl)amino Propionate (Compound 6)

O-tolyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 690.33 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (dd, 1H), 7.74 (s, 1H), 7.71 (d, 2H), 7.33 (td, 1H), 7.29 (dd, 1H), 7.18 (dd, 2H), 7.12 (dd, 1H), 7.08 (dd, 1H), 6.99 (dd, 2H), 6.74 (d, 1H), 6.64 (d, 2H), 5.35 (s, 1H), 4.56 (t, 2H) ), 4.44 (d, 2H), 4.13 (t, 2H), 3.67 (s, 3H), 3.10 (t, 2H), 2.16 (s, 3H), 1.79 - 1.65 (m, 2H), 1.51 - 1.34 ( m, 2H), 1.33 - 1.18 (m, 4H), 0.88 (t, 3H).

Example 7

[2-(Trifluoromethyl)phenyl]3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl-benzimidazole-5- Carbonyl]-(2-pyridyl)amino]propionate (Compound 7)

[2-(trifluoromethyl)phenyl]3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 744.30 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (dd, 1H), 7.72 (d, 3H), 7.64 (d, 1H), 7.56 (t, 1H), 7.32 (m, 3H), 7.25 (d, 1H), 7.05 (d, 1H), 7.02–6.96 (m, 1H), 6.72 (d, 1H), 6.63 (d, 2H), 5.35 (d, 1H), 4.56 (t, 2H), 4.43 (d) , 2H), 4.19–4.05 (m, 2H), 3.66 (s, 3H), 3.08 (t, 2H), 1.76–1.64 (m, 2H), 1.39 (dd, 2H), 1.35–1.26 (m, 4H) ), 0.88 (dd, 3H).

Example 8

(2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-octyloxycarbonylformamidine]phenylamino]methyl]benzimidazole-5-carbonyl]-( 2-pyridyl)amino]propionate (compound 8)

(2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-octoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Example 3 for the preparation method.

LCMS m/z = 734.36 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (dd, 1H), 7.74 (dd, 3H), 7.33 (m, 2H), 7.20-7.14 (m, 1H), 7.09 (d, 1H), 7.04- 6.96 (m, 2H), 6.96 - 6.89 (m, 2H), 6.77 (d, 1H), 6.67 (d, 2H), 5.33 (s, 1H), 4.55 (t, 2H), 4.47 (d, 2H) , 4.13 (t, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 3.10 (t, 2H), 1.71 (dd, 2H), 1.46 - 1.35 (m, 2H), 1.35 - 1.23 (m , 8H), 0.87 (t, 3H).

Example 9

(2-methoxy-6-methyl-phenyl)3-[[2-[[4-[N`-hexyloxycarbonylcarbamimidyl]phenylamino]methyl]-1-methyl-benzo Imidazole-5-carbonyl]-(2-pyridyl)amino]propionate (Compound 9)

(2-methoxy-6-methyl-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propanoate

See Method 1 for the preparation method.

LCMS m/z = 720.34 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (dd, 1H), 7.73 (dd, 3H), 7.35 (td, 1H), 7.31 (dd, 1H), 7.13-7.03 (m, 2H), 7.00 ( Dd, 1H), 6.78 (dd, 3H), 6.67 (d, 2H), 5.33 (t, 1H), 4.61 - 4.50 (m, 2H), 4.47 (d, 2H), 4.13 (t, 2H), 3.77 (s, 3H), 3.69 (s, 3H), 3.16 (t, 2H), 2.15 (s, 3H), 1.71 (dd, 2H), 1.40 (dd, 2H), 1.36 - 1.26 (m, 4H), 0.89 (t, 3H).

Example 10

(2-Fluoro-6-methoxy-phenyl)3-[[2-[[4-[(E)-N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzene And imidazol-5-carbonyl]-(2-pyridyl)amino]propionate (Compound 10)

(2-fluoro-6-methoxy-phenyl)3-[[2-[[4-[(E)-N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2- Pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 724.32 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (dd, 1H), 7.76 (s, 1H), 7.73 (d, 2H), 7.35 (td, 1H), 7.31 (d, 1H), 7.11 (ddd, 2H), 6.99 (dd, 1H), 6.81–6.73 (m, 2H), 6.73–6.64 (m, 3H), 5.35 (s, 1H), 4.54 (t, 2H), 4.48 (d, 2H), 4.14 (t, 2H), 3.81 (s, 3H), 3.70 (s, 3H), 3.18 (t, 2H), 1.77 - 1.68 (m, 2H), 1.40 (dd, 2H), 1.34 - 1.28 (m, 4H) ), 0.89 (t, 3H).

Example 11

3-[[2-[[4-[N'-heptyloxycarbonylmethylindenyl]phenylamino]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl)amino ] 5-fluoro-2-methoxy-phenyl propionate (Compound 11)

(5-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N'-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propanoate

First step: 3-[[2-[[4-[N'-heptyloxycarbonylmethylindenyl]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridine Ethyl]ethyl propionate (11B)

Ethyl 3-[[2-[[4-[N'-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

To a solution of 1-heptanol (1.400 g, 12.05 mmol) in tetrahydrofuran (10 mL), carbodiimidazole (1.95 g, 12.0 mmol) was added, and the mixture was stirred at room temperature for 30 min. 3-(2-(((4-Hydrylphenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-formyl Add acetone (100 mL), water (50 mL), potassium carbonate (2.77 g, 20.0 mmol) to p-toluenesulfonate (11A) (6.77 g, 10.0 mmol) of ethylaminopropionate, stir well and add The reaction solution 1 was reacted at room temperature for 5 hours after the addition. The precipitated white solid was filtered, and the filter cake was washed with acetone/water (acetone: water (v/v) = 1:2), then dissolved in 100 mL of dichloromethane and dried over anhydrous sodium sulfate. [2-[[4-[N'-heptyloxycarbonylmethylindenyl]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid Ester (11B), white solid (6.00 g, yield 93.2%).

^{1 H NMR (400MHz, DMSO)} δ8.43-8.34 (m, 1H), 7.80 (d, 2H), 7.54 (td, 1H), 7.48 (s, 1H), 7.40 (d, 1H), 7.14 (m , 2H), 7.01 (s, 1H), 6.89 (d, 1H), 6.78 (d, 2H), 4.60 (s, 2H), 4.23 (t, 2H), 3.98 (dt, 4H), 3.78 (d, 3H), 2.69 (t, 2H), 2.01–1.79 (m, 1H), 1.77–1.63 (m, 1H), 1.64–1.54 (m, 2H), 1.28 (d, 8H), 1.12 (t, 3H) , 0.86 (t, 3H).

Second step: 3-[[2-[[4-[N'-heptyloxycarbonylmethylindenyl]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridine Amino]propionic acid (11C)

3-[[2-[[4-[N'-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid

3-[[2-[[4-[N'-heptyloxycarbonylmethylindenyl]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl) at room temperature A solution of ethylamino]propionate (11B) (3.0 g, 4.7 mmol) in ethanol (50 mL) was added 5 mL of aqueous sodium hydroxide (390 mg, 9.75 mmol), and the mixture was stirred at room temperature for 3 hours. The pH was adjusted to 3 with a saturated aqueous solution of citric acid, and the precipitated solid was filtered, dissolved in dichloromethane, dried over anhydrous sodium sulfate and evaporated to give the title compound 3-[[2-[[[[[[[[[[[[[[[[[[ Methylamino]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid (11C), white solid (1.3 g, yield 45.0%).

^{1 H NMR (400MHz, DMSO)} δ11.90 (s, 1H), 10.99 (s, 1H), 10.03 (s, 1H), 8.37 (d, 1H), 7.96 (s, 2H), 7.72 (d, 2H ), 7.58 (dt, 3H), 7.24 (d, 1H), 7.14 (dd, 1H), 7.02 (d, 1H), 6.93 (d, 2H), 4.82 (s, 2H), 4.26 (t, 2H) , 4.18 (t, 2H), 3.87 (s, 3H), 2.79 - 2.69 (m, 3H), 2.63 (m, 3H), 1.68 (m, 2H), 1.38 - 1.24 (m, 10H), 0.87 (t , 3H).

The third step: 3-[[2-[[4-[N'-heptyloxycarbonylmethylindenyl]phenylamino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2- Pyridyl)amino]propionic acid 5-fluoro-2-methoxy-phenyl ester (Compound 11)

(5-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N'-heptoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propanoate

3-[[2-[[4-[N'-heptyloxycarbonylmethylindenyl]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl) at room temperature A solution of amino]propionic acid (11C) (1.40 g, 2.28 mmol) in dimethylformamide (15 mL) was added 5-fluoro-2-methoxyphenol (450 mg, 3.17 mmol), 1-ethyl- (3) -Dimethylaminopropyl)carbodiimide hydrochloride (0.900 g, 5.07 mmol) and 4-dimethylaminopyridine (170 mg, 1.39 mmol) were reacted at room temperature for 15 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL×3). The organic phase was combined, and the organic phase was washed with saturated aqueous potassium dihydrochloride (30 mL×2), dried over anhydrous sodium sulfate The title compound (3-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ 5-phenylamino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid 5-fluoro-2-methoxy-phenyl ester (Compound 11), Brown solid (0.20 g, yield 12.0%).

