TW201638080A

TW201638080A - Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof

Info

Publication number: TW201638080A
Application number: TW104127937A
Authority: TW
Inventors: yong-gang Wei; Yan Yu; Guan-Peng Qiu; Bo-Lin Lei
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2015-04-27
Filing date: 2015-08-26
Publication date: 2016-11-01
Also published as: TWI682928B

Abstract

A dabigatran carboalkoxy derivative as indicated in formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and a use thereof in preparing medications for preventing and treating thromboembolic diseases, all substituents being defined as in the description.

Description

達比加群烷酯衍生物及其製備方法和在藥學上的用途 Dabigadine alkyl ester derivative, preparation method thereof and use thereof in pharmacy

本發明關於一種達比加群烷酯衍生物及其立體異構體和藥學上可接受的鹽，以及在製備用於預防和治療血栓栓塞疾病的藥物中的用途。 The present invention relates to a dabigatran group alkyl ester derivative, and stereoisomers thereof and pharmaceutically acceptable salts thereof, and to the use of a medicament for the prevention and treatment of a thromboembolic disease.

目前，心血管疾病是導致人類死亡的主要原因之一，它的一個主要方面是血栓形成，血栓形成是由一系列複雜反應引起凝血而致。血液凝固是生物體的一種保護機制，借此可很快並且可靠地“密封”血管壁的缺損，因此可以避免失血或將其降到最低限度。維持正常止血作用，即出血和凝血平衡，受一個複雜機制的調控。不受調控的活化凝血系統或缺乏活化過程的抑制作用都可能導致多種疾病和併發症，例如靜脈血栓、深靜脈血栓、肺栓塞、動脈粥樣硬化、急性冠狀綜合症、腦血管疾病等。 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.

現已上市的口服抗血凝藥物主要有直接凝血酶抑制劑、Xa因子抑制劑、IX因子抑制劑、組織因子抑制劑和新型維生素K拮抗劑等。其中達比加群酯是一種口服的、選擇性的高效凝血酶抑制劑，臨床已證明能夠替代華法林(Warfarin)成為預防非瓣膜性心房纖維性顫動患者中風和全身栓塞及替代依諾肝素鈉成為預防主要整形術後患者靜脈血栓栓塞事件的首選用藥。 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 proven to replace warfarin as a preventer for stroke and systemic embolism and replacement enoxaparin in patients with non-valvular atrial fibrillation. Sodium is the drug of choice for the prevention of venous thromboembolic events in major postoperative patients.

達比加群酯於2008年上市，被用於預防非瓣膜病性房顫患者的中風或全身性栓塞、深部靜脈血栓(DVT)或肺血管阻塞及其復發。它是達比加群分子中的游離羧基和脒基分別成酯後得到的雙前體藥物，解決了因達比加群強鹼性脒基存在而不能口服的問題，提高了口服生物利用度。達比加群酯口服後，從胃腸道吸收，然後快速在體內轉化為達比加群，從而發揮抗凝血作用。但是達比加群雙酯的口服生物利用度較低，僅有3~7%，所以藥用劑量較高，增加了胃腸道副作用。 Dabigatran etexilate was marketed in 2008 and is used to prevent stroke or systemic embolism, deep vein thrombosis (DVT) or pulmonary vascular occlusion in patients with non-valvular atrial fibrillation. relapse. 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.

目前已有不少文獻報導了達比加群的前體藥物。如WO09837075和WO2004014894專利公開了達比加群及其類似物，以及其烷基羧酸酯、被磺醯基取代的羧酸酯或磺醯基氨基等前體藥物；CN102875533和CN102838588專利報道了達比加群的阿魏酸或川弓嗪前體藥物，並具有一定的抗凝血作用；CN200910211164、CN200910211165和CN201210158600等專利公開了達比加群的碳酸酯、羧酸酯等前體藥物。 A number of literatures have reported prodrugs of dabigatran. Patents such as WO09837075 and WO2004014894 disclose dabigatran and analogs thereof, as well as prodrugs thereof such as alkyl carboxylates, sulfonyl substituted carboxylic acid esters or sulfonylamino groups; CN102875533 and CN102838588 patents have been reported Bijia 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.

本發明的目的在於解決達比加群因其強鹼性而不能口服的問題，提供一種新穎有效的具有良好穩定性、溶解度、生物利用度以及低劑量、低毒副作用或長效的可口服的達比加群前藥。 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 oral administration with good stability, solubility, bioavailability and low dose, low toxic side effect or long-acting effect. Dabigatran group of prodrugs.

本發明提供一種通式(I)所示的化合物及其立體異構體和藥學上可以接受的鹽，其中： The present invention provides a compound represented by the formula (I), and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein:

X₁和X₂各自獨立的選自O或S；R¹選自-(CR^1aR^1bO)_n-(CR^1aR^1bCR^1cR^1dO)_mR^1e；R²選自C_1-10烷基或-(CR^2aR^2bCR^2cR^2dO)_mR^2e，所述烷基任選進一步被0至12個選自H、F、Cl、Br、I、C_1-4烷基或C_1-4烷氧基的取代基所取代；R^1a、R^1b、R^1c、R^1d、R^2a、R^2b、R^2c和R^2d各自獨立的選自H、F、Cl、Br、I、C_1-4烷基或C_1-4烷氧基；R^1e和R^2e各自獨立的選自H、C_1-4烷基、-C(=O)C_1-4烷基、 -C(=O)C_1-4烷氧基或； R^1f各自獨立的選自氨基酸側鏈基團；R^1g和R^1h各自獨立的選自H或氨基保護基；n選自0或1；m選自1、2、3、4、5或6。 X ₁ and X ₂ are each independently selected from O or S; R ^{1 is} selected from -(CR ^1a R ^1b O) _n -(CR ^1a R ^1b CR ^1c R ^1d O) _m R ^1e ; R ^{2 is} selected from C _{1- 10} alkyl or -(CR ^2a R ^2b CR ^2c R ^2d O) _m R ^2e , the alkyl group optionally further from 0 to 12 selected from H, F, Cl, Br, I, C _1-4 alkyl Or a substituent of a C _1-4 alkoxy group; R ^1a , R ^1b , R ^1c , R ^1d , R ^2a , R ^2b , R ^2c and R ^2d are each independently selected from the group consisting of H, F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy; R ^1e and R ^2e are each independently selected from H, C _1-4 alkyl, -C(=O)C _1-4 alkyl, - C(=O)C _1-4 alkoxy or ; R ^1f are each independently selected from the group consisting of amino acid side chain groups; R ^1g and R ^1h are each independently selected from H or an amino protecting group; n is selected from 0 or 1; m is selected from 1, 2, 3, 4, 5 or 6.

本發明較佳方案，一種通式(I)所示的化合物及其立體異構體和藥學上可以接受的鹽，其中：R^1f各自獨立的選自氨基酸側鏈基團；所述氨基酸選自：甘氨酸、丙氨酸、亮氨酸、異亮氨酸、結氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸、絲氨酸、穀氨醯胺、蘇氨酸、半胱氨酸、組氨酸、天冬醯胺、酪氨酸、天冬氨酸、谷氨酸、萘胺酸或精氨酸；R^1g和R^1h各自獨立的選自H或氨基保護基；所述氨基保護基選自苄氧羰基、第三丁氧羰基、芴甲氧羰基、烯丙氧羰基、三甲基矽乙氧羰基、甲氧羰基或乙氧羰基。 A preferred embodiment of the invention, a compound of the formula (I), and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein: R ^1f are each independently selected from an amino acid side chain group; and the amino acid is selected from the group consisting of : glycine, alanine, leucine, isoleucine, tyrosine, valine, phenylalanine, methionine, tryptophan, serine, glutamine, threonine, half Cystine, histidine, aspartame, tyrosine, aspartic acid, glutamic acid, naphthyl acid or arginine; R ^1g and R ^1h are each independently selected from H or an amino protecting group; The amino protecting group is selected from the group consisting of benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsulfonium ethoxycarbonyl, methoxycarbonyl or ethoxycarbonyl.

本發明較佳方案，一種通式(I)所示的化合物及其立體異構體和藥學上可以接受的鹽，其中：R¹選自-(CR^1aR^1bO)_n-(CR^1aR^1bCR^1cR^1dO)_mR^1e；R²選自C_1-8烷基或-(CR^2aR^2bCR^2cR^2dO)_mR^2e，所述烷基任選進一步被0至12個選自H、F、Cl或Br的取代基所取代；R^1a、R^1b、R^1c、R^1d、R^2a、R^2b、R^2c和R^2d各自獨立的選自H、F、Cl、Br、I、甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基；R^1e和R^2e各自獨立的選自H、甲基、乙基、-C(=O)OCH(CH₃)₂ 或； R^1f各自獨立的選自氨基酸側鏈基團，所述氨基酸選自甘氨酸、丙氨酸、亮氨酸、苯丙氨酸或結氨酸；R^1g和R^1h各自獨立的選自H或氨基保護基，所述氨基保護基選自芾氧羰基或第三丁氧羰基；n選自0或1；m選自1、2或3。 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 -(CR ^1a R ^1b O) _n -(CR ^1a R ^1b CR ^1c R ^1d O) _m R ^1e ; R ^{2 is} selected from C _1-8 alkyl or -(CR ^2a R ^2b CR ^2c R ^2d O) _m R ^2e , the alkyl group optionally further being from 0 to 12 Substituted with a substituent selected from H, F, Cl or Br; R ^1a , R ^1b , R ^1c , R ^1d , R ^2a , R ^2b , R ^2c and R ^2d are each independently selected from H, F, Cl, Br , I, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy; R ^1e and R ^2e are each independently selected from H, methyl, ethyl, -C(=O) OCH(CH ₃ ) ₂ or ; R ^1f are each independently selected from the group consisting of amino acid side chain groups selected from glycine, alanine, leucine, phenylalanine or determinine; R ^1g and R ^1h are each independently selected from H or An amino protecting group selected from the group consisting of a fluorenyloxycarbonyl group or a third butoxycarbonyl group; n is selected from 0 or 1; m is selected from 1, 2 or 3.

本發明較佳方案，一種通式(I)所示的化合物及其立體異構體和藥學上可以接受的鹽，其中該化合物選自如下結構之一： A preferred embodiment of the invention is 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:

本發明較佳方案，根據本發明所述化合物及其立體異構體和藥學上可接受的鹽，其中所述的鹽選自鹽酸鹽、氫溴酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、乙酸鹽、馬來酸鹽、琥珀酸鹽、扁桃酸鹽、富馬酸鹽、丙二酸鹽、蘋果酸鹽、2-羥基丙酸鹽、草酸鹽、羥乙酸鹽、水楊酸鹽、葡萄糖醛酸鹽、半乳糖醛酸鹽、枸櫞酸鹽、酒石酸鹽、門冬氨酸鹽、谷氨酸鹽、苯甲酸鹽、肉桂酸鹽、對甲苯磺酸鹽、苯磺酸鹽、甲磺酸鹽、乙磺酸鹽、三氟甲磺酸鹽、阿魏酸鹽或其組合。 Preferred according to the invention, the compound according to the invention and its stereoisomers and pharmaceutically acceptable salts, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate , acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate Glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluene An acid salt, a besylate salt, a methanesulfonate salt, an ethanesulfonate salt, a triflate salt, a ferulic acid salt or a combination thereof.

本發明進一步提供一種藥物組合物，所述藥物組合物含有治療有效劑量的本發明化合物或其立體異構體或藥學上可接受的鹽，以及藥學上可接受的載體或者賦形劑。 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.

本發明進一步提供一種前面任意所述的化合物及其立體異構體和藥學上可接受的鹽，在製備治療與凝血酶抑制劑相關疾病藥物中的用途。 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.

本發明還提供一種前面所述的藥物組合物在製備治療與凝血酶抑制劑相關疾病藥物中的用途。 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.

