TWI678365B - Fluorodabigatran etexilate derivative, preparation method and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to a fluorodabigatran etexilate derivative represented by the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, and a method for preparing a medicament for preventing and treating a thromboembolic disease. use. The structure is shown below, and its definition is consistent with the description.

Description

Fluorodabigatran etexilate derivative, preparation method and pharmaceutical use thereof

The present invention relates to a fluorodabigatran etexilate derivative represented by the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, and a method for preparing a medicament for preventing and treating a thromboembolic disease. use.

At present, cardiovascular disease is one of the main causes of human death. A major aspect of it is thrombosis, which is caused by a series of complex reactions that cause blood clotting. Blood coagulation is a protective mechanism of living organisms, which can quickly and reliably "seal" defects in blood vessel walls, so blood loss can be avoided or minimized. Maintaining a normal hemostatic effect, that is, bleeding and coagulation balance, is regulated by a complex mechanism. Unregulated activation of the coagulation system or the 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, and cerebrovascular disease.

The currently available oral anti-hemagglutination drugs include direct thrombin inhibitors, factor Xa inhibitors, factor IX inhibitors, tissue factor inhibitors, and new vitamin K antagonists. Among them, dabigatran etexilate is an oral, selective and highly effective thrombin inhibitor, which has been clinically proven to replace Warfarin as a stroke and systemic embolism in patients with non-valvular atrial fibrillation and to replace enoxaparin. Sodium has become the drug of choice for preventing venous thromboembolism in patients undergoing major plastic surgery.

Dabigatran etexilate was launched in 2008 and is used to prevent nonvalvular atrial fibrillation Stroke or systemic embolism, deep venous thrombosis (DVT) or pulmonary vascular obstruction and their recurrence. It is a double prodrug obtained after the free carboxyl group and fluorenyl group of dabigatran are respectively esterified, which solves the problem of inability to take orally due to the existence of the strong basic fluorenyl group of dabigatran and improves the oral bioavailability . After oral administration, dabigatran etexilate is absorbed from the gastrointestinal tract, and then quickly converted into dabigatran in the body, thereby exerting an anticoagulant effect. However, the oral bioavailability of dabigatran is low, only 3 to 7%, so the medicinal dose is higher, which increases gastrointestinal side effects.

Many prodrugs of dabigatran have been reported in the literature. For example, WO09837075 and WO2004014894 patents disclose dabigatran and its analogs, as well as prodrugs such as alkyl carboxylic acid esters, carboxylic acid esters substituted with sulfonyl groups or sulfonylamino groups; CN102875533 and CN102838588 patents report Ferulic acid or ligustrazine prodrugs of dabigatran and have certain anticoagulant effects; patents such as CN200910211164, CN200910211165, and CN201210158600 disclose prodrugs such as carbonates and carboxylates of dabigatran.

The purpose of the present invention is to solve the problem that dabigatran cannot be taken orally due to its strong alkalinity, and to provide a novel and effective orally edible drug with good stability, solubility, bioavailability, and low dose, low toxicity or long-acting Dabigatran prodrug.

The invention relates to a fluorodabigatran etexilate derivative and a stereoisomer or a pharmaceutically acceptable salt thereof, and the use in the preparation of a medicament for preventing and treating thromboembolic disease.

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

R ^{1 is} selected from C _1-10 alkyl, said alkyl is optionally further substituted by 1 to 12 R ^1a ; R ^{2 is} selected from C _1-10 alkyl, said alkyl is optionally further substituted by 1 to 12 R ^2a substitution; R ^1a and R ^2a are each independently selected from the group consisting of H, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, or C _6-10 carbocyclic ring, with the proviso that R At least one of ¹ or R ² has a substituent, and at least one of R ^1a or R ^2a is F.

In a preferred embodiment of the present invention, a compound represented by the general formula (I), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein: R ^{1 is} selected from a C _1-6 alkyl group, and the alkyl group is optionally further Is substituted with 1 to 12 R ^1a ; R ^{2 is} selected from C _1-8 alkyl, which alkyl is optionally further substituted with 1 to 12 R ^2a .

In a preferred embodiment of the present invention, a compound represented by the general formula (I), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, wherein: R ^{1 is} selected from a C _1-6 alkyl group, and the alkyl group is optionally further Is substituted with 1 to 12 R ^1a ; R ^{2 is} selected from C _1-8 alkyl, which alkyl is optionally further substituted with 1 to 12 R ^2a ; R ^1a and R ^2a are each independently selected from H, F, Cl, Br, methyl, methoxy or cyclopropyl.

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

According to a preferred embodiment of the present invention, according to the compound of the present invention and a stereoisomer or a pharmaceutically acceptable salt thereof, the salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, and phosphoric acid Salt, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylic acid Salt, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamine, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonic acid Salt, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, ferulate or a combination thereof.

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

The present invention further provides a compound as described in any of the foregoing, and its stereoisomers or pharmaceutically acceptable salts, for the preparation and treatment of diseases related to thrombin inhibitors. Use in medicine.

The invention also provides the use of the aforementioned pharmaceutical composition in the manufacture of a medicament for the treatment of diseases related to a thrombin inhibitor.

According to a preferred embodiment of the present invention, the thrombin inhibitor-related disease is selected from the group consisting of thromboembolic disease.

According to a preferred embodiment of the present invention, the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolism.

The present invention further provides a method for treating a thrombin inhibitor-related disease, wherein the method comprises administering a compound according to the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, or the combination.

According to a preferred embodiment of the present invention, the thrombin inhibitor-related disease is selected from the group consisting of thromboembolic disease.

According to a preferred embodiment of the present invention, the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolism.