LCMS m/z = 738.4 [M+1]

¹ H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.64 (s, 1H), 8.42 (dd, 1H), 7.80 (d, 2H), 7.56 (td, 1H), 7.50 (d, 1H) ), 7.41 (d, 1H), 7.20 (dd, 1H), 7.18-7.08 (m, 3H), 7.05 (dd, 1H), 6.94 (dd, 2H), 6.77 (d, 2H), 4.60 (d, 2H), 4.33 (t, 2H), 3.98 (t, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 2.98 (t, 2H), 1.65 - 1.50 (m, 2H), 1.35 - 1.21. (m, 8H), 0.86 (t, 3H).

Example 12

(2-methoxyphenyl)3-[[2-[[4-[(E)-N`-(2-methoxyethoxycarbonyl)methylindenyl]phenylamino]methyl]-1- Methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propionate (Compound 12)

(2-methoxyphenyl)3-[[2-[[4-[(E)-N`-(2-methoxyethoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl )amino]propanoate

See Example 3 for the preparation method.

LCMS m/z = 680.28 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (dd, 1H), 7.73 (dd, 3H), 7.38-7.28 (m, 2H), 7.21-7.14 (m, 1H), 7.09 (d, 1H), 7.04–6.97 (m, 2H), 6.96–6.88 (m, 2H), 6.77 (d, 1H), 6.66 (d, 2H), 5.34 (s, 1H), 4.55 (t, 2H), 4.47 (d, 2H), 4.35 - 4.24 (m, 2H), 3.80 (s, 3H), 3.73 - 3.65 (m, 5H), 3.40 (d, 3H), 3.10 (t, 2H).

Example 13

(2,3-difluoro-6-methoxy-phenyl)3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl-benzene And imidazol-5-carbonyl]-(2-pyridyl)amino]propionate (Compound 13)

(2,3-difluoro-6-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) Amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 742.31. [M+1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (dd, 1H), 7.74 (s, 1H), 7.71 (s, 2H), 7.34 (td, 1H), 7.28 (d, 1H), 7.07 (d, 1H), 7.02–6.91 (m, 2H), 6.75 (d, 1H), 6.69–6.53 (m, 3H), 5.38 (s, 1H), 4.53 (t, 2H), 4.45 (d, 2H), 4.21. –4.04(m,2H), 3.78(s,3H), 3.68(s,3H), 3.19(t,,2H), 1.78–1.61(m,2H), 1.47–1.35(m,2H),1.35– 1.25 (m, 4H), 0.88 (t, 3H).

Example 14

(3-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5 -carbonyl]-(2-pyridyl)amino]propionate (Compound 14)

(3-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propanoate

See Method 1 for the preparation method.

LCMS m/z = 724.32 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (d, 1H), 7.73 (s, 1H), 7.71 (s, 2H), 7.33 (td, 1H), 7.28 (d, 1H), 7.07 (d, 1H), 6.98 (ddd, 3H), 6.87–6.81 (m, 1H), 6.74 (d, 1H), 6.64 (d, 2H), 5.36 (s, 1H), 4.55 (t, 2H), 4.45 ( s, 2H), 4.13 (t, 2H), 3.89 (d, 3H), 3.68 (s, 3H), 3.11 (t, 2H), 1.77 - 1.63 (m, 2H), 1.39 (dd, 2H), 1.30 (dd, 4H), 0.88 (t, 3H).

Example 15

(2-methoxyphenyl)3-[[1-methyl-2-[[4-[(E)-N`-(2-methylpentyloxycarbonyl)carboxamidine] phenylamine]methyl]benzo Imidazole-5-carbonyl]-(2-pyridyl)amino]propionate (Compound 15)

(2-methoxyphenyl)3-[[1-methyl-2-[[4-[(E)-N`-(2-methylpentoxycarbonyl)carbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl) Amino]propanoate

See Example 3 for the preparation method.

LCMS m/z = 706.33 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (dd, 1H), 7.73 (d, 3H), 7.37-7.28 (m, 2H), 7.21-7.13 (m, 1H), 7.09 (d, 1H), 7.05–6.97 (m, 2H), 6.96–6.88 (m, 2H), 6.77 (d, 1H), 6.66 (d, 2H), 5.36 (s, 1H), 4.55 (t, 2H), 4.47 (d, 2H), 3.97 (ddd, 2H), 3.81 (d, 3H), 3.69 (s, 3H), 3.10 (t, 2H), 1.91 (dd, 1H), 1.52 - 1.35 (m, 2H), 1.30 (ddd , 2H), 0.97 (d, 3H), 0.90 (t, 3H).

Example 16

2-((3-(2-(((4-(N-)-((hexyloxy))))-yl)phenyl)amino)methyl)-1-methyl-N-(pyridine-2 -yl)-1H-benzo[d]imidazol-5-carboxamido)propionyl)oxy)benzoate ethyl ester (Compound 16)

Ethyl 2-((3-(2-((((((())))))))))))))) Benzo[d]imidazole-5-carboxamido)propanoyl)oxy)benzoate

3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-( 2-Pyridyl)amino]propionic acid (Intermediate 1) (1 g, 1.67 mmol), ethyl salicylate (16A) (0.42 g, 2.5 mol), 1-(3-dimethylaminopropyl)-3 Ethyl carbodiimide hydrochloride (0.42 g, 2.17 mmol), 4-dimethylaminopyridine (0.122 g, 1 mmol), then added N,N-dimethylformamide (16 mL). Raise to room temperature and react to 5. The reaction was stopped and ethyl acetate (100 mL) was added, and the organic phase was washed with water (60 mL×5), washed with saturated brine (60 mL×1), dried over anhydrous sodium sulfate Separation and purification (dichloromethane:methanol (v/v)=100:1-20:1) afforded 2-((3-(2-(((((( )methyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propionyl)oxy) Ethyl benzoate (Compound 16) (0.1 g, yield 8%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ8.42 (d, 1H), 8.01-7.99 (m, 1H), 7.78-7.74 (m, 3H), 7.58-7.51 (m, 1H), 7.36-7.30 ( m, 3H), 7.14-7.11 (m, 2H), 7.01-6.98 (m, 1H), 6.78-6.76 (d, 1H), 6.71-6.69 (m, 2H), 5.30 (s, 1H), 4.59- 4.56(t,2H), 4.51-4.50(d,2H),4.34-4.29(m,2H),4.16-4.12(t,2H),3.72(s,3H),3.17-3.13(t,2H), 1.76-1.69 (m, 2H), 1.45 - 1.41 (m, 2H), 1.39-1.29 (m, 7H), 0.91 - 0.87 (t, 3H).

Example 17

(5-Bromo-2-methoxyphenyl)3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl-benzimidazole-5 -carbonyl]-(2-pyridyl)amino]propionate (Compound 17)

(5-bromo-2-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propanoate

See Method 1 for the preparation method.

LCMS m/z = 784.24. [M+1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (dd, 3H), 8.44 (dd, 3H), 7.71 (dd, 9H), 7.38-7.23 (m, 12H), 7.14 (d, 3H), 7.09- 6.96 (m, 6H), 6.76 (dd, 6H), 6.63 (d, 6H), 5.35 (t, 3H), 4.53 (t, 6H), 4.43 (d, 6H), 4.17 - 4.07 (m, 6H) ), 3.77 (s, 8H), 3.66 (s, 8H), 3.09 (t, 6H), 2.03 (s, 1H), 1.71 (dd, 6H), 1.60 - 1.21 (m, 20H), 0.89 (dd, 9H), -0.01 (s, 4H).

Example 18

2-methoxyphenyl 3-[[1-methyl-2-[[4-[N`-pentoxycarbonylcarbamimidoyl]phenylamino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino] Ethyl propionate (compound 18)

2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-pentoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoat

See Example 11 for the preparation method.

LCMS m/z = 692.3 [M + 1].

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (dd, 1H), 7.75-7.71 (m, 3H), 7.38 - 7.27 (m, 2H), 7.21 - 7.13 (m, 1H), 7.07 (d, 1H) ), 7.03-6.98 (m, 2H), 6.95-6.89 (m, 2H), 6.76 (d, 1H), 6.65 (d, 2H), 5.36 (t, 1H), 4.55 (t, 2H), 4.44 ( d, 2H), 4.13 (t, 2H), 3.79 (s, 3H), 3.67 (s, 3H), 3.10 (t, 2H), 1.75-1.69 (m, 2H), 1.41 - 1.33 (m, 4H) , 0.91 (t, 3H).