本發明較佳方案，其中所述的與凝血酶抑制劑相關疾病選自血栓栓塞疾病。 In a preferred embodiment of the invention, the thrombin-related disease is selected from the group consisting of thromboembolic diseases.

本發明較佳方案，其中所述的血栓栓塞疾病選自靜脈血栓和動脈栓塞。 In a preferred embodiment of the invention, the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolization.

本發明進一步提供一種治療與凝血酶抑制劑相關疾病的方法，其中所述方法包括給藥本發明所述的化合物或其立體異構體、或藥學上可接受的鹽，或本發明所述的組合物。 The invention further provides a method of treating a disease associated with a thrombin inhibitor, wherein the method comprises administering a compound of the invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a combination.

氨基酸選自天然或可藥用氨基酸，較佳為甘氨酸、丙氨酸、亮氨酸、異亮氨酸、結氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸、絲氨酸、穀氨醯胺、蘇氨酸、半胱氨酸、組氨酸、天冬醯胺、酪氨酸、天冬氨酸、谷氨酸、萘胺酸或精氨酸，進一步較佳為甘氨酸、丙氨酸、亮氨酸、苯丙氨酸、天冬醯胺或精氨酸，更較佳為甘氨酸、丙氨酸或苯丙氨酸。 The amino acid is selected from natural or pharmaceutically acceptable amino acids, preferably glycine, alanine, leucine, isoleucine, tyrosine, valine, phenylalanine, methionine, color ammonia Acid, serine, glutamine, threonine, cysteine, histidine, aspartame, tyrosine, aspartic acid, glutamic acid, naphthyl acid or arginine, further Preferably, it is glycine, alanine, leucine, phenylalanine, aspartame or arginine, more preferably glycine, alanine or phenylalanine.

氨基保護基主要包括烷基羰基類、醯基類、烷基類。烷基羰基類包括但不限於苄氧羰基、第三丁氧羰基、芴甲氧羰基、烯丙氧羰基、三甲基矽乙氧羰基或甲氧羰基或乙氧羰基；醯基類包括但不限於鄰苯二甲醯基、對甲苯磺醯基、三氟乙醯基、鄰硝基苯磺醯基、對硝基苯磺醯基、特戊醯基或苯甲醯基；烷基類包括但不限於三苯基甲基、2，4-二甲氧基苄基、對甲氧基苄基或苄基。 The amino protecting group mainly includes alkylcarbonyl groups, mercapto groups, and alkyl groups. Alkylcarbonyls include, but are not limited to, benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsulfonium ethoxycarbonyl or methoxycarbonyl or ethoxycarbonyl; sulfhydryl groups include but not Restricted to o-phthalic acid, p-toluenesulfonyl, trifluoroethyl, o-nitrophenylsulfonyl, p-nitrophenylsulfonyl, pentyl or benzhydryl; alkyl includes However, it is not limited to triphenylmethyl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl.

除非有相反的陳述，在說明書和申請專利範圍中使用的術語具有下述含義。 Unless otherwise stated, the terms used in the specification and claims have the following meanings.

本發明所述基團和化合物中所關於的碳、氫、氧、硫、氮或鹵素均包括它們的同位素，及本發明所述基團和化合物中所關於的碳、氫、氧、硫、氮或鹵素任選進一步被一個或多個它們對應的同位素所替代，其中碳的同位素包括¹²C、¹³C和¹⁴C，氫的同位素包括氕(H)、氘(D，又稱為重氫)、氚(T，又稱為超重氫)，氧的同位素包括¹⁶O、¹⁷O和¹⁸O，硫的同位素包括³²S、³³S、³⁴S和³⁶S，氮的同位素包括¹⁴N和¹⁵N，氟的同位素¹⁹F，氯的同位素包括³⁵Cl和³⁷Cl，溴的同位素包括⁷⁹Br和⁸¹Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the related groups and compounds of the present invention. The nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, and the hydrogen isotopes include ruthenium (H), ruthenium (D, also known as heavy hydrogen) , 氚 (T, also known as super heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes including ¹⁴ N and ¹⁵ N The fluorine isotope ¹⁹ F, the chlorine isotope includes ³⁵ Cl and ³⁷ Cl, and the bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

“烷基”是指直鏈和支鏈的飽和脂肪族烴基團，主鏈包括1至20個碳原子，較佳為1至12個碳原子，進一步較佳為1至8個碳原子，更佳為1至6個碳原子，再進一步較佳為1至4個碳原子的直鏈與支鏈基團，最佳為1至2個碳原子；烷基的實例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,2-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基和正癸基；烷基可以是取代的或未取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，取代基較佳為1至5個選自F、Cl、Br、I、烷基、環烷基、烷氧基、鹵代烷基、硫醇、羥基、硝基、巰基、氨基、氰基、異氰基、芳基、雜芳基、雜環基、橋環基、螺環基、並環基、羥基烷基=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或矽烷基等。 "Alkyl" means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 a carbon atom, more preferably 1 to 6 carbon atoms, still more preferably a linear or branched chain group of 1 to 4 carbon atoms, most preferably 1 to 2 carbon atoms; examples of the alkyl group include but not Limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-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, 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-methyl Hexyl, 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 - B Amyl, n-decyl, 2-methyl-2-ethylhexyl and n-decyl; alkyl may be substituted or unsubstituted, when substituted, the substituent may be substituted at any available point of attachment Preferably, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, iso Cyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclo, hydroxyalkyl = O, carbonyl, aldehyde, carboxylic acid, aryl aryl thio, thiocarbonyl Or a decyl group or the like.

“烷氧基”是指-O-烷基，其中烷基如本文上述定義。烷氧基可以是取代的或未取代的，烷氧基實施例包括但不限於甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第三丁氧基、第二丁氧基、正戊氧基和正己氧基；當被取代時，取代基較佳為1至5個選自F、Cl、Br、I、烷基、環烷基、烷氧基、鹵代烷基、硫醇、羥基、硝基、巰基、氨基、氰基、異氰基、芳基、雜芳基、雜環基、橋環基、螺環基、並環基、羥基烷基、=O、羰基、醛、羧酸、羧酸酯芳基硫基、硫代羰基或矽烷基等。 "Alkoxy" means an -O-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Tributoxy, second butoxy, n-pentyloxy and n-hexyloxy; when substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl , alkoxy, haloalkyl, thiol, hydroxy, nitro, fluorenyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, A hydroxyalkyl group, an OX group, a carbonyl group, an aldehyde, a carboxylic acid, a carboxylate arylthio group, a thiocarbonyl group or a decyl group.

“氨基酸的側鏈基團”，氨基酸是指含有氨基和羧基的一類有機化合物的通稱，其通式結構為，所述的“氨基酸的側鏈基團”是指此處的L基團，非限定實施例包括但不限於甘氨酸的側鏈基團為H、丙氨酸的側鏈基團為甲基、苯丙氨酸的側鏈基團為苄基、纈氨酸的側鏈基團為異丙基等。 "A side chain group of an amino acid", an amino acid refers to a general term for a class of organic compounds containing an amino group and a carboxyl group, and has a general structure of The "side chain group of an amino acid" refers to the L group herein, and the non-limiting examples include, but are not limited to, the side chain group of glycine is H, the side chain group of alanine is methyl, The side chain group of phenylalanine is a benzyl group, and a side chain group of valine is an isopropyl group or the like.

“任選”或“任選地”是指隨後所描述的事件或環境可以但不必須發生，該說明包括該事件或環境發生或不發生的場合，如：“任選被F取代的烷基”指烷基可以但不必須被F取代，說明包括烷基被F取代的情形和烷基不被F取代的情形。 "Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur, such as: "Alkyl optionally substituted by F" "Alkyl can be, but is not necessarily, substituted by F, and is meant to include the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

“取代”是指基團中一個或多個氫原子被其它基團取代的情形，如果所述的基團被氫原子取代，形成的基團與被氫原子取代的基團相同。基團被取代的情形，例如氨基、C_1-4烷基、C_1-4烷氧基、C_3-6碳環、3至6元雜環任選進一步被0至4個選自H、F、Cl、Br、I、羥基、氰基、氨基、C_1-4烷基或C_1-4烷氧基的取代基所取代，形成的基團包括但不限於甲基、氯甲基、三氯甲基、羥基甲基、-CH₂OCH₃、-CH₂SH、-CH₂CH₂CN、-CH₂NH₂、-NHOH、-NHCH₃、-OCH₂Cl、-OCH₂OCH₂CH₃、-OCH₂CH₂NH₂、-OCH₂CH₂SH、-OCH₂CH₂OH、1-羥基環丙基、2-羥基環丙基、2-氨基環丙基、4-甲基呋喃基、2-羥基苯基、4-氨基苯基或苯基。 "Substitution" refers to the case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom. Where the group is substituted, for example, amino, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic, 3 to 6 membered heterocyclic ring, optionally further from 0 to 4 selected from H, Substituted by a substituent of F, Cl, Br, I, hydroxy, cyano, amino, C _1-4 alkyl or C _1-4 alkoxy, the groups formed include, but are not limited to, methyl, chloromethyl, 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-methyl Furanyl, 2-hydroxyphenyl, 4-aminophenyl or phenyl.

“取代或未取代的”是指基團可以被取代或不被取代的情形，若在本發明中沒有指出基團可以被取代，則表示該基團為未取代的情形。 "Substituted or unsubstituted" refers to a situation in which a group may be substituted or unsubstituted, and if it is not indicated in the present invention that a group may be substituted, it means that the group is unsubstituted.

“作為選擇”是指“作為選擇”之後的方案與“作為選擇”之前的方案為並列關係，而不是在前方案中的進一步選擇情形。 “As a choice” means that the scheme after “as a choice” is a side-by-side relationship with the scheme before “as a choice” rather than a further selection in the previous scheme.

“藥學上可接受的鹽”或“其藥學上可接受的鹽”指的是保持游離酸或游離鹼的生物有效性和特性，且所述的游離酸通過與無毒的無機鹼或有機鹼，或所述的游離酸通過與無毒的無機酸或有機酸反應獲得的那些鹽，包括鹼金屬鹽，如鈉鹽、鉀鹽、鋰鹽等；鹼土金屬鹽，如鈣鹽、鎂鹽等；其他金屬鹽，如鐵鹽、銅鹽、鈷鹽；有機鹼鹽，如銨鹽、三乙胺鹽、吡啶鹽、甲基吡啶鹽、2,6-二甲基吡啶鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、環己胺鹽、乙二胺鹽、胍鹽、異丙基胺鹽、三甲基胺鹽、三丙基胺鹽、三乙醇胺鹽、二乙醇胺鹽、乙醇胺鹽、二甲基乙醇胺鹽、二環己基胺鹽、咖啡鹼鹽、普魯卡因鹽、膽鹼鹽、甜菜鹼鹽、苯明青黴素鹽、葡萄糖胺鹽、N-甲基葡糖胺鹽、可可鹼鹽、氨丁三醇鹽、嘌呤鹽、呱嗪鹽、嗎啉鹽、呱啶鹽、N-乙基呱啶鹽、四甲基胺鹽、二苄基胺鹽和苯基甘氨酸烷基酯鹽；氫鹵酸鹽，如氫氟酸鹽、鹽酸鹽、氫碘酸鹽、氫溴酸鹽；無機酸鹽，如硝酸鹽、硫酸鹽、高氯酸鹽、磷酸鹽；低級烷磺酸鹽，如甲磺酸鹽、三氟甲磺酸鹽、乙磺酸鹽；芳基磺酸鹽，如苯磺酸鹽、對甲苯磺酸鹽；有機酸鹽，如蟻酸鹽、富馬酸鹽、甲酸鹽、三氟乙酸鹽、糠酸鹽、葡萄糖酸鹽、谷氨酸鹽、乙醇酸鹽、羥乙磺酸鹽、乳酸鹽、馬來酸鹽、蘋果酸鹽、扁桃酸鹽、黏液酸鹽、雙羥萘酸鹽、泛酸鹽、硬脂酸鹽、琥珀酸鹽、磺胺酸鹽、酒石酸鹽、丙二酸鹽、2-羥基丙酸鹽、檸檬酸鹽、水楊酸鹽、草酸鹽、羥乙酸鹽、葡萄糖醛酸鹽、半乳糖醛酸鹽、枸櫞酸鹽、賴氨酸鹽、精氨酸鹽、門冬氨酸鹽或肉桂酸鹽。 "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed and non-toxic. An inorganic base or an organic base, or a salt obtained by reacting the free acid with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts such as calcium Salt, magnesium salt, etc.; other metal salts such as iron salts, copper salts, cobalt salts; organic alkali salts such as ammonium salts, triethylamine salts, pyridinium salts, methylpyridine salts, 2,6-dimethylpyridine salts , ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, sulfonium salt, isopropylamine salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt , ethanolamine salt, dimethylethanolamine salt, dicyclohexylamine salt, caffeine salt, procaine salt, choline salt, betaine salt, phenicillin salt, glucosamine salt, N-methylglucamine salt , theobromine salt, tromethamine salt, sulfonium salt, oxazine salt, morpholine salt, acridine salt, N-ethyl acridine salt, tetramethylamine salt, dibenzylamine salt and phenylglycine alkane Base salt; hydrohalide, such as hydrofluoride, hydrochloride, hydroiodide, hydrobromide; inorganic acid salt, such as nitrate, sulfate Perchlorate, phosphate; lower alkane sulfonate, such as methanesulfonate, triflate, ethanesulfonate; aryl sulfonate, such as besylate, p-toluenesulfonate; Organic acid salts such as formic acid salts, fumarates, formates, trifluoroacetates, citrates, gluconates, glutamates, glycolates, isethionates, lactates, horses Acidate, malate, mandelate, mucate, pamoate, pantothenate, stearate, succinate, sulfonate, tartrate, malonate, 2-hydroxyl Propionate, citrate, salicylate, oxalate, glycolate, glucuronide, galacturonate, citrate, lysine, arginine, aspartame Acid or cinnamate.