Unless stated to the contrary, terms used in the specification and the scope of patent applications have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen mentioned in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, etc. in the groups and compounds of the present invention, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, where carbon isotopes include ¹² C, ¹³ C, and ¹⁴ C, and hydrogen isotopes include tritium (H), deuterium (D, also known as deuterium) , Thallium (T, also known as super heavy hydrogen), the isotopes of oxygen include ¹⁶ O, ¹⁷ O, and ¹⁸ O, the isotopes of sulfur include ³² S, ³³ S, ³⁴ S, and ³⁶ S, and the isotopes of nitrogen include ¹⁴ N and ¹⁵ N The isotopes of fluorine include ¹⁹ F, the isotopes of chlorine include ³⁵ Cl and ³⁷ Cl, and the isotopes of bromine include ⁷⁹ Br and ⁸¹ Br.

"Alkyl" refers to straight and branched chain saturated aliphatic hydrocarbon groups. The main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, more preferably It is preferably from 1 to 6 carbon atoms, even more preferably from 1 to 4 carbon atoms, straight and branched chain groups, and most preferably from 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl and ethyl groups. , N-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl , 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl Methyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl- 2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2- Dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, N-octyl, 2,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl , 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2 -Methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl and n-decyl; the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be any It can be substituted at the available connection point. The substituent is preferably 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, Mercapto, amine, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclic, hydroxyalkyl = 0, carbonyl, aldehyde, carboxylic acid, carboxylic acid Ester arylthio, thiocarbonyl or silane.

"Alkoxy" refers to -O-alkyl, where alkyl is as defined herein above. The alkoxy group may be substituted or unsubstituted. Examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and Tributoxy, second butoxy, n-pentyloxy and n-hexyloxy; when substituted, the substituent is preferably 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amine, cyano, isocyano, aryl , Heteroaryl, heterocyclyl, bridged ring, spiro, cyclic, hydroxyalkyl, = 0, carbonyl, aldehyde, carboxylic acid, carboxylate arylthio, thiocarbonyl, or silyl, etc. .

，所述的“胺基酸的側鏈基團”是指此處的L基團，非限定實施例包括但不限於：甘胺酸的側鏈基團為H、丙胺酸的側鏈基團為甲基、苯丙胺酸的側鏈基團為苄基、纈胺酸的側鏈基團為異丙基等。 "Amino acid side chain group", amino acid is a generic name for a class of organic compounds containing amine groups and carboxyl groups, and its general structure is

The "side chain group of amino acid" refers to the L group herein. Non-limiting examples include, but are not limited to, the side chain group of glycine is H, and the side chain group of alanine Is a methyl group, a side chain group of phenylalanine is benzyl, a side chain group of valine is isopropyl, and the like.

"Optional" or "optionally" means that the event or environment described later can, but does not have to occur, and the description includes situations where the event or environment occurs or does not occur, such as: "alkyl optionally substituted with F "" Means that the alkyl group may be substituted with F, but the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

"Substitution" refers to the case where one or more hydrogen atoms in a group are replaced with other groups. If the group is replaced with a hydrogen atom, the formed group is the same as the group substituted with a hydrogen atom. In the case where the group is substituted, for example, an amine group, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _3-6 carbocyclic ring, a 3 to 6 membered heterocyclic ring is optionally further selected from 0 to 4 selected from H , F, Cl, Br, I, hydroxyl, cyano, amine, C _1-4 alkyl or C _1-4 alkoxy substituents, the formed groups include but are not limited to methyl, chloroform Group, trichloromethyl, hydroxymethyl, -CH ₂ OCH ₃ , -CH ₂ SH, -CH ₂ CH ₂ CN, -CH ₂ NH ₂ , -NHOH, -NHCH ₃ , -OCH ₂ Cl, -OCH ₂ OCH ₂ CH ₃ , -OCH ₂ CH ₂ NH ₂ , -OCH ₂ CH ₂ SH, -OCH ₂ CH ₂ OH, 1-hydroxycyclopropyl, 2-hydroxycyclopropyl, 2-aminocyclopropyl, 4 -Methylfuranyl, 2-hydroxyphenyl, 4-aminophenyl, phenyl.

"Substituted or unsubstituted" refers to a case where a group may be substituted or unsubstituted. If it is not indicated in the present invention that a group may be substituted, it indicates that the group is unsubstituted.

"As a choice" means that the schemes after "as a choice" and the schemes before "as a choice" are in a side-by-side relationship, rather than a further choice in the previous scheme.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to maintaining the biological effectiveness and properties of a free acid or free base, and said free acid is passed through a non-toxic inorganic or organic base, Or those salts obtained by reacting the free acids with non-toxic inorganic or organic acids, including alkali metal salts, such as sodium, potassium, lithium, etc .; alkaline earth metal salts, such as calcium, magnesium, etc .; others Metal salts, such as iron, copper, and cobalt salts; organic base salts, such as ammonium, triethylamine, pyridine, methylpyridine, 2,6-dimethylpyridine, ethanolamine, and diethanolamine salts , Triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, guanidine salt, isopropylamine salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, dimethyl Ethanolamine, dicyclohexylamine, caffeine, procaine, choline, betaine, benzyl penicillin, glucosamine, N-methylglucamine, theobromine, and amine Triolate, purine salt, pyrazine salt, morpholine salt, pyridine salt, N-ethylpyridine salt, tetramethylamine , Dibenzylamine salts and alkyl phenylglycinates; hydrohalates, such as hydrofluoride, hydrochloride, hydroiodate, hydrobromide; inorganic acid salts, such as nitrate, Sulfates, perchlorates, phosphates; lower alkane sulfonates, such as mesylate, trifluoromethane sulfonate, and ethane sulfonate; aryl sulfonates, such as benzene sulfonate, p-toluenesulfonate Acid salts; organic acid salts such as formate, fumarate, formate, trifluoroacetate, furoate, gluconate, glutamate, glycolate, isethionate, lactic acid Salt, maleate, malate, mandelate, mucus, paraben, pantothenate, stearate, succinate, sulfamate, tartrate, malonate, 2-hydroxypropionate, citrate, salicylate, oxalate, glycolate, glucuronate, galacturate, citrate, lysine, spermine, Aspartate, cinnamate.

resolve resolution

method one:

R ² is n-hexyl; the definition of R ^{1 is} the same as that described in the general formula (I).