Example 19

[2-(Difluoromethoxy)phenyl]3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl-benzimidazole-5 -carbonyl]-(2-pyridyl)amino]propionate (Compound 19)

[2-(difluoromethoxy)phenyl]3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

For the preparation method, see Example 1

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.42 (dd, 1H), 7.69 (d, 3H), 7.32 (td, 1H), 7.23 (s, 1H), 7.21 (d, 3H), 7.17 (dt, 1H), 7.07–6.94 (m, 2H), 6.72 (d, 1H), 6.60 (d, 2H), 5.41 (s, 1H), 4.54 (t, 2H), 4.40 (d, 2H), 4.12 ( t, 2H), 3.64 (s, 3H), 3.10 (t, 2H), 1.70 (dd, 2H), 1.39 (dt, 2H), 1.34 - 1.27 (m, 4H), 0.88 (dd, 3H).

Example 20

(4-Fluoro-2-methoxyphenyl)3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5- Carbonyl]-(2-pyridyl)amino]propionate (Compound 20)

(4-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propanoate

See Method 1 for the preparation method.

LCMS m/z = 724.32 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (dd, 1H), 7.73 (s, 1H), 7.72-7.66 (m, 2H), 7.32 (dd, 1H), 7.28 (dd, 1H), 7.06 ( d,1H), 7.03–6.93 (m, 2H), 6.74 (d, 1H), 6.69–6.56 (m, 4H), 5.36 (s, 1H), 4.53 (t, 2H), 4.44 (d, 2H) , 4.13 (t, 2H), 3.77 (s, 3H), 3.67 (s, 3H), 3.08 (t, 2H), 1.80 - 1.62 (m, 2H), 1.47 - 1.34 (m, 2H), 1.30 (dd , 4H), 0.88 (dd, 3H).

Example 21

1-naphthyl 3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl) Amino]propionate (Compound 21)

1-naphthyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 726.33 [M + 1].

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (dd, 1H), 7.87 (dd, 1H), 7.84 - 7.78 (m, 1H), 7.73 - 7.64 (m, 4H), 7.50 - 7.45 (m, 2H) ), 7.45–7.38 (m, 1H), 7.35–7.29 (m, 1H), 7.29–7.26 (m, 1H), 7.25 (d, 1H), 6.99 (ddd, 2H), 6.74 (d, 1H), 6.59 (d, 2H), 5.35 (t, 1H), 4.64 (t, 2H), 4.37 (d, 2H), 4.13 (t, 2H), 3.58 (s, 3H), 3.26 (t, 2H), 1.80 –1.63 (m, 2H), 1.45–1.35 (m, 2H), 1.35–1.23 (m, 4H), 0.88 (dd, 3H).

Example 22

3-(2-((4-(N-((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)- 1H-benzo[d]imidazol-5-carboxamido) 2-isopropylphenylpropionate (Compound 22)

2-isopropylphenyl 3-(2-((((((()))))))))))))) d]imidazole-5-carboxamido)propanoate

See Method 1 for the preparation method.

LCMS m/z = 718.2 [M + 1].

¹ H NMR (400MHz, CDCl ₃ ) δ 8.59–8.35 (m, 1H), 8.02–7.51 (m, 3H), 7.43–7.23 (m, 3H), 7.23–7.09 (m, 2H), 7.09–6.94 (m, 3H), 6.74 (d, 1H), 6.61 (d, 2H), 5.41 (t, 1H), 4.75 - 4.46 (m, 2H), 4.39 (t, 2H), 4.28 - 3.99 (m, 2H) ), 3.73 (d, 3H), 3.20–2.86 (m, 3H), 1.84–1.66 (m, 2H), 1.50–1.26 (m, 6H), 1.21 (t, 6H), 1.01–0.75 (m, 3H) ).

Example 23

(2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-propoxycarbonylformamidine]aniline]methyl]benzimidazole-5-carbonyl]-(2- Pyridyl)amino]propionate (Compound 23)

(2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-propoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

First step: 3-[[1-methyl-2-[[4-[N`-propoxycarbonylformamidine]aniline]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino] Ethyl propionate (23B)

Ethyl 3-[[1-methyl-2-[[4-[N`-propoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

N,N'-carbonyldiimidazole (0.94 g, 5.81 mmol) was added to n-propanol (0.32 g, 5.36 mmol) in tetrahydrofuran (10 mL) at room temperature, and stirred at room temperature for 30 min. 1. Ethyl 3-[[2-[(4-carboxanilide)methyl]-1 methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propionate p-toluenesulfonic acid To the salt (11A) (3 g, 4.47 mmol), acetone (80 mL), water (40 mL), and potassium carbonate (1.85 g, 13.41 mmol) were added, and the mixture was stirred and then added to the reaction mixture 1 and allowed to react at room temperature for 5 hours. After that, water (100 mL) was added, and the mixture was extracted twice with ethyl acetate (150 mL×2), and the organic layer was combined, and the organic layer was washed twice with water (150 mL×2). The title compound 3-[[1-methyl-2-[[4-[N`-propoxycarbonylformamidine]aniline]methyl]benzimidazol-5-carbonyl]-(2-pyridyl)amino]propanoic acid Ethyl ester (23B), white solid (1.8 g, yield 69.2%).

LCMS m/z = 586.27 [M + 1].

Second step: 3-[[1-methyl-2-[[4-[N`-propoxycarbonylformamidine]aniline]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propionic acid (23C)

3-[[1-methyl-2-[[4-[N`-propoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid

3-[[1-Methyl-2-[[4-[N`-propoxycarbonylformamidine]aniline]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propyl To a solution of the acid ester (23B) (1.8 g, 3.07 mmol) in 15 mL of ethanol, 7.5 mL of an aqueous solution of sodium hydroxide (245 mg, 6.14 mmol) was added, and the mixture was reacted at room temperature for 1 hour. Then, the ethanol was depressurized, and the reaction solution was adjusted to pH 4 to 5 with an aqueous solution of citric acid to precipitate a large amount of solid. The solid was filtered, and the solid was added to 20 mL of acetonitrile and stirred for 10 minutes. The solid was again filtered, and the solvent was removed under reduced pressure. Product white solid 3-[[1-methyl-2-[[4-[N`-propoxycarbonylformamidine]aniline]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propyl Acid (23C) (1.30 g, yield 76.47%).

LCMS m/z = 558.24 [M + 1].

Third step: (2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-propoxycarbonylformamidine]aniline]methyl]benzimidazole-5-carbonyl] -(2-pyridyl)amino]propionate (Compound 23)

(2-methoxyphenyl)3-[[1-methyl-2-[[4-[N`-propoxycarbonylcarbamimidoyl]anilino]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

3-[[1-Methyl-2-[[4-[N`-propoxycarbonylformamidine]aniline]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propyl Add guaiacol (0.433 g, 3.5 mmol), 1-ethyl-(3-dimethyl) to a solution of the acid (23C) (1.30 g, 2.33 mmol) in N,N-dimethylformamide (15 mL) Aminopropyl)carbodiimide hydrochloride (0.58 g, 3.03 mmol) and 4-dimethylaminopyridine (171 mg, 1.40 mmol) were reacted at room temperature for 15 hours. Water (30 mL) was added to the reaction mixture, and the mixture was evaporated. Separation and purification (dichloromethane:methanol (v/v) = 50:1 to 30:1) gave the title compound (2-methoxyphenyl) 3-[[1-methyl-2-[[ 4-[N`-propoxycarbonylformamidine]aniline]methyl]benzimidazole-5-carbonyl]-(2-pyridyl)amino]propionate (Compound 23) (0.45 g, yield 30.0%) .

LCMS m/z = 664.28 [M + 1].

^{1 H NMR (400MHz, MeOD)} δ8.31 (dd, 1H), 7.64-7.54 (m, 2H), 7.50 (d, 1H), 7.42 (td, 1H), 7.27 (d, 1H), 7.21 (dd , 1H), 7.14–7.06 (m, 1H), 7.04 (ddd, 1H), 6.95 (dd, 1H), 6.92–6.85 (m, 2H), 6.85–6.77 (m, 1H), 6.72–6.58 (m) , 2H), 4.55 (s, 1H), 4.36 (t, 2H), 3.98 (dd, 2H), 3.72 (s, 3H), 3.68 (s, 3H), 2.94 (t, 2H), 1.61 (dd, 2H), 1.19 (s, 2H), 0.89 (t, 3H).

Example 24

(2-methoxy-5-methyl-phenyl)3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5 -carbonyl]-(2-pyridyl)amino]propionate (Compound 24)

(2-methoxy-5-methyl-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propanoate

See Method 1 for the preparation method.

LCMS m/z = 720.34 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (d, 1H), 7.79 (d, 2H), 7.75 (s, 1H), 7.34 (dd, 2H), 7.15 (d, 1H), 7.03-6.91 ( m, 2H), 6.81 (dd, 3H), 6.72 (d, 2H), 5.27 (s, 1H), 4.54 (dd, 4H), 4.14 (t, 2H), 3.77 (s, 3H), 3.74 (s , 3H), 3.10 (t, 2H), 2.25 (d, 3H), 1.80 - 1.69 (m, 2H), 1.46 - 1.37 (m, 2H), 1.31 (dd, 4H), 0.89 (dd, 3H).