合成方法 resolve resolution

方法一： method one:

X₂為O；R²為正己基； R¹、X₁與前面通式(I)所述定義一致； X ₂ is O; R ² is n-hexyl; R ¹ and X ₁ are the same as defined in the above formula (I);

方法二： Method Two:

R¹、R²、X₁、X₂與前面通式(I)所述定義一致。 R ¹ , R ² , X ₁ and X _{2 are} identical to the definitions of the above formula (I).

以下結合附圖及實施例詳細說明本發明的技術方案，但本發明的保護範圍包括但是不限於此。 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.

化合物的結構是通過核磁共振(NMR)或(和)質譜(MS)來確定的。NMR位移(δ)以10^-6(ppm)的單位給出。NMR的測定是用(Bruker Avance III 400和Bruker Avance 300)核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d6)，氘代氯仿(CDCl₃)，氘代甲醇(CD₃OD)，內標為四甲基矽烷(TMS)。 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 hydrazine (DMSO-d6), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD). The internal standard is tetramethyl decane (TMS).

MS的測定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。 The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

HPLC的測定使用安捷倫1260DAD高壓液相色譜儀(Zorbax SB-C18 100×4.6mm)。 The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.15mm~0.20mm，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。 The thin layer chromatography gelatin plate uses Yantai Huanghai HSGF254 or Qingdao GF254 gelatin plate. The specification of the 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.

管柱層析一般使用煙臺黃海矽膠200~300目矽膠為載體。 Pipe column chromatography generally uses Yantai Huanghai Tanji 200~300 mesh silicone as carrier.

本發明的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買於泰坦科技、安耐吉化學、上海德默、成都科龍化工、韶遠化學科技、百靈威科技等公司。 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, Anike Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.

氮氣氣氛是指反應瓶連接一個約1L容積的氮氣氣球。 The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.

氫氣氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

氫化反應通常抽真空，充入氫氣，反復操作3次。 The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

實施例中無特殊說明，反應在氮氣氣氛下進行。 Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.

實施例中無特殊說明，溶液是指水溶液。 Unless otherwise stated in the examples, the solution means an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫。 There is no particular description in the examples, and the reaction temperature is room temperature.

室溫為最適宜的反應溫度，為20℃~30℃。 The optimum reaction temperature at room temperature is 20 ° C to 30 ° C.

中間體1 Intermediate 1

3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中間體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 3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid

第一步：3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中間體1) First step: 3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazol-5-carbonyl]-(2-pyridyl Amino]propionic acid (intermediate 1)

將3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸乙酯(1a)(63g,100mmol)加入到乙醇(600mL)和水(300mL)的混合溶劑中，加入氫氧化鈉(8g,200mmol)，室溫下攪拌半個小時，至反應液澄清。濃縮反應液，旋蒸掉大部分乙醇，加入水(200mL)，用10%的檸檬酸水溶液調節pH至4~5，大量黏稠狀固體析出，過濾，將固體轉移入反應瓶中，加入甲醇(300mL)，加熱至固體溶解，繼續攪拌至固體呈顆粒狀，冷卻至零度，更多產品析出，過濾並乾燥，得到白色固體狀的標題化合物3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中間體1)(50g，產率83%)。 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 and stirred at room temperature for half an hour until the reaction liquid was clarified. . The reaction solution was concentrated, and most of the ethanol was distilled off, water (200 mL) was added, and the pH was adjusted to 4 to 5 with a 10% aqueous citric acid solution. A large amount of a viscous solid was precipitated, filtered, and the solid was transferred to a reaction flask, and methanol was added thereto. 300 mL), heating until the solids are dissolved, stirring is continued until the solids are in the form of granules, which are cooled to zero, 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]。 LCMS m/z = 600.2 [M + 1].

¹H 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(m,2H),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,2H),1.58(dd,2H),1.29(d,6H),0.87(t,3H)。 ^{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 (m, 2H ), 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, 2H), 1.58 (dd, 2H), 1.29 (d, 6H), 0.87 (t, 3H).

實施例1 Example 1

(2R)-2-甲氧基丙基3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物1) (2R)-2-methoxypropyl 3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl] -(2-pyridyl)amino]propionate (Compound 1)

(2R)-2-methoxypropyl (2R)-2-methoxypropyl

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

室溫下在3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中間體1)(1.00g,1.67mmol)的二甲基甲醯胺(15mL)溶液中加入(R)-2-甲氧基-1-丙醇(1A)(0.226mg,2.505mmol)、1-乙基-(3-二甲基氨基丙基)碳二亞胺鹽酸鹽(0.832g,4.34mmol)和4-二甲氨基吡啶(122mg,1.00mmol)，室溫反應15小時。向反應液中加入水(30mL)，用乙酸乙酯萃取(50mL×3)，合併有機相，有機相用水溶液洗滌(30mL×2)，並用無水硫酸鈉乾燥，濃縮，殘留物用矽膠柱色譜分離純化(二氯甲烷：甲醇(v/v)=50：1~30：1)得到標題化合物(2R)-2-甲氧基丙基3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物1)，白色固體，(0.5g，產率44.64%)。 3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) at room temperature Add (R)-2-methoxy-1-propanol (1A) (0.226 mg) to a solution of amino]propionic acid (Intermediate 1) (1.00 g, 1.67 mmol) in dimethylformamide (15 mL) , 2.505 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.832 g, 4.34 mmol) and 4-dimethylaminopyridine (122 mg, 1.00 mmol), room temperature Reaction for 15 hours. Water (30 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL×3), EtOAc (EtOAc) /v)=50:1~30:1) The title compound (2R)-2-methoxypropyl 3-[[2-[[4-[N.-hexyloxycarbonylmethylhydrazide]aniline]methyl 1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate (Compound 1), white solid (0.5 g, yield 44.64%).

LCMS m/z=672.34[M+1]。 LCMS m/z =672.34 [M+1].

¹H NMR(400MHz,CDCl₃)δ 8.41(d,1H),7.76(d,2H),7.71(s,1H),7.32(dd,2H),7.12(d,1H),6.98(dd,1H),6.75-6.62(m,3H),5.34(s,1H),4.50(s,2H),4.43(t,2H),4.14(t,2H),4.02(dd,2H),3.72(d,3H),3.57-3.49(m,1H),3.36(s,2H),2.85(dd,2H),1.72(m,2H),1.40(dd,2H),1.31(dd,2H),1.25(s,3H),1.15(d,3H),0.89(dd,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 8.41 (d, 1H), 7.76 (d, 2H), 7.71 (s, 1H), 7.32 (dd, 2H), 7.12 (d, 1H), 6.98 (dd, 1H ), 6.75-6.62 (m, 3H), 5.34 (s, 1H), 4.50 (s, 2H), 4.43 (t, 2H), 4.14 (t, 2H), 4.02 (dd, 2H), 3.72 (d, 3H), 3.57-3.49 (m, 1H), 3.36 (s, 2H), 2.85 (dd, 2H), 1.72 (m, 2H), 1.40 (dd, 2H), 1.31 (dd, 2H), 1.25 (s) , 3H), 1.15 (d, 3H), 0.89 (dd, 3H).

實施例2 Example 2

[(1R)-2-甲氧-1-甲基-乙基]3-[[2-[[4-[N`-己氧羰基甲眯基]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物2) [(1R)-2-methoxy-1-methyl-ethyl]3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]aniline]methyl]-1-methyl- Benzimidazole-5-carbonyl]-(2-pyridyl)amino]propionate (Compound 2)

[(1R)-2-methoxy-1-methyl-ethyl] [(1R)-2-methoxy-1-methyl-ethyl]

製備方法參見實施例1。 See Method 1 for the preparation method.

LCMS m/z=672.34.[M+1]。 LCMS m/z =672.34.[M+1].

¹H NMR(400MHz,CDCl₃)δ 8.41(dd,1H),7.73(d,2H),7.68(s,1H),7.32(m,1H),7.28(d,1H),7.25(s,1H),7.07-6.98(m,1H),6.71(d,1H),6.65(d,2H),5.37(s,1H),5.04(m,1H),4.55-4.33(m,4H),4.13(dd,2H),3.69(s,3H),3.44-3.36(m,2H),3.34(s,3H),2.81(t,2H),1.71(dd,2H),1.39(dd,2H),1.31(dd,4H),1.20(d,3H),0.88(t,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 8.41 (dd, 1H), 7.73 (d, 2H), 7.68 (s, 1H), 7.32 (m, 1H), 7.28 (d, 1H), 7.25 (s, 1H ), 7.07-6.98 (m, 1H), 6.71 (d, 1H), 6.65 (d, 2H), 5.37 (s, 1H), 5.04 (m, 1H), 4.55 - 4.33 (m, 4H), 4.13 ( Dd, 2H), 3.69 (s, 3H), 3.44 - 3.36 (m, 2H), 3.34 (s, 3H), 2.81 (t, 2H), 1.71 (dd, 2H), 1.39 (dd, 2H), 1.31 (dd, 4H), 1.20 (d, 3H), 0.88 (t, 3H).

實施例3 Example 3

2-(2-甲氧基乙氧基)乙基3-[[2-[[4-[(Z)-N`-3-[[2-[[4-[(Z)-N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸脂(化合物3) 2-(2-methoxyethoxy)ethyl 3-[[2-[[4-[(Z)-N`-3-[[2-[[4-[(Z)-N`-) Hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate (Compound 3)

2-(2-methoxyethoxy)ethyl 2-(2-methoxyethoxy)ethyl

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

製備方法參見實施例1。 See Method 1 for the preparation method.

LCMS m/z=702.3[M+1]。 LCMS m/z = 702.3 [M + 1].