Method Two:

R ^{1 is} selected from C _1-10 alkyl, said alkyl is optionally further substituted by 1 to 12 R ^1a ; R ^{2 is} selected from C _1-10 alkyl, said alkyl is optionally further substituted by 1 to 12 R ^2a substitution; R ^1a and R ^2a are each independently selected from the group consisting of H, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, or C _6-10 carbocyclic ring, with the proviso that R At least one of ¹ or R ² has a substituent, and at least one of R ^1a or R ^2a is F.

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

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). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic analyzers, and the solvents used were deuterated dimethylsulfinium (DMSO-d6), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD) , The internal standard is tetramethylsilane (TMS).

For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

For HPLC measurement, an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm) was used.

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silicone plate. The thin-layer chromatography (TLC) silicon plate uses a size of 0.15mm ~ 0.20mm, and the thin-layer chromatography separation and purification product uses a size of 0.4mm. ~ 0.5mm.

Column chromatography generally uses Yantai Yellow Sea Silicone 200-300 mesh silica gel as the carrier.

The known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bellingville Technology. And other companies.

Nitrogen atmosphere refers to the reaction bottle connected to a nitrogen balloon with a volume of about 1L.

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

The hydrogenation reaction is usually evacuated and charged with hydrogen, and the operation is repeated 3 times.

There is no special description in the examples, and the reaction was performed under a nitrogen atmosphere.

There is no special description in the examples, and the solution means an aqueous solution.

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

Room temperature is the most suitable reaction temperature, ranging from 20 ° C to 30 ° C.

Intermediate 1

3-[[2-[[4-[(Z) -N`-Hexyloxycarbonylformamidine] aniline] methyl] -1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl ) Amino] propionic acid (Intermediate 1)

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

First step: 3-[[2-[[4-[(Z) -N`-Hexyloxycarbonylformamidine] aniline] methyl] -1-methyl-benzimidazole-5-carbonyl]-( 2-pyridyl) amino] propanoic acid (Intermediate 1)

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

3-[[2-[[4-[(Z) -N`-Hexyloxycarbonylformamidine] aniline] methyl] -1-methyl-benzimidazole-5-carbonyl]-(2-pyridine (Amino) amino] ethyl propionate (1a) (63 g, 100 mmol) plus The mixture was poured into a mixed solvent of ethanol (600 mL) and water (300 mL), sodium hydroxide (8 g, 200 mmol) was added, and the mixture was stirred at room temperature for half an hour until the reaction solution became clear. Concentrate the reaction solution, spin off most of the ethanol, add water (200 mL), adjust the pH to 4-5 with 10% citric acid aqueous solution, a large amount of viscous solids precipitate, filter, transfer the solids to the reaction flask, and add methanol ( 300mL), heated to dissolve the solid, continued to stir until the solid was granular, cooled to zero, more product precipitated, filtered and dried to give the title compound 3-[[2-[[4-[(Z) -N`-hexyloxycarbonylformamidine] aniline] methyl] -1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) amino] propionic acid (Intermediate 1) (50g, 83% yield).

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

¹ H NMR (400MHz, DMSO): δ 8.38 (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) methylamido) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid 3,3,3, -trifluoropropyl ester ( Compound 1 )

3,3,3-trifluoropropyl 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-[(Z) -N`-hexyloxycarbonylformamidine] aniline] methyl] -1-methyl-benzimidazole-5- Carbonyl]-(2-pyridyl) amino] propanoic acid (Intermediate 1) (0.6g, 0.001mol), 3,3,3-trifluoroprop-1-ol (1A) (0.17g, 0.0015mol) , 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.25g, 0.0013mol), 4-dimethylaminopyridine (0.073g, 0.0006mol), and then added N, N-dimethylformamide (10 mL) was kept under stirring for 0.5 hours, and the temperature was raised to room temperature for 5 hours. The reaction was stopped. Ethyl acetate (60 mL) was added to the reaction solution, and the organic phase was washed with water (40 mL × 5), washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, concentrated, and the residue was separated by column chromatography. Purification (dichloromethane: methanol (v / v) = 100: 1-20: 1) to give 3- (2-(((4- (N '-((hexyloxy) carbonyl) methyl) methyl) as a white solid) Phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid 3,3,3,- Trifluoropropyl ester ( Compound 1 ) (0.05 g, 7.32%).

¹ H NMR (400MHz, CDCl ₃ ): δ 8.42 (d, 1H), 7.73-7.63 (m, 3H), 7.35-7.30 (m, 1H), 7.25-7.17 (m, 1H), 7.10-7.07 (m , 1H), 7.00-6.97 (m, 1H), 6.71-6.64 (m, 3H), 5.37 (s, 1H), 4.47-4.41 (m, 4H), 4.27-4.24 (t, 2H), 4.15-4.11 (m, 2H), 3.70 (s, 3H), 2.85-2.81 (t, 3H), 2.46-2.39 (m, 2H), 1.74-1.70 (m, 2H), 1.43-1.40 (m, 2H), 1.32 -1.27 (m, 4H), 0.89-0.87 (t, 3H).