Example 25

2-Chlorophenyl 3-(2-((4-(N'-((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N-(pyridine-2 -yl-1H-benzo[d]imidazol-5-formylamino)propionic acid ethyl ester (Compound 25)

2-chlorophenyl 3-(2-((((((()))))))))))))))) d]imidazole-5-carboxamido)propanoate

3-(2-(((4-(N'-((hexyloxy)))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N-(pyridine-2-) 2-Chlorophenol (25A) was added to a solution of -1H-benzo[d]imidazole-5-formylamino)propanoic acid (Intermediate 1) (1.40 g, 2.3 mmol) in dimethylformamide (15 mL) (0.450 mg, 3.50 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.900 g, 5.07 mmol) and 4-dimethylaminopyridine (170 mg, 1.39 mmol) ), react at room temperature for 15 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL×3). The organic phase was combined, and the organic phase was washed with saturated aqueous potassium dihydrochloride (30 mL×2), dried over anhydrous sodium sulfate The title compound was purified by silica gel column chromatography (dichloromethane:methanol (v/v) = 100:1 to 30:1) to give the title compound 2-chlorophenyl 3-(2-((4-(N--) Hexyloxy)carbonyl)carboxyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl-1H-benzo[d]imidazol-5-formylamino)propanoic acid Ethyl ester (Compound 25), brown solid (0.65 g, yield 39.0%).

LCMS m/z = 710.2 [M + 1].

^{1 H NMR (400MHz, DMSO)} δ9.01 (s, 1H), 8.65 (s, 1H), 8.48-8.37 (m, 1H), 7.80 (d, 2H), 7.56 (m, 2H), 7.51 (d , 1H), 7.42–7.38 (m, 2H), 7.33–7.28 (m, 2H), 7.19 (dd, 1H), 7.14 (m, 1H), 7.00–6.89 (m, 2H), 6.77 (d, 2H) ), 4.60 (d, 2H), 4.38 (t, 2H), 4.03 - 3.93 (m, 2H), 3.77 (s, 3H), 3.06 (t, 2H), 1.67 - 1.58 (m, 2H), 1.36 - 1.28 (m, 6H), 0.87 (t, 3H).

Example 26

(2-methoxyphenyl)3-[[2-[[4-[N`-ethoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2 -pyridyl)amino]propionate (Compound 26)

(2-methoxyphenyl)3-[[2-[[4-[N`-ethoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Example 11 for the preparation method.

LCMS m/z = 650.26 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.45 (d, 1H), 7.79 (d, 2H), 7.75 (s, 1H), 7.39-7.30 (m, 2H), 7.17 (dd, 2H), 7.01 ( Dd,2H), 6.97–6.89 (m, 2H), 6.78 (d, 1H), 6.72 (d, 2H), 5.29 (s, 1H), 4.59–4.47 (m, 4H), 4.21 (q, 2H) , 3.80 (s, 3H), 3.74 (s, 3H), 3.11 (t, 2H), 1.35 (t, 3H).

Example 27

3-(2-((4-(N-((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)- 1H-benzo[d]imidazol-5-carboxamido)propionic acid 2,3,-dihydro-1H-4-decyl ester (Compound 27)

2,3-dihydro-1H-inden-4-yl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin -2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate

3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-( 2-Pyridyl)amino]propionic acid (Intermediate 1) (0.6 g, 0.001 mol), 4-nonanol (27A) (0.2 g, 0.0015 mol), 1-(3-dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (0.25 g, 0.0013 mol), 4-dimethylaminopyridine (0.073 g, 0.0006 mol), then added N,N-dimethylformamide (10 mL) and stirred for 0.5 hour. The reaction was allowed to rise to room temperature for 5 hours. The reaction was stopped and ethyl acetate (60 mL) was added, and the organic phase was washed with water (40 mL×5), washed with brine (50 mL×1), dried over anhydrous sodium sulfate Separation and purification (dichloromethane:methanol (v/v) = 100:1 to 20:1) to give 3-(2-((((((((())))) Phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionic acid 2,3,-dihydro- 1H-4-decyl ester (Compound 27) (0.08 g, yield 6%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ8.42 (d, 1H), 7.76-7.73 (m, 3H), 7.36-7.30 (m, 2H), 7.12-7.07 (m, 3H), 7.00-6.98 ( m, 1H), 6.84-6.82 (d, 1H), 6.76-6.74 (d, 1H), 6.69-6.67 (d, 2H), 5.33 (s, 1H), 4.57-4.53 (t, 2H), 4.49- 4.48(d,2H), 4.16-4.12(t,2H), 3.71(s,3H), 3.10-3.06(t,2H), 2.95-2.91(t,2H), 2.79-2.75(t,2H), 2.09-2.02 (m, 2H), 1.76-1.69 (m, 2H), 1.42-1.38 (m, 2H), 1.33-1.29 (m, 4H), 0.91 - 0.87 (t, 3H).

Example 28

(2,6-Dimethoxyphenyl)3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl ]-(2-Pyridyl)amino]propionate (Compound 28)

(2,6-dimethoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 736.34 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.40 (dd, 1H), 7.69 (dd, 3H), 7.35 (td, 1H), 7.29-7.19 (m, 1H), 7.08 (t, 1H), 7.04- 6.92 (m, 2H), 6.80 (d, 1H), 6.57 (dd, 4H), 5.44 (t, 1H), 4.60 - 4.44 (m, 2H), 4.37 (d, 2H), 4.12 (t, 2H) , 3.76 (s, 6H), 3.59 (s, 3H), 3.25 - 3.03 (m, 2H), 1.83 - 1.59 (m, 2H), 1.51 - 1.35 (m, 2H), 1.31 (dd, 4H), 0.88 (t, 3H).

Example 29

3-(2-((4-(N-((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)- 1H-benzo[d]imidazole-5-carboxamido)propionic acid 3-fluorophenyl ester (Compound 29)

3-fluorophenyl 3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5- Carboxamido)propanoate

See Method 1 for the preparation method.

LCMS m/z = 694.1 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.45 (dd, 1H), 7.74 (dd, 3H), 7.36-7.27 (m, 3H), 7.11 (d, 1H), 7.05-6.97 (m, 1H), 6.97–6.83 (m, 3H), 6.70 (dd, 3H), 5.32 (s, 1H), 4.56 (t, 2H), 4.48 (d, 2H), 4.14 (t, 2H), 3.71 (s, 3H) , 3.05 (t, 2H), 1.81 - 1.67 (m, 2H), 1.46 - 1.28 (m, 6H), 0.89 (dd, 3H).

Example 30

2,3-Dihydro-1H-indol-5-yl 3-(2-((4-(N'-((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1 -ethyl-N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-formylamino)propionic acid ethyl ester (Compound 30)

2,3-dihydro-1H-inden-5-yl 3-(2-((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin -2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate

See Method 1 for the preparation method.

LCMS m/z = 716.3 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (dd, 1H), 7.79-7.68 (m, 3H), 7.37-7.27 (m, 2H), 7.16 (d, 1H), 7.08 (d, 1H), 6.99 (ddd, 1H), 6.90 (s, 1H), 6.80 (dd, 1H), 6.74 (d, 1H), 6.65 (d, 2H), 5.34 (s, 1H), 4.55 (t, 2H), 4.45 (d, 2H), 4.14 (t, 2H), 3.68 (s, 3H), 3.04 (t, 2H), 2.87 (dd, 4H), 2.15 - 2.00 (m, 2H), 1.78 - 1.66 (m, 2H) ), 1.48–1.35 (m, 2H), 1.37–1.27 (m, 4H), 0.89 (dd, 3H).

Example 31

3-(2-((4-(N-((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)- 1H-benzo[d]imidazol-5-carboxamido)propionic acid 2-(2-methoxy-2-ethoxy)phenyl ester (Compound 31)

2-(2-methoxy-2-oxoethyl)phenyl 3-(2-(((4-(N-)-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin- 2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate

3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-( 2-Pyridyl)amino]propionic acid (Intermediate 1) (0.6 g, 0.001 mol), methyl 2-hydroxyphenylacetate (31A) (0.25 g, 0.0015 mol), 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.25 g, 0.0013 mol), 4-dimethylaminopyridine (0.073 g, 0.0006 mol), then added with N,N-dimethylformamide (20 mL) The mixture was stirred for 0.5 hours and allowed to react to room temperature for 5 hours. The reaction was stopped, ethyl acetate (60 mL) was added to the reaction mixture, and the organic phase was washed with water (40 mL×5), washed with brine (50 mL×1), dried over anhydrous sodium sulfate Separation and purification (dichloromethane:methanol (v/v)=100:1-20:1) afforded 3-(2-((4-(N)-((hexyloxy))carbonyl) Phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionic acid 2-(2-methoxy Benzyl-2-ethoxy)phenyl ester (0.1 g, yield 13.4%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ8.45 (d, 1H), 7.76-7.65 (m, 3H), 7.36-7.27 (m, 3H), 7.21-7.17 (t, 1H), 7.13-7.11 ( d, 2H), 7.02-6.99 (m, 2H), 6.76-6.69 (m, 3H), 5.37 (s, 1H), 4.57-4.50 (m, 4H), 4.16-4.11 (m, 2H), 3.72 ( s, 3H), 3.66 (s, 3H), 3.58 (s, 2H), 3.10-3.07 (t, 2H), 1.74-1.70 (m, 2H), 1.43-1.37 (m, 2H), 1.33-1.31 ( m, 4H), 0.89-0.86 (t, 3H).