¹H NMR(400MHz,CDCl₃)δ 8.44-8.38(m,1H),7.77(d,2H),7.71(s,1H),7.36-7.29(m,2H),7.13(d,1H),6.98(dd,1H),6.71(t,3H),5.31(d,1H),4.50(d,2H),4.43(t,2H),4.17(m,4H),3.73(s,3H),3.71-3.66(m,2H),3.63(dd,2H),3.54(dd,2H),3.37(s, 3H),2.85(t,2H),1.77-1.67(m,2H),1.40(dd,2H),1.31(dd,4H),0.89(t,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 8.44-8.38 (m, 1H), 7.77 (d, 2H), 7.71 (s, 1H), 7.36-7.29 (m, 2H), 7.13 (d, 1H), 6.98 (dd, 1H), 6.71 (t, 3H), 5.31 (d, 1H), 4.50 (d, 2H), 4.43 (t, 2H), 4.17 (m, 4H), 3.73 (s, 3H), 3.71 3.66 (m, 2H), 3.63 (dd, 2H), 3.54 (dd, 2H), 3.37 (s, 3H), 2.85 (t, 2H), 1.77-1.67 (m, 2H), 1.40 (dd, 2H) , 1.31 (dd, 4H), 0.89 (t, 3H).

實施例4 Example 4

2-[3-[[2-[[4-[N'-己氧基羰基甲脒基]苯氨基]甲基]-1-甲基-苯並[d]咪唑-5-羰基]-(2-吡啶基)氨基)丙醯氧基)乙基(2S)-2-氨基-3-甲基丁酸酯(化合物4) 2-[3-[[2-[[4-[N'-Hexyloxycarbamoyl]phenylamino]methyl]-1-methyl-benzo[d]imidazole-5-carbonyl]-( 2-pyridyl)amino)propanoxy)ethyl(2S)-2-amino-3-methylbutyrate (Compound 4)

2-[3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoyloxy]ethyl(2S)-2-amino-3-methyl-butanoate 2-[3-[[2-[[4-[N`-hexoxycarbonylcarbamimidoyl]anilino]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoyloxy]ethyl(2S)-2 -amino-3-methyl-butanoate

製備方法參見實施例1。 See Method 1 for the preparation method.

¹H NMR(400MHz,CDCl₃)δ 8.41(dd,1H),7.74(d,2H),7.70(s,1H),7.37-7.27(m,2H),7.12(d,1H),6.99(m,1H),6.70(t,3H),5.47(s,1H),4.50(d,2H),4.42(t,2H),4.31(dd,2H),4.26(dd,2H),4.14(t,2H),3.71(s,3H),3.48(s,2H),3.32(d,1H),2.83(t,2H),2.08-1.98(m,1H),1.76-1.66(m,2H),1.45-1.36(m,2H),1.35-1.28(m,2H),0.96(d,3H),0.91-0.86(m,6H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 8.41 (dd, 1H), 7.74 (d, 2H), 7.70 (s, 1H), 7.37-7.27 (m, 2H), 7.12 (d, 1H), 6.99 (m , 1H), 6.70 (t, 3H), 5.47 (s, 1H), 4.50 (d, 2H), 4.42 (t, 2H), 4.31 (dd, 2H), 4.26 (dd, 2H), 4.14 (t, 2H), 3.71 (s, 3H), 3.48 (s, 2H), 3.32 (d, 1H), 2.83 (t, 2H), 2.08-1.98 (m, 1H), 1.76-1.66 (m, 2H), 1.45 - 1.36 (m, 2H), 1.35-1.28 (m, 2H), 0.96 (d, 3H), 0.91 - 0.86 (m, 6H).

實施例5 Example 5

2-(2-羥基乙氧基)乙基3-[[2-[[4-[(Z)-N`己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸脂(化合物5) 2-(2-Hydroxyethoxy)ethyl 3-[[2-[[4-[(Z)-N`hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole -5-carbonyl]-(2-pyridyl)amino]propionic acid ester (Compound 5)

2-(2-hydroxyethoxy)ethyl 2-(2-hydroxyethoxy)ethyl

製備方法參見實施例1。 See Method 1 for the preparation method.

LCMS m/z=688.3[M+1]。 LCMS m/z = 688.3 [M + 1].

¹H NMR(400MHz,CDCl₃)δ 8.40(dd,1H),7.77-7.68(m,3H),7.37-7.29(m,2H),7.11(d,1H),7.01-6.94(m,1H),6.73(d,1H),6.66(d,2H),5.43(s,1H),4.51-4.37(m,4H),4.27-4.19(m,2H),4.19-4.10(m,2H),3.78-3.64(m,7H),3.62-3.57(m,2H),2.83(t,2H),1.76-1.68(m,2H),1.40(dd,2H),1.36-1.28(m,4H),0.89(dd,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 8.40 (dd, 1H), 7.77-7.68 (m, 3H), 7.37-7.29 (m, 2H), 7.11 (d, 1H), 7.01-6.94 (m, 1H) , 6.73 (d, 1H), 6.66 (d, 2H), 5.43 (s, 1H), 4.51-4.37 (m, 4H), 4.27-4.19 (m, 2H), 4.19-4.10 (m, 2H), 3.78 -3.64 (m, 7H), 3.62-3.57 (m, 2H), 2.83 (t, 2H), 1.76-1.68 (m, 2H), 1.40 (dd, 2H), 1.36-1.28 (m, 4H), 0.89 (dd, 3H).

實施例6 Example 6

(S)-1-甲氧基丙-2-基3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙酸酯(化合物6) (S)-1-methoxypropan-2-yl 3-(2-(((4-(N'-((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1 -methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-methylamino)propionate (Compound 6)

(S)-1-methoxypropan-2-yl (S)-1-methoxypropan-2-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-((((((((()))))))))))))))))))))))))) -5-carboxamido)propanoate

室溫下在3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中間體1)(1.50g,2.50mmol)的二甲基甲醯胺(15mL)溶液中加入S-1-甲氧基-2-丙醇(0.450mg,4.99mmol)、1-乙基-(3-二甲基氨基丙基)碳二亞胺鹽酸鹽(0.90g,5.1mmol)和4-二甲氨基吡啶(185mg,1.51mmol)，室溫反應15小時。向反應液中加入水(30mL)，用二氯甲烷萃取(50mL×3)，合併有機相，有機相用飽和磷酸二氫鉀溶液洗滌(30mL×2)，無水硫酸鈉乾燥，濃縮，殘留物用矽膠柱色譜分離純化(二氯甲烷：甲醇(v/v)=100：1~30：1)得到標題化合物(S)-1-甲氧基丙-2-基3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙酸酯(化合物6)，橙紅色固體(0.400g，產率23.8%)。 3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) at room temperature To a solution of amino]propionic acid (Intermediate 1) (1.50 g, 2.50 mmol) in dimethylformamide (15 mL), 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.90 g, 5.1 mmol) and 4-dimethylaminopyridine (185 mg, 1.51 mmol) were reacted at room temperature for 15 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (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 Purification by gel column chromatography (dichloromethane:methanol (v/v) = 100:1 to 30:1) to give the title compound (S)-1-methoxypropan-2-yl 3-(2-(( (4-(N'-((hexyloxy)carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d] Imidazole-5-methylamino)propionate (Compound 6), orange-red solid (0.400 g, yield 23.8%).

LCMS m/z=672.3[M+1]。 LCMS m/z = 672.3 [M + 1].

¹H NMR(400MHz,DMSO)δ 9.01(s,1H),8.67(s,1H),8.39(dd,1H),7.80(d,2H),7.54(m,1H),7.47(d,1H),7.39(d,1H),7.16(dd,1H),7.12(dd,1H),6.98-6.86(m,2H),6.76(d,2H),4.90(m,1H),4.59(d,2H),4.22(t,2H),3.98(t,2H),3.76(s,3H),3.38- 3.27(m,4H),3.31(s,2H),3.23(s,3H),2.68(t,2H),1.58(m,2H),1.39-1.22(m,6H),1.07(d,3H),0.87(t,3H)。 ^{1 H NMR (400MHz, DMSO)} δ 9.01 (s, 1H), 8.67 (s, 1H), 8.39 (dd, 1H), 7.80 (d, 2H), 7.54 (m, 1H), 7.47 (d, 1H) , 7.39 (d, 1H), 7.16 (dd, 1H), 7.12 (dd, 1H), 6.98-6.86 (m, 2H), 6.76 (d, 2H), 4.90 (m, 1H), 4.59 (d, 2H) ), 4.22 (t, 2H), 3.98 (t, 2H), 3.76 (s, 3H), 3.38 - 3.27 (m, 4H), 3.31 (s, 2H), 3.23 (s, 3H), 2.68 (t, 2H), 1.58 (m, 2H), 1.39-1.22 (m, 6H), 1.07 (d, 3H), 0.87 (t, 3H).

實施例7 Example 7

[(2S)-2-甲氧基丙基]3-[[2-[[4-[N`-己氧羰基甲脒基]苯氨基]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物7) [(2S)-2-methoxypropyl]3-[[2-[[4-[N`-hexyloxycarbonylmethylindenyl]phenylamino]methyl]-1-methyl-benzimidazole- 5-carbonyl]-(2-pyridyl)amino]propionate (Compound 7)

[(2S)-2-methoxypropyl] [(2S)-2-methoxypropyl]

製備方法參見實施例1。 See Method 1 for the preparation method.

LCMS m/z=672.34[M+1]。 LCMS m/z =672.34 [M+1].

¹H NMR(400MHz,CDCl₃)δ 8.38(d,1H),7.67(d,3H),7.32(m,1H),7.23(dd,1H),7.04(d,1H),6.99-6.92(m,1H),6.70(d,1H),6.58(d,2H),5.61(s,1H),4.42(dd,4H),4.13(t,2H),4.01(m,2H),3.64(d,3H),3.56-3.45(m,1H),3.35(s,3H),2.84(t,2H),1.78-1.55(m,2H),1.46-1.34(m,2H),1.34-1.21(m,4H),1.14(d,3H),0.88(t,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 8.38 (d, 1H), 7.67 (d, 3H), 7.32 (m, 1H), 7.23 (dd, 1H), 7.04 (d, 1H), 6.99-6.92 (m , 1H), 6.70 (d, 1H), 6.58 (d, 2H), 5.61 (s, 1H), 4.42 (dd, 4H), 4.13 (t, 2H), 4.01 (m, 2H), 3.64 (d, 3H), 3.56-3.45 (m, 1H), 3.35 (s, 3H), 2.84 (t, 2H), 1.78-1.55 (m, 2H), 1.46-1.34 (m, 2H), 1.34-1.21 (m, 4H), 1.14 (d, 3H), 0.88 (t, 3H).

實施例8 Example 8

2-甲氧乙氧甲基3-[[2-[[4-[N`-己氧羰基甲脒基]苯氨基]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物8) 2-methoxyethoxymethyl 3-[[2-[[4-[N`-hexyloxycarbonylmethyl)phenylamino]methyl]-1-methyl-benzimidazole-5-carbonyl]- (2-pyridyl)amino]propionate (Compound 8)

2-methoxyethoxymethyl 2-methoxyethoxymethyl

製備方法參見實施例1。 See Method 1 for the preparation method.

LCMS m/z=688.34[M+1]。 LCMS m/z = 688.34 [M + 1].

¹H NMR(400MHz,CDCl₃)δ 8.40(dd,1H),7.72(d,2H),7.67(d,1H),7.32(m,1H),7.27-7.24(d,1H),7.06(d,1H),7.01-6.93(m,1H),6.70(d,1H),6.63(d,2H),5.39(s,1H),5.28(s,2H),4.43(dd,4H),4.12(t,2H),3.80-3.73(m,2H),3.68(s,3H),3.57-3.48(m,2H),3.36(s,3H),2.85(t,2H),1.70(dd,2H),1.39(dd,2H),1.30(dd,4H),0.88(dd,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 8.40 (dd, 1H), 7.72 (d, 2H), 7.67 (d, 1H), 7.32 (m, 1H), 7.27-7.24 (d, 1H), 7.06 (d , 1H), 7.01-6.93 (m, 1H), 6.70 (d, 1H), 6.63 (d, 2H), 5.39 (s, 1H), 5.28 (s, 2H), 4.43 (dd, 4H), 4.12 ( t, 2H), 3.80-3.73 (m, 2H), 3.68 (s, 3H), 3.57-3.48 (m, 2H), 3.36 (s, 3H), 2.85 (t, 2H), 1.70 (dd, 2H) , 1.39 (dd, 2H), 1.30 (dd, 4H), 0.88 (dd, 3H).