Example 2

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

2,2,3,3,4,4,4-heptafluorobutyl 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-[(Z) -N`-hexyloxycarbonylformamidine] aniline] methyl] -1-methyl-benzimidazole-5- Carbonyl]-(2-pyridyl) amino] propionic acid (Intermediate 1) (0.6 g, 0.001 mol), heptafluorobutanol (2A) (0.3 g, 0.0015 mol), 1- (3-dimethylamine Propyl) -3-ethylcarbodiimide hydrochloride (0.25 g, 0.0013 mol), 4-dimethylaminopyridine (0.073 g, 0.0006 mol), then N, N-dimethylformamide was added Amidine (10 mL) was kept under stirring for 0.5 hours, and the temperature was raised to room temperature for 5 hours. The reaction was stopped, and ethyl acetate (60 mL) was added to the reaction solution. The organic phase was washed with water (40 mL × 5), washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to column chromatography. Isolation and purification (dichloromethane: methanol (v / v) = 100: 1-20: 1) to obtain 3- (2-(((4- (N '-((hexyloxy) carbonyl) formyl) methyl) ) Phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid 2,2,3, 3,4,4,4-Heptafluorobutyl ester ( Compound 2 ) (0.113 g, 14.5%).

¹ H NMR (400MHz, CDCl ₃ ): δ 8.42 (d, 1H), 7.75-7.70 (m, 3H), 7.34-7.29 (m, 2H), 7.12-7.10 (d, 2H), 7.01-6.97 (m , 1H), 6.68-6.65 (m, 3H), 5.38 (s, 1H), 4.59-4.52 (t, 2H), 4.49-4.44 (m, 4H), 4.16-4.12 (t, 2H), 3.72 (s , 3H), 2.95-2.91 (t, 3H), 1.76-1.68 (m, 2H), 1.42-1.38 (m, 2H), 1.33-1.29 (m, 4H), 0.90-0.87 (t, 3H).

Example 3

3- (2-(((4- (N '-((hexyloxy) carbonyl) methylamido) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoic acid 2,2,3,3,4,4,5,5,6,6,6-undecfluorohexyl ester ( Compound 3 )

2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyl 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-[(Z) -N`-hexyloxycarbonylformamidine] benzene Amine] methyl] -1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) amino] propanoic acid (Intermediate 1) (0.6 g, 0.001 mol), undecafluoron-hexane- 1-alcohol (3A) (0.45 g, 0.0015 mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.25 g, 0.0013 mol), 4-dimethyl Aminopyridine (0.073 g, 0.0006 mol), then N, N-dimethylformamide (10 mL) was added, the mixture was kept under stirring for 0.5 hours, and the temperature was raised to room temperature for 5 hours. The reaction was stopped. Ethyl acetate (60 mL) was added to the reaction solution, and the organic phase was washed with water (40 mL × 5), washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, concentrated, and the residue was separated by column chromatography. Purification (dichloromethane: methanol (v / v) = 100: 1-20: 1) to give 3- (2-(((4- (N '-((hexyloxy) carbonyl) methyl) methyl) as a white solid) Phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid 2,2,3,3 , 4,4,5,5,6,6,6-Undecafluorohexyl (Compound 3) (0.113 g, 14.5%).

¹ H NMR (400MHz, CDCl ₃ ): δ 8.42 (d, 1H), 7.75-7.70 (m, 3H), 7.34-7.29 (m, 2H), 7.14-7.12 (d, 2H), 7.01-6.98 (m , 1H), 6.71-6.65 (m, 3H), 5.38 (s, 1H), 4.60-4.44 (m, 6H), 4.16-4.13 (t, 2H), 3.74 (s, 3H), 2.95-2.92 (t , 2H), 1.76-1.69 (m, 2H), 1.42-1.38 (m, 2H), 1.33-1.31 (m, 4H), 0.89-0.87 (t, 3H).

Example 4

3- (2-(((4- (N '-((hexyloxy) carbonyl) methylamido) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) trifluoroethyl propionate (Compound 4)

(Z) -2,2,2-trifluoroethyl 3- (2-((4- (N '-(hexyloxycarbonyl) carbamimidoyl) phenylamino) methyl) -1-methyl-N- (pyridin-2-yl) -1H- benzo [d] imidazole-5-carboxamido) propanoate

3-[[2-[[4-[(Z) -N`-Hexyloxycarbonylformamidine] aniline] methyl] -1-methyl-benzimidazole-5-carbonyl]-(2-pyridine (Amino) amino] propanoic acid (Intermediate 1) (0.85 g, 1.4 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.43 g, 2.24 mmol ), 4-Dimethylaminopyridine (0.1 g, 0.84 mmol), added to N, N-dimethylformamide (5 mL), stirred at room temperature for 1 hour, and then added trifluoroethanol (4A) (0.14 g , 1.4 mmol), react at room temperature for 16 hours, and then add water (100 mL) to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, and the organic phase was washed with saturated brine (100 mL × 1). ), Dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 100: 1-20: 1) to give the title compound: 3- (2-(((4 -(N '-((hexyloxy) carbonyl) methylamido) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole -5-Formamido) trifluoroethyl propionate (Compound 4), white solid (100 mg, yield 10.4%).

LCMS m / z = 682.2 [M + 1].

¹ H NMR (400MHz, CDCl ₃ ) δ 8.43 (d, 1H), 7.81-7.68 (m, 3H), 7.31 (d, 2H), 7.14 (d, 1H), 6.99 (dd, 1H), 6.69 (dd , 3H), 5.33 (s, 1H), 4.69-4.39 (m, 6H), 4.14 (dd, 2H), 3.74 (s, 3H), 2.93 (t, 2H), 1.85-1.62 (m, 3H), 1.44-1.23 (m, 6H), 0.88 (d, 3H).