Example 32

(2-methoxyphenyl)3-[[2-[[4-[N`methoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2- Pyridyl)amino]propionate (compound 32)

(2-methoxyphenyl)3-[[2-[[4-[N`-methoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Example 11 for the preparation method.

LCMS m/z = 636.25 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (d, 1H), 7.81-7.66 (m, 3H), 7.34 (d, 2H), 7.15 (dd, 2H), 7.01 (t, 2H), 6.93 ( Dd, 2H), 6.78 (d, 1H), 6.72 (d, 2H), 5.31 (s, 1H), 4.55 (t, 2H), 4.51 (d, 2H), 3.80 (s, 3H), 3.78 (s) , 3H), 3.73 (s, 3H), 3.11 (t, 2H).

Example 33

3-Chlorophenyl 3-(2-(((4-(N'-((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N-(pyridine- 2-yl)-1H-benzo[d]imidazol-5-formylamino)propionate (Compound 33)

3-chlorophenyl 3-(2-((((((()))))))))))))))) d]imidazole-5-carboxamido)propanoate

See Method 1 for the preparation method.

LCMS m/z = 710.0 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.45 (m, 1H), 7.74 (m, 3H), 7.36-7.27 (m, 3H), 7.23-7.16 (m, 1H), 7.14-7.08 (m, 2H ), 7.05–6.96 (m, 2H), 6.69 (m, 3H), 5.31 (d, 1H), 4.56 (t, 2H), 4.48 (d, 2H), 4.14 (t, 2H), 3.70 (s, 3H), 3.05 (t, 2H), 1.77 - 1.68 (m, 2H), 1.46 - 1.36 (m, 2H), 1.36 - 1.27 (m, 4H), 0.89 (t, 3H).

Example 34

2,3-Dimethoxyphenyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl Amino]ethyl propionate (compound 34)

2,3-dimethoxyphenyl 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 736.2 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.42 (dd, 1H), 7.71-7.68 (m, 3H), 7.33 (m, 1H), 7.23 (d, 1H), 7.03-6.95 (m, 3H), 6.76 (t, 2H), 6.66 (dd, 1H), 6.58 (d, 2H), 5.43 (t, 1H), 4.54 (t, 2H), 4.37 (d, 2H), 4.12 (t, 2H), 3.80 (d,6H),3.59(s,3H),3.11(t,2H),1.77–1.60(m,2H),1.47–1.35(m,2H),1.32-1.28(m,4H),0.90-0.87 (m, 3H).

Example 35

(2-methoxyphenyl)3-[[2-[[4-[N`-butoxycarbonylmethylindenyl]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]- (2-pyridyl)amino]propionic acid ethyl ester (Compound 35)

2-methoxyphenyl 3-[[2-[[4-[N`-butoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Example 11 for the preparation method.

LCMS m/z = 678.2 [M + 1].

^{1 H NMR (400MHz, DMSO)} δ8.48-8.39 (m, 1H), 7.81 (d, 2H), 7.57 (td, 1H), 7.52 (d, 1H), 7.42 (d, 1H), 7.29-7.17 (m, 2H), 7.18–7.09 (m, 2H), 7.06 (dd, 1H), 7.01–6.90 (m, 3H), 6.78 (d, 2H), 4.61 (d, 2H), 4.35 (t, 2H) ), 4.00 (t, 2H), 3.76 (d, 6H), 2.99 (t, 2H), 1.71 - 1.47 (m, 2H), 1.37-1.33 (m, 2H), 0.91 (t, 3H).

Example 36

(4-methoxyphenyl)3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-( 2-pyridyl)amino]propionate (Compound 36)

(4-methoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 706.33 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (dd, 1H), 7.73 (s, 1H), 7.72-7.67 (m, 2H), 7.35-7.29 (m, 1H), 7.28 (dd, 1H), 7.07(d,1H),7.02–6.94(m,3H),6.89–6.82(m,2H),6.72(d,1H),6.64(d,2H),5.36(s,1H),4.55(t, 2H), 4.45 (d, 2H), 4.13 (td, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 3.02 (t, 2H), 1.71 (dd, 2H), 1.44 - 1.34 (m , 2H), 1.34 - 1.27 (m, 4H), 0.89 (dd, 3H).

Example 37

(3-methoxyphenyl)3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-( 2-pyridyl)amino]propionate (Compound 37)

(3-methoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 706.33 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (dd, 1H), 7.73 (dd, 3H), 7.36-7.27 (m, 2H), 7.23 (d, 1H), 7.08 (d, 1H), 6.99 ( Dd,1H), 6.80–6.69 (m, 2H), 6.69–6.60 (m, 4H), 5.33 (s, 1H), 4.55 (t, 2H), 4.46 (d, 2H), 4.13 (td, 2H) , 3.77 (s, 3H), 3.69 (s, 3H), 3.05 (t, 2H), 1.71 (dd, 2H), 1.40 (dd, 2H), 1.31 (dd, 4H), 0.89 (t, 3H).

Example 38

2-methoxyphenyl 3-(1-methyl-2-((4-(N'-(((methylamino))))carbonyl))indolyl)phenyl)amino) Methyl)-N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-formylamino)propionate (Compound 38)

2-methoxyphenyl 3-(1-methyl-2-(((4-(((4-((()))))) -1H-benzo[d]imidazole-5-carboxamido)propanoate

First step: 3-(1-methyl-2-((4-(N-)-(((4-methylpentyl)oxy))carbonyl)methyl) phenyl)amino)methyl) -N-(pyridyl Ethyl-2-yl)-1H-benzo[d]imidazol-5-formylamino)propanoate (38B)

Ethyl 3-(1-methyl-2-(((4-(methyl))))carbamimidoyl)phenyl)amino)methyl)-N-(pyridin-2-yl)-1H -benzo[d]imidazole-5-carboxamido)propanoate

To a solution of 4-methylpentanol (1.50 g, 14.7 mmol) in tetrahydrofuran (10 mL), carbodiimidazole (2.40 g, 1.48 mmol) was stirred at room temperature for 30 min. . 3-(2-(((4-Hydrylphenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-formyl Add acetone (160 mL), water (80 mL), potassium carbonate (4.20 g, 30.4 mmol) to p-toluenesulfonate (11A) (6.71 g, 10.0 mmol) of ethylaminopropionate, stir well and add The reaction solution 1 was reacted at room temperature for 5 hours after the addition. The precipitated white solid was filtered, and the filter cake was washed with acetone/water mixed solvent (acetone: water (v/v) = 1:2), then dissolved in dichloromethane (100 mL), dried over anhydrous sodium sulfate The compound 3-(1-methyl-2-(((4-(4-(4-(4-(4-(4-(4-(4-(4-)))))))))))))))) Ethyl (pyridin-2-yl)-1H-benzo[d]imidazole-5-formylamino)propanoate (38B), white solid ( 6.00 g, yield 95.5%).

LCMS m/z = 628.2 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.42 (d, 1H), 7.78 (d, 2H), 7.70 (s, 1H), 7.37-7.28 (m, 2H), 7.11 (d, 1H), 7.04- 6.94 (m, 1H), 6.70 (t, 3H), 5.25 (s, 1H), 4.48 (d, 2H), 4.43 (t, 2H), 4.10 (dt, 4H), 3.71 (s, 3H), 2.81 (t, 2H), 1.72 (dd, 3H), 1.66 - 1.53 (m, 2H), 1.29 (dd, 2H), 1.22 (t, 3H), 0.90 (d, 6H).

Second step: 3-(1-methyl-2-((4-(N'-((4-methylpentyl)oxy)carbonyl)methyl) phenyl)amino)methyl)- N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-formylamino)propionic acid (38C)

3-(1-methyl-2-(((4-())))carbamimidoyl)phenyl)amino)methyl)-N-(pyridin-2-yl)-1H- Benzo[d]imidazole-5-carboxamido)propanoic acid

3-(1-(2-(N-)-(((4-methylpentyl)oxy)carbonyl)methyl)phenyl)amino)methyl)methyl)- Ethyl N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-formylamino)propanoate (38B) (2.00 g, 3.19 mmol) in ethanol A solution of sodium hydroxide (320 mg, 8.00 mmol) in water (5 mL) was added to the solution (50 mL), and the mixture was reacted at room temperature for 2 hours. The pH was adjusted to 4 with dilute hydrochloric acid (2 mol/L), and the precipitated solid was filtered, dissolved in dichloromethane, dried over anhydrous sodium sulfate and evaporated to give the title compound 3-(1-methyl-2-(((4- (N'-((4-Methylpentyl)oxy)carbonyl)methyl)phenyl)amino)methyl)-N-(pyridin-2-yl)-1H-benzo[d]imidazole -5-formylamino)propionic acid (38C), white solid (1.50 g, yield: 79.0%).

LCMS m/z = 600.2 [M + 1].

The third step: 2-methoxyphenyl 3-(1-methyl-2-((4-(N'-(((4-(methyl)))carbonyl))) Amino)methyl)-N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionate (Compound 38)

2-methoxyphenyl 3-(1-methyl-2-(((4-(((4-((()))))) -1H-benzo[d]imidazole-5-carboxamido)propanoate

3-(1-(2-(N-)-((4-methylpentyl)oxy)carbonyl)carboxamido)phenyl)amino)methyl)-N at room temperature -(pyridin-2-yl)-1H-benzo[d]imidazol-5-formylamino)propanoic acid (38C) (2.00 g, 3.30 mmol) in dimethylformamide (15 mL) Inulin (0.790 mg, 6.36 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.80 g, 10.1 mmol) and 4-dimethylaminopyridine (244 mg, 2.00 mmol), reacted at room temperature for 15 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL×3). The organic phase was combined, and the organic phase was washed with saturated aqueous potassium dihydrochloride (30 mL×2), dried over anhydrous sodium sulfate The title compound (methylene chloride:methanol (v/v) = 100:1 to 30:1) was obtained to give the title compound 2-methoxyphenyl 3-(1-methyl-2-((( 4-(N'-(((4-methylpentyl)oxy)carbonyl))carbonyl)phenyl)amino)methyl)-N-(pyridin-2-yl)-1H-benzo[d Imidazole-5-formylamino)propionate (Compound 38), brown solid (0.80 g, yield 30.0%).

LCMS m/z = 706.2 [M + 1].

^{1 H NMR (400MHz, DMSO)} δ9.08 (s, 1H), 8.59 (d, 1H), 8.42 (dd, 1H), 7.80 (d, 2H), 7.57 (td, 1H), 7.51 (d, 1H ), 7.41 (d, 1H), 7.26 - 7.17 (m, 2H), 7.12 (ddd, 2H), 7.05 (dd, 1H), 7.00 - 6.89 (m, 3H), 6.77 (d, 2H), 4.60 ( d,2H), 4.34(t,2H), 3.97(t,2H),3.77(s,3H),3.74(s,3H),2.98(t,2H),1.57(m,3H),1.21(dt , 2H), 0.87 (d, 6H).

Example 39

3-[[2-[[4-[N'-(2-ethylbutoxycarbonyl)methylindolyl]anilinyl]methyl]-1-methyl-benzimidazole-5-carbonyl]-( 2-pyridyl)amino]propanoic acid 2-methoxyphenyl ester (Compound 39)

(2-methoxyphenyl)3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

First step: 3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)methylindolyl]anilino]methyl]-1-methyl-benzimidazole-5- Ethyl carbonyl]-(2-pyridyl)amino]propanoate (39B)

Ethyl 3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

Add carbonyl diimidazole (1.08 g, 10.4 mmol) to a solution of 2-ethyl-1-butanol (1.00 g, 9.79 mmol) in tetrahydrofuran (10 mL) at room temperature, stir at room temperature for 30 min. Into the reaction solution 1. 3-(2-(((4-Hydrylphenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-formyl Add acetone (100 mL), water (50 mL), potassium carbonate (2.16 g, 15.6 mmol) to p-toluenesulfonate (11A) (3.35 g, 5.00 mmol) of ethylaminopropionate, stir well and add The reaction solution 1 was reacted at room temperature for 5 hours after the addition. The precipitated white solid was filtered, and the filter cake was washed with acetone/water (acetone: water (v/v) = 1:2), then dissolved in 100 mL of dichloromethane and dried over anhydrous sodium sulfate. [2-[[4-[N'-(2-ethylbutoxycarbonyl)methanyl]anilinyl]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridine Ethylamino]propionic acid ethyl ester (39B), white solid (3.00 g, yield 96.0%).

LCMS m/z = 628.2 [M + 1].

^{1 H NMR (400MHz, DMSO)} δ8.39 (s, 1H), 7.79 (d, 2H), 7.53 (d, 1H), 7.50 (d, 1H), 7.40 (d, 1H), 7.26-7.02 (m , 2H), 7.03–6.83 (m, 2H), 6.77 (d, 2H), 4.59 (d, 2H), 4.22 (s, 2H), 4.04–3.94 (m, 2H), 3.92 (d, 2H), 3.76 (s, 3H), 2.68 (s, 2H), 1.49 (d, 1H), 1.33 (s, 4H), 1.12 (t, 3H), 0.87 (t, 6H).

Second step: 3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)methylindolyl]anilino]methyl]-1-methyl-benzimidazole-5- Carbonyl]-(2-pyridyl)amino]propionic acid (39C)

3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanic acid

3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)methylindolyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl at room temperature A solution of sodium hydroxide (390 mg, 9.75 mmol) in water (5 mL) was added to a solution of ethyl 2-(2-pyridyl)amino]propanoate (39B) (3.00 g, 4. After the reaction at room temperature for 2 hours. The pH was adjusted to 4 with dilute hydrochloric acid (2 mol/L), and the precipitated solid was filtered, dissolved in dichloromethane, dried over anhydrous sodium sulfate and evaporated to give the title compound 3-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ 2-ethylbutoxycarbonyl)methanesulfonyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid (39C), white solid (1.50 g, yield 52.0%).

^{1 H NMR (400MHz, DMSO)} δ12.03 (m, 2H), 9.25 (s, 1H), 8.37 (s, 1H), 7.77 (s, 2H), 7.476 (t, 3H), 7.12 (s, 2H ), 6.99 (d, 2H), 6.79 (s, 2H), 4.61 (s, 2H), 4.18 (s, 2H), 3.96 (s, 2H), 3.77 (s, 3H), 2.67 (d, 2H) , 1.51 (s, 1H), 1.34 (s, 4H), 0.87 (s, 6H).

The third step: 3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)methylindolyl]anilino]methyl]-1-methyl-benzimidazole-5- 2-methoxyphenyl carbonyl]-(2-pyridyl)amino]propanoate (compound 39)

(2-methoxyphenyl)3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)carbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

3-[[2-[[4-[N`-(2-ethylbutoxycarbonyl)methylindolyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl at room temperature ]-(2-Pyridyl)amino]propionic acid (39C) (2.00 g, 3.30 mmol) in dimethylformamide (15 mL) Add guaiacol (0.790 mg, 6.36 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.80 g, 10.1 mmol) and 4-dimethylaminopyridine (244 mg, 2.00 mmol), reacted at room temperature for 15 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL×3). The organic phase was combined, and the organic phase was washed with saturated aqueous potassium dihydrochloride (30 mL×2), dried over anhydrous sodium sulfate The title compound (3-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ Oxycarbonylcarbonyl)methylamino]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid 2-methoxyphenyl ester (Compound 39) , brown solid (0.250 g, yield 11.0%).

LCMS m/z = 706.2 [M + 1].

^{1 H NMR (400MHz, DMSO)} δ9.08 (s, 1H), 8.84 (s, 1H), 8.42 (dd, 1H), 7.80 (d, 2H), 7.57 (td, 1H), 7.51 (d, 1H ), 7.41 (d, 1H), 7.21 (m, 2H), 7.12 (m, 2H), 7.05 (dd, 1H), 6.94 (dt, 3H), 6.77 (d, 2H), 4.60 (d, 2H) , 4.34 (t, 2H), 3.77 (s, 3H), 3.74 (d, 3H), 2.98 (t, 2H), 1.50 (dd, 1H), 1.32 (m, 4H), 0.87 (t, 6H).

Example 40

3-[[2-[[4-[N'-hexyloxycarbonylmethyl)phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl)amino] 2,4-dimethoxyphenyl propionate (Compound 40)

(2,4-dimethoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propionic acid (Intermediate 1) (2 g, 3.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.82 g, 4.3 mmol), 4-dimethylamino Pyridine (0.24 g, 2 mmol), 2,4-dimethoxyphenol (40A) (0.72 g, 5.0 mmol), EtOAc (5 mL) Water (50 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was combined, and the organic phase was washed with water (50 mL×2) The title compound (3-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ -hexyloxycarbonylmethionyl]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl)amino]propionic acid 2,4-dimethoxyphenyl ester (compound) 40), white solid (0.70 g, yield 29.1%).

LCMS m/z = 736.2 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (dd, 1H), 7.80-7.68 (m, 3H), 7.40-7.29 (m, 2H), 7.11 (d, 1H), 6.99 (dd, 1H), 6.93 (d, 1H), 6.77 (d, 1H), 6.68 (d, 2H), 6.51 (d, 1H), 6.42 (dd, 1H), 5.33 (s, 1H), 4.54 (t, 2H), 4.48 (d, 2H), 4.14 (t, 2H), 3.76 (d, 6H), 3.69 (d, 3H), 3.08 (t, 2H), 1.71 (dd, 2H), 1.47 - 1.37 (m, 2H), 1.31 (dd, 4H), 0.89 (t, 3H).

Example 41

3-[[2-[[4-[N'-hexyloxycarbonylmethyl)phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl)amino] 2,5-dimethoxyphenyl propionate (Compound 41)

(2,5-dimethoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propionic acid (Intermediate 1) (1 g, 1.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.41 g, 2.17 mmol), 4-dimethylamino Pyridine (0.12 g, 1 mmol), 2,5-dimethoxyphenol (41A) (0.38 g, 2.5 mmol), added to N,N-dimethylformamide (5 mL), and allowed to react at room temperature for 6 hours. Water (50 mL) was added to the reaction mixture, and the mixture was evaporated. Chromatographic separation and purification (dichloromethane:methanol (v/v) = 100:1 to 20:1) afforded the title compound 3-[[2-[[4-[N--hexyloxycarbonylmethylmethyl]phenylamino Methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid 2,5-dimethoxyphenyl ester (Compound 41), white solid (1.0 g, yield 83.3%).

LCMS m/z = 736.2 [M + 1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.44 (dd, 1H), 7.85-7.66 (m, 3H), 7.40-7.31 (m, 2H), 7.13 (d, 1H), 7.00 (dd, 1H), 6.87 (d, 1H), 6.78 (d, 1H), 6.75 - 6.68 (m, 3H), 6.65 (d, 1H), 5.30 (s, 1H), 4.58 - 4.49 (m, 4H), 4.14 (t, 2H), 3.76-3.71 (m, 9H), 3.11 (t, 2H), 1.76-1.69 (m, 2H), 1.43-1.38 (m, 2H), 1.33-1.29 (m, 4H), 0.89 (t, 3H).

Example 42

(5-Cyano-2-methoxy-phenyl)3-[[2-[[4-[N`-hexyloxycarbonylmethyl) aniline]methyl]-1-methyl-benzimidazole -5-carbonyl]-(2-pyridyl)amino]propionate (Compound 42)

(5-cyano-2-methoxy-phenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino] Propanoate

See Method 1 for the preparation method.

LCMS m/z = 731.32. [M+1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.45 (dd, 1H), 7.73 (dd, 3H), 7.50 (dd, 1H), 7.37-7.27 (m, 3H), 7.10 (d, 1H), 7.01 ( Dd,1H), 6.98(d,1H), 6.72(d,1H),6.66(d,2H),5.34(s,1H),4.55(t,2H),4.47(d,2H),4.13(t , 2H), 3.86 (s, 3H), 3.70 (s, 3H), 3.11 (t, 2H), 1.71 (dd, 2H), 1.39 (m, 2H), 1.35 - 1.28 (m, 4H), 0.89 ( Dd, 3H).

Example 43

(2-Isopropoxyphenyl)3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]- (2-pyridyl)amino]propionate (Compound 43)

(2-isopropoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 734.36. [M+1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (dd, 1H), 7.75 (s, 1H), 7.73-7.67 (m, 2H), 7.38-7.31 (m, 1H), 7.30 (dd, 1H), 7.16–7.10 (m, 1H), 7.08 (d, 1H), 7.00 (m, 2H), 6.96–6.85 (m, 2H), 6.76 (d, 1H), 6.65 (d, 2H), 5.35 (s, 1H), 4.54 (dd, 2H), 4.51 - 4.47 (m, 1H), 4.45 (d, 2H), 4.13 (t, 2H), 3.68 (s, 3H), 3.15 - 3.01 (m, 2H), 1.71 (dd, 2H), 1.46 - 1.36 (m, 2H), 1.33 (t, 2H), 1.30 (s, 4H), 1.29 (s, 4H), 0.89 (dd, 3H).

Example 44

(2-Methylthiophenyl)3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]- (2-pyridyl)amino]propionate (Compound 44)

(2-methylsulfanylphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 722.30. [M+1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.43 (dd, 1H), 7.74 (s, 1H), 7.72 (d, 2H), 7.33 (td, 1H), 7.29 (d, 1H), 7.24 (d, 1H), 7.18 (m, 2H), 7.06 (dd, 2H), 6.99 (dd, 1H), 6.76 (d, 1H), 6.64 (d, 2H), 5.33 (t, 1H), 4.57 (t, 2H) ), 4.43 (d, 2H), 4.13 (t, 2H), 3.66 (s, 3H), 3.13 (t, 2H), 2.39 (s, 3H), 1.71 (dd, 2H), 1.45 - 1.35 (m, 2H), 1.35 - 1.27 (m, 4H), 0.88 (t, 3H).

Example 45

(2-ethoxyphenyl)3-[[2-[[4-[N`-hexyloxycarbonylmethyl) anilide]methyl]-1-methyl-benzimidazole-5-carbonyl]-( 2-pyridyl)amino]propionate (Compound 45)

(2-ethoxyphenyl)3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate

See Method 1 for the preparation method.

LCMS m/z = 720.34. [M+1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.41 (dd, 1H), 7.70 (s, 1H), 7.68 (s, 2H), 7.32 (td, 1H), 7.24 (d, 1H), 7.15-7.09 ( m,1H), 7.02–7.00 (m,1H), 7.00–6.94 (m, 2H), 6.88 (m, 2H), 6.74 (d, 1H), 6.58 (d, 2H), 5.40 (t, 1H) , 4.53 (t, 2H), 4.38 (d, 2H), 4.12 (t, 2H), 4.00 (q, 2H), 3.61 (s, 3H), 3.09 (t, 2H), 1.70 (dd, 2H), 1.39 (dd, 2H), 1.34 (t, 4H), 1.30 (dd, 4H), 0.88 (dd, 3H).

Example 46

3-(2-((4-(N-((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)- 1H-benzo[d]imidazol-5-carboxamido)propionic acid 2-(trifluoromethoxy)phenyl ester (Compound 46)

2-(trifluoromethoxy)phenyl 3-(2-((((((((((())))))))))))))))) -benzo[d]imidazole-5-carboxamido)propanoate

3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-( 2-Pyridyl)amino]propionic acid (Intermediate 1) (1 g, 1.67 mmol), 2-(trifluoromethoxy)phenol (46A) (0.45 g, 2.5 mol), 1-(3-dimethylamino) Propyl)-3-ethylcarbodiimide hydrochloride (0.42 g, 2.17 mmol), 4-dimethylaminopyridine (0.122 g, 1 mmol), then N,N-dimethylformamide (16 mL) The mixture was stirred for 0.5 hour with heat and raised to room temperature for reaction 5. The reaction was stopped and ethyl acetate (100 mL) was added, and the organic phase was washed with water (60 mL×5), washed with brine (60 mL×1), dried over anhydrous sodium sulfate Separation and purification (dichloromethane:methanol (v/v) = 100:1 to 20:1) to give 3-(2-((((((((())))) Phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionic acid 2-(trifluoromethoxy) Phenyl ester (Compound 46) (0.136 g, yield 10.8%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ8.46 (d, 1H), 7.80-7.75 (m, 3H), 7.34-7.29 (m, 5H), 7.23-7.21 (m, 1H), 7.17-7.15 ( m, 1H), 7.02-6.99 (m, 1H), 6.75-6.72 (m, 3H), 5.25 (s, 1H), 4.59-4.52 (m, 4H), 4.16-4.13 (t, 2H), 3.75 ( s, 3H), 3.13-3.10 (t, 2H), 1.75-1.69 (m, 2H), 1.42-1.38 (m, 2H), 1.33-1.29 (m, 4H), 0.91 - 0.87 (t, 3H).