實施例9 Example 9

(S)-2-((3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙醯基)氧基)乙基2-((第三丁氧羰基)氨基)-3-苯基丙酸酯(化合物9) (S)-2-((3-(2-(((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N- (pyridin-2-yl)-1H-benzo[d]imidazol-5-carboxamidoamino)propanyl)oxy)ethyl 2-((t-butoxycarbonyl)amino)-3-phenylpropane Acid ester (compound 9)

(S)-2-((3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoyl)oxy)ethyl (S)-2-((3-(2-((((((())))))))))))))))))))))))) -1H-benzo[d]imidazole-5-carboxamido)propanoyl)oxy)ethyl

2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate

第一步：(S)-2-羥基乙基2-((第三丁氧羰基)氨基)-3-苯丙酸酯(9B) First step: (S)-2-hydroxyethyl 2-((t-butoxycarbonyl)amino)-3-phenylpropionate (9B)

(S)-2-hydroxyethyl (S)-2-hydroxyethyl

冰浴下在S-N-第三丁氧羰基苯丙氨酸(5.3g,20mmol)的二氯甲烷(150mL)溶液中加入乙二醇(5.0g,81mmol)、4-二甲氨基吡啶(0.50g,4mmol)和N,N’-二環己基碳二亞胺(4.3g,21mmol)，室溫反應10小時。向反應液中加入水(100mL)，用二氯甲烷萃取(100mL×2)，合併有機相，無水硫酸鈉乾燥，濃縮，殘留物用矽膠柱色譜分離純化(二氯甲烷：甲醇(v/v)=100：1~30：1)得到標題化合物(S)-2-羥基乙基2-((第三丁氧羰基)氨基)-3-苯丙酸酯(9B)，無色油狀物(5.0g，產率81.0%)。 Ethyl glycol (5.0 g, 81 mmol), 4-dimethylaminopyridine (0.50 g) was added to a solution of SN-t-butoxycarbonylphenylalanine (5.3 g, 20 mmol) in dichloromethane (150 mL). 4 mmol) and N,N'-dicyclohexylcarbodiimide (4.3 g, 21 mmol) were reacted at room temperature for 10 hours. Water (100 mL) was added to the reaction mixture, and the mixture was combined with methylene chloride (100 mL × 2). =100:1~30:1) The title compound (S)-2-hydroxyethyl 2-((t-butoxycarbonyl)amino)-3-phenylpropionate (9B) is obtained as a colorless oil. 5.0 g, yield 81.0%).

1H NMR(400MHz,CDCl3)δ 7.34-7.27(m,2H),7.25(dd,1H),7.19-7.17(m,2H),5.00(s,1H),4.53(d,1H),4.29-4.17(m,2H),3.72(m,2H),3.09(d,2H),1.45-1.37(m,9H)。 1H NMR (400MHz, CDCl3) δ 7.34-7.27 (m, 2H), 7.25 (dd, 1H), 7.19-7.17 (m, 2H), 5.00 (s, 1H), 4.53 (d, 1H), 4.29-4. (m, 2H), 3.72 (m, 2H), 3.09 (d, 2H), 1.45-1.37 (m, 9H).

第二步：(S)-2-((3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙醯基)氧基)乙基2-((第三丁氧羰基)氨基)-3-苯基丙酸酯(化合物9) The second step: (S)-2-((3-(2-(((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl --N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-carbamimidino)propanyl)oxy)ethyl 2-((t-butoxycarbonyl)amino)-3 -Phenylpropionate (Compound 9)

室溫下在3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中間體1)(3.0g,5.0mmol)的二甲基甲醯胺(15mL)溶液中加入(S)-2-羥基乙基2-((第三丁氧羰基)氨基)-3-苯丙酸酯(9B)(2.85g,9.21mmol)、1-乙基-(3-二甲基氨基丙基)碳二亞胺鹽酸鹽(1.80g,10.1mmol)和4-二甲氨基吡啶(370mg,3.03mmol)，室溫反應15小時。向反應液中加入水(30mL)，用二氯甲烷萃取(50mL×3)，合併有機相，有機相用飽和磷酸二氫鉀溶液洗滌(30mL×2)，無水硫酸鈉乾燥，濃縮，殘留物用矽膠柱色譜分離純化(二氯甲烷：甲醇(v/v)=100：1~30：1)得到標題化合物(S)-2-((3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙醯基)氧基)乙基2-((第三丁氧羰基)氨基)-3-苯基丙酸酯(化合物9)，棕色固體(2.00g，產率45.0%)。 3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) at room temperature Add (S)-2-hydroxyethyl 2-((t-butoxycarbonyl)amino group to a solution of amino]propionic acid (intermediate 1) (3.0 g, 5.0 mmol) in dimethylformamide (15 mL) --3-Phenylpropionate (9B) (2.85 g, 9.21 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.80 g, 10.1 mmol) and 4 -Dimethylaminopyridine (370 mg, 3.03 mmol) was reacted at room temperature for 15 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (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 (S)-2-((3-(2-(((4-(N))) -((hexyloxy)carbonyl)carbamido)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-formamidine Amino)propanyl)oxy)ethyl 2-((t-butoxycarbonyl)amino)-3-phenylpropanoate (Compound 9), brown solid (2.00 g, yield 45.0%).

LCMS m/z=446.4[M+2]/2。 LCMS m/z = 446.4 [M+2]/2.

¹H NMR(400MHz,DMSO)δ 9.07(s,1H),8.92-8.50(m,1H),8.38(dd,1H),7.79(d,2H),7.52(m,1H),7.47(d,1H),7.38(d,1H),7.29-7.15(m,7H),7.10(dd,1H),6.92(t,1H),6.88(d,1H),6.76(d,2H),4.59(d,2H),4.19(m,5H),4.13-4.05(m,2H),3.97(t,2H),3.75(s,3H),2.97(dd,1H),2.91-2.81(m,1H),2.71(dd,2H),1.57(dd,2H),1.39-1.20(m,15H),0.87(t,3H)。 ^{1 H NMR (400MHz, DMSO)} δ 9.07 (s, 1H), 8.92-8.50 (m, 1H), 8.38 (dd, 1H), 7.79 (d, 2H), 7.52 (m, 1H), 7.47 (d, 1H), 7.38 (d, 1H), 7.29-7.15 (m, 7H), 7.10 (dd, 1H), 6.92 (t, 1H), 6.88 (d, 1H), 6.76 (d, 2H), 4.59 (d , 2H), 4.19 (m, 5H), 4.13-4.05 (m, 2H), 3.97 (t, 2H), 3.75 (s, 3H), 2.97 (dd, 1H), 2.91-2.81 (m, 1H), 2.71 (dd, 2H), 1.57 (dd, 2H), 1.39-1.20 (m, 15H), 0.87 (t, 3H).

實施例10 Example 10

(S)-2-((3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙醯基)氧基)乙基-2-氨基-3-苯基丙酸酯(化合物10) (S)-2-((3-(2-(((hexyloxy))carbonyl)methyl)phenyl)amino)methyl)-1-methyl-N- (pyridin-2-yl)-1H-benzo[d]imidazol-5-methylamino)propenyl)oxy)ethyl-2-amino-3-phenylpropionate (Compound 10)

(S)-2-((3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoyl)oxy)ethyl-2-amino-3-phenylpropanoate (S)-2-((3-(2-((((((())))))))))))))))))))))))) -1H-benzo[d]imidazole-5-carboxamido)propanoyl)oxy)ethyl-2-amino-3-phenylpropanoate

冰浴下在(S)-2-((3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙醯基)氧基)乙基2-((第三丁氧羰基)氨基)-3-苯基丙酸酯(化合物9) (700mg,0.786mmol)的二氯甲烷(10mL)溶液中加入三氟乙酸(5.0mL)，室溫反應1小時。減壓除去溶劑，向反應液中加入水(10mL)，用飽和碳酸氫鈉水溶液調pH到13，二氯甲烷萃取(50mL×3)，合併有機相，無水硫酸鈉乾燥，濃縮，殘留物用矽膠柱色譜分離純化(二氯甲烷：甲醇(v/v)=100：2~30：1)得到標題化合物(S)-2-((3-(2-(((4-(N'-((己氧基)羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙醯基)氧基)乙基-2-氨基-3-苯基丙酸酯(化合物10)，黃色固體(580mg，產率93.3%)。 (S)-2-((3-(2-(((hexyloxy))carbonyl)methyl)amino)methyl)-1-yl) --N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-carbamimidino)propanyl)oxy)ethyl 2-((t-butoxycarbonyl)amino)-3 -Phenylpropionate (Compound 9) Trifluoroacetic acid (5.0 mL) was added to a solution of (700 mg, 0.786 mmol) in dichloromethane (10 mL). The solvent was removed under reduced pressure. Water (3 mL) was evaporated, evaporated, evaporated, evaporated. The title compound (S)-2-((3-(2-(((4-(N-) ((hexyloxy)carbonyl)methyl hydrazino)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido Propionyl)oxy)ethyl-2-amino-3-phenylpropanoate (Compound 10), yellow solid (580 mg, yield 93.3%).

LCMS m/z=791.2[M+1]。 LCMS m/z = 791.2 [M + 1].

¹H NMR(400MHz,DMSO)δ 9.09(s,1H),8.67(s,1H),8.38(m,1H),7.80(d,2H),7.53(m,1H),7.48(d,1H),7.39(d,1H),7.22(dd,2H),7.19-7.13(m,4H),7.11(m,1H),6.93(t,1H),6.89(d,1H),6.77(d,2H),4.59(d,2H),4.23(t,2H),4.16(dd,2H),4.14-4.04(m,2H),3.98(t,2H),3.76(s,3H),3.57(t,1H),2.91-2.81(m,1H),2.77(dd,1H),2.71(dd,2H),1.75(s,2H),1.57(dd,2H),1.38-1.25(m,6H),0.87(t,3H)。 ^{1 H NMR (400MHz, DMSO)} δ 9.09 (s, 1H), 8.67 (s, 1H), 8.38 (m, 1H), 7.80 (d, 2H), 7.53 (m, 1H), 7.48 (d, 1H) , 7.39 (d, 1H), 7.22 (dd, 2H), 7.19-7.13 (m, 4H), 7.11 (m, 1H), 6.93 (t, 1H), 6.89 (d, 1H), 6.77 (d, 2H) ), 4.59 (d, 2H), 4.23 (t, 2H), 4.16 (dd, 2H), 4.14 - 4.04 (m, 2H), 3.98 (t, 2H), 3.76 (s, 3H), 3.57 (t, 1H), 2.91-2.81 (m, 1H), 2.77 (dd, 1H), 2.71 (dd, 2H), 1.75 (s, 2H), 1.57 (dd, 2H), 1.38-1.25 (m, 6H), 0.87 (t, 3H).

實施例11 Example 11

2-((異丙基)氧基)乙基3-(2-(((4-(N'-(丁氧基羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)--1H-苯並[d]咪唑-5-甲醯氨基)丙酸酯(化合物11) 2-((Isopropyl)oxy)ethyl 3-(2-(((4-(N'-(butoxycarbonyl)methyl)methyl)amino)methyl)-1-methyl -N-(pyridin-2-yl)--1H-benzo[d]imidazol-5-methylamino)propionate (Compound 11)

2-((isopropoxycarbonyl)oxy)ethyl 2-((isopropoxycarbonyl)oxy)ethyl

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

第一步：3-((2-((4-(N'-二丁氧基羰基甲脒基)苯氨基)甲基)-1-甲基苯並咪唑-5-羰基)-(2-吡啶基)氨基)丙酸乙酯(11B) First step: 3-((2-((4-(N'-dibutoxycarbonyl)methyl)phenylamino)methyl)-1-methylbenzimidazole-5-carbonyl)-(2- Pyridyl)amino)propionic acid ethyl ester (11B)

Ethyl Ethyl

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

室溫下在1-丁醇(0.685g,9.24mmol)的四氫呋喃(10mL)中加入碳醯二咪唑(1.50g,9.25mmol)，室溫攪拌30分鐘，減壓除去溶劑，製備成反應液1。在3-(2-(((4-脒基苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙酸乙酯對甲基苯磺酸鹽(11A)(3.00g,6.00mmol)中加入丙酮(100mL)、水(50mL)、碳酸鉀(2.50g,18.1mmol)，攪拌均勻後加入反應液1，加完後室溫反應5小時。過濾析出的白色固體，丙酮/水(丙酮：水(v/v)=1：2)洗滌濾餅，之後用二氯甲烷(100mL)溶解、無水硫酸鈉乾燥，濃縮除去溶劑得標題化合物3-((2-((4-(N'-二丁氧基羰基甲脒基)苯氨基)甲基)-1-甲基苯並咪唑-5-羰基)-(2-吡啶基)氨基)丙酸乙酯(11B)，白色固體(3.00g，產率83.3%)。 Carbonium diimidazole (1.50 g, 9.25 mmol) was added to 1-butanol (0.685 g, 9.24 mmol) in tetrahydrofuran (10 mL) at room temperature, 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-carboxamidine Amino)ethyl propionate To the benzenesulfonate (11A) (3.00 g, 6.00 mmol), acetone (100 mL), water (50 mL), potassium carbonate (2.50 g, 18.1 mmol) was added, and the mixture was stirred and then added to the reaction mixture 1 Reaction for 5 hours. The precipitated white solid was filtered, and the filter cake was washed with acetone/water (acetone: water (v/v) = 1:2), then dissolved in dichloromethane (100 mL), dried over anhydrous sodium sulfate ((2-((4-(N'-Dibutoxycarbonyl)methyl)phenylamino)methyl)-1-methylbenzimidazole-5-carbonyl)-(2-pyridyl)amino)propyl Ethyl acetate (11B), white solid (3.00 g, yield 83.3%).

第二步：3-[[2-[[4-[N'-氧羰基甲脒基]苯氨基]甲基]-1-甲基苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(11C) Second step: 3-[[2-[[4-[N'-oxycarbonylmethylindenyl]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl) Amino]propionic acid (11C)

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

室溫下在3-((2-((4-(N'-二丁氧基羰基甲脒基)苯氨基)甲基)-1-甲基苯並咪唑-5-羰基)-(2-吡啶基)氨基)丙酸乙酯(11B)(2.3g,3.84mmol)的乙醇(50mL)溶液中加入氫氧化鈉(450mg,11.3mmol)的水(5mL)溶液，加完後室溫反應2小時。用檸檬酸飽和水溶液調pH到3，過濾析出的固體，二氯甲烷溶解，無水硫酸鈉乾燥、濃縮除去溶劑得標題化合物3-[[2-[[4-[N'-氧羰基甲脒基]苯氨基]甲基]-1-甲基苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(11C)，白色固體(2.00g，產率91.2%)。 3-((2-((4-(N'-dibutoxycarbonyl)methyl)phenylamino)methyl)-1-methylbenzimidazole-5-carbonyl)-(2-) To a solution of sodium pyridyl)amino)propionate (11B) (2.3 g, 3.84 mmol) in ethanol (50 mL), a solution of sodium hydroxide (450 mg, 11.3 mmol) in water (5 mL) hour. The pH was adjusted to 3 with a saturated aqueous solution of citric acid, and the precipitated solid was filtered, dissolved in methylene chloride, dried over anhydrous sodium sulfate and evaporated to give the title compound 3-[[[[[[[[[[[[[[[[[[[[[[[[[[[ Phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid (11C), white solid (2.00 g, yield 91.2%).

第三步：2-羥乙基異丙基碳酸酯(11E) The third step: 2-hydroxyethyl isopropyl carbonate (11E)

2-hydroxyethyl isopropyl carbonate 2-hydroxyethyl isopropyl carbonate

冰浴下在乙二醇(11D)(25.0g,403mmol)的二氯甲烷(150mL)溶液中加入三乙胺(12.1g,120mmol)。冷卻到-50℃，緩慢滴加異丙基碳醯氯(12.26g,100mmol)，加完後室溫反應3小時。向反應液中加入水(100mL)，用二氯甲烷萃取(100mL×2)，合併有機相，無水硫酸鈉乾燥，濃縮，殘留物用矽膠柱色譜分離純化(二氯甲烷：甲醇(v/v)=100：0~30：1)得到標題化合物2-羥乙基異丙基碳酸酯(11E)，無色油狀物(8.0g，產率54.0%)。 A solution of ethylene glycol (11D) (25.0 g, 403 mmol) in dichloromethane (150 mL) After cooling to -50 ° C, isopropyl carbon ruthenium chloride (12.26 g, 100 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 3 hours. Water (100 mL) was added to the reaction mixture, and the mixture was combined with methylene chloride (100 mL × 2). The title compound 2-hydroxyethyl isopropyl carbonate (11E) was obtained as a colorless oil (8.0 g, yield 54.0%).

¹H NMR(400MHz,CDCl₃)δ 4.89(dt,1H),4.32-4.17(m,2H),3.91-3.78(m,2H),2.00(s,1H),1.31(d,6H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.89 (dt, 1H), 4.32-4.17 (m, 2H), 3.91-3.78 (m, 2H), 2.00 (s, 1H), 1.31 (d, 6H).

第四步：2-((異丙基)氧基)乙基3-(2-(((4-(N'-(丁氧基羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙酸酯(化合物11) Fourth step: 2-((isopropyl)oxy)ethyl 3-(2-(((4-(N'-(butoxycarbonyl))methyl)phenyl)amino)methyl)- 1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-methylamino)propionate (Compound 11)

2-((isopropoxycarbonyl)oxy)ethyl 2-((isopropoxycarbonyl)oxy)ethyl

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

室溫下在3-[[2-[[4-[N'-氧羰基甲脒基]苯氨基]甲基]-1-甲基苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(11C)(1.0g,1.7mmol)的 15mL二甲基甲醯胺溶液中加入2-羥乙基異丙基碳酸酯(11E)(400mg,2.70mmol)、1-乙基-(3-二甲基氨基丙基)碳二亞胺鹽酸鹽(0.620g,3.49mmol)和4-二甲氨基吡啶(128mg,1.05mmol)，室溫反應15小時。向反應液中加入水30mL，用二氯甲烷萃取(50mL×3)，合併有機相，有機相用飽和磷酸二氫鉀溶液洗滌(30mL×2)，無水硫酸鈉乾燥，濃縮，殘留物用矽膠柱色譜分離純化(二氯甲烷：甲醇(v/v)=100：1~30：1)得到標題化合物2-((異丙基)氧基)乙基3-(2-(((4-(N'-(丁氧基羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)--1H-苯並[d]咪唑-5-甲醯氨基)丙酸酯(化合物11)，棕色固體(300mg，產率24.0%)。 3-[[2-[[4-[N'-oxycarbonylmethylindenyl]phenylamino]methyl]-1-methylbenzimidazole-5-carbonyl]-(2-pyridyl) at room temperature Amino]propionic acid (11C) (1.0g, 1.7mmol) 2-Hydroxyethyl isopropyl carbonate (11E) (400 mg, 2.70 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide salt was added to 15 mL of dimethylformamide solution. The acid salt (0.620 g, 3.49 mmol) and 4-dimethylaminopyridine (128 mg, 1.05 mmol) were reacted at room temperature for 15 hours. 30 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (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 and concentrated. Purification by column chromatography (dichloromethane:methanol (v/v)=100:1 to 30:1) to give the title compound 2-((isopropyl)oxy)ethyl 3-(2-(((4- (N'-(Butoxycarbonyl)methanyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)--1H-benzo[d]imidazole-5- Formamidine amino) propionate (Compound 11), brown solid (300 mg, yield 24.0%).

LCMS m/z=702.4[M+1]。 LCMS m/z = 702.4 [M + 1].

¹H NMR(400MHz,DMSO)δ 9.11(s,1H),8.71(s,1H),8.39(dd,1H),7.79(d,2H),7.53(td,1H),7.48(d,1H),7.39(d,1H),7.15(dd,1H),7.12(dd,1H),6.94(t,1H),6.89(d,1H),6.76(d,2H),4.80-4.69(m,1H),4.59(d,2H),4.22(dd,4H),4.17(dd,2H),3.99(t,2H),3.76(s,3H),2.71(t,2H),1.57(dt,2H),1.42-1.30(m,2H),1.20(d,6H),0.91(dd,3H)。 ^{1 H NMR (400MHz, DMSO)} δ 9.11 (s, 1H), 8.71 (s, 1H), 8.39 (dd, 1H), 7.79 (d, 2H), 7.53 (td, 1H), 7.48 (d, 1H) , 7.39 (d, 1H), 7.15 (dd, 1H), 7.12 (dd, 1H), 6.94 (t, 1H), 6.89 (d, 1H), 6.76 (d, 2H), 4.80-4.69 (m, 1H) ), 4.59 (d, 2H), 4.22 (dd, 4H), 4.17 (dd, 2H), 3.99 (t, 2H), 3.76 (s, 3H), 2.71 (t, 2H), 1.57 (dt, 2H) , 1.42-1.30 (m, 2H), 1.20 (d, 6H), 0.91 (dd, 3H).

實施例12 Example 12

2-甲氧基乙基3-[[2-[[4-[N`-3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸脂(化合物12) 2-methoxyethyl 3-[[2-[[4-[N`-3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1- Methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid ester (Compound 12)

2-methoxyethyl 2-methoxyethyl

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

將3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中間體1)(3g,5mmol)溶于無水N,N-二甲基甲醯胺(10mL)中，加入乙二醇單甲醚(12A)(0.76g,10mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亞胺鹽酸鹽(1.92g,10mmol)、4-二甲氨基吡啶(0.12g,1mmol)，室溫下反應過夜。加入水(30mL)，用二氯甲烷(30mL×3)萃取，合併有機層，用飽和氯化鈉(20mL×2)洗滌，無水硫酸鈉乾燥，減壓濃縮得粗產物加入二氯甲烷(24mL)，加熱至回流使完全溶解，加入甲基第三丁基醚(48mL)，室溫攪拌30分鐘，過濾，濾餅用二氯甲烷/甲基第三丁基醚(v/v=1/2)的混合溶劑(20mL)洗滌，收集濾餅，減壓乾燥，得標題化合物2-甲氧基乙基3-[[2-[[4-[N`-3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸脂(化合物12)，白色固體(1.9g，產率57.7%)。 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 (10 mL), and ethyl ether monomethyl ether (12A) (0.76 g, 10 mmol). 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10 mmol), 4-dimethylaminopyridine (0.12 g, 1 mmol). Water (30 mL) was added, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ), heated to reflux to dissolve completely, added methyl tert-butyl ether (48 mL), stirred at room temperature for 30 minutes, filtered, and filtered cake with dichloromethane / methyl t-butyl ether (v / v = 1 / 2) The mixed solvent (20 mL) was washed, and the filter cake was collected and dried under reduced pressure to give the title compound 2-methoxyethyl 3-[[2-[[[[[[[[[[[[[[[[[[[[[[ 4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate (Compound 12), white Solid (1.9 g, yield 57.7%).

LCMS m/z=658.4[M+1]。 LCMS m/z = 658.4 [M + 1].

¹H NMR(400MHz,CDCl₃)δ 8.41(d,1H),7.76(d,2H),7.70(s,1H),7.36-7.28(m,2H),7.11(d,1H),6.98(dd,1H),6.70(dd,3H),5.32(s,1H),4.49(d,2H),4.44(t,2H),4.21-4.17(m,2H),4.14(t, 2H),3.72(s,3H),3.60-3.54(m,2H),3.37(s,3H),2.85(t,2H),1.77-1.68(m,2H),1.40(dd,2H),1.31(dd,4H),0.89(t,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 8.41 (d, 1H), 7.76 (d, 2H), 7.70 (s, 1H), 7.36-7.28 (m, 2H), 7.11 (d, 1H), 6.98 (dd , 1H), 6.70 (dd, 3H), 5.32 (s, 1H), 4.49 (d, 2H), 4.44 (t, 2H), 4.21-4.17 (m, 2H), 4.14 (t, 2H), 3.72 ( s, 3H), 3.60-3.54 (m, 2H), 3.37 (s, 3H), 2.85 (t, 2H), 1.77-1.68 (m, 2H), 1.40 (dd, 2H), 1.31 (dd, 4H) , 0.89 (t, 3H).

化合物12的鹽酸鹽：將2-甲氧基乙基3-[[2-[[4-[N`-3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸脂(化合物12)(0.3g，0.5mmol)溶於丙酮(10mL)中，0℃通入過量的鹽酸氣體，室溫反應2小時。反應結束減壓濃縮得到化合物12的鹽酸鹽，類白色固體(0.15g，產率50%)。 Hydrochloride salt of compound 12: 2-methoxyethyl 3-[[2-[[4-[N`-3-[[2-[[4-[N[N-]-hexyloxycarbonyl]] Aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid ester (Compound 12) (0.3 g, 0.5 mmol) was dissolved in acetone (10 mL). An excess of hydrochloric acid gas was introduced at 0 ° C and reacted at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give the title compound (md.

MS m/z(ESI)：658.2[M+1]。 MS m/z (ESI): 658.2 [M+1].

¹H NMR(400MHz,DMSO)δ 11.99(s,1H),11.11(s,1H),10.10(s,1H),8.38(d,1H),7.82(d,,1H),7.74(d,2H),7.69(s,1H),7.64(t,1H),7.38(d,1H),7.22-7.14(m,1H),7.10(d,1H),6.98(d,2H),5.04(s,2H),4.25(dt,4H),4.13-4.03(m,2H),3.99(s,3H),3.53-3.43(m,2H),3.24(s,3H),2.72(t,2H),2.09(s,1H),1.68(dd,2H),1.38(s,2H),1.34-1.23(m,4H),0.87(d,3H)。 ^{1 H NMR (400MHz, DMSO)} δ 11.99 (s, 1H), 11.11 (s, 1H), 10.10 (s, 1H), 8.38 (d, 1H), 7.82 (d ,, 1H), 7.74 (d, 2H ), 7.69 (s, 1H), 7.64 (t, 1H), 7.38 (d, 1H), 7.22-7.14 (m, 1H), 7.10 (d, 1H), 6.98 (d, 2H), 5.04 (s, 2H), 4.25 (dt, 4H), 4.13-4.03 (m, 2H), 3.99 (s, 3H), 3.53-3.43 (m, 2H), 3.24 (s, 3H), 2.72 (t, 2H), 2.09 (s, 1H), 1.68 (dd, 2H), 1.38 (s, 2H), 1.34-1.23 (m, 4H), 0.87 (d, 3H).

化合物12的甲磺酸鹽：將2-甲氧基乙基3-[[2-[[4-[N`-3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸脂(化合物12)(0.33g，0.44mmol)溶於丙酮(10mL)中，加入甲磺酸(42.3mg，0.44mmol)，室溫反應2小時。反應結束後，過濾固體，得到化合物12的甲磺酸鹽，白色固體1(0.3g，產率90%)。 Methanesulfonate salt of compound 12: 2-methoxyethyl 3-[[2-[[4-[N`-3-[[2-[[4-[N. Aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid ester (Compound 12) (0.33 g, 0.44 mmol) was dissolved in acetone (10 mL) Methanesulfonic acid (42.3 mg, 0.44 mmol) was added and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the solid was filtered to give the methanesulfonic acid salt of Compound 12 as a white solid 1 (0.3 g, yield 90%).

LCMS m/z=658.2[M+1]。 LCMS m/z = 658.2 [M + 1].

¹H NMR(400MHz,DMSO)δ 11.87(s,1H),10.69(s,1H),10.04(s,1H),8.39(dd,1H),7.66(d,,3H),7.56(td,1H),7.50(d,1H), 7.46(d,1H),7.20(dd,1H),7.16-7.10(m,1H),6.94(d,1H),6.88(d,2H),4.73(s,2H),4.25(dt,4H),4.07(dd,2H),3.80(s,3H),3.48(dd,2H),3.24(s,3H),2.71(t,2H),2.31(s,3H),1.68(dd,2H),1.38(dd,2H),1.35-1.26(m,4H),0.89(t,3H)。 ^{1 H NMR (400MHz, DMSO)} δ 11.87 (s, 1H), 10.69 (s, 1H), 10.04 (s, 1H), 8.39 (dd, 1H), 7.66 (d ,, 3H), 7.56 (td, 1H ), 7.50 (d, 1H), 7.46 (d, 1H), 7.20 (dd, 1H), 7.16-7.10 (m, 1H), 6.94 (d, 1H), 6.88 (d, 2H), 4.73 (s, 2H), 4.25 (dt, 4H), 4.07 (dd, 2H), 3.80 (s, 3H), 3.48 (dd, 2H), 3.24 (s, 3H), 2.71 (t, 2H), 2.31 (s, 3H) ), 1.68 (dd, 2H), 1.38 (dd, 2H), 1.35-1.26 (m, 4H), 0.89 (t, 3H).

實施例13 Example 13

2-((異丙基)氧基)乙基3-(2-(((4-(N'-(己氧基羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙酸酯(化合物13) 2-((Isopropyl)oxy)ethyl 3-(2-(((4-(N'-(hexyloxycarbonyl))methyl)phenyl)amino)methyl)-1-methyl -N-(pyridin-2-yl)-1H-benzo[d]imidazol-5-methylamino)propionate (Compound 13)

2-((isopropoxycarbonyl)oxy)ethyl 2-((isopropoxycarbonyl)oxy)ethyl

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

室溫下在3-[[2-[[4-[N`-己氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸(中間體1)(1.5g,2.50mmol)的二甲基甲醯胺(15mL)溶液中加入2-羥乙基異丙基碳酸酯(11E)(655mg,4.42mmol)、1-乙基-(3-二甲基氨基丙基)碳二亞胺鹽酸鹽(0.900g,5.07mmol)和4-二甲氨基吡啶(185mg, 1.51mmol)，室溫反應15小時。向反應液中加入水(30mL)，用二氯甲烷萃取(50mL×3)，合併有機相，有機相用飽和磷酸二氫鉀溶液洗滌(30mL×2)，無水硫酸鈉乾燥，濃縮，殘留物用矽膠柱色譜分離純化(二氯甲烷：甲醇(v/v)=100：1~30：1)得到標題化合物2-((異丙基)氧基)乙基3-(2-(((4-(N'-(己氧基羰基)甲脒基)苯基)氨基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯並[d]咪唑-5-甲醯氨基)丙酸酯(化合物13)，棕色固體(550mg，產率30.0%)。 3-[[2-[[4-[N`-Hexoxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl) at room temperature To a solution of amino]propionic acid (Intermediate 1) (1.5 g, 2.50 mmol) in dimethylformamide (15 mL) was added 2-hydroxyethyl isopropyl carbonate (11E) (655 mg, 4.42 mmol). 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.900 g, 5.07 mmol) and 4-dimethylaminopyridine (185 mg, 1.51 mmol), reacted at room temperature for 15 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (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 Purification by gel column chromatography (dichloromethane:methanol (v/v)=100:1 to 30:1) to give the title compound 2-((isopropyl)oxy)ethyl 3-(2-((( 4-(N'-(Hexyloxycarbonyl)methane)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5 -Methylamino)propionate (Compound 13), brown solid (550 mg, yield 30.0%).

LCMS m/z=730.2[M+1]。 LCMS m/z = 730.2 [M + 1].

¹H NMR(400MHz,CDCl3)δ 8.45-8.37(m,1H),7.80-7.63(m,3H),7.33(td,1H),7.29-7.23(m,2H),7.08(d,1H),6.98(dd,1H),6.70(d,1H),6.65(d,2H),5.41(s,1H),4.87(dt,1H),4.49-4.39(m,4H),4.30-4.27(m,2H),4.25(dd,2H),4.14(t,2H),3.69(s,3H),2.85(t,2H),1.71(dd,2H),1.49-1.36(m,2H),1.37-1.23(m,10H),0.89(t,3H)。 ^{1 H NMR (400MHz, CDCl3)} δ 8.45-8.37 (m, 1H), 7.80-7.63 (m, 3H), 7.33 (td, 1H), 7.29-7.23 (m, 2H), 7.08 (d, 1H), 6.98 (dd, 1H), 6.70 (d, 1H), 6.65 (d, 2H), 5.41 (s, 1H), 4.87 (dt, 1H), 4.49-4.39 (m, 4H), 4.30-4.27 (m, 2H), 4.25 (dd, 2H), 4.14 (t, 2H), 3.69 (s, 3H), 2.85 (t, 2H), 1.71 (dd, 2H), 1.49-1.36 (m, 2H), 1.37-1.23 (m, 10H), 0.89 (t, 3H).

實施例14 Example 14

2-異丙氧基乙基3-[[2-[[4-[N`-己氧羰基甲眯]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物14) 2-Isopropoxyethyl 3-[[2-[[4-[N`-hexyloxycarbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2 -pyridyl)amino]propionate (Compound 14)

2-isopropoxyethyl 2-isopropoxyethyl

製備方法參見實施例1。 See Method 1 for the preparation method.

LCMS m/z=686.36[M+1]。 LCMS m/z = 686.36 [M + 1].

¹H NMR(400MHz,CDCl₃)δ 8.41(dd,1H),7.75(d,2H),7.70(s,1H),7.32(m,2H),7.10(d,1H),6.98(dd,1H),6.72(d,1H),6.68(d,2H),5.36(s,1H),4.48(d,2H),4.43(t,2H),4.14(dd,4H),3.71(s,3H),3.63-3.60(m,1H),3.60-3.55(m,2H),2.84(t,2H),1.77-1.67(m,2H),1.40(dd,2H),1.31(dd,6H),1.15(d,4H),0.89(t,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 8.41 (dd, 1H), 7.75 (d, 2H), 7.70 (s, 1H), 7.32 (m, 2H), 7.10 (d, 1H), 6.98 (dd, 1H ), 6.72 (d, 1H), 6.68 (d, 2H), 5.36 (s, 1H), 4.48 (d, 2H), 4.43 (t, 2H), 4.14 (dd, 4H), 3.71 (s, 3H) , 3.63-3.60 (m, 1H), 3.60-3.55 (m, 2H), 2.84 (t, 2H), 1.77-1.67 (m, 2H), 1.40 (dd, 2H), 1.31 (dd, 6H), 1.15 (d, 4H), 0.89 (t, 3H).

實施例15 Example 15

(1S)-1-甲基-2-甲氧基乙基3-[[2-[[4-[N`-3-[[2-[[4-[N`-庚氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸脂(化合物15) (1S)-1-methyl-2-methoxyethyl 3-[[2-[[4-[N`-3-[[2-[[4-[N[-]]]] Aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoic acid ester (Compound 15)

(1S)-1-methyl-2-methoxyethyl (1S)-1-methyl-2-methoxyethyl

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

製備方法參見實施例11。 See Example 11 for the preparation method.

實施例16 Example 16

2-甲氧基乙基3-[[2-[[4-[N`-3-[[2-[[4-[N`-庚氧基羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸脂(化合物16) 2-methoxyethyl 3-[[2-[[4-[N`-3-[[2-[[4-[N`-heptyloxycarbonyl)]] Methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propionate Compound 16)

2-methoxyethyl 2-methoxyethyl

製備方法參見實施例11。 See Example 11 for the preparation method.

實施例17 Example 17

2-甲氧基乙基3-[[2-[[4-[N`-(3,3,3-三氟丙氧基)羰基甲眯]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸酯(化合物17) 2-methoxyethyl 3-[[2-[[4-[N`-(3,3,3-trifluoropropoxy)carbonylformamidine]aniline]methyl]-1-methyl-benzene And imidazol-5-carbonyl]-(2-pyridyl)amino]propionate (Compound 17)

2-methoxyethyl 2-methoxyethyl

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

製備方法參見實施例11。 See Example 11 for the preparation method.

實施例18 Example 18

(1S)-1-甲基-2-甲氧基乙基3-[[2-[[4-[N`-3-[[2-[[4-[N`-(3,3,3-三氟丙氧基)羰基甲脒]苯胺]甲基]-1-甲基-苯並咪唑-5-羰基]-(2-吡啶基)氨基]丙酸脂(化合物18) (1S)-1-methyl-2-methoxyethyl 3-[[2-[[4-[N`-3-[[2-[[4-[N`-(3,3,3 -trifluoropropoxy)carbonylformamidine]aniline]methyl]-1-methyl-benzimidazole-5-carbonyl]-(2-pyridyl)amino]propanoate (Compound 18)

(1S)-1-methyl-2-methoxyethyl (1S)-1-methyl-2-methoxyethyl

製備方法參見實施例11。 See Example 11 for the preparation method.

測試例 Test case

1、藥代動力學評價 1. Pharmacokinetic evaluation

健康成年SD大鼠(雌雄各半，購自北京維通利華實驗動物中心，動物生產許可證號SCXK(京)2012-0001)，給藥前一天禁食不禁水。6只大鼠灌胃給藥5mg/kg(以達比加群原形藥物計)，化合物以0.5% CMC-Na(含1%吐溫80)配製成0.5mg×mL^-1(以達比加群原形藥物計)的懸浮液，於給藥前(0h)及給藥後5min,15min,30min,1.0,2.0,4.0,8.0,24.0h由眼眶採血，肝素抗凝，4℃ 3000rpm離心10min後分離血漿，於-80℃保存待測。取30ul各時間點大鼠血漿，加入內標溶液(7.5ng/mL維拉帕米)200ul，渦流混合1min，於4℃ 13000rpm離心10min，取上清液190ul進行 LC-MS/MS(島津公司lc-20A科技有限公司，API4000+)分析。主要藥代動力學參數用WinNonlin 6.3軟體非房室模型分析，結果如表1所示。 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 × mL ^-1 with 0.5% CMC-Na (containing 1% Tween 80). The suspension of the original drug was added to the eyelids before administration (0h) and 5min, 15min, 30min, 1.0, 2.0, 4.0, 8.0, 24.0h after administration, heparin was anticoagulated, and centrifuged at 3000C for 10min at 4°C. The plasma was 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), vortex for 1min, centrifuge at 13000rpm for 10min at 4°C, and take 190ul of supernatant for LC-MS/MS (Shimadzu Corporation) lc-20A Technology Co., Ltd., API4000+) analysis. The main pharmacokinetic parameters were analyzed using the WinNonlin 6.3 software non-compartmental model. The results are shown in Table 1.

結論：本發明化合物與達比加群酯相比，具有良好的藥代動力學特徵，特別是化合物6、12、14、15各項指數明顯優於達比加群酯。 Conclusion: Compared with dabigatran etexilate, the compound of the present invention has good pharmacokinetic characteristics, especially the compounds 6, 12, 14, 15 have significantly better indexes than dabigatran etexilate.

Claims

一種通式(I)所示的化合物及其立體異構體和藥學上可以接受的鹽，其中： X₁和X₂各自獨立的選自O或S；R¹選自-(CR^1aR^1bO)_n-(CR^1aR^1bCR^1cR^1dO)_mR^1e；R²選自C_1-10烷基或-(CR^2aR^2bCR^2cR^2dO)_mR^2e，所述烷基任選進一步被0至12個選自H、F、Cl、Br、I、C_1-4烷基或C_1-4烷氧基的取代基所取代；R^1a、R^1b、R^1c、R^1d、R^2a、R^2b、R^2c和R^2d各自獨立的選自H、F、Cl、Br、I、C_1-4烷基或C_1-4烷氧基；R^1e和R^2e各自獨立的選自H、C_1-4烷基、-C(=O)C_1-4烷基、 -C(=O)C_1-4烷氧基或； R^1f各自獨立的選自氨基酸側鏈基團；R^1g和R^1h各自獨立的選自H或氨基保護基；n選自0或1；m選自1、2、3、4、5或6。 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 -(CR ^1a R ^1b O) _n -(CR ^1a R ^1b CR ^1c R ^1d O) _m R ^1e ; R ^{2 is} selected from C _{1- 10} alkyl or -(CR ^2a R ^2b CR ^2c R ^2d O) _m R ^2e , the alkyl group optionally further from 0 to 12 selected from H, F, Cl, Br, I, C _1-4 alkyl Or a substituent of a C _1-4 alkoxy group; R ^1a , R ^1b , R ^1c , R ^1d , R ^2a , R ^2b , R ^2c and R ^2d are each independently selected from the group consisting of H, F, Cl, Br, I, C _1-4 alkyl or C _1-4 alkoxy; R ^1e and R ^2e are each independently selected from H, C _1-4 alkyl, -C(=O)C _1-4 alkyl, - C(=O)C _1-4 alkoxy or ; R ^1f are each independently selected from the group consisting of amino acid side chain groups; R ^1g and R ^1h are each independently selected from H or an amino protecting group; n is selected from 0 or 1; m is selected from 1, 2, 3, 4, 5 or 6.

根據申請專利範圍第1項所述的化合物及其立體異構體和藥學上可以接受的鹽，其中：所述氨基酸選自甘氨酸、丙氨酸、亮氨酸、異亮氨酸、結氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸、絲氨酸、穀氨醯胺、蘇氨酸、半胱氨酸、組氨酸、天冬醯胺、酪氨酸、天冬氨酸、谷氨酸、萘胺酸或精氨酸；所述氨基保護基選自苄氧羰基、第三丁氧羰基、芴甲氧羰基、烯丙氧羰基、三甲基矽乙氧羰基、甲氧羰基或乙氧羰基。 a compound according to claim 1 and its stereoisomers and a pharmaceutically acceptable salt, wherein: the amino acid is selected from the group consisting of glycine, alanine, leucine, isoleucine, tyrosine, valine, phenylalanine, methionine, tryptophan , serine, glutamine, threonine, cysteine, histidine, aspartame, tyrosine, aspartic acid, glutamic acid, naphthyl acid or arginine; The protecting group is selected from the group consisting of benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsulfonium ethoxycarbonyl, methoxycarbonyl or ethoxycarbonyl.

根據申請專利範圍第2項所述的化合物及其立體異構體和藥學上可以接受的鹽，其中：R²選自C_1-8烷基或-(CR^2aR^2bCR^2cR^2dO)_mR^2e，所述烷基任選進一步被0至12個選自H、F、Cl或Br的取代基所取代；R^1a、R^1b、R^1c、R^1d、R^2a、R^2b、R^2c和R^2d各自獨立的選自H、F、Cl、Br、I、甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基；R^1e和R^2e各自獨立的選自H、甲基、乙基、-C(=O)OCH(CH₃)₂ 或； R^1f各自獨立的選自氨基酸側鏈基團，所述氨基酸選自甘氨酸、丙氨酸、亮氨酸、苯丙氨酸或結氨酸；R^1g和R^1h各自獨立的選自H或氨基保護基，所述氨基保護基選自苄氧羰基或第三丁氧羰基； n選自0或1；m選自1、2或3。 The compound according to claim 2, and a stereoisomer thereof and a pharmaceutically acceptable salt thereof, wherein: R ^{2 is} selected from C _1-8 alkyl or -(CR ^2a R ^2b CR ^2c R ^2d O) _m R ^2e , the alkyl group optionally further substituted by 0 to 12 substituents selected from H, F, Cl or Br; R ^1a , R ^1b , R ^1c , R ^1d , R ^2a , R ^2b , R ^2c and R ^2d are each independently selected from H, F, Cl, Br, I, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy; R ^1e and R ^2e are each independently Selected from H, methyl, ethyl, -C(=O)OCH(CH ₃ ) ₂ or ; R ^1f are each independently selected from the group consisting of amino acid side chain groups selected from glycine, alanine, leucine, phenylalanine or determinine; R ^1g and R ^1h are each independently selected from H or An amino protecting group selected from the group consisting of a benzyloxycarbonyl group or a third butoxycarbonyl group; n is selected from 0 or 1; m is selected from 1, 2 or 3.

根據申請專利範圍第3項所述的化合物及其立體異構體和藥學上可以接受的鹽，其中該化合物選自如下結構之一： 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:

根據申請專利範圍第1~4項中任一項所述的化合物及其立體異構體和藥學上可接受的鹽，其中所述的鹽選自鹽酸鹽、氫溴酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、乙酸鹽、馬來酸鹽、琥珀酸鹽、扁桃酸鹽、富馬酸鹽、丙二酸鹽、蘋果酸鹽、2-羥基丙酸鹽、草酸鹽、羥乙酸鹽、水楊酸鹽、葡萄糖醛酸鹽、半乳糖醛酸鹽、枸櫞酸鹽、酒石酸鹽、門冬氨酸鹽、谷氨酸鹽、苯甲酸鹽、肉桂酸鹽、對甲苯磺酸鹽、苯磺酸鹽、甲磺酸鹽、乙磺酸鹽、三氟甲磺酸鹽、阿魏酸鹽或其組合。 The compound according to any one of claims 1 to 4, wherein the salt is selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a sulfate salt, and a pharmaceutically acceptable salt thereof. Nitrate, phosphate, acetate, maleate, succinate, Mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronide, galacturonate, guanidine Citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, besylate, methanesulfonate, ethanesulfonate, trifluoro Mesylate, ferulic acid or a combination thereof.

一種藥物組合物，所述藥物組合物含有治療有效劑量的根據申請專利範圍第1~5項中任意一項所述的化合物或其立體異構體或藥學上可接受的鹽，以及藥學上可接受的載體或者賦形劑。 A pharmaceutical composition, which comprises 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 Accepted carrier or excipient.

申請專利範圍第1~5項中任意一項所述的化合物及其立體異構體和藥學上可接受的鹽，以及申請專利範圍6所述的組合物在製備治療與凝血酶抑制劑相關疾病藥物中的用途。 The compound of any one of claims 1 to 5, and the stereoisomers and pharmaceutically acceptable salts thereof, and the composition of claim 6 in the preparation of a therapeutic and thrombin inhibitor-related disease Use in medicine.

根據申請專利範圍第7項所述的用途，其中所述的與凝血酶抑制劑相關疾病選自血栓栓塞疾病。 The use according to the invention of claim 7, wherein the thrombin-related disease is selected from the group consisting of thromboembolic diseases.

根據申請專利範圍第8項所述的用途，其中所述的血栓栓塞疾病選自靜脈血栓和動脈栓塞。 The use according to the invention of claim 8, wherein the thromboembolic disease is selected from the group consisting of venous thrombosis and arterial embolism.

一種治療與凝血酶抑制劑相關疾病的方法，其中所述方法包括給藥申請專利範圍第1~5項中任意一項所述的化合物或其立體異構體、或藥學上可接受的鹽，或申請專利範圍6所述的組合物。 A method for treating a disease associated with a thrombin inhibitor, wherein the method comprises administering the compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Or the composition described in Patent Range 6.

根據申請專利範圍第10項所述的方法，其中所述的與凝血酶抑制劑相關疾病選自血栓栓塞疾病。 According to the method of claim 10, wherein the The thrombin inhibitor-related disease is selected from thromboembolic diseases.

根據申請專利範圍第11項所述的方法，其中所述的血栓栓塞疾病選自靜脈血栓和動脈栓塞。 The method of claim 11, wherein the thromboembolic disease is selected from the group consisting of a venous thrombosis and an arterial embolization.