Example 5

3- (1-methyl-N- (pyridin-2-yl) -2-((((4- (N '-((3,3,3-trifluoropropoxy) carbonyl) methyl) methyl) benzene (Amino) amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) ethyl propionate (compound 5)

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

Carbobiimidazole (1.00 g, 6.17 mmol) was added to 3,3,3-trifluoro-1-propanol (0.685 g, 6.01 mmol) in tetrahydrofuran (10 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure to prepare a reaction solution 1. In 3- (2-(((4-fluorenylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-methyl (Amido) ethyl propionate p-toluenesulfonate (5A) (2.67 g, 4.00 mmol) was added with acetone (100 mL), water (50 mL), potassium carbonate (1.65 g, 11.9 mmol), and stirred well The reaction solution 1 was added, and the reaction was performed 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), and then dissolved with dichloromethane (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography. Isolation and purification (dichloromethane: methanol (v / v) = 100: 1 ~ 30: 1) to obtain the title compound 3- (1-methyl-N- (pyridin-2-yl)- 2-(((4- (N '-((3,3,3-trifluoropropoxy) carbonyl) methylamido) phenyl) amino) methyl) -1H-benzo [d] imidazole- Ethyl 5-formamido) propionate (Compound 5), brown solid (0.60 g, 23.0% yield).

LCMS m / z = 640.3 [M + 1].

¹ H NMR (400MHz, DMSO) δ 9.12 (s, 1H), 8.75 (s, 1H), 8.39 (dd, 1H), 7.81 (d, 2H), 7.54 (m, 1H), 7.48 (d, 1H) , 7.40 (d, 1H), 7.16 (dd, 1H), 7.14-7.06 (m, 1H), 6.97 (t, 1H), 6.89 (d, 1H), 6.77 (d, 2H), 4.60 (d, 2H ), 4.22 (m, 4H), 3.98 (q, 2H), 3.77 (s, 3H), 2.76-2.59 (m, 4H), 1.12 (t, 3H).

Example 6

3- (2-(((4- (N '-((hexyloxy) carbonyl) methylamido) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid 2-fluoroethyl ester (compound 6)

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

3-[[2-[[4-[(Z) -N`-Hexyloxycarbonylformamidine] aniline] methyl] -1-methyl-benzimidazole-5-carbonyl]-(2-pyridine (Amino) amino] propanoic acid (Intermediate 1) (1 g, 1.67 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.96 g, 5.01 mmol), 4-dimethylaminopyridine (0.3 g, 2.5 mmol), N, N-dimethylformamide (5 mL) was stirred at room temperature for 1 hour, and then fluoroethanol (10A) (0.106 g, 01.67 mmol) was added, and the mixture was reacted at room temperature for 16 hours. Water (100 mL) was added to the reaction solution. The phases were extracted with ethyl acetate (50 ml x 2), and the organic phases were combined. The organic phases were washed with saturated brine (100 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol). (v / v) = 100: 1 ~ 20: 1) to give the title compound 3- (2-(((4- (N '-((hexyloxy) carbonyl) methylamido) phenyl) amino) formaldehyde ) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazol-5-carboxamido) propionic acid 2-fluoroethyl ester (Compound 6), white solid (300 mg , Yield 28%).

LCMS m / z = 646.4 [M + 1].

¹ H NMR (400MHz, CDCl ₃ ) δ 8.42 (d, 1H), 7.80-7.64 (m, 3H), 7.31 (m, 2H), 7.11 (d, 1H), 6.98 (dd, 1H), 6.69 (t , 3H), 5.34 (s, 1H), 4.67-4.59 (m, 1H), 4.55-4.39 (m, 5H), 4.36-4.28 (m, 1H), 4.28-4.22 (m, 1H), 4.14 (t , 2H), 3.72 (s, 3H), 2.86 (t, 2H), 1.80-1.62 (m, 3H), 1.46-1.22 (m, 6H), 0.89 (t, 3H).

Example 7

3-(-1-methyl-N- (pyridin-2-yl) -2 (((4- (N '-(((2,2,3,3,4,4,5,5,6, 6,6-Undecylfluoro) oxy) carbonyl) methylamino) phenyl) amino) methyl) -1H-benzo [d] imidazole-5-methylamido) ethyl propionate ( Compound 7 )

ethyl 3- (1-methyl-N- (pyridin-2-yl) -2-((((4- (N '-(((2,2,3,3,4,4,5,5,6, 6,6-undecafluorohexyl) oxy) carbonyl) carbamimidoyl) phenyl) amino) met hyl) -1H-benzo [d] imidazole-5-carboxamido) propanoate

To the reaction flask were added undecafluoron-hexane-1-ol (0.58 g, 1.93 mmol) and tetrahydrofuran (3 mL), and then N, N'-carbonyldiimidazole (0.34 g, 2.08 mmol) was added, followed by stirring at room temperature for 1 hour. Concentrated under reduced pressure to give an oil. Add another reaction flask and add 3- (2-(((4-fluorenylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole -5-Formamyl) ethyl propionate (7A) (1 g, 1.49 mmol), and an oil, acetone (30 mL), water (15 mL). Stir for 5 hours at room temperature, evaporate the acetone under reduced pressure, add water (60 mL) to the residue, extract with ethyl acetate (70 mL x 3), combine the organic phases, wash with saturated brine (90 mL), dry over anhydrous sodium sulfate, and concentrate. The residue was separated and purified by column chromatography (dichloromethane: methanol (v / v) = 30: 1-10: 1) to obtain 3-(-1-methyl-N- (pyridin-2-yl)-as a white solid. 2 (((4- (N '-(((2,2,3,3,4,4,5,5,6,6,6-undecylfluoro) oxy) carbonyl) methanyl) phenyl ) Amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) ethyl propionate ( Compound 7 ) (0.609 g, 49%).