Example 47

3-(2-(((4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-((4-) 2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionic acid 2-methoxyphenyl ester (Compound 47)

2-methoxyphenyl 3-(2-(((4-(4-(propyl)))carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H- Benzo[d]imidazole-5-carboxami do)propanoate

First step: 3-(2-((4-cyclopropylbutoxy)carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N -(pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionic acid ethyl ester (47B)

Ethyl 3-(2-(((4-(4-(propyl))))carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[ d]imidazole-5-carboxamido)propanoate

4-cyclopropylbutyl-1-ol (1 g, 8.76 mmol) and tetrahydrofuran (12 mL) were added to the reaction flask, then N,N'-carbonyldiimidazole (1.54 g, 9.49 mmol) was added and stirred at room temperature for 1 hour. The oil was concentrated under reduced pressure. Another reaction flask was added 3-(2-(((4-methylphenyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole -5-carboxamido)ethyl propionate (47A) (4.9 g, 7.3 mmol), EtOAc m. After stirring at room temperature for 5 hours, acetone was evaporated to dryness, and water (60 mL) was evaporated. The combined organic layer was washed with EtOAc (EtOAc) (EtOAc m. Solid 3-(2-(((4-cyclopropylbutoxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N-(pyridine) Ethyl-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate (47B) (2.5 g, yield 53.5%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.42 - 8.41 (d, 1H), 7.78-7.76 (m, 2H), 7.71-7.69 (m, 1H), 7.32-7.30 (m, 2H), 7.14 7.11(d,1H), 7.00-6.97(m,1H),6.73-6.69(m,3H), 5.30(s,1H),4.51-4.50(d,2H),4.45-4.41(m,2H), 4.17-4.13(t,3H),4.11-4.05(m,2H),3.73(s,3H),2.83-2.79(t,2H),1.78-1.73(m,2H),1.56-1.48(m,2H) ), 1.7-1.20 (m, 5H), 0.68-0.63 (m, 1H), 0.40-0.37 (m, 2H), 0.09-0.02 (m, 2H).

Second step: 3-(2-((4-cyclopropylbutoxy)carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N -(pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionic acid (47C)

3-(2-((4-(N'-((4-cyclopropylbutoxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d ]imidazole-5-carboxamido)propanoic acid

3-(2-((4-(N-((4-cyclopropyloxy))carbonyl)methyl) phenyl)amino)methyl)-1-methyl-N-(() Pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionic acid ethyl ester (47B) (0.85 g, 1.33 mmol) and sodium hydroxide (0.106 g, 2.66 mmol) Add water (5mL) and ethanol (10mL), stir at room temperature for 1 hour, concentrate dry ethanol under reduced pressure, adjust the pH to 4-5 with 10% citric acid, precipitate a white solid, and vacuum dry to give white solid 3- (2-((4-(N'-((4-cyclopropylbutoxy)carbonyl))indolyl)phenyl)amino)methyl)-1-methyl-N-(pyridine-2- -1H-benzo[d]imidazole-5-carboxamido)propanoic acid (47C) (0.62 g, yield 76.5%).

The third step: 3-(2-((4-cyclopropylbutoxy)carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N -(pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propionic acid 2-methoxyphenyl ester (Compound 47)

2-methoxyphenyl 3-(2-(((4-(4-(propyl)))carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H- Benzo[d]imidazole-5-carboxami do)propanoate

3-(2-((4-(4-(N-)-((4-cyclopropylbutoxy))carbonyl)methyl)phenyl)amino)amino) was added to a 3-neck bottle at 0 °C 1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamido)propanoic acid (47C) (0.61 g, 1 mmol), 2-methoxy Phenol (0.189 g, 1.5 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.25 g, 1.3 mmol), 4-dimethylaminopyridine (0.073 g, 0.6 mmol), then added with N,N-dimethylformamide (10 mL) and stirred for 0.5 hour, and allowed to react to room temperature 5 . The reaction was stopped and ethyl acetate (80 mL) was added, and the organic phase was washed with water (50 mL×5), washed with brine (50 mL×1), dried over anhydrous sodium sulfate Separation and purification (dichloromethane:methanol (v/v)=100:1-20:1) to give 3-(2-((4-(N-)-) Carbonyl)carbenyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanate 2-methyl Oxyphenyl ester (Compound 47) (0.43 g, yield 59%).

Example 48

3-[[2-[[4-[N'-(3,3,3-Trifluoropropoxy)carbonylmethylindenyl]phenylamino]methyl]-1-methyl-benzimidazole-5- Carbonyl]-(2-pyridyl)amino]propionic acid 5-fluoro-2-methoxy-phenyl ester (Compound 48)

(5-fluoro-2-methoxy-phenyl)3-[[2-[[4-[N'-(3,3,3-trifluoropropoxy)carbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl ]-(2-pyridyl)amino]propanoate

For the preparation method, see Example 47;

LCMS m/z = 736.2. [M+1].

Example 49

3-[[2-[[4-[N'-(3,3,3-Trifluoropropoxy)carbonylmethylindenyl]phenylamino]methyl]-1-methyl-benzimidazole-5- 2-methoxy-phenyl carbonyl]-(2-pyridyl)amino]propanoate (Compound 49)

(2-methoxy-phenyl)3-[[2-[[4-[N'-(3,3,3-trifluoropropoxy)carbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2 -pyridyl)amino]propanoate

See Example 47 for the preparation method.

LCMS m/z = 718.1. [M+1].

Test case

1. Pharmacokinetic evaluation

Healthy adult SD rats (both male and female, purchased from Beijing Weitong Lihua Experimental Animal Center, animal production license number SCXK (Beijing) 2012-0001), fasted one day before the administration of water. 6 rats were intragastrically administered with 5 mg/kg (based on dabigatran group), and the compound was formulated into 0.5 mg CmL-Na (containing 1% Tween 80) to make 0.5 mg × mL ^-1 (in Dabiga). The suspension of the group prototype drug was collected from the eyelids, anticoagulated by heparin, and centrifuged at 3000 ° C for 10 min at 4 ° C for 5 min before administration (0 h) and 5 min, 15 min, 30 min, 1.0, 2.0, 4.0, 8.0, 24.0 h after administration. The plasma was separated and stored at -80 ° C for testing. Rat plasma was taken at 30 uL at each time point, 200 uL of internal standard solution (7.5 ng/mL verapamil) was added, vortex mixed for 1 min, centrifuged at 13000 rpm for 10 min at 4 ° C, and supernatant 190 uL was taken for LC-MS/MS (Shimadzu Company lc-20A Technology Co., Ltd., API4000+) analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 6.3 software non-compartmental model. The results are shown in Table 1.

Table 1: Results of pharmacokinetic parameters

Conclusion: The compounds of the present invention have good pharmacokinetic characteristics, especially compounds 1, 2, and 3 are significantly superior to dabigatran etexilate.

Claims (12)

A compound of the formula (I): a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein:

X ₁ and X ₂ are each independently selected from O or S; R ^{1 is} selected from a C _6-10 carbocyclic ring, and the carbocyclic ring is optionally further substituted with 0 to 4 R ^1a ; R ^{1a is} independently selected from H, F, Cl, Br, I, CN, C _1-4 alkyl, C _1-4 alkoxy, -SC _1-4 alkyl or -(CH ₂ ) _n COO C _1-4 alkyl, said alkyl or alkoxy optionally further from 0 to 4 selected from H, F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy Substituted by a substituent; R ^{2 is} selected from C _1-10 alkyl, and the alkyl group is optionally further substituted with from 0 to 12 R ^2a ; R ^{2a is} independently selected from H, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 carbocyclic, said alkyl, alkoxy or carbon The ring is optionally further substituted with from 0 to 4 substituents selected from H, F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy; n is selected from 0, 1, or 2. The compound according to claim 1 and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein: R ^{1 is} selected from substituted or unsubstituted phenyl, benzocyclopentyl or naphthyl, and when substituted, is optionally further substituted with from 0 to 4 R ^1a ; R ^{2 is} selected from C _1-8 alkyl groups, and the alkyl group is optionally further substituted with from 0 to 12 R ^2a . The compound according to claim 2, and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein: R ^{1a is} independently selected from the group consisting of H, F, Cl, Br, CN, CF ₃ , -CHF ₂ , -SCH ₃ , -OCF ₃ , -OCHF ₂ , methyl, ethyl, isopropyl, methoxy, Ethoxy, isopropoxy, -COOCH ₂ CH ₃ or -CH ₂ COOCH ₃ ; R ^2a are each independently selected from the group consisting of H, F, Cl, Br, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl; The compound according to claim 3, and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:

The compound according to any one of claims 1 to 4, and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein the salt is selected from the group consisting of a hydrochloride, a hydrobromide, a sulfate, a nitrate, Phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, Salicylate, glucuronide, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, Benzene sulfonate, methanesulfonate, ethanesulfonate, triflate, ferulic acid or a combination thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 5, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Carrier or excipient. Use of a compound according to any one of claims 1 to 5, and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, and a composition according to claim 6 for the preparation of a medicament for treating a thrombin inhibitor-related disease . The use according to claim 7, wherein the thrombin inhibitor-related disease is selected from the group consisting of thromboembolic diseases. The use according to claim 8, wherein said thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolism. A method of treating a disease associated with a thrombin inhibitor, wherein the method comprises administering a compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt, or a right The composition of claim 6. The method of claim 10 wherein said thrombin inhibitor associated disease is selected from the group consisting of a thromboembolic disorder. The method of claim 11 wherein said thromboembolic disorder is selected from the group consisting of venous thrombosis and arterial embolism.