¹ H NMR (400MHz, CDCl ₃ ): δ 8.43-8.41 (d, 1H), 7.76-7.75 (m, 2H), 7.69-7.67 (m, 1H), 7.34-7.28 (m, 2H), 7.10-7.08 (d, 1H), 7.00-6.97 (m, 1H), 6.73-6.71 (d, 1H), 6.67-6.64 (m, 2H), 5.38 (s, 1H), 4.73-4.66 (t, 2H), 4.47 -4.41 (m, 4H), 4.11-4.05 (m, 2H), 3.70 (s, 3H), 2.83-2.79 (t, 2H), 1.24-1.20 (t, 3H).

Example 8

3- (2-(((4- (N '-((hexyloxy) carbonyl) methylamido) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid 2,2,3,3,3, -pentafluoropropyl ester ( Compound 8 )

2,2,3,3,3-pentafluoropropyl 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-[(Z) -N`-hexyloxycarbonylformamidine] aniline] methyl] -1-methyl-benzimidazole-5- Carbonyl]-(2-pyridyl) amino] propanoic acid (Intermediate 1) (0.6g, 0.001mol), 2,2,3,3,3, -pentafluoropropanol (8A) (0.225g, 0.0015 mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.25 g, 0.0013 mol), 4-dimethylaminopyridine (0.073 g, 0.0006 mol), Then, N, N-dimethylformamide (10 mL) was added, the mixture was kept under stirring for 0.5 hours, and the temperature was raised to room temperature for 5 hours to react. The reaction was stopped. Ethyl acetate (60 mL) was added to the reaction solution, and the organic phase was washed with water (40 mL × 5), washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, concentrated, and the residue was separated by column chromatography. Purification (dichloromethane: methanol (v / v) = 100: 1-20: 1) to give 3- (2-(((4- (N '-((hexyloxy) carbonyl) methyl) methyl) as a white solid) Phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid 2,2,3,3 , 3, -pentafluoropropyl ester ( Compound 8 ) (0.11 g, 15%).

¹ H NMR (400MHz, CDCl ₃ ): δ 8.42 (d, 1H), 7.75-7.70 (m, 3H), 7.34-7.29 (m, 2H), 7.12-7.10 (d, 2H), 7.01-6.98 (m , 1H), 6.69-6.65 (m, 3H), 5.39 (s, 1H), 4.55-4.44 (m, 6H), 4.16-4.12 (t, 2H), 3.72 (s, 3H), 2.94-2.91 (t , 3H), 1.76-1.68 (m, 2H), 1.42-1.38 (m, 2H), 1.33-1.31 (m, 4H), 0.91-0.87 (t, 3H).

Example 9

3- (2-(((4- (N '-(((6,6-difluorohexyl) oxy) carbonyl) methylamino) phenyl) amino) methyl) -1-methyl-N -(Pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) ethyl propionate (compound 9)

ethyl 3- (2-(((4- (N '-(((6,6-difluorohexyl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate

Step 1: 6-((Third-butyldimethylsilyl) oxy) hexyl-1-ol (9B)

6-((tert-butyldimethylsilyl) oxy) hexan-1-ol

Imidazole (8.85 g, 130 mmol) was added to 1,6-hexanediol (9A) (10 g, 85 mmol) in dichloromethane (150 mL) under an ice bath, and the third butyl dimethyl chloride was added dropwise after stirring for 10 minutes. A solution of silane (12.8 g, 84.9 mmol) in dichloromethane (100 mL) was reacted at room temperature for 5 hours after the addition. Water (200 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 10: 1 ~ 3: 1) to give the title compound 6-((third butyldimethylsilyl) oxy) hexyl-1-ol (9B), colorless liquid (8.0 g, yield 41%) ).

¹ H NMR (400MHz, CDCl ₃ ) δ 3.62 (m, 4H), 1.55 (m, 4H), 1.40 (s, 1H), 1.40-1.33 (m, 4H), 0.89 (s, 9H), 0.04 (s , 6H).

Second step: 6-((third butyldimethylsilyl) oxy) hexanal (9C)

6-((tert-butyldimethylsilyl) oxy) hexanal

Add 6 g of silicone and pyridinium chlorochromate (150 g of 6-((third-butyldimethylsilyl) oxy) hexyl-1-ol (9B) (5 g, 22 mmol) at room temperature to 150 mL of dichloromethane. 7.0 g, 33 mmol), and reacted at room temperature for 3 hours after the addition. It was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 100: 1-20: 1) to obtain the title compound 6-((third butyldimethylsilyl) oxy ) Hexaldehyde (9C), a colorless liquid (2.0 g, yield 40%).

¹ H NMR (400MHz, CDCl ₃ ) δ 9.72 (t, 1H), 3.57 (dd, 2H), 2.39 (td, 2H), 1.65-1.57 (m, 2H), 1.52-1.46 (m, 2H), 1.37 -1.30 (m, 2H), 0.85 (s, 9H), -0.00 (s, 6H).

Step 3: Third butyl ((6,6-difluorohexyl) oxy) dimethylsilane (9D)

tert-butyl ((6,6-difluorohexyl) oxy) dimethylsilane

To a solution of 6-((third butyldimethylsilyl) oxy) hexanal (9C) (1.8 g, 7.1 mmol) in toluene (15 mL) under ice bath was added diethylaminosulfur trifluoride ( 2.3 g, 14 mmol), and reacted at room temperature for 2 hours after the addition. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 100: 0 ~ 20: 1) The title compound is tert-butyl ((6,6-difluorohexyl) oxy) dimethylsilane (9D), a colorless liquid (1.4 g, yield 78%). .

¹ H NMR (400MHz, CDCl ₃ ) δ 5.79 (tt, 1H), 3.60 (td, 2H), 1.84 (m, 2H), 1.58-1.32 (m, 6H), 0.90 (d, 9H), 0.05 (d , 6H).

Step 4: 6,6-Difluorohexyl-1-ol (9E)

6,6-difluorohexan-1-ol

To a solution of tert-butyl ((6,6-difluorohexyl) oxy) dimethylsilane (9D) (1.4 g, 5.5 mmol) in 15 mL of tetrahydrofuran under ice bath was added tetrabutylamine fluoride (2.2 g , 8.4 mmol), and reacted at room temperature for 3 hours after the addition. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 100: 0 to 20: 1) The title compound 6,6-difluorohexyl-1-ol (9E) was obtained as a colorless liquid (0.45 g, yield 59%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.80 (tt, 1H), 3.66 (t, 2H), 1.84 (m, 2H), 1.60 (m, 2H), 1.48 (m, 4H).

Step 5: 3- (2-(((4- (N '-(((6,6-difluorohexyl) oxy) carbonyl) methylamido) phenyl) amino) methyl) -1- Methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) ethyl propionate (Compound 9)

ethyl 3- (2-(((4- (N '-(((6,6-difluorohexyl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate

Carboximidine diimidazole (0.470 g, 2.90 mmol) was added to tetrahydrofuran (10 mL) of 6,6-difluorohexyl-1-ol (9E) (0.400 g, 2.90 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure to prepare a reaction solution 1. 3- (2-(((4-fluorenylphenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H- Benzo [d] imidazole-5-carboxamido) propionic acid ethyl p-toluenesulfonate (5A) (2.44 g, 3.60 mmol) was added with acetone (100 mL), water (50 mL), and potassium carbonate ( 1.65 g, 11.9 mmol), after stirring, add reaction liquid 1 and react 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), and then dissolved with dichloromethane (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography. Isolation and purification (dichloromethane: methanol (v / v) = 100: 1 ~ 30: 1) to obtain the title compound 3- (2-(((4- (N '-(((6,6-difluorohexyl)) (Oxy) carbonyl) methylamino) phenyl) amino) methyl) -1-methyl-N- (Pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) ethyl propionate (Compound 9), white solid (0.400 g, yield 16.7%).

LCMS m / z = 664.2 [M + 1].

¹ H NMR (400MHz, DMSO) δ 9.08 (s, 1H), 8.69 (s, 1H), 8.39 (dd, 1H), 7.80 (d, 2H), 7.54 (m, 1H), 7.47 (d, 1H) , 7.40 (d, 1H), 7.16 (dd, 1H), 7.12 (m, 1H), 6.94 (t, 1H), 6.89 (d, 1H), 6.77 (d, 2H), 6.05 (tt, 1H), 4.59 (d, 2H), 4.23 (t, 2H), 3.98 (q, 4H), 3.76 (s, 3H), 2.68 (t, 2H), 1.85-1.74 (m, 1H), 1.68-1.53 (m, 2H), 1.49-1.30 (m, 4H), 1.12 (t, 3H).

Example 10

3- (2-(((4- (N '-(((6,6-difluoropentyl) oxy) carbonyl) methylamino) phenyl) amino) methyl) -1-methyl- N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) ethyl propionate (compound 10)

ethyl 3- (2-(((4- (N '-(((6,6-difluoropentyl) oxy) carbonyl) carbamimidoyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate

For the preparation method, see Example 9.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.42 (d, 1H), 7.82-7.67 (m, 3H), 7.32 (d, 2H), 7.13 (d, 1H), 7.02-6.95 (m, 1H), 6.71 (d, 3H), 5.81 (dd, 1H), 5.30 (s, 1H), 4.51 (d, 2H), 4.43 (t, 2H), 4.17 (t, 2H), 4.08 (q, 2H), 3.73 ( s, 3H), 2.81 (t, 2H), 1.87 (s, 2H), 1.83-1.74 (m, 2H), 1.61 (d, 2H), 1.22 (t, 3H).

Example 11

3- (2-(((4- (N '-((ethoxy) carbonyl) methylamido) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoic acid 2,2,3,3,4,4,5,5,6,6,6-undecylfluorohexyl ester ( Compound 11 )

2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyl 3- (2-((((4- (N '-((ethyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl ) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate

First step: 3- (2-(((4- (N '-((ethoxy) carbonyl) methylamido) phenyl) amino) methyl) -1-methyl-N- (pyridine- 2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid ( 11B )

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

Add 3-[[2-[[4-[(Z) -N`-ethoxycarbonylfluorenyl] aniline] methyl] -1-methyl-benzimidazole-5-carbonyl]- (2-Pyridine) amino] ethyl propionate (11A) (0.80 g, 1.40 mmol), water (16 ml), ethanol (8 ml), sodium hydroxide (0.18 g, 4.5 mmol), and reacted at room temperature for 2 hours. Add acetic acid to make it neutral, and filter to give white solid 3- (2-(((4- (N '-((ethoxy) carbonyl) methylamido) phenyl) amino) methyl) -1-form -N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid ( 11B ) (0.38 g, yield: 50.0%).

LCMS m / z = 544.3 [M + 1].

¹ HNMR (400MHz, DMSO) δ 8.37 (dd, 1H), 7.80 (d, 2H), 7.56 (m, 1H), 7.48 (d, 1H), 7.39 (d, 1H), 7.28-7.08 (m, 3H ), 6.94 (dd, 2H), 6.76 (d, 2H), 4.59 (d, 2H), 4.19-4.10 (m, 2H), 4.03 (q, 2H), 3.76 (s, 3H), 2.59-2.52 ( m, 2H), 2.30 (s, 1H), 1.90 (s, 1H), 1.21 (m, 3H).

Second step: 3- (2-(((4- (N '-((ethoxy) carbonyl) methylamido) phenyl) amino) methyl) -1-methyl-N- (pyridine- 2-yl) -1H-benzo [d] imidazol-5-carboxamido) propionic acid 2,2,3,3,4,4,5,5,6,6,6-undecfluorohexyl ester ( Compound 11 )

2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyl 3- (2-((((4- (N '-((ethyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl ) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propanoate

Add 3- (2-(((4- (N '-((ethoxy) carbonyl) methylamido) phenyl) amino) methyl) -1-methyl-N- (pyridine -2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid ( 11B ) (0.38 g, 0.70 mmol) and undecafluoron-hexane-1-ol (0.31 g, 1.00 mmol ), N, N-dimethylformamide (14ml), stir well, cool to 0 ° C, add 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.21 g, 1.10 mmol) and 4-dimethylaminopyridine (0.05 g, 0.42 mmol), stirred at 0 ° C for 0.5 hours, and raised to room temperature to react for 5 hours. Water (20 ml) and ethyl acetate (30 mL) were added and stirred. The organic layer was separated and washed with water (20 mL × 2) to obtain an organic layer, which was dried, filtered, and concentrated. Separation and purification by silica gel column chromatography (dichloromethane / methanol (v / v) = 40: 1-30: 1) to obtain white solid 3- (2-(((4- (N '-((ethoxy) carbonyl)) Formamyl) phenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzo [d] imidazole-5-carboxamido) propionic acid 2,2 , 3,3,4,4,5,5,6,6,6-Undecylfluorohexyl ester ( Compound 11 ) (0.38 g, yield: 66.0%).

LCMS m / z = 826.0 [M + 1].

Example 12

3- (1-methyl-N- (pyridin-2-yl) -2-((((4- (N '-((3,3,3-trifluoroethoxy) carbonyl) methylamido)) benzene (Amino) amino) methyl) -1H-benzo [d] imidazole-5-carboxamido) ethyl propionate (Compound 12)

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

Please refer to Example 5 for the preparation method.

LCMS m / z = 626.1 [M + 1].

1H NMR (400MHz, CDCl3) δ 8.41 (dd, 1H), 7.70 (d, 2H), 7.64 (d, 1H), 7.32 (t, 1H), 7.24 (dd, 1H), 7.01 (d, 1H), 7.00-6.95 (m, 1H), 6.70 (s, 1H), 6.56 (d, 2H), 5.41 (s, 1H), 4.55 (q, 2H), 4.46-4.29 (m, 4H), 4.07 (q, 2H), 3.65 (s, 3H), 2.79 (t, 3H), 1.21 (t, 3H).

Test case

1.Pharmacokinetic evaluation

Healthy adult SD rats (half male and female, purchased from Beijing Weitong Lihua Experimental Animal Center, animal production license number SCXK (Beijing) 2012-0001), fasted and watered one day before administration. Six rats were orally administered with 5 mg / kg (based on the original drug of dabigatran), and the compound was formulated with 0.5% CMC-Na (containing 1% Tween 80) to 0.5 mg × mL ^-1 (as dabbit Add the group of original drugs) suspension, before the administration (0h) and 5min, 15min, 30min, 1.0, 2.0, 4.0, 8.0, 24.0h after the administration of blood from the orbital, heparin anticoagulation, centrifugation at 3000 rpm for 10min Plasma was then separated and stored at -80 ° C for testing. Take 30ul of rat plasma at each time point, add 200ul of internal standard solution (7.5ng / ml verapamil), mix by vortex for 1min, centrifuge at 4 ° C, 13000rpm for 10min, take 190ul of supernatant and perform LC-MS / MS (Shimadzu Corporation) lc-20A Technology Co., Ltd., API4000 +) analysis. The main pharmacokinetic parameters were analyzed using the non-compartment model of WinNonlin 6.3 software. The results are shown in Table 1.

Conclusion: The compounds of the present invention have good pharmacokinetic characteristics. In particular, the indexes of compounds 5 and 12 were significantly better than dabigatran etexilate.

Claims (9)

A compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R ^{1 is} selected from C _1-10 alkyl; R ^{2 is} selected from C _1-10 alkyl, said alkyl is optionally further substituted by 1 to 12 R ^2a ; R ^{2a is} selected from H, F, Cl, Br, Or I; provided that at least one R ^2a is F. The compound, stereoisomers or pharmaceutically acceptable salts thereof according to item 1 of the scope of the patent application, wherein: R ^{1 is} selected from C _1-6 alkyl; R ^{2 is} selected from C _1-8 alkyl; The alkyl group is optionally further substituted with 1 to 12 R ^2a . The compound, stereoisomers or pharmaceutically acceptable salts thereof according to item 2 of the scope of the patent application, wherein: R ^{2a is} each independently selected from H, F, Cl, or Br. The compound according to item 3 of the scope of patent application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures: The compound, stereoisomers, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 4 of the scope of the patent application, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, and sulfuric acid Salt, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, hydroxyl Acetate, salicylate, glucuronide, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonic acid Acid salt, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, ferulate or a combination thereof. A pharmaceutical composition containing a therapeutically effective dose of a compound according to any one of items 1 to 5 of the scope of patent application, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable An acceptable carrier or excipient. A compound according to any one of claims 1 to 5 and a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a composition according to claim 6 in the preparation of a therapeutic and thrombin Use in medicines related to inhibitors. The use according to item 7 of the scope of the patent application, wherein the thrombin inhibitor-related disease is selected from the group consisting of thromboembolic disease. The use according to item 8 of the scope of patent application, wherein the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolism.