KR20010101950A - Substituted aromatic amidine derivative and medicinal composition comprising same - Google Patents

Substituted aromatic amidine derivative and medicinal composition comprising same Download PDF

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KR20010101950A
KR20010101950A KR1020017009771A KR20017009771A KR20010101950A KR 20010101950 A KR20010101950 A KR 20010101950A KR 1020017009771 A KR1020017009771 A KR 1020017009771A KR 20017009771 A KR20017009771 A KR 20017009771A KR 20010101950 A KR20010101950 A KR 20010101950A
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ethyl
oxo
ethylindol
amidino
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구본암
남응현
박찬희
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이경하
주식회사 씨앤드씨신약연구소
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Abstract

본 발명은 강력한 선탁적 트롬빈 억제활성을 가지며 또한 경구적으로 투여할수 있는 신규의 방향족 아미딘 유도체 및 이를 활성성분으로 함유하는 트롬빈 억제용 조성물에 관한 것이다.The present invention relates to a novel aromatic amidine derivative having a strong opioid thrombin inhibitory activity and orally administrable and a composition for inhibiting thrombin containing the same as an active ingredient.

Description

치환된 방향족 아미딘 유도체 및 이를 함유하는 의약조성물{Substituted aromatic amidine derivative and medicinal composition comprising same}Substituted aromatic amidine derivative and medicinal composition comprising same

혈전증은 혈소판의 응집이나 섬유소 응괴가 혈관을 폐색시키는 병변이다. 따라서, 섬유소 형성을 차단하는 항응혈제는 혈전증의 예방에 사용될 수 있다.Thrombosis is a lesion in which platelet aggregation or fibrin clot obstructs blood vessels. Thus, anticoagulants that block fibrin formation can be used for the prevention of thrombosis.

혈액응고시스템에는 다단계의 효소반응에 의해 활성화되는 다수의 자이모겐 (비활성화 효소)이 관여한다. 혈액응고과정의 마지막 단계는 인자 Xa의 작용에 의해 프로트롬빈으로부터 생성된 트롬빈에 의해 섬유소원으로부터 섬유소 응괴가 형성되는 단계이다. 따라서, 혈액응고효소인 트롬빈은 지혈 및 혈전증에 있어서 중심적인 역할을 수행하며, 이에 따라 트롬빈 활성을 억제할 수 있는 물질은 혈소판 활성을 억제하고 섬유소 생성 및 안정화를 억제함으로써 효과적인 항응혈제로 사용할 수 있으리라 기대된다. 트롬빈 억제제는 또한 포지티브 피드백 반응(positive feed back reaction)에 의해 인자 Ⅴ 및 인자 Ⅷ을 활성화 시킨다.Blood coagulation systems involve a number of zymogens (inactivating enzymes) that are activated by multiple stages of enzyme reactions. The final stage of the coagulation process is the formation of fibrin clots from fibrinogen by thrombin produced from prothrombin by the action of factor Xa. Therefore, thrombin, a blood coagulation enzyme, plays a central role in hemostasis and thrombosis. Accordingly, a substance capable of inhibiting thrombin activity may be used as an effective anticoagulant by inhibiting platelet activity and inhibiting fibrin production and stabilization. It is expected. Thrombin inhibitors also activate factor V and factor V by a positive feed back reaction.

최근에, 다수의 트롬빈 억제제가 효과적인 혈전증 치료제 및 항응혈제로서 개발되었으며, 예를 들어 PPACK[D-Phe-Pro-Arg-CH2Cl](참조: Thromb. Res., 14, 969(1979), D-Phe-Pro-Arg, Boc-D-Phe-Pro-Arg 및 D-MePhe-Pro-Arg(참조: J. Med.Chem., 33, 1729 (1990), DuP-714[Ac-(D)-Phe-Pro-boroArg-OH](참조: J. Biol. Chem., 265, 18289(1990), 에페가트란(Efegatran)[D-MePhe-Pro-Arg·H2SO4](참조: Thromb. Haemost., 67, 325 (1992), 이노가트란(Inogatran)[HOOC-CH2-(R)Cha-Pic- Nag, 여기에서 Cha는 사이클로헥실아민이고, Pic는 피페콜산(pipecolic acid)이며, Nag는 노르아그마틴(noragmatine)이다](참조:WO 93/11152, Blood Coag. Fibrinol., 7, 69 (1996) 및 CVS-1123[(CH3CH2CH2)2-CHCO-Asp(OCH3)-Pro-Arg](참조:WO 93/ 15756)과 같은 트리펩타이드 유도체 및 아가트로반(Argatroban)(참조: US 4258192; Thromb. Haemost., 18, 13 (1992) 및 NAPAP(참조: J. Biol. Chem., 266, 20085(1991)와 같은 피페리딘아미드 유도체를 언급할 수 있다. 그러나, 이들 화합물은 경구투여에 의한 생체내 이용율, 다른 세린 프로테아제에 대한 트롬빈의 선택적 억제능, 안정성, 작용의 지속성 및 치료학적 용량에서 나타나는 독성 등의 관점에서 실제 사용하기에 충분히 만족스럽지 못한 단점을 지니고 있다.Recently, many thrombin inhibitors have been developed as effective thrombosis therapeutics and anticoagulants, for example PPACK [D-Phe-Pro-Arg-CH 2 Cl] (Thromb. Res., 14, 969 (1979)). , D-Phe-Pro-Arg, Boc-D-Phe-Pro-Arg and D-MePhe-Pro-Arg (J. Med. Chem., 33, 1729 (1990), DuP-714 [Ac- ( D) -Phe-Pro-boroArg-OH] (J. Biol. Chem., 265, 18289 (1990), Efegatran [D-MePhe-Pro-Arg.H 2 SO 4 ] (see : Thromb. Haemost., 67, 325 (1992), Inogatran [HOOC-CH 2- (R) Cha-Pic- Nag, where Cha is cyclohexylamine, Pic is pipecolic acid Nag is noragmatine] (WO 93/11152, Blood Coag. Fibrinol., 7, 69 (1996) and CVS-1123 [(CH 3 CH 2 CH 2 ) 2 -CHCO- Tripeptide derivatives such as Asp (OCH 3 ) -Pro-Arg] (WO 93/15756) and agatroban (US Pat. No. 4,258,192; Thromb. Haemost., 18, 13 (1992) and NAPAP ( See piperidine, such as J. Biol. Chem., 266, 20085 (1991). However, these compounds may be referred to in practice, in view of their bioavailability by oral administration, selective inhibition of thrombin for other serine proteases, stability, persistence of action and toxicity at therapeutic doses. It has a disadvantage that is not satisfactory enough.

본 발명은 경구투여용으로 특별히 바람직하게 사용할 수 있으며, 강력한 선택적 트롬빈 억제활성을 나타내는 하기 화학식 (1)의 방향족 아미딘 유도체, 그의 염 및 이성체, 그의 제조방법, 및 이 화합물을 활성성분으로 함유함을 특징으로 하는 트롬빈 억제제 조성물에 관한 것이다.The present invention can be particularly preferably used for oral administration, and contains an aromatic amidine derivative of the following formula (1), a salt and an isomer thereof, a method for preparing the same, and a compound as an active ingredient, which exhibits strong selective thrombin inhibitory activity. It relates to a thrombin inhibitor composition characterized in.

(1) (One)

상기식에서In the above formula

A 는 C1-C4-알킬, 할로게노-C1-C4-알킬, C1-C4-알콕시-C1-C4-알킬, 하이드록시-C1-C4-알킬에 의해 치환될 수 있는 C2-C6-알킬렌을 나타내고,A is substituted by C 1 -C 4 -alkyl, halogeno-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl C 2 -C 6 -alkylene, which may be

R1은 수소원자를 나타내거나, C1-C4-알킬 또는 페닐에 의해 치환될 수 있는 C1-C4-알킬을 나타내며,R 1 is represents a hydrogen atom, or, C 1 -C 4 - represents an alkyl, - C 1 -C 4 optionally substituted with alkyl or phenyl

R2및 R3는 각각 독립적으로 수소원자를 나타내거나, 각각 카복시, 할로겐, 카바모일, 아미노, 메틸설포닐아미노, C1-C4-알킬아미노, 디(C1-C4-알킬)아미노, 하이드록시, C1-C4-알콕시카보닐 또는 C1-C4-알콕시카바모일에 의해 일치환되거나 다치환될 수 있는 C1-C4-알킬 또는 C1-C5-알카노일을 나타낸다.R 2 and R 3 each independently represent a hydrogen atom or each represents carboxy, halogen, carbamoyl, amino, methylsulfonylamino, C 1 -C 4 -alkylamino, di (C 1 -C 4 -alkyl) amino C 1 -C 4 -alkyl or C 1 -C 5 -alkanoyl which may be mono- or polysubstituted by hydroxy, C 1 -C 4 -alkoxycarbonyl or C 1 -C 4 -alkoxycarbamoyl Indicates.

이에 본 발명자들은 경구투여가 가능하고 트롬빈을 선택적으로 억제함으로해서 효과적으로 사용될 수 있는 트롬빈 억제제를 개발하고자 집중적인 연구를 수행하였으며, 그 결과 상기 정의한 바와 같은 화학식 (1)의 화합물이 경구투여에 의해서도 탁월한 트롬빈 억제 활성을 나타냄을 확인하고 본 발명을 완성하게 되었다.Accordingly, the present inventors have conducted intensive studies to develop a thrombin inhibitor that can be orally administered and effectively used by selectively inhibiting thrombin, and as a result, the compound of formula (1) as defined above is excellent even by oral administration. The present invention was confirmed to show thrombin inhibitory activity.

따라서, 본 발명은 개선된 약물동력학적 성질로 인하여 경구투여용 트롬빈 억제제로 사용하기에 바람직한, 상기 정의된 화학식 (1)의 방향족 아미딘 유도체,그의 약제학적으로 허용되는 염 및 입체화학적 이성체를 제공한다.Accordingly, the present invention provides aromatic amidine derivatives of formula (1) as defined above, pharmaceutically acceptable salts and stereochemical isomers, which are suitable for use as thrombin inhibitors for oral administration due to improved pharmacokinetic properties. do.

본 발명은 또한, 화학식 (1)의 화합물, 그의 염 또는 입체화학적 이성체를 제조하는 방법 및 이 화합물을 유효성분으로 함유함을 특징으로 하는 트롬빈 억제제 조성물을 제공한다.The present invention also provides a method for preparing a compound of formula (1), a salt thereof, or a stereochemical isomer thereof, and a thrombin inhibitor composition comprising the compound as an active ingredient.

본 발명은 하기 화학식 (1)로 표시되는 신규한 방향족 아미딘 유도체, 그의 약제학적으로 허용되는 염 및 입체화학적 이성체에 관한 것이다:The present invention relates to novel aromatic amidine derivatives represented by the following formula (1), pharmaceutically acceptable salts and stereochemical isomers thereof:

(1) (One)

상기식에서In the above formula

A 는 C1-C4-알킬, 할로게노-C1-C4-알킬, C1-C4-알콕시-C1-C4-알킬, 하이드록시-C1-C4-알킬에 의해 치환될 수 있는 C2-C6-알킬렌을 나타내고,A is substituted by C 1 -C 4 -alkyl, halogeno-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl C 2 -C 6 -alkylene, which may be

R1은 수소원자를 나타내거나, C1-C4-알킬 또는 페닐에 의해 치환될 수 있는 C1-C4-알킬을 나타내며,R 1 is represents a hydrogen atom, or, C 1 -C 4 - represents an alkyl, - C 1 -C 4 optionally substituted with alkyl or phenyl

R2및 R3는 각각 독립적으로 수소원자를 나타내거나, 각각 카복시, 할로겐, 카바모일, 아미노, 메틸설포닐아미노, C1-C4-알킬아미노, 디(C1-C4-알킬)아미노, 하이드록시, C1-C4-알콕시카보닐 또는 C1-C4-알콕시카바모일에 의해 일치환되거나 다치환될 수 있는 C1-C4-알킬 또는 C1-C5-알카노일을 나타낸다.R 2 and R 3 each independently represent a hydrogen atom or each represents carboxy, halogen, carbamoyl, amino, methylsulfonylamino, C 1 -C 4 -alkylamino, di (C 1 -C 4 -alkyl) amino C 1 -C 4 -alkyl or C 1 -C 5 -alkanoyl which may be mono- or polysubstituted by hydroxy, C 1 -C 4 -alkoxycarbonyl or C 1 -C 4 -alkoxycarbamoyl Indicates.

상기 화학식 (1)의 화합물 중에서도 바람직한 화합물은 A 가 메틸, 에틸, 플루오로메틸, 메톡시메틸 또는 하이드록시메틸에 의해 치환될 수 있는 에틸렌, 프로필렌 또는 부틸렌을 나타내는 화합물이다.Among the compounds of the formula (1), preferred compounds are those in which A represents ethylene, propylene or butylene, which may be substituted by methyl, ethyl, fluoromethyl, methoxymethyl or hydroxymethyl.

또한, 화학식 (1)의 화합물 중에서도 바람직한 화합물은 R1이 수소원자, 메틸, 이소프로필 또는 벤질을 나타내는 화합물이다.Among the compounds of the formula (1), preferred compounds are those in which R 1 represents a hydrogen atom, methyl, isopropyl or benzyl.

또한, 화학식 (1)의 화합물 중에서도 바람직한 화합물은 R2및 R3가 각각 독립적으로 수소원자, 메틸, 에틸, 3-카복시프로필, 카복시메틸, 3-아미노-3-카복시-프로파노일, 3-카바모일-3-아미노-프로파노일, 4-아미노-4-카복시-부티릴, 4-카바모일-4-아미노-부티릴, 3-메틸설포닐아미노-3-카복시-프로파노일, 3-디에틸아미노-3-카복시-프로파노일, 3-하이드록시-3-카복시-프로파노일 또는 3-카바모일-2-아미노-프로파노일을 나타내는 화합물이다.Among the compounds of the formula (1), preferred compounds include those in which R 2 and R 3 are each independently a hydrogen atom, methyl, ethyl, 3-carboxypropyl, carboxymethyl, 3-amino-3-carboxy-propanoyl, 3- Carbamoyl-3-amino-propanoyl, 4-amino-4-carboxy-butyryl, 4-carbamoyl-4-amino-butyryl, 3-methylsulfonylamino-3-carboxy-propanoyl, 3 -Diethylamino-3-carboxy-propanoyl, 3-hydroxy-3-carboxy-propanoyl or 3-carbamoyl-2-amino-propanoyl.

본 발명에 따르는 화학식 (1)의 화합물의 대표적인 예로는 다음과 같은 화합물이 언급될 수 있으며, 이들 화합물은 하기 표 1에 요약하여 나타내었다:Representative examples of compounds of formula (1) according to the invention may be mentioned the following compounds, which are summarized in Table 1 below:

2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소아자퍼하이드로에피닐)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 1);2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxoazahydrohydropinyl) acetyl) pyrrolidin-2-yl] ethyl} -1-ethylindole -6-carboxamidine (Compound 1);

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노산(화합물 2);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} butanoic acid (Compound 2);

2-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}아세트산(화합물 3);2-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} acetic acid (compound 3);

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-메틸-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노산(화합물 4);4-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -1-methyl-2 -Oxoethyl) -2-oxoazahydrohydroepin-3-yl] amino} butanoic acid (Compound 4);

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]에틸아미노}부타노산(화합물 5);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] ethylamino} butanoic acid (Compound 5);

(2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]카바모일}-2-아미노프로파노산(화합물 6);(2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] carbamoyl} -2-aminopropanoic acid (compound 6);

2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소피롤리디닐)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 7);2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxopyrrolidinyl) acetyl) pyrrolidin-2-yl] ethyl} -1-ethylindole-6 Carboxamidine (compound 7);

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]아미노}부타노산(화합물 8);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] amino} butanoic acid (compound 8);

(2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]카바모일}-2-아미노프로파노산(화합물 9);(2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] carbamoyl} -2-aminopropanoic acid (compound 9);

2-{2-[(2S)-1-((2S)-2-((3S)-3-아미노-2-옥소피롤리디닐)-3-메틸부타노일)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 10);2- {2-[(2S) -1-((2S) -2-((3S) -3-amino-2-oxopyrrolidinyl) -3-methylbutanoyl) pyrrolidin-2-yl] Ethyl} -1-ethylindole-6-carboxamidine (compound 10);

4-{[(3S)-1-((1S)-2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-(이소프로필)-2-옥소에틸)-2-옥소피롤리딘-3-일]아미노}부타노산(화합물 11);4-{[(3S) -1-((1S) -2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -1 -(Isopropyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] amino} butanoic acid (Compound 11);

2-{[(3S)-1-((1S)-2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소-1-벤질에틸)-2-옥소피롤리딘-3-일]아미노}아세트산(화합물 12);2-{[(3S) -1-((1S) -2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 -Oxo-1-benzylethyl) -2-oxopyrrolidin-3-yl] amino} acetic acid (compound 12);

2-{2-[1-(2-((3S)-3-아미노-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 13);2- {2- [1- (2-((3S) -3-Amino-2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl] ethyl} -1-ethylindole- 6-carboxamidine (Compound 13);

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-3-피페리딜]아미노}부타노산(화합물 14);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo-3-piperidyl] amino} butanoic acid (Compound 14);

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노프로파노산(화합물 15);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminopropanoic acid (compound 15);

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]-N-에틸카바모일}-(2S)-2-아미노프로파노산(화합물 16);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)]-N-ethylcarbamoyl}-(2S) -2-aminopropanoic acid (compound 16);

2-{2-[1-(2-((3S)-3-((3S)-3-아미노-3-카바모일-N-에틸프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 17);2- (2- [1- (2-((3S) -3-((3S) -3-amino-3-carbamoyl-N-ethylpropanoylamino) -2-oxopiperidyl) acetyl) -(2S) -pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 17);

(2R)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 18);(2R) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 18);

2-{2-[1-(2-((3S)-3-((3R)-3-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 19);2- {2- [1- (2-((3S) -3-((3R) -3-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) -Pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 19);

4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노부타노산(화합물 20);4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminobutanoic acid (compound 20);

2-{2-[1-(2-((3S)-3-((4S)-4-아미노-4-카바모일부타노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 21);2- {2- [1- (2-((3S) -3-((4S) -4-amino-4-carbamoylbutanoylamino) -2-oxopiperidyl) acetyl)-(2S)- Pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 21);

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-[(메틸설포닐)아미노]프로파노산(화합물 22);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-[(methylsulfonyl) amino] propanoic acid (compound 22);

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-(디에틸아미노)프로파노산(화합물 23);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2- (diethylamino) propanoic acid (compound 23);

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-하이드록시프로파노산(화합물 24);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-hydroxypropanoic acid (compound 24);

(2R)-4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노부타노산(화합물 25);(2R) -4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminobutanoic acid (compound 25);

2-{2-[1-(2-((3S)-3-((2S)-2-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 26);2- {2- [1- (2-((3S) -3-((2S) -2-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) -Pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 26);

2-{2-[1-(2-((3S)-3-((2R)-2-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 27);2- {2- [1- (2-((3S) -3-((2R) -2-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) -Pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 27);

2-{2-[(2S)-1-(2-((3S,6S)-3-아미노-6-(플루오로메틸)-2-옥소피페리딜)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 28);2- {2-[(2S) -1- (2-((3S, 6S) -3-amino-6- (fluoromethyl) -2-oxopiperidyl) acetyl) pyrrolidin-2-yl ] Ethyl} -1-ethylindole-6-carboxamidine (Compound 28);

(2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-(6S,3S)-6-(플루오로메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 29); 및(2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl)-(6S, 3S) -6- (fluoromethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 29); And

(2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-6-(메톡시메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 30).(2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -6- (methoxymethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 30).

상기 대표적인 화합물 중에서도 특히 바람직한 화합물의 예로는 다음과 같은 화합물이 언급될 수 있다:Among the representative compounds mentioned above, examples of particularly preferred compounds may include the following compounds:

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노산(화합물 2);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} butanoic acid (Compound 2);

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]에틸아미노}부타노산(화합물 5);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] ethylamino} butanoic acid (Compound 5);

(2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]카바모일}-2-아미노프로파노산(화합물 6);(2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] carbamoyl} -2-aminopropanoic acid (compound 6);

(2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]카바모일}-2-아미노프로파노산(화합물 9);(2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] carbamoyl} -2-aminopropanoic acid (compound 9);

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-3-피페리딜]아미노}부타노산(화합물 14);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo-3-piperidyl] amino} butanoic acid (Compound 14);

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노프로파노산(화합물 15);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminopropanoic acid (compound 15);

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]-N-에틸카바모일}-(2S)-2-아미노프로파노산(화합물 16);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)]-N-ethylcarbamoyl}-(2S) -2-aminopropanoic acid (compound 16);

4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노부타노산(화합물 20);4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminobutanoic acid (compound 20);

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-(디에틸아미노)프로파노산(화합물 23);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2- (diethylamino) propanoic acid (compound 23);

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-하이드록시프로파노산(화합물 24);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-hydroxypropanoic acid (compound 24);

(2R)-4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노부타노산(화합물 25);(2R) -4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminobutanoic acid (compound 25);

(2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-(6S,3S)-6-(플루오로메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 29); 및(2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl)-(6S, 3S) -6- (fluoromethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 29); And

(2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-6-(메톡시메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 30)(2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -6- (methoxymethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 30)

본 발명에 따른 화학식 (1)의 화합물은 또한 약제학적으로 허용되는 염을 형성할 수 있다. 이러한 약제학적으로 허용되는 염에는 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들면, 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산 또는 트리플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산 등과 같은 유기 카본산, 메탄설폰산, 벤젠설폰산, p-톨루엔설폰산 또는 나프탈설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함되며, 아울러 나트륨, 칼륨 등 알칼리금속과의 염이 포함된다. 그밖에도 방향족 아미딘 유도체 또는 락탐 유도체가 속하는 기술분야에서 공지되어 사용되고 있는 다른 산 또는 염기와의 염을 언급할 수 있다. 이들은 통상의 전환공정에 의하여 제조된다.The compounds of formula (1) according to the invention may also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, tartaric acid, formic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like. , Organic carbonic acids such as citric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalsulfonic acid Acid addition salts formed by phonic acid and the like are included, and salts with alkali metals such as sodium and potassium are also included. In addition, mention may be made of salts with other acids or bases known and used in the art to which the aromatic amidine derivatives or lactam derivatives belong. These are manufactured by the usual conversion process.

화학식 (1)의 화합물에서 피롤환의 2-번에 위치한 탄소원자는 비대칭중심을 이루고 있으며, 그밖에도 치환기 A, R1, R2및 R3의 종류에 따라 추가의 비대칭중심을 가질 수 있다. 따라서 화학식 (1)의 화합물은 R 이성체, S 이성체와 같은 거울상이성체(enantiomer), 부분입체이성체(diastereomer) 등의 순수 이성체 상태로 존재하거나, 라세미체를 포함한 그의 혼합물 상태로 존재할 수 있다. 따라서, 본 발명의 범위에는 이러한 입체화학적 이성체도 포함된다.In the compound of the formula (1), the carbon atom positioned at 2-position of the pyrrole ring forms an asymmetric center, and may have an additional asymmetric center depending on the type of substituents A, R 1 , R 2 and R 3 . Accordingly, the compound of formula (1) may exist in pure isomeric state such as enantiomers such as R isomers, S isomers, diastereomers, or mixtures thereof including racemates. Therefore, such stereochemically isomers are included in the scope of the present invention.

상기 정의한 바와 같은 신규한 화학식 (1)의 화합물은 하기 기술하는 방법에 의거하여 제조할 수 있으며, 따라서 본 발명은 또한 이러한 화학식 (1) 화합물의 제조방법을 제공함을 목적으로 한다.The novel compounds of formula (1) as defined above can be prepared based on the methods described below, and the present invention therefore also aims to provide a process for preparing such compounds of formula (1).

좀더 구체적으로, 화학식 (1)의 화합물은More specifically, the compound of formula (1)

(a) 하기 화학식 (6)의 화합물을 하기 화학식 (5)의 화합물과 축합반응시켜 하기 화학식 (4)의 화합물을 수득한 다음, 화학식 (4)의 화합물을 탈보호기화시켜 하기 화학식 (3)의 화합물을 수득하고, 생성된 화학식 (3) 화합물의 시아노 그룹을 아미디노 그룹으로 전환시켜 하기 화학식 (1a)의 화합물을 수득하거나,(a) Condensation reaction of a compound of formula (6) with a compound of formula (5) to yield a compound of formula (4), followed by deprotection of a compound of formula (4) To obtain a compound of formula (3) and convert the cyano group of the compound of formula (3) to an amidino group to obtain a compound of formula (1a)

(b) 화학식 (3)의 화합물을 하기 화학식 (7)의 화합물 및 하기 화학식 (8)의 화합물 중에서 선택된 어느 하나 또는 둘다와 커플링반응시켜 하기 화학식 (2)의 화합물을 수득한 다음, 생성된 화학식 (2) 화합물의 시아노 그룹을 아미디노 그룹으로 전환시켜 하기 화학식 (1b)의 화합물을 수득하거나,(b) coupling the compound of formula (3) with either or both of the compound of formula (7) and the compound of formula (8) to obtain a compound of formula (2) Converting the cyano group of the compound of formula (2) to an amidino group to obtain a compound of formula (1b)

(c) 필요에 따라 화학식 (1b)의 화합물을 가수분해시켜 카복시 그룹을 함유하는 화학식 (1)의 화합물을 수득함을 특징으로 하여 제조할 수 있다:(c) if necessary, hydrolysis of the compound of formula (1b) to obtain a compound of formula (1) containing a carboxy group:

(6) (6)

(5) (5)

(4) (4)

(3) (3)

(1a) (1a)

R2'-X (7)R 2 '-X (7)

R3'-X (8)R 3 '-X (8)

(2) (2)

(1b) (1b)

상기식에서In the above formula

A 및 R1은 앞에서 정의한 바와 같고,A and R 1 are as defined above,

P 는 아미노 보호기를 나타내며,P represents an amino protecting group,

R2'및 R3'는 각각 독립적으로 수소를 제외한 R2및 R3를 나타내고,R 2 ' and R 3' each independently represent R 2 and R 3 excluding hydrogen,

X 는 반응성 이탈기, 바람직하게는 하이드록시 또는 할로겐을 나타내며,X represents a reactive leaving group, preferably hydroxy or halogen,

m 및 n 은 각각 독립적으로 0 또는 1 의 정수를 나타내고,m and n each independently represent an integer of 0 or 1,

p 는 2-(m+n)의 정수를 나타낸다.p represents the integer of 2- (m + n).

상기 제조방법을 이하 보다 구체적으로 설명한다.The manufacturing method will be described in more detail below.

먼저, 방법 (a)에서 화학식 (6)의 화합물을 화학식 (5)의 화합물과 축합시키는 반응은 적절한 용매 및 축합제의 존재하에 통상적인 방법에 따라 수행된다. 이때, 용매로는 일반적으로 반응에 악영향을 미치지 않는 통상적인 것을 사용할 수 있으며, 바람직한 용매의 예로는 디클로로메탄, 디클로로에탄 등을 들 수 있다.또한, 바람직하게 사용되어질 수 있는 축합제로는 N,N-디에틸카보디이미드, 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 하이드로클로라이드[WSCI·HCl], N,N-디사이클로헥실카보디이미드 등과 같은 카보이미드 화합물을 언급할 수 있다. 이 반응은 필요에 따라 반응촉진제로서 1-하이드록시벤조트리아졸[HOBT] 등을, 산 수용체로서 N,N-디이소프로필에틸아민[DIPEA] 등을 사용하여 진행시킬 수 있다. 반응은 일반적으로 냉각 또는 가열하에서, 바람직하게는 0℃ 내지 20℃에서 수행한다.First, in the method (a), the reaction of condensing the compound of formula (6) with the compound of formula (5) is carried out according to a conventional method in the presence of a suitable solvent and condensing agent. In this case, as the solvent, a conventional solvent which generally does not adversely affect the reaction may be used, and examples of the preferred solvent include dichloromethane, dichloroethane, and the like. Further, as a condensing agent, which may be preferably used, N, N Carbodiimide compounds such as -diethylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride [WSCI.HCl], N, N-dicyclohexylcarbodiimide and the like can be mentioned. have. This reaction can be advanced if necessary using 1-hydroxybenzotriazole [HOBT] as a reaction promoter and N, N-diisopropylethylamine [DIPEA] as an acid acceptor. The reaction is generally carried out under cooling or heating, preferably at 0 ° C to 20 ° C.

출발물질로 사용된 화학식 (5)의 화합물은 문헌(참조:J. Med. Chem, 1996, 39,4531-4536;J. Org. Chem, 1982, 47,104-109;J. Org. Chem, 1984, 49,2286-2288;Tetrahedron: Asymmetry,Vol. 8, No. 2, 327-335, 1997 등)에 기재된 방법을 참고하여 제조할 수 있으며, 화학식 (6)의 화합물은 선출원인 대한민국 특허원 제97-22566호 명세서에 기재된 내용을 참고하여 제조할 수 있다.Compounds of formula (5) used as starting materials are described in J. Med. Chem, 1996, 39, 4531-4536; J. Org. Chem, 1982, 47, 104-109; J. Org.Chem , 1984, 49, 2286-2288; Tetrahedron: Asymmetry, Vol. 8, No. 2, 327-335, 1997, etc.), and the compounds of formula (6) are It may be prepared with reference to the contents described in the specification of 97-22566.

다음 단계로서, 상기 방법에 따라 수득된 화학식 (4)의 화합물에 존재하는 아미노 보호기를 제거하기 위한 탈보호기화 반응을 통하여 화학식 (3)의 화합물을 제조한다. 아미노 보호기로는 예를들어 3급-부톡시카보닐기를 사용할 수 있는데, 이 경우에는 카바메이트계 아미노 보호기를 제거하는 통상의 방법, 즉 산(포름산, 아세트산, 트리플루오로아세트산, 벤젠설폰산 등의 유기산 또는 염산, 황산, 인산 등의 무기산) 존재하에 가수분해시키는 방법을 이용하여 탈보호기화를 수행한다. 탈보호기화 반응은 일반적으로 반응에 악영향을 미치지 않는 통상적인 용매의 존재하에 수행하며, 바람직하게는 디클로로메탄, 클로로포름, 1,4-디옥산 등을 사용한다. 이때, 반응온도는 중요하지 않으며, 일반적으로 0℃ 내지 30℃에서 수행한다.As a next step, the compound of formula (3) is prepared through a deprotection reaction to remove amino protecting groups present in the compound of formula (4) obtained according to the above process. As the amino protecting group, for example, tert-butoxycarbonyl group may be used. In this case, a conventional method of removing a carbamate-based amino protecting group, that is, an acid (formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, etc.) In the presence of an organic acid or an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid) or the like. The deprotection reaction is generally carried out in the presence of a conventional solvent which does not adversely affect the reaction, preferably dichloromethane, chloroform, 1,4-dioxane and the like are used. At this time, the reaction temperature is not important and is generally performed at 0 ° C to 30 ° C.

화학식 (3)의 화합물에 존재하는 시아노 그룹을 아미디노 그룹으로 전환시켜 목적하는 화학식 (1)의 화합물을 제조하는 마지막 단계에서는, 화학식 (3)의 화합물을 할로겐화수소, 바람직하게는 염화수소 가스의 존재하에 반응시킨 다음 암모니아 가스를 반응액중에 주입하여 반응시키는 방법을 이용할 수 있다. 이 반응은 일반적으로 용매, 예를들면 에탄올, 프로판올 등의 C1-C4-알콜류, 디에틸에테르 등의 지방족 에테르류, 클로로포름 등의 할로겐화 탄화수소류, 벤젠 등의 비양자성 용매, N,N-디메틸포름아미드, 디메틸설폭사이드 등의 극성 용매 또는 이들의 혼합용매 중에서 수행할 수 있다. 특히 바람직하게는 에탄올 등과 같은 C1-C4-알콜을 용매로서 사용한다. 반응온도 및 시간은 특별히 중요하지 않으나, 일반적으로 냉각 또는 가열하에서 2 내지 72시간, 바람직하게는 0℃ 내지 30℃ 의 온도에서 12 내지 40시간 동안 수행한다.In the final step of converting the cyano group present in the compound of formula (3) to an amidino group to produce the desired compound of formula (1), the compound of formula (3) is subjected to hydrogen halide, preferably hydrogen chloride gas. After the reaction in the presence of ammonia gas can be injected into the reaction solution to react. This reaction is generally a solvent such as C 1 -C 4 -alcohols such as ethanol and propanol, aliphatic ethers such as diethyl ether, halogenated hydrocarbons such as chloroform, aprotic solvents such as benzene, and N, N- It may be carried out in a polar solvent such as dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof. Especially preferably, C 1 -C 4 -alcohol such as ethanol or the like is used as the solvent. The reaction temperature and time are not particularly important, but are generally carried out under cooling or heating for 2 to 72 hours, preferably for 12 to 40 hours at a temperature of 0 ° C to 30 ° C.

방법 (b)에서는 상기 방법 (a)의 두 번째 단계에서 생성된 화학식 (3)의 화합물을 출발물질로 사용한다. 즉, 화학식 (3)의 화합물을 화학식 (7)의 화합물 및 화학식 (8)의 화합물 중의 어느 하나 또는 이들 화합물 둘다와 커플링 반응시켜 화학식 (2)의 화합물을 수득한 후, 화학식 (2)의 화합물에 존재하는 시아노 그룹을 아미디노 그룹으로 전환시킴으로써 화학식 (1b)의 화합물을 제조한다. 커플링 반응은 바람직하게는 반응-불활성 용매의 존재하에서 수행할 수 있다. 이러한 목적으로 바람직하게 사용되어질 수 있는 용매로는 아세톤, 1,4-디옥산, 아세토니트릴, 클로로포름, 디클로로메탄, 디클로로에탄, 테트라하이드로푸란, 디메틸설폭사이드,N,N-디메틸포름아미드 또는 이들의 혼합물이 언급될 수 있다. 이 반응은 또한 필요에 따라 산수용체의 존재하에서 수행할 수 있으며, 이러한 목적으로 바람직하게 사용할 수 있는 산수용체로는 수산화나트륨, 수산화칼륨, 탄산나트륨, 탄산칼륨, 탄산마그네슘, 중탄산나트륨 등의 알칼리금속 또는 알칼리토금속의 수산화물, 탄산염 또는 중탄산염과 같은 무기염기 또는 트리에틸아민, 트리메틸아민, 피리딘, N,N-디이소프로필에틸아민 등의 유기염기 등을 언급할 수 있다. 특히 바람직한 산수용체는 트리에틸아민, 탄산칼륨, 탄산나트륨 또는 N,N-디이소프로필에틸아민이다. 이 반응은 또한, 필요에 따라 축합제의 존재하에 수행할 수 있으며, 이러한 목적으로 바람직하게 사용할 수 있는 축합제로는 N,N-디에틸카보디이미드, 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 하이드로클로라이드, N,N-디사이클로헥실카보디이미드 등과 같은 카보이미드 화합물을 들 수 있다. 축합제를 사용하는 경우, 반응 촉진제로서 1-하이드록시벤조트리아졸 등을, 산 수용체로서 N,N-디이소프로필에틸아민 등을 사용할 수 있다. 반응온도 및 시간은 특별히 중요하지 않으나, 일반적으로 냉각 내지 가열하에서 2 내지 24시간, 바람직하게는 0℃ 내지 70℃의 온도에서 2 내지 18시간 동안 반응을 수행하는 것이 적합하다.In method (b), the compound of formula (3) produced in the second step of method (a) is used as starting material. That is, the compound of formula (3) is reacted with any one or both of the compound of formula (7) and compound of formula (8) to obtain a compound of formula (2), and then Compounds of formula (1b) are prepared by converting cyano groups present in the compounds to amidino groups. The coupling reaction can preferably be carried out in the presence of a reaction-inert solvent. Solvents that may be preferably used for this purpose include acetone, 1,4-dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, dimethylsulfoxide, N, N-dimethylformamide or their Mixtures may be mentioned. This reaction can also be carried out in the presence of an acid acceptor, if necessary, and an acid acceptor which can be preferably used for this purpose includes alkali metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate or Inorganic bases such as hydroxides, carbonates or bicarbonates of alkaline earth metals or organic bases such as triethylamine, trimethylamine, pyridine, N, N-diisopropylethylamine, and the like. Particularly preferred acid acceptors are triethylamine, potassium carbonate, sodium carbonate or N, N-diisopropylethylamine. This reaction can also be carried out in the presence of a condensing agent if necessary, and condensing agents which can be preferably used for this purpose include N, N-diethylcarbodiimide, 1- (3-dimethylaminopropyl) -3 Carbodiimide compounds such as -ethylcarbodiimide hydrochloride, N, N-dicyclohexylcarbodiimide, and the like. When using a condensing agent, 1-hydroxybenzotriazole etc. can be used as a reaction promoter, N, N- diisopropylethylamine etc. can be used as an acid acceptor. The reaction temperature and time are not particularly important, but it is generally suitable to carry out the reaction for 2 to 24 hours under cooling to heating, preferably for 2 to 18 hours at a temperature of 0 ° C to 70 ° C.

상기 방법에 따라 수득된 화학식 (2)의 화합물에 존재하는 시아노 그룹을 아미디노 그룹으로 전환시켜 화학식 (1b)의 화합물을 수득하는 과정은 상기 방법 (a)에 대해 설명한 것을 참고로 하여 수행할 수 있다.The process of converting the cyano group present in the compound of formula (2) obtained according to the above method into an amidino group to obtain the compound of formula (1b) can be carried out with reference to the above description for the method (a). Can be.

한편, 상기 방법 (c)에서 설명한 바와 같이, 방법 (b)에서 수득된 화학식 (1b)의 화합물에서 R2'및 R3'중의 어느 하나 또는 둘다가 카바모일 또는 에스테르형태인 경우에는, 이를 가수분해 반응시켜 에스테르 또는 카바모일이 카복시로 전환된 화학식 (1)의 화합물을 제조할 수 있다. 가수분해 반응은 물, 알콜류 및 테트라하이드로푸란 중에서 선택된 1종 이상의 용매중에서 알칼리금속의 수산화물과 같은 염기 또는 무기산의 존재하에 수행할 수 있다. 특히 바람직한 용매로는 물과 알콜의 혼합용매를 들 수 있고, 염기로는 수산화칼륨, 수산화나트륨 또는 수산화리튬을 바람직하게 사용할 수 있으며, 무기산으로는 염산이 바람직하다. 반응온도 및 시간은 특별히 중요하지 않으나, 일반적으로 냉각 또는 가열하에서 2 내지 72시간, 바람직하게는 0℃ 내지 30℃ 의 온도에서 12 내지 24시간 동안 수행한다.On the other hand, as described in the above method (c), when either or both of R 2 ' and R 3' in the compound of the formula (1b) obtained in the method (b) is carbamoyl or ester form, The decomposition reaction may produce a compound of formula (1) in which ester or carbamoyl is converted to carboxy. The hydrolysis reaction can be carried out in the presence of a base or an inorganic acid such as a hydroxide of an alkali metal in at least one solvent selected from water, alcohols and tetrahydrofuran. As a particularly preferable solvent, a mixed solvent of water and an alcohol is mentioned, and as a base, potassium hydroxide, sodium hydroxide, or lithium hydroxide can be used preferably, and hydrochloric acid is preferable as an inorganic acid. The reaction temperature and time are not particularly important but are generally carried out under cooling or heating for 2 to 72 hours, preferably for 12 to 24 hours at a temperature of 0 ° C to 30 ° C.

상기 설명된 제조방법들은 후술하는 실시예를 통하여 보다 구체적으로 설명될 것이다.The manufacturing methods described above will be described in more detail through the following examples.

한편, 본 발명에 따른 화학식 (1)의 화합물은 상술한 바와 같이 우수한 선택적 트롬빈 억제활성을 가지고 있으며, 따라서 본 발명은 활성성분으로서 유효량의 화학식 (1)의 화합물, 그의 약제학적으로 허용되는 염 또는 입체화학적 이성체와 약제학적으로 허용되는 담체를 함유하는 트롬빈 억제제 조성물에 관한 것이다.On the other hand, the compound of formula (1) according to the present invention has excellent selective thrombin inhibitory activity as described above, and therefore the present invention provides an effective amount of the compound of formula (1), a pharmaceutically acceptable salt thereof or A thrombin inhibitor composition containing a stereochemical isomer and a pharmaceutically acceptable carrier.

본 발명에 따르는 조성물은 강력한 트롬빈 억제활성을 나타내기 때문에 혈전증 예방 및 치료제로서 유용하게 사용될 수 있다. 특히, 본 발명에 따른 화학식 (1)의 화합물은 특히 경구투여에 의해서 강력한 효과를 나타내기 때문에 이러한 목적에 매우 유용하게 사용될 수 있을 것으로 기대된다.Since the composition according to the present invention exhibits strong thrombin inhibitory activity, it can be usefully used as an agent for preventing and treating thrombosis. In particular, it is expected that the compound of the formula (1) according to the present invention can be very useful for this purpose because it shows a strong effect, especially by oral administration.

본 발명의 화합물은 임상적인 목적으로 투여시에 1일 유효용량은 일반적으로 체중 1㎏당 0.1 내지 50㎎, 바람직하게는 0.5 내지 20㎎의 범위가 적당하나, 개개환자에게 적합한 투여용량은 투여될 특정화합물, 환자의 체중, 성, 건강상태, 식이, 투여시간, 투여방법, 배설률, 병용하는 약제의 종류 및 질환의 중증도 등을 고려하여 전문가에 의해 임의로 결정될 수도 있다.The compound of the present invention, when administered for clinical purposes, generally has a suitable daily dose in the range of 0.1 to 50 mg, preferably 0.5 to 20 mg, per kg of body weight. It may be arbitrarily determined by an expert in consideration of the specific compound, the weight of the patient, sex, health condition, diet, time of administration, method of administration, rate of excretion, the type of medication used and the severity of the disease.

본 발명의 화합물은 목적하는 바에 따라 경구용 제제 및 주사용 제제로 투여 할 수 있다.The compounds of the present invention can be administered in oral and injectable formulations as desired.

경구투여용 고체투여 형태는 캅셀제, 정제, 환제, 산제 및 입제가 가능하고, 그 중에서도 특히 캅셀제와 정제가 유용하다. 정제 및 환제는 장용피제로 제조하는 것이 바람직하다. 고체투여 형태는 본 발명에 따른 화학식 (1)의 활성화합물을 슈크로오즈, 락토오즈, 전분 등과 같은 하나 이상의 불활성 희석제, 마그네슘 스테아레이트와 같은 윤활제, 붕해제, 결합제 등과 같은 담체와 혼합시킴으로써 제조할 수 있다.Solid dosage forms for oral administration may be capsules, tablets, pills, powders, and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably prepared with enteric coatings. Solid dosage forms may be prepared by mixing the active compound of formula (1) according to the invention with a carrier such as one or more inert diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrants, binders and the like. Can be.

상기 언급한 바와 같이, 본 발명에 따른 화학식 (1)의 화합물을 함유하는 조성물은 경구투여용 제제로 제형화하여 사용하는 경우 우수한 약효를 나타낸다는 특징을 가지고 있으며, 이러한 사실은 쥐 및 개를 실험동물로 약물동력학 실험을 수행한 결과 본 발명의 약제학적 조성물을 경구로 투여한 경우 약물이 혈중에서 오래 유지되는 특성이 있음을 확인함으로써 입증되었다.As mentioned above, the composition containing the compound of the formula (1) according to the present invention is characterized by excellent efficacy when formulated and used as an oral dosage form, and this fact indicates that mice and dogs have been tested. Pharmacokinetic experiments with animals have been demonstrated by confirming that the drug has a long lasting property in the blood when orally administered the pharmaceutical composition of the present invention.

따라서, 본 발명에 따른 화합물은 기존에 개발된 어떠한 트롬빈 억제제 보다도 경구형 제제로서 효과적으로 사용될 수 있으며, 이점에서 더욱 유용하리라고 생각된다.Thus, the compounds according to the invention can be used more effectively as oral formulations than any previously developed thrombin inhibitors, and are believed to be more useful in this respect.

화학식 (1)의 화합물을 함유하는 조성물은 또한 당업계에 공지된 기술에 따라 적합한 분산제, 습윤제 또는 현탁화제를 사용하여 주사용 제제, 예를 들면 멸균 주사용 수성 또는 유성 현탁액 형태로 제조할 수도 있다. 이때, 사용될 수 있는 수성 용매에는 물, 링거액 또는 등장성 NaCl용액이 있으며, 멸균 고정오일은 통상적으로 용매 또는 현탁매질로서 사용한다. 모노-, 디-글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있으며, 또한 올레산과 같은 지방산도 주사용 제제에 사용할 수 있다.Compositions containing a compound of formula (1) may also be prepared in the form of injectable preparations, for example sterile injectable aqueous or oily suspensions, using suitable dispersing, wetting or suspending agents according to techniques known in the art. . At this time, the aqueous solvent that can be used is water, Ringer's solution or isotonic NaCl solution, sterile fixed oil is usually used as a solvent or suspending medium. Any non-irritating fixed oil may be used for this purpose, including mono- and diglycerides, and fatty acids such as oleic acid may also be used in the preparation of injectables.

또한, 실험결과에 따르면 화학식 (1)의 화합물은 쥐 및 개와 같은 포유류에 대해 급성독성을 나타내지 않으면서 목적하는 강력한 트롬빈 억제효과를 나타내는 것을 확인할 수 있었다.In addition, the experimental results showed that the compound of formula (1) exhibited the desired powerful thrombin inhibitory effect without showing acute toxicity against mammals such as mice and dogs.

이하, 본 발명을 하기 실시예 및 실험예에 의하여 더욱 구체적으로 설명한다. 그러나, 이들 실시예 및 실험예는 하나의 예시일 뿐, 어떤 식으로든 본 발명의 범위가 이들에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following Examples and Experimental Examples. However, these Examples and Experimental Examples are only examples and the scope of the present invention is not limited by them in any way.

실시예 1:Example 1:

2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소아자퍼하이드로에피닐)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 1)의 합성2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxoazahydrohydropinyl) acetyl) pyrrolidin-2-yl] ethyl} -1-ethylindole Synthesis of -6-Carboxamidine (Compound 1)

a) 2-{(3S)-3-[(t-부톡시)카보닐아미노]-2-옥소아자퍼하이드로에피닐}아세트 산의 합성a) Synthesis of 2-{(3S) -3-[(t-butoxy) carbonylamino] -2-oxoazahydrohydroepinyl} acetic acid

N-(3S)-2-옥소아자퍼하이드로에핀-3-일(t-부톡시)카복스아미드(1.0g)를 THF (20㎖)에 녹인 후, 리튬 비스(트리메틸실릴)아미드 1.0M THF 용액(5.26㎖)을 적가하고 실온에서 30분동안 교반하였다. 반응액을 빙욕(ice bath)중에서 냉각시키고에틸 브로모아세테이트(0.64㎖)를 적가한 후 2시간 동안 더 교반하였다. 반응액에 물을 가하고 메틸렌클로라이드로 추출한 후 유기층을 무수 황산나트륨으로 건조시켰다. 이것을 여과하고 감압농축하여 얻은 잔류물을 n-헥산:에틸아세테이트=2:1 (v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 미황색의 오일을 수득하였다. 이를 물(10㎖)과 메탄올(20㎖)의 혼합용매에 용해시키고 수산화칼륨(85%; 756mg)을 가한 후 실온에서 3시간동안 교반하였다. 감압농축하여 용매를 제거하고 10% 시트르산 용액으로 pH 4까지 산성화시킨 후 에틸아세테이트로 추출하였다. 유기층을 무수 황산마그네슘으로 건조시키고, 여과하고, 감압농축하고, 진공건조시켜 흰색의 거품상으로 표제화합물(1.68g)을 수득하였다.N- (3S) -2-oxoazahydrohydropin-3-yl (t-butoxy) carboxamide (1.0 g) was dissolved in THF (20 mL), followed by 1.0 M of lithium bis (trimethylsilyl) amide. THF solution (5.26 mL) was added dropwise and stirred at room temperature for 30 minutes. The reaction solution was cooled in an ice bath, ethyl bromoacetate (0.64 mL) was added dropwise, and further stirred for 2 hours. Water was added to the reaction mixture, the mixture was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by filtration and concentration under reduced pressure was purified by silica gel column chromatography using n-hexane: ethyl acetate = 2: 1 (v / v) as eluent to obtain a pale yellow oil. This was dissolved in a mixed solvent of water (10 mL) and methanol (20 mL), potassium hydroxide (85%; 756 mg) was added, followed by stirring at room temperature for 3 hours. The solvent was removed by concentration under reduced pressure, acidified to pH 4 with 10% citric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried in vacuo to yield the title compound (1.68 g) as a white foam.

1H-NMR(300MHz, CDCl3) δ: 5.90(d, 1H, J=6.2Hz), 4.43-4.38(m, 1H), 4.21 (d, 2H, J=1.9Hz), 3.66-3.75(m, 1H), 3.20-3.25(m, 1H), 1.98-2.09(m, 2H), 1.83- 1.76(m, 3H), 1.63-1.58(m, 1H), 1.44(s, 9H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 5.90 (d, 1H, J = 6.2 Hz), 4.43-4.38 (m, 1H), 4.21 (d, 2H, J = 1.9 Hz), 3.66-3.75 (m , 1H), 3.20-3.25 (m, 1H), 1.98-2.09 (m, 2H), 1.83-1.76 (m, 3H), 1.63-1.58 (m, 1H), 1.44 (s, 9H)

b) N-{(3S)-1-[2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2 -옥소에틸]-2-옥소아자퍼하이드로에핀-3-일}(t-부톡시)카복스아미드의 합성b) N-{(3S) -1- [2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl ] -2-Oxoazahydrohydropin-3-yl} (t-butoxy) carboxamide

2-[2-((2S)-피롤리딘-2-일)에틸]-1-에틸인돌-6-카보니트릴(400mg, 참조: 대한민국 특허출원 제97-22566호)과 상기 a)에서 수득한 화합물(515mg)을 메틸렌클로라이드(20㎖)에 용해시킨 후, 여기에 DIPEA(0.32㎖), HOBT(238mg) 및 WSCI·HCl (373mg)을 차례로 가하고 실온에서 3시간동안 교반하였다. 반응액에 물을 가하고 메틸렌클로라이드로 추출한 후 유기층을 무수 황산나트륨으로 건조시켰다. 여과하고 감압농축하여 얻은 잔류물을 메틸렌클로라이드:메탄올=40:1(v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 흰색 거품상의 표제화합물 (590mg)을 수득하였다.Obtained from 2- [2-((2S) -pyrrolidin-2-yl) ethyl] -1-ethylindole-6-carbonitrile (400 mg, see Korean Patent Application No. 97-22566) and a) above. One compound (515 mg) was dissolved in methylene chloride (20 mL), then DIPEA (0.32 mL), HOBT (238 mg) and WSCI.HCl (373 mg) were added sequentially and stirred at room temperature for 3 hours. Water was added to the reaction mixture, the mixture was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by filtration and concentrated under reduced pressure was purified by silica gel column chromatography using methylene chloride: methanol = 40: 1 (v / v) as an eluent to obtain the title compound (590 mg) as a white foam.

1H-NMR(300MHz, CDCl3) δ: 7.61-7.53(m, 2H), 7.29-7.26(m, 1H), 6.36(s, 1H), 5.77-5.75(m, 1H), 4.43-4.41(m, 1H), 4.26-4.05(m, 5H), 3.75-3.72(m, 1H), 3.52-3.49(m, 2H), 3.26-3.21(m, 1H), 2.78-2.75(m, 2H), 2.27-2.24(m, 1H), 2.08-1.97(m, 5H), 1.79-1.74(m, 6H), 1.44(s, 9H), 1.38-1.34(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.61-7.53 (m, 2H), 7.29-7.26 (m, 1H), 6.36 (s, 1H), 5.77-5.75 (m, 1H), 4.43-4.41 ( m, 1H), 4.26-4.05 (m, 5H), 3.75-3.72 (m, 1H), 3.52-3.49 (m, 2H), 3.26-3.21 (m, 1H), 2.78-2.75 (m, 2H), 2.27-2.24 (m, 1H), 2.08-1.97 (m, 5H), 1.79-1.74 (m, 6H), 1.44 (s, 9H), 1.38-1.34 (m, 3H)

c) 2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소아자퍼하이드로에피닐)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘의 합성c) 2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxoazahydrohydropinyl) acetyl) pyrrolidin-2-yl] ethyl} -1- Synthesis of ethylindole-6-carboxamidine

상기 b)에서 수득한 화합물(100mg)을 HCl 가스로 포화시킨 에탄올(5㎖)에 용해시킨 후 실온에서 18시간동안 교반하였다. 반응액을 감압하에 농축하고 진공건조시켜 얻은 잔류물을 암모니아 가스로 포화시킨 에탄올(5㎖)에 용해시키고 실온에서 2일간 교반하였다. 반응액을 감압하에 농축시켜 얻은 잔류물을 에틸아세테이트:메탄올=3:1(v/v)을 용출제로 사용하는 NH-실리카 칼럼 크로마토그래피로 정제하여 미황색 고체상의 표제화합물(15mg)을 수득하였다.The compound (100 mg) obtained in b) was dissolved in ethanol (5 mL) saturated with HCl gas, and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained by vacuum drying was dissolved in ethanol (5 ml) saturated with ammonia gas and stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by NH-silica column chromatography using ethyl acetate: methanol = 3: 1 (v / v) as eluent to obtain the title compound (15 mg) as a pale yellow solid.

ES-MS : 453(M+1)+ ES-MS: 453 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.83-7.81(m, 1H), 7.57-7.52(m, 1H), 7.35-7.31 (m, 1H), 6.38(s, 1H), 4.35-4.19(m, 5H), 4.00-3.93(m, 1H), 3.82-3.78(m, 1H),3.52-3.46(m, 3H), 2.77-2.74(m, 2H), 2.16-2.12(m, 1H), 1.96-1.91(m, 5H), 1.77-1.51(m, 6H), 1.31-1.27(m, 3H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.83-7.81 (m, 1H), 7.57-7.52 (m, 1H), 7.35-7.31 (m, 1H), 6.38 (s, 1H), 4.35-4.19 (m, 5H), 4.00-3.93 (m, 1H), 3.82-3.78 (m, 1H), 3.52-3.46 (m, 3H), 2.77-2.74 (m, 2H), 2.16-2.12 (m, 1H) , 1.96-1.91 (m, 5H), 1.77-1.51 (m, 6H), 1.31-1.27 (m, 3H)

IR(KBr) cm-1: 3300, 1640, 1530, 1470IR (KBr) cm -1 : 3300, 1640, 1530, 1470

실시예 2:Example 2:

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노산 (화합물 2)의 합성4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) Synthesis of -2-oxoazahydrohydropin-3-yl] amino} butanoic acid (Compound 2)

a) 2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소아자퍼하이드로에피닐)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카보니트릴의 합성a) 2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxoazahydrohydropinyl) acetyl) pyrrolidin-2-yl] ethyl} -1- Synthesis of Ethylindole-6-carbonitrile

실시예 1-b)에서 수득한 화합물(480mg)을 메틸렌클로라이드(10㎖)에 용해시킨 후 빙냉하에서 트리플루오로아세트산(5㎖)을 적가하고 3시간동안 교반하였다. 용매를 감압농축하여 제거한 후 포화 중탄산나트륨 수용액을 가하여 pH 9로 조절하고 메틸렌클로라이드로 추출하였다. 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압농축하여 얻은 잔류물을 메틸렌클로라이드:메탄올=10:1(v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 미황색 거품상의 표제화합물(320mg)을 수득하였다.The compound (480 mg) obtained in Example 1-b) was dissolved in methylene chloride (10 mL), and then trifluoroacetic acid (5 mL) was added dropwise under ice cooling, followed by stirring for 3 hours. The solvent was removed by concentration under reduced pressure, and then saturated aqueous sodium bicarbonate solution was adjusted to pH 9 and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methylene chloride: methanol = 10: 1 (v / v) as eluent to give a pale yellow foamy title compound (320 mg). ) Was obtained.

1H-NMR(300MHz, CDCl3) δ: 7.61-7.53(m, 2H), 7.29-7.26(m, 1H), 6.37(s, 1H), 4.36-3.98(m, 5H), 3.75-3.71(m, 2H), 3.52-3.48(m, 2H), 3.21-3.17(m, 1H), 2.78-2.74(m, 2H), 2.26-2.22(m, 1H), 2.09-1.97(m, 5H), 1.78-1.67(m, 6H), 1.35(3t, H, J=7.2Hz) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.61-7.53 (m, 2H), 7.29-7.26 (m, 1H), 6.37 (s, 1H), 4.36-3.98 (m, 5H), 3.75-3.71 ( m, 2H), 3.52-3.48 (m, 2H), 3.21-3.17 (m, 1H), 2.78-2.74 (m, 2H), 2.26-2.22 (m, 1H), 2.09-1.97 (m, 5H), 1.78-1.67 (m, 6H), 1.35 (3t, H, J = 7.2 Hz)

b) 에틸 4-{[(3S)-1-(2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노에이트의 합성b) ethyl 4-{[(3S) -1- (2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2- Synthesis of oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} butanoate

상기 a)에서 수득한 화합물(180mg)을 아세토니트릴(10㎖)에 녹인 후, 여기에 디이소프로필에틸아민(0.097㎖)과 에틸 4-브로모부티레이트(0.072㎖)를 가하고 환류온도에서 3시간동안 교반하였다. 반응액을 감압농축하여 얻은 잔류물을 메틸렌클로라이드:메탄올=20:1(v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 흰색 거품상의 표제화합물(110mg)을 수득하였다.The compound (180 mg) obtained in a) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (0.097 mL) and ethyl 4-bromobutyrate (0.072 mL) were added thereto, and the mixture was refluxed for 3 hours. Was stirred. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography using methylene chloride: methanol = 20: 1 (v / v) as an eluent to obtain the title compound (110 mg) as a white foam.

1H-NMR(300MHz, CDCl3) δ: 7.63-7.53(m, 2H), 7.32-7.27(m, 1H), 6.37(s, 1H), 4.29-3.96(m, 8H), 3.74-3.69(m, 2H), 3.46-3.43(m, 1H), 3.26-3.12(m, 3H), 2.89-2.78(m, 2H), 2.54-2.47(m, 2H), 2.30-2.25(m, 1H), 2.09-2.01(m, 5H), 1.80-1.75(m, 6H), 1.62-1.57(m, 2H), 1.35(t, 3H, J=7.2Hz), 1.24(t, 3H, J=7.1Hz) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.63-7.53 (m, 2H), 7.32-7.27 (m, 1H), 6.37 (s, 1H), 4.29-3.96 (m, 8H), 3.74-3.69 ( m, 2H), 3.46-3.43 (m, 1H), 3.26-3.12 (m, 3H), 2.89-2.78 (m, 2H), 2.54-2.47 (m, 2H), 2.30-2.25 (m, 1H), 2.09-2.01 (m, 5H), 1.80-1.75 (m, 6H), 1.62-1.57 (m, 2H), 1.35 (t, 3H, J = 7.2 Hz), 1.24 (t, 3H, J = 7.1 Hz)

c)4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노산의 합성c) 4-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of ethyl) -2-oxoazahydrohydropin-3-yl] amino} butanoic acid

상기 b)에서 수득한 화합물(140mg)을 HCl 가스로 포화시킨 에탄올(10㎖)에 용해시킨 후 실온에서 18시간동안 교반하였다. 반응액을 감압하에 농축시키고 진공건조시켜 얻은 잔류물을 암모니아 가스로 포화시킨 에탄올(10㎖)에 용해시킨 후 실온에서 2일간 교반하였다. 용매를 감압농축하여 제거함으로써 수득한 잔류물을 물(3㎖)과 에탄올(6㎖)의 혼합용매에 용해시키고, 85% 수산화칼륨(27mg)을 가한 후 실온에서 1일간 교반하였다. 용매를 감압농축하여 제거함으로써 수득한 잔류물을에틸아세테이트:메탄올=1:1(v/v)을 용출제로 사용하는 NH-실리카 칼럼 크로마토그래피로 정제하여 흰색 고체상의 표제화합물(40mg)을 수득하였다.Compound (140 mg) obtained in b) was dissolved in ethanol (10 mL) saturated with HCl gas and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained by vacuum drying was dissolved in ethanol (10 ml) saturated with ammonia gas and stirred at room temperature for 2 days. The residue obtained by concentration of the solvent under reduced pressure was dissolved in a mixed solvent of water (3 ml) and ethanol (6 ml), and 85% potassium hydroxide (27 mg) was added, followed by stirring at room temperature for 1 day. The residue obtained by concentration of the solvent under reduced pressure was purified by NH-silica column chromatography using ethyl acetate: methanol = 1: 1 (v / v) as eluent to obtain the title compound (40 mg) as a white solid. .

ES-MS : 539(M+1)+ ES-MS: 539 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.88-7.86(m, 1H), 7.54-7.50(m, 1H), 7.36-7.33 (m, 1H), 6.33(s, 1H), 4.39-4.36(m, 1H), 4.22-4.18(m, 3H), 3.96-3.88(m, 2H), 3.58-3.50(m, 4H), 3.25-3.21(m, 2H), 2.76-2.73(m, 2H), 2.53-2.48(m, 2H), 2.08-1.66(m, 14H), 1.26(t, 3H, J=7.2Hz) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.88-7.86 (m, 1H), 7.54-7.50 (m, 1H), 7.36-7.33 (m, 1H), 6.33 (s, 1H), 4.39-4.36 (m, 1H), 4.22-4.18 (m, 3H), 3.96-3.88 (m, 2H), 3.58-3.50 (m, 4H), 3.25-3.21 (m, 2H), 2.76-2.73 (m, 2H) , 2.53-2.48 (m, 2H), 2.08-1.66 (m, 14H), 1.26 (t, 3H, J = 7.2 Hz)

IR(KBr) cm-1: 3400, 1640, 1570, 1410IR (KBr) cm -1 : 3400, 1640, 1570, 1410

실시예 3:Example 3:

2-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}아세트산 (화합물 3)의 합성2-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) Synthesis of 2-oxoazahydrohydropin-3-yl] amino} acetic acid (Compound 3)

a) 에틸 2-{[(3S)-1-(2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}아세테이트의 합성a) ethyl 2-{[(3S) -1- (2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2- Synthesis of oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} acetate

실시예 2-a)에서 수득한 화합물(140mg)을 메틸렌클로라이드(7㎖)에 용해시키고, 여기에 트리에틸아민(0.059㎖)과 에틸 브로모아세테이트(0.043㎖)를 가한 후 실온에서 2시간 교반하였다. 반응액을 환류온도에서 다시 3시간 동안 교반하였다. 용매를 감압농축하여 수득한 잔류물을 메틸렌클로라이드:메탄올=20:1(v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 미황색 거품상의 표제화합물(130mg)을 수득하였다.The compound (140 mg) obtained in Example 2-a) was dissolved in methylene chloride (7 mL), to which triethylamine (0.059 mL) and ethyl bromoacetate (0.043 mL) were added, followed by stirring at room temperature for 2 hours. It was. The reaction solution was stirred again at reflux for 3 hours. The residue obtained by concentration of the solvent under reduced pressure was purified by silica gel column chromatography using methylene chloride: methanol = 20: 1 (v / v) as an eluent to obtain the title compound (130 mg) as a slightly yellow foam.

1H-NMR(300MHz, CDCl3) δ: 7.61-7.53(m, 2H), 7.31-7.23(m, 1H), 6.37(s, 1H), 4.36-3.96(m, 8H), 3.61-3.38(m, 6H), 2.80-2.74(m, 2H), 2.30-2.24(m, 1H), 1.98-1.85(m, 5H), 1.80-1.73(m, 6H), 1.35(t, 3H, J=7.2Hz), 1.27-1.22(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.61-7.53 (m, 2H), 7.31-7.23 (m, 1H), 6.37 (s, 1H), 4.36-3.96 (m, 8H), 3.61-3.38 ( m, 6H), 2.80-2.74 (m, 2H), 2.30-2.24 (m, 1H), 1.98-1.85 (m, 5H), 1.80-1.73 (m, 6H), 1.35 (t, 3H, J = 7.2 Hz), 1.27-1.22 (m, 3H)

b) 2-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}아세트산의 합성b) 2-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of Ethyl) -2-oxoazahydrohydropin-3-yl] amino} acetic acid

상기 a)에서 수득한 화합물(120mg)을 실시예 2-c)에서와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(35mg)을 수득하였다.The compound (120 mg) obtained in a) was reacted in the same manner as in Example 2-c) to give the title compound (35 mg) in white solid state.

ES-MS : 511(M+1)+ ES-MS: 511 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.89-7.82(m, 1H), 7.52-7.48(m, 1H), 7.35-7.29 (m, 1H), 6.31(s, 1H), 4.38-4.35(m, 1H), 4.23-4.16(m, 3H), 3.95-3.81(m, 2H), 3.55-3.48(m, 4H), 3.21-3.10(m, 2H), 2.74-2.71(m, 2H), 2.07-1.79(m, 6H), 1.63-1.46(m, 6H), 1.26(t, 3H, J=7.2Hz) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.89-7.82 (m, 1H), 7.52-7.48 (m, 1H), 7.35-7.29 (m, 1H), 6.31 (s, 1H), 4.38-4.35 (m, 1H), 4.23-4.16 (m, 3H), 3.95-3.81 (m, 2H), 3.55-3.48 (m, 4H), 3.21-3.10 (m, 2H), 2.74-2.71 (m, 2H) , 2.07-1.79 (m, 6H), 1.63-1.46 (m, 6H), 1.26 (t, 3H, J = 7.2 Hz)

IR(KBr) cm-1: 3350, 1640, 1590, 1530, 1470, 1410IR (KBr) cm -1 : 3350, 1640, 1590, 1530, 1470, 1410

실시예 4:Example 4:

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-메틸-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노산(화합물 4)의 합성4-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -1-methyl-2 Synthesis of -oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} butanoic acid (Compound 4)

a) 2-{(3S)-3-[(t-부톡시)카보닐아미노]-2-옥소아자퍼하이드로에피닐}프로파노산의 합성a) Synthesis of 2-{(3S) -3-[(t-butoxy) carbonylamino] -2-oxoazahydrohydropinyl} propanoic acid

N-(3S)-2-옥소아자퍼하이드로에핀-3-일(t-부톡시)카복스아미드(1g)와 에틸 2-브로모프로파노에이트(0.74㎖)를 실시예 1-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(869mg)을 수득하였다.Example 1-a) N- (3S) -2-oxoazahydrohydropin-3-yl (t-butoxy) carboxamide (1 g) and ethyl 2-bromopropanoate (0.74 mL) The reaction was carried out in the same manner as in to obtain the title compound (869 mg) in the form of a white foam.

1H-NMR(300MHz, CDCl3) δ: 5.95(brs, 1H), 5.20-5.04(m, 1H), 4.40-4.28(m, 1H), 3.48-3.18(m, 2H), 2.06-1.50(m, 6H), 1.42(s, 9H), 1.34-1.32(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 5.95 (brs, 1H), 5.20-5.04 (m, 1H), 4.40-4.28 (m, 1H), 3.48-3.18 (m, 2H), 2.06-1.50 ( m, 6H), 1.42 (s, 9H), 1.34-1.32 (m, 3H)

b) 2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소아자퍼하이드로에피닐)프로파노일)피롤리딘-2-일]에틸}-1-에틸인돌-6-카보니트릴의 합성b) 2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxoazahydrohydroepinyl) propanoyl) pyrrolidin-2-yl] ethyl}- Synthesis of 1-ethylindole-6-carbonitrile

2-[2-((2S)-피롤리딘-2-일)에틸]-1-에틸인돌-6-카보니트릴(700mg)과 상기 a)에서 수득한 화합물(837mg)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 미황색 오일상의 N-{(3S)-1-[2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)- 1-메틸-2-옥소에틸]-2-옥소아자퍼하이드로에핀-3-일}(t-부톡시)카복스아미드를 수득하였다. 이것을 다시 실시예 2-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(628mg)을 수득하였다.2- [2-((2S) -pyrrolidin-2-yl) ethyl] -1-ethylindole-6-carbonitrile (700 mg) and the compound obtained in a) (837 mg) were prepared in Example 1-b. N-{(3S) -1- [2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) in light yellow oil Pyrrolidinyl) -1-methyl-2-oxoethyl] -2-oxoazahydrohydropin-3-yl} (t-butoxy) carboxamide was obtained. This was again reacted in the same manner as in Example 2-a) to give the title compound (628 mg) in the form of a white foam.

ES-MS : 550(M+1)+ ES-MS: 550 (M + 1) +

1H-NMR(300MHz, CDCl3) δ: 7.59-7.53(m, 2H), 7.30-7.28(m, 1H), 6.40-6.37 (m, 1H), 5.41-5.36(m, 1H), 4.40-4.31(m, 1H), 4.22-4.10(m, 2H), 3.67-3.61(m,1H), 3.54-3.40(m, 2H), 3.30-3.16(m, 2H), 2.78-2.72(m, 2H), 2.38-2.22(m, 2H), 2.05-1.63(m, 11H), 1.38-1.32(m, 6H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.59-7.53 (m, 2H), 7.30-7.28 (m, 1H), 6.40-6.37 (m, 1H), 5.41-5.36 (m, 1H), 4.40- 4.31 (m, 1H), 4.22-4.10 (m, 2H), 3.67-3.61 (m, 1H), 3.54-3.40 (m, 2H), 3.30-3.16 (m, 2H), 2.78-2.72 (m, 2H ), 2.38-2.22 (m, 2H), 2.05-1.63 (m, 11H), 1.38-1.32 (m, 6H)

c) 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-메틸-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노산의 합성c) 4-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -1-methyl 2-oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} butanoic acid

상기 b)에서 수득한 화합물(417mg)을 실시예 2-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 에틸 4-{[(3S)-1-(2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-메틸-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노에이트를 수득하였다. 이것을 다시 실시예 2-c)에서와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(130mg)을 수득하였다.The compound (417 mg) obtained in the above b) was reacted in the same manner as in Example 2-b) to obtain ethyl 4-{[(3S) -1- (2-((2S) -2- (2) as a white foam. -(6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -1-methyl-2-oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} butano Obtained. This was again reacted in the same manner as in Example 2-c) to give the title compound (130 mg) as a pale yellow solid.

ES-MS : 277(1/2M+1)+ ES-MS: 277 (1 / 2M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.92(s, 1H), 7.61-7.58(m, 1H), 7.42-7.38(m, 1H), 6.42(s, 1H), 5.30-5.26(m, 1H), 4.30-4.16(m, 4H), 3.60-3.38(m, 6H), 2.83- 2.78(m, 2H), 2.60-2.50(m, 2H), 2.15-1.65(m, 14H), 1.36-1.24(m, 6H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.92 (s, 1H), 7.61-7.58 (m, 1H), 7.42-7.38 (m, 1H), 6.42 (s, 1H), 5.30-5.26 (m , 1H), 4.30-4.16 (m, 4H), 3.60-3.38 (m, 6H), 2.83-2.78 (m, 2H), 2.60-2.50 (m, 2H), 2.15-1.65 (m, 14H), 1.36 -1.24 (m, 6H)

IR(KBr) cm-1: 3400, 2950, 1630, 1570, 1530, 1470IR (KBr) cm -1 : 3400, 2950, 1630, 1570, 1530, 1470

실시예 5:Example 5:

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]에틸아미노}부타노산(화합물 5)의 합성4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) Synthesis of -2-oxoazahydrohydropin-3-yl] ethylamino} butanoic acid (Compound 5)

a) 에틸 4-{[(3S)-1-(2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]에틸아미노}부타노에이트의 합성a) ethyl 4-{[(3S) -1- (2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2- Synthesis of oxoethyl) -2-oxoazahydrohydropin-3-yl] ethylamino} butanoate

실시예 2-b)에서 수득한 화합물(160mg)을 DMF(1㎖)에 녹인 후, 여기에 탄산칼륨(162mg)과 에틸요오다이드(0.047㎖)를 가하고 실온에서 18시간 동안 교반하였다. 반응액에 물을 가하고 메틸렌클로라이드로 추출한 후 유기층을 무수 황산나트륨으로 건조시켰다. 여과하고 감압농축하여 얻은 잔류물을 메틸렌클로라이드:메탄올=40:1(v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 미황색 오일상의 표제화합물(100mg)을 수득하였다.After dissolving the compound (160 mg) obtained in Example 2-b) in DMF (1 mL), potassium carbonate (162 mg) and ethyl iodide (0.047 mL) were added thereto, followed by stirring at room temperature for 18 hours. Water was added to the reaction mixture, the mixture was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by filtration and concentrated under reduced pressure was purified by silica gel column chromatography using methylene chloride: methanol = 40: 1 (v / v) as eluent to give the title compound (100 mg) as pale yellow oil.

1H-NMR(300MHz, CDCl3) δ: 7.58-7.50(m, 2H), 7.27-7.23(m, 1H), 6.34(s, 1H), 4.25-4.00(m, 8H), 3.65-3.60(m, 2H), 3.47-3.41(m, 4H), 2.76-2.62(m, 4H), 2.29-2.23(m, 3H), 2.02-1.92(m, 5H), 1.80-1.65(m, 8H), 1.32(t, 3H, J=7.2Hz), 1.22(t, 3H, J=7.1Hz), 0.98(t, 3H, J=7.2Hz) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.58-7.50 (m, 2H), 7.27-7.23 (m, 1H), 6.34 (s, 1H), 4.25-4.00 (m, 8H), 3.65-3.60 ( m, 2H), 3.47-3.41 (m, 4H), 2.76-2.62 (m, 4H), 2.29-2.23 (m, 3H), 2.02-1.92 (m, 5H), 1.80-1.65 (m, 8H), 1.32 (t, 3H, J = 7.2 Hz), 1.22 (t, 3H, J = 7.1 Hz), 0.98 (t, 3H, J = 7.2 Hz)

b) 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]에틸아미노}부타노산의 합성b) 4-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of Ethyl) -2-oxoazahydrohydropin-3-yl] ethylamino} butanoic acid

싱기 a)에서 수득한 화합물(145mg)을 실시예 2-c)에서와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(60mg)을 수득하였다.Compound (145 mg) obtained in Singh (a) was reacted in the same manner as in Example 2-c) to give the title compound (60 mg) as a white solid.

ES-MS : 567(M+1)+ ES-MS: 567 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.92(s, 1H), 7.62-7.58(m, 1H), 7.40-7.35(m, 1H), 6.40(s, 1H), 4.35-4.20(m, 4H), 4.10-4.02(m, 1H), 3.80-3.76(m, 1H), 3.52-3.42(m, 4H), 2.82-2.68(m, 6H), 2.12-1.98(m, 6H), 1.78-1.62(m, 8H), 1.36(t, 3H, J=7.2Hz), 1.03-0.98(m, 3H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.92 (s, 1H), 7.62-7.58 (m, 1H), 7.40-7.35 (m, 1H), 6.40 (s, 1H), 4.35-4.20 (m , 4H), 4.10-4.02 (m, 1H), 3.80-3.76 (m, 1H), 3.52-3.42 (m, 4H), 2.82-2.68 (m, 6H), 2.12-1.98 (m, 6H), 1.78 -1.62 (m, 8H), 1.36 (t, 3H, J = 7.2 Hz), 1.03-0.98 (m, 3H)

실시예 6:Example 6:

(2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]카바모일}-2-아미노프로파노산(화합물 6)의 합성(2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) Synthesis of -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] carbamoyl} -2-aminopropanoic acid (compound 6)

a) 벤질 (2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]카바모일}-2-[(t-부톡시)카보닐아미노]프로파노에이트의 합성a) benzyl (2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pi Synthesis of Lolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] carbamoyl} -2-[(t-butoxy) carbonylamino] propanoate

실시예 2-a)에서 수득한 화합물(150mg)을 메틸렌클로라이드(10㎖)에 녹인 후, 여기에 빙냉하에서 (3S)-3-[(t-부톡시)카보닐아미노]-3-[벤질옥시카보닐]프로파노산(134mg), HOBT(56mg), DIPEA(54mg) 및 WSCI·HCl(99mg)을 차례로 가하고 3시간 동안 교반하였다. 반응액에 물을 가하고 메틸렌클로라이드로 추출한 후 유기층을 무수 황산마그네슘으로 건조시켰다. 여과하고 감압농축하여 얻은 잔류물을 메틸렌클로라이드:메탄올=30:1(v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 흰색 거품상의 표제화합물(242mg)을 수득하였다.The compound (150 mg) obtained in Example 2-a) was dissolved in methylene chloride (10 mL), and then (3S) -3-[(t-butoxy) carbonylamino] -3- [benzyl under ice-cooling. Oxycarbonyl] propanoic acid (134 mg), HOBT (56 mg), DIPEA (54 mg) and WSCI.HCl (99 mg) were added sequentially and stirred for 3 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride, and then the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by filtration and concentrated under reduced pressure was purified by silica gel column chromatography using methylene chloride: methanol = 30: 1 (v / v) as an eluent to obtain the title compound (242 mg) as a white foam.

1H-NMR(300MHz, CDCl3) δ: 7.57-7.51(m, 2H), 7.30-7.25(m, 6H), 6.90(brs,1H), 6.34(s, 1H), 5.75(brs, 1H), 5.20-5.10(s, 2H), 4.58-4.51(m, 2H), 4.22- 4.00(m, 5H), 3.68-3.59(m, 1H), 3.48-3.44(m, 2H), 3.26-3.20(m, 1H), 2.94-2.88 (m, 1H), 2.76-2.65(m, 3H), 2.32-2.25(m, 1H), 2.01-1.89(m, 6H), 1.74-1.68(m, 5H), 1.38(s, 9H), 1.34-1.31(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.57-7.51 (m, 2H), 7.30-7.25 (m, 6H), 6.90 (brs, 1H), 6.34 (s, 1H), 5.75 (brs, 1H) , 5.20-5.10 (s, 2H), 4.58-4.51 (m, 2H), 4.22- 4.00 (m, 5H), 3.68-3.59 (m, 1H), 3.48-3.44 (m, 2H), 3.26-3.20 ( m, 1H), 2.94-2.88 (m, 1H), 2.76-2.65 (m, 3H), 2.32-2.25 (m, 1H), 2.01-1.89 (m, 6H), 1.74-1.68 (m, 5H), 1.38 (s, 9 H), 1.34-1.31 (m, 3 H)

b) (2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]카바모일}-2-아미노프로파노산의 합성b) (2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrroli Synthesis of diyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] carbamoyl} -2-aminopropanoic acid

상기 a)에서 수득한 화합물(242mg)을 실시예 2-c)에서와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(72mg)을 수득하였다.The compound (242 mg) obtained in a) was reacted in the same manner as in Example 2-c) to give the title compound (72 mg) as a white solid.

ES-MS : 569(M+1)+ ES-MS: 569 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.96-7.92(m, 1H), 7.64-7.59(m, 1H), 7.43-7.38 (m, 1H), 6.40(s, 1H), 4.76-4.72(m, 1H), 4.50-4.42(m, 1H), 4.28-4.20(m, 4H), 4.00-3.96(m, 1H), 3.72-3.51(m, 4H), 3.42-3.25(m, 2H), 2.82-2.77(m, 2H), 2.46-2.41(m, 1H), 2.15-1.56(m, 11H), 1.36-1.32(m, 3H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.96-7.92 (m, 1H), 7.64-7.59 (m, 1H), 7.43-7.38 (m, 1H), 6.40 (s, 1H), 4.76-4.72 (m, 1H), 4.50-4.42 (m, 1H), 4.28-4.20 (m, 4H), 4.00-3.96 (m, 1H), 3.72-3.51 (m, 4H), 3.42-3.25 (m, 2H) , 2.82-2.77 (m, 2H), 2.46-2.41 (m, 1H), 2.15-1.56 (m, 11H), 1.36-1.32 (m, 3H)

실시예 7:Example 7:

2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소피롤리디닐)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 7)의 합성2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxopyrrolidinyl) acetyl) pyrrolidin-2-yl] ethyl} -1-ethylindole-6 Synthesis of Carboxamidine (Compound 7)

a) N-{(3S)-1-[2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)- 2-옥소에틸]-2-옥소피롤리딘-3-일}(t-부톡시)카복스아미드의 합성a) N-{(3S) -1- [2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl ] -2-Oxopyrrolidin-3-yl} (t-butoxy) carboxamide

2-[2-((2S)-피롤리딘-2-일)에틸]-1-에틸인돌-6-카보니트릴(500mg)과 2-{(3S) -3-[(t-부톡시)카보닐아미노]-2-옥소피롤리디닐}아세트산(483mg, 참조:J. Org. Chem. 1982, 47,104-109)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(600mg)을 수득하였다.2- [2-((2S) -pyrrolidin-2-yl) ethyl] -1-ethylindol-6-carbonitrile (500 mg) and 2-{(3S) -3-[(t-butoxy) Carbonylamino] -2-oxopyrrolidinyl} acetic acid (483 mg, see J. Org. Chem. 1982, 47, 104-109) in the same manner as in Example 1-b) to give the title of a white foam. Compound (600 mg) was obtained.

1H-NMR(300MHz, CDCl3) δ: 7.54-7.48(m, 2H), 7.26-7.22(m, 1H), 6.35(s, 1H), 5.08(brs, 1H), 4.22-3.98(m, 6H), 3.48-3.36(m, 4H), 2.77-2.72(m, 2H), 2.62-2.55(m, 1H), 2.30-2.24(m, 1H), 2.00-1.68(m, 6H), 1.42(s, 9H), 1.32(t, 3H, J=7.1Hz) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.54-7.48 (m, 2H), 7.26-7.22 (m, 1H), 6.35 (s, 1H), 5.08 (brs, 1H), 4.22-3.98 (m, 6H), 3.48-3.36 (m, 4H), 2.77-2.72 (m, 2H), 2.62-2.55 (m, 1H), 2.30-2.24 (m, 1H), 2.00-1.68 (m, 6H), 1.42 ( s, 9H), 1.32 (t, 3H, J = 7.1 Hz)

b) 2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소피롤리디닐)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카보니트릴의 합성b) 2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxopyrrolidinyl) acetyl) pyrrolidin-2-yl] ethyl} -1-ethylindole Synthesis of -6-carbonitrile

상기 a)에서 수득한 화합물(600mg)을 실시예 2-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(420mg)을 수득하였다.The compound (600 mg) obtained in a) was reacted in the same manner as in Example 2-a) to give the title compound (420 mg) in the form of a white foam.

1H-NMR(300MHz, CDCl3) δ: 7.58-7.52(m, 2H), 7.27-7.24(m, 1H), 6.34(s, 1H), 4.20-3.90(m, 5H), 3.60-3.38(m, 5H), 2.76-2.72(m, 2H), 2.46-2.25(m, 2H), 2.06-1.92(m, 4H), 1.80-1.70(m, 2H), 1.32(t, 3H, J=7.2Hz) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.58-7.52 (m, 2H), 7.27-7.24 (m, 1H), 6.34 (s, 1H), 4.20-3.90 (m, 5H), 3.60-3.38 ( m, 5H), 2.76-2.72 (m, 2H), 2.46-2.25 (m, 2H), 2.06-1.92 (m, 4H), 1.80-1.70 (m, 2H), 1.32 (t, 3H, J = 7.2 Hz)

c) 2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소피롤리디닐)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘의 합성c) 2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxopyrrolidinyl) acetyl) pyrrolidin-2-yl] ethyl} -1-ethylindole Synthesis of -6-carboxamidine

상기 b)에서 수득한 화합물(150mg)을 실시예 1-c)에서와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(94mg)을 수득하였다.The compound (150 mg) obtained in b) was reacted in the same manner as in Example 1-c) to give the title compound (94 mg) as a pale yellow solid.

ES-MS : 425(M+1)+ ES-MS: 425 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.86(s, 1H), 7.61-7.57(m, 1H), 7.38-7.35(m, 1H), 6.42(s, 1H), 4.28-4.01(m, 5H), 3.56-3.34(m, 5H), 2.86-2.80(m, 2H), 2.44- 2.20(m, 2H), 2.10-1.96(m, 4H), 1.85-1.76(m, 2H), 1.36(t, 3H, J=7.2Hz) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.86 (s, 1H), 7.61-7.57 (m, 1H), 7.38-7.35 (m, 1H), 6.42 (s, 1H), 4.28-4.01 (m , 5H), 3.56-3.34 (m, 5H), 2.86-2.80 (m, 2H), 2.44- 2.20 (m, 2H), 2.10-1.96 (m, 4H), 1.85-1.76 (m, 2H), 1.36 (t, 3H, J = 7.2 Hz)

실시예 8:Example 8:

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]아미노}부타노산(화합물 8)의 합성4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) 2-Oxopyrrolidin-3-yl] amino} butanoic acid (Compound 8)

a) 에틸 4-{[(3S)-1-(2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]아미노}부타노에이트의 합성a) ethyl 4-{[(3S) -1- (2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2- Synthesis of oxoethyl) -2-oxopyrrolidin-3-yl] amino} butanoate

실시예 7-b)에서 수득한 화합물(24mg)을 실시예 2-b)에서와 동일한 방법으로 반응시켜 미황색 거품상의 표제화합물(280mg)을 수득하였다.Compound (24 mg) obtained in Example 7-b) was reacted in the same manner as in Example 2-b) to give the title compound (280 mg) in a slightly yellow foam.

1H-NMR(300MHz, CDCl3) δ: 7.56-7.50(m, 2H), 7.27-7.24(m, 1H), 6.36(s, 1H), 4.20-4.08(m, 6H), 3.90-3.86(m, 1H), 3.72-3.42(m, 7H), 2.96-2.72(m, 4H), 2.40-2.26(m, 2H), 2.05-1.68(m, 10H), 1.34-1.31(m, 3H), 1.23-1.19(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.56-7.50 (m, 2H), 7.27-7.24 (m, 1H), 6.36 (s, 1H), 4.20-4.08 (m, 6H), 3.90-3.86 ( m, 1H), 3.72-3.42 (m, 7H), 2.96-2.72 (m, 4H), 2.40-2.26 (m, 2H), 2.05-1.68 (m, 10H), 1.34-1.31 (m, 3H), 1.23-1.19 (m, 3H)

b) 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐) -2-옥소에틸)-2-옥소피롤리딘-3-일]아미노}부타노산의 합성b) 4-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of Ethyl) -2-oxopyrrolidin-3-yl] amino} butanoic acid

상기 a)에서 수득한 화합물(270mg)을 실시예 2-c)에서와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(30mg)을 수득하였다.The compound (270 mg) obtained in a) was reacted in the same manner as in Example 2-c) to give the title compound (30 mg) as a pale yellow solid.

ES-MS : 511(M+1)+ ES-MS: 511 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.92(s, 1H), 7.63-7.59(m, 1H), 7.42-7.38(m, 1H), 6.45(s, 1H), 4.28-3.90(m, 6H), 3.58-3.36(m, 6H), 2.86-2.65(m, 4H), 2.42- 2.36(m, 1H), 2.23-1.98(m, 6H), 1.86-1.78(m, 3H), 1.40-1.36(m, 3H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.92 (s, 1H), 7.63-7.59 (m, 1H), 7.42-7.38 (m, 1H), 6.45 (s, 1H), 4.28-3.90 (m , 6H), 3.58-3.36 (m, 6H), 2.86-2.65 (m, 4H), 2.42- 2.36 (m, 1H), 2.23-1.98 (m, 6H), 1.86-1.78 (m, 3H), 1.40 -1.36 (m, 3H)

실시예 9:Example 9:

(2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]카바모일}-2-아미노프로파노산(화합물 9)의 합성(2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] carbamoyl} -2-aminopropanoic acid (Compound 9)

a) 벤질 (2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]카바모일}-2-[(t-부톡시)카보닐아미노]프로파노에이트의 합성a) benzyl (2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pi Synthesis of Lolidinyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] carbamoyl} -2-[(t-butoxy) carbonylamino] propanoate

실시예 7-b)에서 수득한 화합물(505mg)을 실시예 6-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(669mg)을 수득하였다.Compound (505 mg) obtained in Example 7-b) was reacted in the same manner as in Example 6-a) to give the title compound (669 mg) in white foam.

1H-NMR(300MHz, CDCl3) δ: 7.58-7.52(m, 2H), 7.29-7.25(m, 1H), 6.34(s, 1H), 4.54-4.50(m, 1H), 4.20-4.08(m, 6H), 3.90-3.83(m, 1H), 3.72-3.68(m, 1H), 3.54-3.40(m, 4H), 2.90-2.82(m, 2H), 2.51-2.44(m, 2H), 2.28-2.21(m, 1H), 2.08- 1.82(m, 7H), 1.34-1.31(m, 3H), 1.23-1.19(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.58-7.52 (m, 2H), 7.29-7.25 (m, 1H), 6.34 (s, 1H), 4.54-4.50 (m, 1H), 4.20-4.08 ( m, 6H), 3.90-3.83 (m, 1H), 3.72-3.68 (m, 1H), 3.54-3.40 (m, 4H), 2.90-2.82 (m, 2H), 2.51-2.44 (m, 2H), 2.28-2.21 (m, 1H), 2.08-1.82 (m, 7H), 1.34-1.31 (m, 3H), 1.23-1.19 (m, 3H)

b) (2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]카바모일}-2-아미노프로파노산의 합성b) (2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrroli Synthesis of diyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] carbamoyl} -2-aminopropanoic acid

상기 a)에서 수득한 화합물(369mg)을 실시예 2-c)에서와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(127mg)을 수득하였다.The compound obtained in the above a) (369 mg) was reacted in the same manner as in Example 2-c) to give the title compound (127 mg) as a pale yellow solid.

ES-MS : 540(M+1)+ ES-MS: 540 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.88(s, 1H), 7.61-7.58(m, 1H), 7.42-7.38(m, 1H), 6.45(s, 1H), 4.64-4.56(m, 1H), 4.28-4.14(m, 4H), 4.06-3.98(m, 1H), 3.75- 3.70(m, 1H), 3.56-3.40(m, 4H), 2.88-2.80(m, 2H), 2.60-2.40(m, 2H), 2.26-1.80 (m, 8H), 1.35-1.30(m, 3H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.88 (s, 1 H), 7.61-7.58 (m, 1 H), 7.42-7.38 (m, 1 H), 6.45 (s, 1H), 4.64-4.56 (m , 1H), 4.28-4.14 (m, 4H), 4.06-3.98 (m, 1H), 3.75-3.70 (m, 1H), 3.56-3.40 (m, 4H), 2.88-2.80 (m, 2H), 2.60 -2.40 (m, 2H), 2.26-1.80 (m, 8H), 1.35-1.30 (m, 3H)

실시예 10:Example 10:

2-{2-[(2S)-1-((2S)-2-((3S)-3-아미노-2-옥소피롤리디닐)-3 -메틸부타노일)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 10)의 합성2- {2-[(2S) -1-((2S) -2-((3S) -3-amino-2-oxopyrrolidinyl) -3-methylbutanoyl) pyrrolidin-2-yl] Synthesis of ethyl} -1-ethylindole-6-carboxamidine (Compound 10)

a) N-{(3S)-1-[(1S)-2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-(이소프로필)-2-옥소에틸]-2-옥소피롤리딘-3-일}(t-부톡시)카복스아미드의 합성a) N-{(3S) -1-[(1S) -2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl)- Synthesis of 1- (isopropyl) -2-oxoethyl] -2-oxopyrrolidin-3-yl} (t-butoxy) carboxamide

2-[2-((2S)-피롤리딘-2-일)에틸]-1-에틸인돌-6-카보니트릴(310mg)과 (2R)-2-{(3S)-3-[(t-부톡시)카보닐아미노]-2-옥소피롤리디닐}-3-메틸부타노산(370mg, 참조 :J. Org. Chem 1982, 47,104-109)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 미황색 거품상의 표제화합물(500mg)을 수득하였다.2- [2-((2S) -pyrrolidin-2-yl) ethyl] -1-ethylindol-6-carbonitrile (310 mg) and (2R) -2-{(3S) -3-[(t -Butoxy) carbonylamino] -2-oxopyrrolidinyl} -3-methylbutanoic acid (370 mg, see J. Org. Chem 1982, 47, 104-109) as in Example 1-b). Reaction was carried out to give the title compound (500 mg) in light yellow foam.

1H-NMR(300MHz, CDCl3) δ: 7.60-7.52(m, 2H), 7.28-7.24(m, 1H), 6.36(s, 1H), 5.00(brs, 1H), 4.53-4.46(m, 1H), 4.24-4.10(m, 3H), 3.86-3.68(m, 1H) 3.60-3.24(m, 4H), 2.78-2.71(m, 2H), 2.64-2.50(m, 1H), 2.38-2.20(m, 2H), 2.05- 1.88(m, 5H), 1.76-1.68(m, 3H), 1.42(s, 9H), 1.36-1.30(m, 3H), 0.97-0.92(m, 3H), 0.88-0.80(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.60-7.52 (m, 2H), 7.28-7.24 (m, 1H), 6.36 (s, 1H), 5.00 (brs, 1H), 4.53-4.46 (m, 1H), 4.24-4.10 (m, 3H), 3.86-3.68 (m, 1H) 3.60-3.24 (m, 4H), 2.78-2.71 (m, 2H), 2.64-2.50 (m, 1H), 2.38-2.20 (m, 2H), 2.05- 1.88 (m, 5H), 1.76-1.68 (m, 3H), 1.42 (s, 9H), 1.36-1.30 (m, 3H), 0.97-0.92 (m, 3H), 0.88 -0.80 (m, 3H)

b) 2-{2-[(2S)-1-((2S)-2-((3S)-3-아미노-2-옥소피롤리디닐)-3-메틸부타노일)피롤리딘-2-일]에틸}-1-에틸인돌-6-카보니트릴의 합성b) 2- {2-[(2S) -1-((2S) -2-((3S) -3-amino-2-oxopyrrolidinyl) -3-methylbutanoyl) pyrrolidine-2- Synthesis of ethyl] -1-ethylindole-6-carbonitrile

상기 a)에서 수득한 화합물(600mg)을 실시예 2-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(315mg)을 수득하였다.The compound (600 mg) obtained in a) was reacted in the same manner as in Example 2-a), to obtain the title compound (315 mg) in white foam.

1H-NMR(300MHz, CDCl3) δ: 7.61-7.54(m, 2H), 7.27-7.24(m, 1H), 6.34(s, 1H), 4.51-4.45(m, 1H), 4.26-4.16(m, 3H), 3.83-3.68(m, 1H), 3.62-3.24(m, 4H), 2.78-2.73(m, 2H), 2.64-2.54(m, 1H), 2.38-2.20(m, 2H), 2.03-1.88(m, 5H), 1.70-1.58(m, 3H), 1.34(t, 3H, J=7.2Hz), 0.96-0.92(m, 3H), 0.86-0.80(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.61-7.54 (m, 2H), 7.27-7.24 (m, 1H), 6.34 (s, 1H), 4.51-4.45 (m, 1H), 4.26-4.16 ( m, 3H), 3.83-3.68 (m, 1H), 3.62-3.24 (m, 4H), 2.78-2.73 (m, 2H), 2.64-2.54 (m, 1H), 2.38-2.20 (m, 2H), 2.03-1.88 (m, 5H), 1.70-1.58 (m, 3H), 1.34 (t, 3H, J = 7.2 Hz), 0.96-0.92 (m, 3H), 0.86-0.80 (m, 3H)

c) 2-{2-[(2S)-1-((2S)-2-((3S)-3-아미노-2-옥소피롤리디닐)-3-메틸부타노일)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘의 합성c) 2- {2-[(2S) -1-((2S) -2-((3S) -3-amino-2-oxopyrrolidinyl) -3-methylbutanoyl) pyrrolidine-2- Synthesis of ethyl] -1-ethylindole-6-carboxamidine

상기 b)에서 수득한 화합물(49mg)을 실시예 1-c)에서와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(40mg)을 수득하였다.The compound (49 mg) obtained in b) was reacted in the same manner as in Example 1-c) to obtain the title compound (40 mg) as a pale yellow solid.

ES-MS : 234(1/2M+1)+, 467(M+1)+ ES-MS: 234 (1 / 2M + 1) + , 467 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.84(s, 1H), 7.59-7.56(m, 1H), 7.41-7.38(m, 1H), 6.42(s, 1H), 4.56-4.50(m, 1H), 4.35-4.20(m, 3H), 3.82-3.54(m, 3H), 3.46- 3.20(m, 2H), 2.87-2.80(m, 2H), 2.42-2.17(m, 3H), 2.05-1.68(m, 6H), 1.39-1.36 (m, 3H), 0.96-0.84(m, 6H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.84 (s, 1 H), 7.59-7.56 (m, 1 H), 7.41-7.38 (m, 1 H), 6.42 (s, 1 H), 4.56-4.50 (m , 1H), 4.35-4.20 (m, 3H), 3.82-3.54 (m, 3H), 3.46- 3.20 (m, 2H), 2.87-2.80 (m, 2H), 2.42-2.17 (m, 3H), 2.05 -1.68 (m, 6H), 1.39-1.36 (m, 3H), 0.96-0.84 (m, 6H)

IR(KBr) cm-1: 3360, 1680, 1630, 1530, 1470, 1430IR (KBr) cm -1 : 3360, 1680, 1630, 1530, 1470, 1430

실시예 11:Example 11:

4-{[(3S)-1-((1S)-2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-(이소프로필)-2-옥소에틸)-2-옥소피롤리딘-3-일]아미노}부타노산(화합물 11)의 합성4-{[(3S) -1-((1S) -2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -1 Synthesis of-(isopropyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] amino} butanoic acid (Compound 11)

a) 에틸 4-{[(3S)-1-((1S)-2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-(이소프로필)-2-옥소에틸)-2-옥소피롤리딘-3-일]아미노}부타노에이트의 합성a) ethyl 4-{[(3S) -1-((1S) -2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl ) -1--1-isopropyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] amino} butanoate

실시예 10-b)에서 수득한 화합물(265mg)을 실시예 2-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(190mg)을 수득하였다.The compound (265 mg) obtained in Example 10-b) was reacted in the same manner as in Example 2-b) to give the title compound (190 mg) in white foam.

1H-NMR(300MHz, CDCl3) δ: 7.57-7.52(m, 2H), 7.27-7.24(m, 1H), 6.36(s, 1H), 4.52-4.46(m, 1H), 4.21-4.06(m, 5H), 3.81-3.22(m, 7H), 2.78-2.60(m, 3H), 2.38-2.20(m, 5H), 2.02-1.70(m, 7H), 1.35-1.31(m, 3H), 1.24-1.20(m, 3H), 0.93- 0.90(m, 3H), 0.85-0.80(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.57-7.52 (m, 2H), 7.27-7.24 (m, 1H), 6.36 (s, 1H), 4.52-4.46 (m, 1H), 4.21-4.06 ( m, 5H), 3.81-3.22 (m, 7H), 2.78-2.60 (m, 3H), 2.38-2.20 (m, 5H), 2.02-1.70 (m, 7H), 1.35-1.31 (m, 3H), 1.24-1.20 (m, 3H), 0.93- 0.90 (m, 3H), 0.85-0.80 (m, 3H)

b) 4-{[(3S)-1-((1S)-2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-(이소프로필)-2-옥소에틸)-2-옥소피롤리딘-3-일]아미노}부타노산의 합성b) 4-{[(3S) -1-((1S) -2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) Synthesis of -1- (isopropyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] amino} butanoic acid

상기 a)에서 수득한 화합물(190mg)을 실시예 2-c)에서와 동일한 방법으로 반응시켜 흰색 고체상의 표제화합물(20mg)을 수득하였다.The compound obtained in (a) (190 mg) was reacted in the same manner as in Example 2-c) to give the title compound (20 mg) as a white solid.

ES-MS : 277(1/2M+1)+, 554(M+1)+ ES-MS: 277 (1 / 2M + 1) + , 554 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.94-7.90(m, 1H), 7.65-7.62(m, 1H), 7.45-7.41 (m, 1H), 6.46-6.40(m, 1H), 4.53-4.48(m, 1H), 4.38-4.18(m, 4H), 3.76-3.18(m, 6H), 2.88-2.52(m, 3H), 2.38-1.68(m, 12H), 1.40-1.36(m, 3H), 0.95-0.84(m, 6H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.94-7.90 (m, 1H), 7.65-7.62 (m, 1H), 7.45-7.41 (m, 1H), 6.46-6.40 (m, 1H), 4.53 -4.48 (m, 1H), 4.38-4.18 (m, 4H), 3.76-3.18 (m, 6H), 2.88-2.52 (m, 3H), 2.38-1.68 (m, 12H), 1.40-1.36 (m, 3H), 0.95-0.84 (m, 6H)

실시예 12:Example 12:

2-{[(3S)-1-((1S)-2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소-1-벤질에틸)-2-옥소피롤리딘-3-일]아미노}아세트산(화합물 12)의 합성2-{[(3S) -1-((1S) -2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 Synthesis of -oxo-1-benzylethyl) -2-oxopyrrolidin-3-yl] amino} acetic acid (compound 12)

a) 2-{2-[(2S)-1-((2S)-2-((3S)-3-아미노-2-옥소피롤리디닐)-3-페닐프로파노일)피롤리딘-2-일]에틸}-1-에틸인돌-6-카보니트릴의 합성a) 2- {2-[(2S) -1-((2S) -2-((3S) -3-amino-2-oxopyrrolidinyl) -3-phenylpropanoyl) pyrrolidine-2 Synthesis of -yl] ethyl} -1-ethylindole-6-carbonitrile

2-[2-((2S)-피롤리딘-2-일)에틸]-1-에틸인돌-6-카보니트릴(500mg)과 (2R)-2-{(3S)-3-[(t-부톡시)카보닐아미노]-2-옥소피롤리디닐}-3-페닐프로파노산(694mg, 참조:J. Org. Chem 1982, 47,104-109)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 미황색 오일상의 N-{(3S)-1-[(1S)-2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소-1-벤질에틸]-2-옥소피롤리딘-3-일}(t-부톡시)카복스아미드를 수득하였다. 이것을 다시 실시예 2-a)에서와 동일한 방법으로 반응시켜 미황색 거품상의 표제화합물(100mg)을 수득하였다.2- [2-((2S) -pyrrolidin-2-yl) ethyl] -1-ethylindol-6-carbonitrile (500 mg) and (2R) -2-{(3S) -3-[(t -Butoxy) carbonylamino] -2-oxopyrrolidinyl} -3-phenylpropanoic acid (694 mg, see J. Org. Chem 1982, 47, 104-109) in Example 1-b) and The reaction was carried out in the same manner to give N-{(3S) -1-[(1S) -2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl as light yellow oil. ) Pyrrolidinyl) -2-oxo-1-benzylethyl] -2-oxopyrrolidin-3-yl} (t-butoxy) carboxamide. This was again reacted in the same manner as in Example 2-a) to give the title compound (100 mg) as pale yellow foam.

1H-NMR(300MHz, CDCl3) δ: 7.56-7.52(m, 2H), 7.28-7.08(m, 6H), 6.34(s, 1H), 5.16-5.08(m, 1H), 4.16-4.08(m, 2H), 3.86-3.69(m, 2H), 3.41-3.12(m, 5H), 2.96-2.90(m, 1H), 2.72-2.60(m, 2H), 2.40-2.10(m, 2H), 2.01-1.50(m, 6H), 1.36- 1.32(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.56-7.52 (m, 2H), 7.28-7.08 (m, 6H), 6.34 (s, 1H), 5.16-5.08 (m, 1H), 4.16-4.08 ( m, 2H), 3.86-3.69 (m, 2H), 3.41-3.12 (m, 5H), 2.96-2.90 (m, 1H), 2.72-2.60 (m, 2H), 2.40-2.10 (m, 2H), 2.01-1.50 (m, 6H), 1.36-1.32 (m, 3H)

b) 에틸 2-{[(3S)-1-((1S)-2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소-1-벤질에틸)-2-옥소피롤리딘-3-일]아미노}아세테이트의 합성b) ethyl 2-{[(3S) -1-((1S) -2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl ) -2-oxo-1-benzylethyl) -2-oxopyrrolidin-3-yl] amino} acetate

상기 a)에서 수득한 화합물(100mg)을 실시예 3-a)에서와 동일한 방법으로 반응시켜 미황색 오일상의 표제화합물(70mg)을 수득하였다.The compound (100 mg) obtained in a) was reacted in the same manner as in Example 3-a) to give the title compound (70 mg) in a pale yellow oil.

1H-NMR(300MHz, CDCl3) δ: 7.56-7.53(m, 2H), 7.26-7.12(m, 6H), 6.32(s, 1H), 5.18-5.11(m, 1H), 4.20-4.06(m, 7H), 3.84-3.66(m, 2H), 3.40-3.16(m, 5H), 2.94-2.86(m, 1H), 2.68-2.59(m, 2H), 2.30-2.05(m, 3H), 1.90-1.70(m, 5H), 1.41 (t, 3H, J=7.2Hz), 1.24-1.20(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.56-7.53 (m, 2H), 7.26-7.12 (m, 6H), 6.32 (s, 1H), 5.18-5.11 (m, 1H), 4.20-4.06 ( m, 7H), 3.84-3.66 (m, 2H), 3.40-3.16 (m, 5H), 2.94-2.86 (m, 1H), 2.68-2.59 (m, 2H), 2.30-2.05 (m, 3H), 1.90-1.70 (m, 5H), 1.41 (t, 3H, J = 7.2 Hz), 1.24-1.20 (m, 3H)

c) 2-{[(3S)-1-((1S)-2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소-1-벤질에틸)-2-옥소피롤리딘-3-일]아미노}아세트산의 합성c) 2-{[(3S) -1-((1S) -2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) Synthesis of -2-oxo-1-benzylethyl) -2-oxopyrrolidin-3-yl] amino} acetic acid

상기 b)에서 수득한 화합물(70mg)을 실시예 2-c)에서와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(25mg)을 수득하였다.The compound (70 mg) obtained in the above b) was reacted in the same manner as in Example 2-c) to give the title compound (25 mg) as a pale yellow solid.

ES-MS : 287(1/2M+1)+, 573(M+1)+ ES-MS: 287 (1 / 2M + 1) + , 573 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.98-7.90(m, 1H), 7.68-7.64(m, 1H), 7.45-7.42 (m, 1H), 7.23-7.02(m, 5H), 6.46-6.42(m, 1H), 5.12-5.02(m, 1H), 4.40-3.95(m, 3H), 3.70-3.35(m, 4H), 3.20-3.04(m, 3H), 2.98-2.70(m, 4H), 2.35-2.00(m, 3H), 1.82-1.55(m, 5H), 1.38-1.30(m, 3H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.98-7.90 (m, 1H), 7.68-7.64 (m, 1H), 7.45-7.42 (m, 1H), 7.23-7.02 (m, 5H), 6.46 -6.42 (m, 1H), 5.12-5.02 (m, 1H), 4.40-3.95 (m, 3H), 3.70-3.35 (m, 4H), 3.20-3.04 (m, 3H), 2.98-2.70 (m, 4H), 2.35-2.00 (m, 3H), 1.82-1.55 (m, 5H), 1.38-1.30 (m, 3H)

실시예 13:Example 13:

2-{2-[1-(2-((3S)-3-아미노-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 13)의 합성2- {2- [1- (2-((3S) -3-Amino-2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl] ethyl} -1-ethylindole- Synthesis of 6-Carboxamidine (Compound 13)

a) (2S)-5-아미노-2-[(t-부톡시)카보닐아미노]펜타노산의 합성a) Synthesis of (2S) -5-amino-2-[(t-butoxy) carbonylamino] pentanoic acid

500㎖ 용량 플라스크에 (2S)-2-[(t-부톡시)카보닐아미노]-5-[(벤질옥시)카보닐아미노]펜타노산(6.0g)을 넣고 메탄올(100㎖)에 녹인 후, 팔라듐/활성화탄소 (900mg, 15w/w%)를 가하고 수소분위기하에서 14시간동안 교반하였다. 반응이 완결된 후 반응액을 셀라이트로 여과하고 감압하에 용매를 증발시켜 흰색 고체상의 표제화합물(3.80g)을 수득하였다.(2S) -2-[(t-butoxy) carbonylamino] -5-[(benzyloxy) carbonylamino] pentanoic acid (6.0 g) was added to a 500 ml flask, and dissolved in methanol (100 ml). Palladium / activated carbon (900 mg, 15 w / w%) was added and stirred under hydrogen atmosphere for 14 hours. After the reaction was completed, the reaction solution was filtered through celite and the solvent was evaporated under reduced pressure to give the title compound (3.80 g) as a white solid.

1H NMR(300MHz, CDCl3) δ: 3.95(brs, 1H), 3.02(brs, 2H), 1.95-1.50(m, 2H), 1.45(s, 9H) 1 H NMR (300 MHz, CDCl 3 ) δ: 3.95 (brs, 1H), 3.02 (brs, 2H), 1.95-1.50 (m, 2H), 1.45 (s, 9H)

b) N-[(3S)-2-옥소-(3-피페리딜)](t-부톡시)카복스아미드의 합성b) Synthesis of N-[(3S) -2-oxo- (3-piperidyl)] (t-butoxy) carboxamide

500㎖ 용량 플라스크에 상기 a)에서 수득한 화합물(3.8g)을 넣고 실온에서 CH3CN/H2O(90㎖/9㎖)에 녹였다. 여기에, WSCI·HCl(6.3g) 및 HOBT(4.4g)을 넣고 교반하면서 N,N-디이소프로필에틸아민(11.4㎖)을 적가한 후, 테트라-n-부틸암모늄요오다이드(촉매량)를 가하였다. 반응액을 실온에서 14시간동안 교반하여 반응을 완결시킨 후 반응액을 물로 희석하고 에틸아세테이트로 3회 추출하였다. 유기성 추출물을 혼합하고 감압하에 증발시켜 백색 거품상의 표제화합물(2.83g)을 수득하였다.In a 500 mL flask, the compound (3.8 g) obtained in a) was added and dissolved in CH 3 CN / H 2 O (90 mL / 9 mL) at room temperature. To this was added dropwise N, N-diisopropylethylamine (11.4 mL) with stirring and adding WSCI.HCl (6.3 g) and HOBT (4.4 g), followed by tetra-n-butylammonium iodide (catalyst amount). Was added. The reaction solution was stirred at room temperature for 14 hours to complete the reaction, and the reaction solution was diluted with water and extracted three times with ethyl acetate. The organic extracts were mixed and evaporated under reduced pressure to give the title compound (2.83 g) as a white foam.

1H NMR(300MHz, CDCl3) δ: 6.70(brs, 1H), 5.50(brs, 1H), 3.95-3.90(m, 1H), 3.47-3.10(m, 2H), 2.48-2.40(m, 1H), 1.95-1.65(m, 2H), 1.65-1.50(m, 1H), 1.45(s, 9H) 1 H NMR (300 MHz, CDCl 3 ) δ: 6.70 (brs, 1H), 5.50 (brs, 1H), 3.95-3.90 (m, 1H), 3.47-3.10 (m, 2H), 2.48-2.40 (m, 1H ), 1.95-1.65 (m, 2H), 1.65-1.50 (m, 1H), 1.45 (s, 9H)

c) 2-{(3S)-3-[(t-부톡시)카보닐아미노]-2-옥소피페리딜}아세트산의 합성c) Synthesis of 2-{(3S) -3-[(t-butoxy) carbonylamino] -2-oxopiperidyl} acetic acid

250㎖ 용량 플라스크에 상기 b)에서 수득한 화합물(3.1g)을 가하고, 실시예 1-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(3.99g)을 수득하였다.To a 250 ml volumetric flask was added the compound (3.1 g) obtained in b) and reacted in the same manner as in Example 1-a to give the title compound (3.99 g) as a white foam.

1H NMR(300MHz, CDCl3) δ: 5.47(brs, 1H), 4.45-3.65(m, 3H), 2.55-2.25(m, 1H), 2.00-1.85(m, 2H), 1.60-1.56(m, 1H), 1.45(s, 9H) 1 H NMR (300 MHz, CDCl 3 ) δ: 5.47 (brs, 1H), 4.45-3.65 (m, 3H), 2.55-2.25 (m, 1H), 2.00-1.85 (m, 2H), 1.60-1.56 (m , 1H), 1.45 (s, 9H)

d) 2-{2-[1-(2-((3S)-3-아미노-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카보니트릴의 합성d) 2- {2- [1- (2-((3S) -3-amino-2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl] ethyl} -1-ethyl Synthesis of Indole-6-carbonitrile

500㎖ 용량 플라스크에 2-[2-((2S)-피롤리딘-2-일)에틸]-1-에틸인돌-6-카보니트릴(2.59g)과 상기 c)에서 수득한 화합물(2.12g)을 가하고 실시예 1-b)에서와 동일한 방법으로 반응시켜 엷은 노란색의 거품상 화합물을 수득하였다. 이렇게 수득한 화합물을 다시 실시예 2-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의표제화합물(1.14g)을 수득하였다.In a 500 mL flask, 2- [2-((2S) -pyrrolidin-2-yl) ethyl] -1-ethylindole-6-carbonitrile (2.59 g) and the compound obtained in c) (2.12 g) ) Was added and reacted in the same manner as in Example 1-b) to obtain a pale yellow foamy compound. The compound thus obtained was reacted again in the same manner as in Example 2-a) to obtain a white foamy title compound (1.14 g).

1H NMR(300MHz, CDCl3) δ: 7.50-7.45(m, 2H), 7.20-7.16(m, 1H), 6.32(s, 1H), 4.25-4.05(m, 5H), 3.90-3.85(m, 1H), 3.58-3.30(m, 4H), 3.15-3.10(m, 2H), 2.71-2.65(m, 2H), 2.35-1.65(m, 10H), 1.30(t, 3H, J = 8.33Hz) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.50-7.45 (m, 2H), 7.20-7.16 (m, 1H), 6.32 (s, 1H), 4.25-4.05 (m, 5H), 3.90-3.85 (m , 1H), 3.58-3.30 (m, 4H), 3.15-3.10 (m, 2H), 2.71-2.65 (m, 2H), 2.35-1.65 (m, 10H), 1.30 (t, 3H, J = 8.33 Hz )

e) 2-{2-[1-(2-((3S)-3-아미노-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘의 합성e) 2- {2- [1- (2-((3S) -3-amino-2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl] ethyl} -1-ethyl Synthesis of indole-6-carboxamidine

상기 d)에서 수득한 화합물(200mg)을 실시예 1-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(100mg)을 수득하였다.The compound (200 mg) obtained in the above d) was reacted in the same manner as in Example 1-c) to obtain the title compound (100 mg) in the form of a white foam.

ES-MS : 439(M+1)+ ES-MS: 439 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.75(s, 1H), 7.45-7.41(m, 1H), 7.30-7.26(m, 1H), 6.45(s, 1H), 4.20-3.80(m, 5H), 3.50-3.35(m, 3H), 3.35-3.20(m, 2H), 2.65-2.60(m, 2H), 2.30-1.50(m, 10H), 1.25-1.20(m, 3H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.75 (s, 1 H), 7.45-7.41 (m, 1 H), 7.30-7.26 (m, 1 H), 6.45 (s, 1H), 4.20-3.80 (m , 5H), 3.50-3.35 (m, 3H), 3.35-3.20 (m, 2H), 2.65-2.60 (m, 2H), 2.30-1.50 (m, 10H), 1.25-1.20 (m, 3H)

실시예 14:Example 14:

4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-3-피페리딜]아미노}부타노산(화합물 14)의 합성4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) Synthesis of 2-oxo-3-piperidyl] amino} butanoic acid (Compound 14)

a) 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-3-피페리딜]아미노}부타노산의 합성a) 4-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of ethyl) -2-oxo-3-piperidyl] amino} butanoic acid

실시예 13-d)에서 수득한 화합물(630mg)을 실시예 2-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(600mg)을 수득하였다. 이렇게 얻어진 화합물을 실시예 2-c)에서와 동일한 방밥으로 반응시켜 흰색 거품상의 표제화합물(200mg)을 수득하였다.The compound (630 mg) obtained in Example 13-d) was reacted in the same manner as in Example 2-b) to give a white foamy compound (600 mg). The compound thus obtained was reacted in the same manner as in Example 2-c) to give the title compound (200 mg) in the form of a white foam.

ES-MS : 525(M+1)+ ES-MS: 525 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.90(s, 1H), 7.60-7.55(m, 1H), 7.40-7.35(m, 1H), 6.48(s, 1H), 4.40-4.18(m, 3H), 4.12-4.08(m, 2H), 3.65-3.20(m, 5H), 2.90- 2.85(m, 2H), 2.40-1.80(m, 16H), 1.38(t, 3H, J = 8.33Hz) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.90 (s, 1H), 7.60-7.55 (m, 1H), 7.40-7.35 (m, 1H), 6.48 (s, 1H), 4.40-4.18 (m , 3H), 4.12-4.08 (m, 2H), 3.65-3.20 (m, 5H), 2.90-2.85 (m, 2H), 2.40-1.80 (m, 16H), 1.38 (t, 3H, J = 8.33 Hz )

실시예 15:Example 15:

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노프로파노산(화합물 15)의 합성3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminopropanoic acid (compound 15)

a) 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노프로파노산의 합성a) 3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 Synthesis of -oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminopropanoic acid

실시예 13-d)에서 수득한 화합물(466mg)을 실시예 6-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(546mg)을 수득하였다. 이렇게 얻어진 화합물을 실시예 2-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(120mg)을 수득하였다.The compound (466 mg) obtained in Example 13-d) was reacted in the same manner as in Example 6-a) to give a white foamy compound (546 mg). The compound thus obtained was reacted in the same manner as in Example 2-c) to give the title compound (120 mg) in the form of a white foam.

ES-MS : 554(M+1)+ ES-MS: 554 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.90(s, 1H), 7.65-7.30(m, 2H), 6.48(s, 1H), 4.50-4.46(m, 1H), 4.38-4.00(m, 5H), 3.65-3.30(m, 4H), 2.75-2.70(m, 2H), 2.35- 1.80(m, 16H), 1.38(t, 3H, J = 8.33Hz) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.90 (s, 1H), 7.65-7.30 (m, 2H), 6.48 (s, 1H), 4.50-4.46 (m, 1H), 4.38-4.00 (m , 5H), 3.65-3.30 (m, 4H), 2.75-2.70 (m, 2H), 2.35- 1.80 (m, 16H), 1.38 (t, 3H, J = 8.33 Hz)

실시예 16:Example 16:

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]-N-에틸카바모일}-(2S)-2-아미노프로파노산(화합물 16) 및 2-{2-[1-(2-((3S)-3-((3S)-3-아미노-3-카바모일-N-에틸프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 17)의 합성3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)]-N-ethylcarbamoyl}-(2S) -2-aminopropanoic acid (compound 16) and 2- {2- [1- (2- ( (3S) -3-((3S) -3-amino-3-carbamoyl-N-ethylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl ] Synthesis of ethyl} -1-ethylindole-6-carboxamidine (Compound 17)

a) 2-{2-[1-(2-((3S)-3-(디프로프-2-에닐아미노)-2-옥소피페리딜)아세틸)- (2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카보니트릴의 합성a) 2- {2- [1- (2-((3S) -3- (diprop-2-enylamino) -2-oxopiperidyl) acetyl)-(2S) -pyrrolidine-2- Synthesis of ethyl] -1-ethylindole-6-carbonitrile

250㎖ 용량 플라스크에 실시예 13-d)에서 수득한 화합물(521mg)을 넣고 THF /DMF(4/1, v/v, 100㎖)에 녹였다. 여기에 실온에서 중탄산나트륨(229mg)과 소듐요오다이드(촉매량)를 첨가한 후 알릴브로마이드(0.43㎖)를 천천히 적가하였다. 4시간정도 교반, 환류하여 반응을 완료시킨 후 물을 넣어 종결시키고, 메틸렌클로라이드로 3회 추출하였다. 유기성 추출물을 혼합하고 감압하에 증발시킨 후, 메틸렌클로라이드:메탄올(10:1, v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 노란색 오일상의 표제화합물(411mg)을 수득하였다.The compound (521 mg) obtained in Example 13-d) was added to a 250 ml flask and dissolved in THF / DMF (4/1, v / v, 100 ml). After adding sodium bicarbonate (229 mg) and sodium iodide (catalyst amount) at room temperature, allyl bromide (0.43 mL) was slowly added dropwise. After stirring for 4 hours to reflux to complete the reaction, water was terminated, and extracted three times with methylene chloride. The organic extracts were mixed and evaporated under reduced pressure, and then purified by silica gel column chromatography using methylene chloride: methanol (10: 1, v / v) as eluent. Fractions containing product were combined and evaporated to yield the title compound (411 mg) as a yellow oil.

1H NMR(300MHz, CDCl3) δ: 7.55-7.50(m, 2H), 7.25-7.21(m, 1H), 6.48(s, 1H), 6.00-5.70(m, 2H), 5.25-5.00(m, 4H), 4.31-3.85(m, 5H), 3.60-3.30(m, 6H), 3.30-3.10(m, 3H), 2.80-2.76(m, 2H), 2.30-2.25(m, 1H), 2.20-1.69(m, 9H), 1.35 (t, 3H, J = 7.41Hz) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.55-7.50 (m, 2H), 7.25-7.21 (m, 1H), 6.48 (s, 1H), 6.00-5.70 (m, 2H), 5.25-5.00 (m , 4H), 4.31-3.85 (m, 5H), 3.60-3.30 (m, 6H), 3.30-3.10 (m, 3H), 2.80-2.76 (m, 2H), 2.30-2.25 (m, 1H), 2.20 -1.69 (m, 9H), 1.35 (t, 3H, J = 7.41 Hz)

b) 2-{2-[1-(2-((3S)-2-옥소-3-(프로프-2-에닐아미노)피페리딜)아세틸)-(2S) -피롤리딘-2-일]에틸}-1-에틸인돌-6-카보니트릴의 합성b) 2- {2- [1- (2-((3S) -2-oxo-3- (prop-2-enylamino) piperidyl) acetyl)-(2S) -pyrrolidine-2- Synthesis of ethyl] -1-ethylindole-6-carbonitrile

100㎖ 용량 플라스크에 상기 a)에서 수득한 화합물(400mg)을 넣고 무수 THF(30㎖)에 녹인 후, 여기에 Pd2(디벤질리덴아세톤;dba)3·CHCl3(37mg), dppb(1,4-비스(디페닐포스피노부탄))(64mg) 및 2-머캅토벤조산(120mg)을 첨가하고 실온에서 1시간동안 교반하였다. 반응완료 후 물을 넣어 종결시키고, 에틸아세테이트로 3회 추출하였다. 유기성 추출물을 혼합하고 감압하에 증발시킨 후, 잔류물을 에틸아세테이트:에탄올(3:1, v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 연갈색 거품상의 표제화합물(283mg)을 수득하였다.In a 100 ml flask, the compound (400 mg) obtained in a) was added and dissolved in anhydrous THF (30 ml), followed by Pd 2 (dibenzylideneacetone; dba) 3 CHCl 3 (37 mg) and dppb (1). , 4-bis (diphenylphosphinobutane)) (64 mg) and 2-mercaptobenzoic acid (120 mg) were added and stirred at room temperature for 1 hour. After completion of the reaction, water was added to terminate the mixture, and extracted three times with ethyl acetate. After mixing the organic extracts and evaporating under reduced pressure, the residue was purified by silica gel column chromatography using ethyl acetate: ethanol (3: 1, v / v) as eluent. Fractions containing product were combined and evaporated to give the title compound (283 mg) as light brown foam.

1H NMR(300MHz, CDCl3) δ: 7.65-7.60(m, 2H), 7.20-7.16(m, 1H), 6.45(s, 1H), 5.95-5.75(m, 1H), 5.70-5.50(m, 2H), 4.30-3.85(m, 5H), 3.60-3.15(m, 6H), 2.75-2.70(m, 2H), 2.30-2.25(m, 2H), 2.25-1.69(m, 10H), 1.35(t, 3H, J=7.40Hz) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.65-7.60 (m, 2H), 7.20-7.16 (m, 1H), 6.45 (s, 1H), 5.95-5.75 (m, 1H), 5.70-5.50 (m , 2H), 4.30-3.85 (m, 5H), 3.60-3.15 (m, 6H), 2.75-2.70 (m, 2H), 2.30-2.25 (m, 2H), 2.25-1.69 (m, 10H), 1.35 (t, 3H, J = 7.40 Hz)

c) 2-{2-[1-(2-((3S)-3-(에틸프로프-2-에닐아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카보니트릴의 합성c) 2- {2- [1- (2-((3S) -3- (ethylprop-2-enylamino) -2-oxopiperidyl) acetyl)-(2S) -pyrrolidine-2 Synthesis of -yl] ethyl} -1-ethylindole-6-carbonitrile

100㎖ 용량 플라스크에 상기 b)에서 수득한 화합물(282mg)을 넣고 THF/ DMF(4/1, v/v, 50㎖)에 녹인 후, 실온에서 중탄산나트륨(103mg)을 첨가하였다. 반응액을 10분정도 교반한 후 에틸요오다이드(0.2㎖)를 천천히 적가하고 4시간정도 교반, 환류하였다. 반응 완료후 물을 넣어 종결시키고, 에틸아세테이트로 3회 추출하고, 유기성 추출물을 혼합한 후, 감압하에 증발시켰다. 잔류물을 에틸아세테이트:에탄올(4:1, v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 노란색 오일상의 표제화합물(299mg)을 수득하였다.In a 100 ml flask, the compound (282 mg) obtained in b) was dissolved in THF / DMF (4/1, v / v, 50 ml), and sodium bicarbonate (103 mg) was added at room temperature. After stirring the reaction solution for about 10 minutes, ethyl iodide (0.2 ml) was slowly added dropwise, and stirred and refluxed for about 4 hours. After completion of the reaction, water was added to terminate the mixture, extracted three times with ethyl acetate, and the organic extracts were mixed and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate: ethanol (4: 1, v / v) as eluent. Fractions containing product were combined and evaporated to yield the title compound (299 mg) as a yellow oil.

1H NMR(300MHz, CDCl3) δ: 7.55-7.50(m, 2H), 7.25-7.20(m, 1H), 6.47(s, 1H), 5.95-5.75(m, 1H), 5.20-5.00(m, 2H), 4.30-3.80(m, 5H), 3.60-3.42(m, 5H), 3.30-3.15(m, 2H), 2.75-2.71(m, 2H), 2.28-2.25(m, 1H), 2.10-1.65(m, 9H), 1.35(t, 3H, J = 8.82Hz), 1.05(t, 3H, J = 8.83Hz) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.55-7.50 (m, 2H), 7.25-7.20 (m, 1H), 6.47 (s, 1H), 5.95-5.75 (m, 1H), 5.20-5.00 (m , 2H), 4.30-3.80 (m, 5H), 3.60-3.42 (m, 5H), 3.30-3.15 (m, 2H), 2.75-2.71 (m, 2H), 2.28-2.25 (m, 1H), 2.10 -1.65 (m, 9H), 1.35 (t, 3H, J = 8.82 Hz), 1.05 (t, 3H, J = 8.83 Hz)

d) 2-{2-[1-(2-((3S)-3-(에틸아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카보니트릴의 합성d) 2- {2- [1- (2-((3S) -3- (ethylamino) -2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl] ethyl}- Synthesis of 1-ethylindole-6-carbonitrile

250㎖ 용량 플라스크에 상기 c)에서 수득한 화합물(1.34g)을 넣고 무수 THF(50㎖)에 녹인 후, Pd2(디벤질리덴아세톤;dba)3·CHCl3(79mg), dppb(1,4-비스(디페닐포스피노부탄))(233mg) 및 2-머캅토벤조산(465mg)을 첨가하고 실온에서 2시간동안 교반하였다. 반응완료후 물을 넣어 종결시키고, 에틸아세테이트로 3회 추출하였다. 유기성 추출물을 혼합하고 감압하에 증발시켰다. 잔류물을 에틸아세테이트:에탄올(3:1, v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 연갈색 거품상의 표제화합물(608mg)을 수득하였다.In a 250 mL flask, the compound (1.34 g) obtained in c) was added and dissolved in anhydrous THF (50 mL), followed by Pd 2 (dibenzylideneacetone; dba) 3 CHCl 3 (79 mg), dppb (1, 4-bis (diphenylphosphinobutane)) (233 mg) and 2-mercaptobenzoic acid (465 mg) were added and stirred at room temperature for 2 hours. After completion of the reaction, water was added to terminate the mixture, and extracted three times with ethyl acetate. The organic extracts were mixed and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate: ethanol (3: 1, v / v) as eluent. Fractions containing product were combined and evaporated to give the title compound (608 mg) as light brown foam.

1H NMR(300MHz, CDCl3) δ: 7.60-7.55(m, 2H), 7.28-7.25(m, 1H), 6.35(s, 1H), 4.25-4.20(m, 1H), 4.20-3.90(m, 4H), 3.60-3.00(m, 7H), 2.87-2.60(m, 2H), 2.40-1.65(m, 10H), 1.30(t, 3H, J = 8.32Hz), 1.15(t, 3H, J = 8.33Hz) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.60-7.55 (m, 2H), 7.28-7.25 (m, 1H), 6.35 (s, 1H), 4.25-4.20 (m, 1H), 4.20-3.90 (m , 4H), 3.60-3.00 (m, 7H), 2.87-2.60 (m, 2H), 2.40-1.65 (m, 10H), 1.30 (t, 3H, J = 8.32 Hz), 1.15 (t, 3H, J = 8.33 Hz)

e) 에틸 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]-N-에틸카바모일}-(2S)-2-아미노프로파노에이트(a) 및 2-{2-[1-(2-((3R)-3-((3S)-3-아미노-3-카바모일-N-에틸프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 17)의 합성e) ethyl 3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl)- 2-oxoethyl) -2-oxo- (3-piperidyl)]-N-ethylcarbamoyl}-(2S) -2-aminopropanoate (a) and 2- {2- [1- (2 -((3R) -3-((3S) -3-Amino-3-carbamoyl-N-ethylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) -pyrrolidine-2 -Yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 17)

상기 d)에서 수득한 화합물(322mg)을 실시예 6-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(257mg)을 수득하였다. 이렇게 얻은 화합물을 실시예 1-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(a)(140mg)와 화합물 17(45mg)을 수득하였다.The compound (322 mg) obtained in the above d) was reacted in the same manner as in Example 6-a to give a white foamy compound (257 mg). The compound thus obtained was reacted in the same manner as in Example 1-c) to obtain white foamy compound (a) (140 mg) and compound 17 (45 mg).

화합물 (a);Compound (a);

1H NMR(300MHz, CD3OD) δ: 7.90(s, 1H), 7.60-7.56(m, 1H), 7.40-7.37(m, 1H), 6.45(s, 1H), 4.50-4.00(m, 5H), 3.95-3.20(m, 8H), 3.05-2.55(m, 4H), 2.30-1.80(m, 12H), 1.40-1.36(m, 3H), 1.30-1.26(m, 3H), 1.25-1.21(m, 3H) 1 H NMR (300 MHz, CD 3 OD) δ: 7.90 (s, 1 H), 7.60-7.56 (m, 1 H), 7.40-7.37 (m, 1 H), 6.45 (s, 1 H), 4.50-4.00 (m, 5H), 3.95-3.20 (m, 8H), 3.05-2.55 (m, 4H), 2.30-1.80 (m, 12H), 1.40-1.36 (m, 3H), 1.30-1.26 (m, 3H), 1.25- 1.21 (m, 3H)

화합물 17;Compound 17;

ES-MS : 581(M+1)+ ES-MS: 581 (M + 1) +

1H NMR(300MHz, CD3OD) δ: 7.90(s, 1H), 7.60-7.56(m, 1H), 7.40-7.37(m, 1H), 6.45(s, 1H), 4.50-4.00(m, 3H), 3.95-3.20(m, 8H), 3.00-2.55(m, 4H), 2.30- 1.80(m, 12H), 1.40-1.36(m, 3H), 1.30-1.26(m, 3H) 1 H NMR (300 MHz, CD 3 OD) δ: 7.90 (s, 1 H), 7.60-7.56 (m, 1 H), 7.40-7.37 (m, 1 H), 6.45 (s, 1 H), 4.50-4.00 (m, 3H), 3.95-3.20 (m, 8H), 3.00-2.55 (m, 4H), 2.30- 1.80 (m, 12H), 1.40-1.36 (m, 3H), 1.30-1.26 (m, 3H)

f) 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]-N-에틸카바모일}-(2S)-2-아미노프로파노산(화합물 16)의 합성f) 3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 Synthesis of -oxoethyl) -2-oxo- (3-piperidyl)]-N-ethylcarbamoyl}-(2S) -2-aminopropanoic acid (compound 16)

상기 e)에서 수득한 화합물(a)(140mg)를 물(1㎖)과 에탄올(2㎖)의 혼합용매에 용해시키고, 여기에 85% 수산화칼륨(35mg)을 가한 후 실온에서 1일간 교반하였다. 용매를 감압하에 농축, 제거하여 얻은 잔류물을 에틸아세테이트:메탄올=1:1 (v/v)을 용출제로 사용하는 NH-실리카 칼럼 크로마토그래피로 정제하여 흰색 고체상의 표제화합물(100mg)을 수득하였다.Compound (a) (140 mg) obtained in the above e) was dissolved in a mixed solvent of water (1 mL) and ethanol (2 mL), and 85% potassium hydroxide (35 mg) was added thereto, followed by stirring at room temperature for 1 day. . The residue obtained by concentration and removal of the solvent under reduced pressure was purified by NH-silica column chromatography using ethyl acetate: methanol = 1: 1 (v / v) as eluent to obtain the title compound (100 mg) as a white solid. .

ES-MS : 582(M+1)+ ES-MS: 582 (M + 1) +

1H NMR(300MHz, CD3OD) δ: 8.00-7.95(m, 1H), 7.65-7.62(m, 1H), 7.43-7.40 (m, 1H), 6.50(s, 1H), 4.50-3.90(m, 6H), 3.70-3.65(m, 1H), 3.55-3.40(m, 6H), 3.10-2.60(m, 4H), 2.30-1.90(m, 10H), 1.40-1.36(m, 3H), 1.30(t, 3H, J=8.33Hz) 1 H NMR (300 MHz, CD 3 OD) δ: 8.00-7.95 (m, 1H), 7.65-7.62 (m, 1H), 7.43-7.40 (m, 1H), 6.50 (s, 1H), 4.50-3.90 ( m, 6H), 3.70-3.65 (m, 1H), 3.55-3.40 (m, 6H), 3.10-2.60 (m, 4H), 2.30-1.90 (m, 10H), 1.40-1.36 (m, 3H), 1.30 (t, 3H, J = 8.33 Hz)

실시예 17:Example 17:

(2R)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 18) 및 2-{2-[1-(2-((3S)-3-((3R)-3-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 19)의 합성(2R) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 18) and 2- {2- [1- (2-((3S)-) 3-((3R) -3-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl] ethyl} -1-ethylindole Synthesis of -6-carboxamidine (Compound 19)

a) 에틸 (2R)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노에이트(a) 및 2-{2-[1-(2-((3S)-3-((3R)-3-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 19)의 합성a) ethyl (2R) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) blood Lolidinyl) -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoate (a) and 2- {2- [1- (2-((3S ) -3-((3R) -3-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl] ethyl} -1- Synthesis of Ethylindole-6-Carboxamidine (Compound 19)

실시예 13-d)에서 수득한 화합물(300mg)과 (3R)-3-[(t-부톡시)카보닐아미노] -3-[벤질옥시카보닐]프로파노산(350mg)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(400mg)을 수득하였다. 이렇게 수득한 화합물을 실시예 1-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(a)(120mg)와 화합물 19(20mg)를 수득하였다.Example 1 Compound (300 mg) obtained in Example 13-d) and (3R) -3-[(t-butoxy) carbonylamino] -3- [benzyloxycarbonyl] propanoic acid (350 mg) were prepared in Example 1 The reaction was carried out in the same manner as in -b), to obtain a white foamy compound (400 mg). The compound thus obtained was reacted in the same manner as in Example 1-c) to obtain white foamy compound (a) (120 mg) and compound 19 (20 mg).

화합물 (a);Compound (a);

1H NMR(300MHz, CD3OD) δ: 7.81(s, 1H), 7.50(d, 1H, J = 8.29Hz), 7.30(d, 1H, J = 8.34Hz), 6.45(s, 1H), 4.40-4.35(m, 1H), 4.30-4.00(m, 6H), 3.68-3.15(m, 6H), 2.75-2.71(m, 2H), 2.60-2.57(m, 1H), 2.45-2.41(m, 1H), 2.20-1.60(m, 10H), 1.35(t, 3H, J = 8.33Hz), 1.30-1.26(m, 3H) 1 H NMR (300 MHz, CD 3 OD) δ: 7.81 (s, 1H), 7.50 (d, 1H, J = 8.29 Hz), 7.30 (d, 1H, J = 8.34 Hz), 6.45 (s, 1H), 4.40-4.35 (m, 1H), 4.30-4.00 (m, 6H), 3.68-3.15 (m, 6H), 2.75-2.71 (m, 2H), 2.60-2.57 (m, 1H), 2.45-2.41 (m , 1H), 2.20-1.60 (m, 10H), 1.35 (t, 3H, J = 8.33 Hz), 1.30-1.26 (m, 3H)

화합물 19;Compound 19;

ES-MS : 553(M+1)+ ES-MS: 553 (M + 1) +

1H NMR(300MHz, CD3OD) δ: 7.81(s, 1H), 7.50(d, 1H, J = 8.29Hz), 7.30(d, 1H, J = 8.34Hz), 6.45(s, 1H), 4.40-4.35(m, 1H), 4.30-4.00(m, 4H), 3.68-3.15 (m, 6H), 2.75-2.70(m, 2H), 2.60-2.55(m, 1H), 2.45-2.35(m, 1H), 2.20-1.60(m, 10H), 1.35(t, 3H, J = 8.33Hz) 1 H NMR (300 MHz, CD 3 OD) δ: 7.81 (s, 1H), 7.50 (d, 1H, J = 8.29 Hz), 7.30 (d, 1H, J = 8.34 Hz), 6.45 (s, 1H), 4.40-4.35 (m, 1H), 4.30-4.00 (m, 4H), 3.68-3.15 (m, 6H), 2.75-2.70 (m, 2H), 2.60-2.55 (m, 1H), 2.45-2.35 (m , 1H), 2.20-1.60 (m, 10H), 1.35 (t, 3H, J = 8.33 Hz)

b) (2R)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 18)의 합성b) (2R) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrroli Synthesis of diyl) -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 18)

상기 a)에서 수득한 화합물(a)(120mg)를 실시예 16-f)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(80mg)을 수득하였다.Compound (a) (120 mg) obtained in a) was reacted in the same manner as in Example 16-f, to obtain the title compound (80 mg) in the form of a white foam.

ES-MS : 554(M+1)+ ES-MS: 554 (M + 1) +

1H NMR(300MHz, CD3OD) δ: 7.95(s, 1H), 7.50-7.30(m, 2H), 6.35(s, 1H), 4.50-4.45(m, 1H), 4.30-4.00(m, 4H), 3.60-3.30(m, 9H), 2.80-2.74(m, 2H), 2.20-1.70(m, 10H), 1.35-1.31(m, 3H) 1 H NMR (300 MHz, CD 3 OD) δ: 7.95 (s, 1 H), 7.50-7.30 (m, 2 H), 6.35 (s, 1 H), 4.50-4.45 (m, 1 H), 4.30-4.00 (m, 4H), 3.60-3.30 (m, 9H), 2.80-2.74 (m, 2H), 2.20-1.70 (m, 10H), 1.35-1.31 (m, 3H)

실시예 18:Example 18:

4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노부타노산(화합물 20) 및 2-{2-[1-(2-((3S)-3-((4S)-4-아미노-4-카바모일부타노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 21)의 합성4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminobutanoic acid (compound 20) and 2- {2- [1- (2-((3S) -3) -((4S) -4-amino-4-carbamoylbutanoylamino) -2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl] ethyl} -1-ethylindole-6 Synthesis of Carboxamidine (Compound 21)

a) 에틸 4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노부타노에이트(a) 및 2-{2-[1-(2-((3S)-3-((4S)-4-아미노-4-카바모일부타노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 21)의 합성a) ethyl 4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl)- 2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminobutanoate (a) and 2- {2- [1- (2-((3S ) -3-((4S) -4-amino-4-carbamoylbutanoylamino) -2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl] ethyl} -1-ethyl Synthesis of indole-6-carboxamidine (Compound 21)

실시예 13-d)에서 수득한 화합물(300mg)과 (4S)-4-[(t-부톡시)카보닐아미노] -4-[벤질옥시카보닐]부타노산(330mg)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(450mg)을 수득하였다. 이렇게 수득한 화합물을 실시예 1-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(a)(200mg) 및 화합물 21(40mg)을 수득하였다.Compound (300 mg) and (4S) -4-[(t-butoxy) carbonylamino] -4- [benzyloxycarbonyl] butanoic acid (330 mg) obtained in Example 13-d) were prepared in Example 1-. The reaction was carried out in the same manner as in b), to obtain a white foamy compound (450 mg). The compound thus obtained was reacted in the same manner as in Example 1-c) to give white foamy compound (a) (200 mg) and compound 21 (40 mg).

화합물 (a);Compound (a);

1H NMR(300MHz, CD3OD) δ: 7.90(s, 1H), 7.60-7.57(m, 1H), 7.40-7.37(m, 1H), 6.47(s, 1H), 4.50-4.43(m, 1H), 4.35-4.05(m, 5H), 3.60-3.25(m, 5H), 2.85- 2.81(m, 2H), 2.50-1.75(m, 6H), 1.37(t, 3H, J = 7.12Hz), 1.30-1.26(m, 3H) 1 H NMR (300 MHz, CD 3 OD) δ: 7.90 (s, 1 H), 7.60-7.57 (m, 1 H), 7.40-7.37 (m, 1 H), 6.47 (s, 1 H), 4.50-4.43 (m, 1H), 4.35-4.05 (m, 5H), 3.60-3.25 (m, 5H), 2.85-2.81 (m, 2H), 2.50-1.75 (m, 6H), 1.37 (t, 3H, J = 7.12 Hz) , 1.30-1.26 (m, 3H)

화합물 21;Compound 21;

ES-MS : 567(M+1)+ ES-MS: 567 (M + 1) +

1H NMR(300MHz, CD3OD) δ: 7.90(s, 1H), 7.60-7.56(m, 1H), 7.40-7.36(m, 1H), 6.47(s, 1H), 4.50-4.45(m, 1H), 4.35-4.05(m, 3H), 3.60-3.25(m, 5H), 2.85- 2.80(m, 2H), 2.50-1.75(m, 6H), 1.37(t, 3H, J = 7.12Hz) 1 H NMR (300 MHz, CD 3 OD) δ: 7.90 (s, 1 H), 7.60-7.56 (m, 1 H), 7.40-7.36 (m, 1 H), 6.47 (s, 1 H), 4.50-4.45 (m, 1H), 4.35-4.05 (m, 3H), 3.60-3.25 (m, 5H), 2.85-2.80 (m, 2H), 2.50-1.75 (m, 6H), 1.37 (t, 3H, J = 7.12 Hz)

b) 4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노부타노산(화합물 20)의 합성b) 4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 Synthesis of -oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminobutanoic acid (compound 20)

상기 a)에서 수득한 화합물(a)(200mg)를 실시예 16-f)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(150mg)을 수득하였다.Compound (a) (200 mg) obtained in a) was reacted in the same manner as in Example 16-f) to give the title compound (150 mg) as a white foam.

ES-MS : 568(M+1)+ ES-MS: 568 (M + 1) +

1H NMR(300MHz, CD3OD) δ: 7.95(s, 1H), 7.60-7.56(m, 1H), 7.50-7.47(m, 1H), 6.45(s, 1H), 4.50-4.00(m, 4H), 3.60-3.27(m, 5H), 2.70-2.65(m, 2H), 2.47-1.75(m, 16H), 1.37(t, 3H, J = 7.23Hz) 1 H NMR (300 MHz, CD 3 OD) δ: 7.95 (s, 1 H), 7.60-7.56 (m, 1 H), 7.50-7.47 (m, 1 H), 6.45 (s, 1H), 4.50-4.00 (m, 4H), 3.60-3.27 (m, 5H), 2.70-2.65 (m, 2H), 2.47-1.75 (m, 16H), 1.37 (t, 3H, J = 7.23 Hz)

실시예 19:Example 19:

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-[(메틸설포닐)아미노]프로파노산(화합물 22)의 합성3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-[(methylsulfonyl) amino] propanoic acid (compound 22)

a) 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-[(메틸설포닐)아미노]프로파노산의 합성a) 3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 Synthesis of -oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-[(methylsulfonyl) amino] propanoic acid

실시예 13-d)에서 수득한 화합물(500mg)을 실시예 6-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(600mg)을 수득하였다. 이렇게 수득한 화합물(600mg)을 메틸렌클로라이드(50㎖)에 녹인 후, 여기에 트리에틸아민(0.3㎖)과 메탄설포닐클로라이드(1.5㎖)를 천천히 적가하고 실온에서 1시간동안 교반하였다. 반응완료 후 물을 넣어 종결시키고, 메틸렌클로라이드로 3회 추출하였다. 유기성 추출물을 혼합하고 감압하에 증발시킨 후, 잔류물을 메틸렌클로라이드:메탄올(10:1, v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 흰색 거품상의 화합물(700mg)을 수득하였다. 이렇게 수득한 화합물을 다시 실시예 2-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(220mg)을 수득하였다.The compound (500 mg) obtained in Example 13-d) was reacted in the same manner as in Example 6-a) to give a white foamy compound (600 mg). The compound (600 mg) thus obtained was dissolved in methylene chloride (50 mL), and triethylamine (0.3 mL) and methanesulfonyl chloride (1.5 mL) were slowly added dropwise thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, water was added to terminate the mixture, and extracted three times with methylene chloride. After mixing the organic extracts and evaporating under reduced pressure, the residue was purified by silica gel column chromatography using methylene chloride: methanol (10: 1, v / v) as eluent. Fractions containing product were combined and evaporated to give a white foamy compound (700 mg). The compound thus obtained was reacted again in the same manner as in Example 2-c) to give the title compound (220 mg) in the form of a white foam.

1H NMR(300MHz, CD3OD) δ: 7.94(s, 1H), 7.62(d, 1H, J = 30Hz), 7.49(d, 1H, J = 28Hz), 6.49(s, 1H), 5.42-5.38(m, 1H), 4.32-4.20(m, 4H), 4.18-4.00(m, 1H), 3.54-3.50(m, 2H), 3.39-3.20(m, 3H), 3.12-2.60(m, 5H), 2.42-1.34(m, 12H), 1.30-1.26(m, 3H) 1 H NMR (300 MHz, CD 3 OD) δ: 7.94 (s, 1 H), 7.62 (d, 1 H, J = 30 Hz), 7.49 (d, 1 H, J = 28 Hz), 6.49 (s, 1H), 5.42- 5.38 (m, 1H), 4.32-4.20 (m, 4H), 4.18-4.00 (m, 1H), 3.54-3.50 (m, 2H), 3.39-3.20 (m, 3H), 3.12-2.60 (m, 5H ), 2.42-1.34 (m, 12H), 1.30-1.26 (m, 3H)

실시예 20:Example 20:

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-(디에틸아미노)프로파노산(화합물 23)의 합성3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2- (diethylamino) propanoic acid (compound 23)

a) 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-(디에틸아미노)프로파노산의 합성a) 3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 Synthesis of -oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2- (diethylamino) propanoic acid

실시예 13-d)에서 수득한 화합물(500mg)을 실시예 6-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(620mg)을 수득하였다. 이렇게 수득한 화합물(620mg)을 메틸렌클로라이드(50㎖)에 녹인 후, 여기에 트리에틸아민(0.3㎖)과 에틸요오다이드(1.3㎖)를 천천히 적가하고 실온에서 1시간동안 교반하였다. 반응완료후 물을 넣어 종결시키고, 메틸렌클로라이드로 3회 추출하였다. 유기성 추출물을 혼합하고 감압하에 증발시킨 후, 잔류물을 메틸렌클로라이드:메탄올(10:1, v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하였다. 생성물을 함유하는 분획을 합하고 증발시켜 흰색 거품상의 화합물(250mg)을 수득하였다. 이렇게 수득한 화합물을 다시 실시예 2-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(80mg)을 수득하였다.The compound (500 mg) obtained in Example 13-d) was reacted in the same manner as in Example 6-a) to give a white foamy compound (620 mg). The compound (620 mg) thus obtained was dissolved in methylene chloride (50 mL), and triethylamine (0.3 mL) and ethyl iodide (1.3 mL) were slowly added dropwise thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, water was added to terminate the mixture, and extracted three times with methylene chloride. After mixing the organic extracts and evaporating under reduced pressure, the residue was purified by silica gel column chromatography using methylene chloride: methanol (10: 1, v / v) as eluent. Fractions containing product were combined and evaporated to yield a white foamy compound (250 mg). The compound thus obtained was reacted again in the same manner as in Example 2-c) to give the title compound (80 mg) as a white foam.

1H NMR(300MHz, CD3OD) δ: 8.03(s, 1H), 7.70(d, 1H, J = 24.0Hz), 7.50(d, 1H, J = 23.0Hz), 6.52(d, 1H, J = 31.0Hz), 4.62-4.18(m, 7H), 3.58-3.50(m, 2H), 2.95-2.85(m, 2H), 2.78-2.57(m, 4H), 2.55-1.92(m, 10H), 1.55-1.10(m, 9H) 1 H NMR (300 MHz, CD 3 OD) δ: 8.03 (s, 1H), 7.70 (d, 1H, J = 24.0 Hz), 7.50 (d, 1H, J = 23.0 Hz), 6.52 (d, 1H, J = 31.0 Hz), 4.62-4.18 (m, 7H), 3.58-3.50 (m, 2H), 2.95-2.85 (m, 2H), 2.78-2.57 (m, 4H), 2.55-1.92 (m, 10H), 1.55-1.10 (m, 9H)

실시예 21:Example 21:

3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-하이드록시프로파노산(화합물 24)의 합성3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-hydroxypropanoic acid (compound 24)

a) 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-하이드록시프로파노산의 합성a) 3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 Synthesis of -oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-hydroxypropanoic acid

실시예 13-d)에서 수득한 화합물(300mg)과 (4S)-2,2-디메틸-5-옥소-1,3-디옥솔란-4-카복실산(250mg)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(280mg)을 수득하였다. 이렇게 수득한 화합물(280mg)을 실시예 2-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(100mg)을 수득하였다.Compound (300 mg) and (4S) -2,2-dimethyl-5-oxo-1,3-dioxolane-4-carboxylic acid (250 mg) obtained in Example 13-d) were prepared in Example 1-b) and The reaction was carried out in the same manner to obtain a white foamy compound (280 mg). The compound (280 mg) thus obtained was reacted in the same manner as in Example 2-c) to give the title compound (100 mg) in the form of a white foam.

ES-MS : 555(M+1)+ ES-MS: 555 (M + 1) +

1H NMR(300MHz, CD3OD) δ: 7.90(s, 1H), 7.60-7.56(m, 1H), 7.49-7.46(m, 1H), 6.48(s, 1H), 4.50-4.45(m, 1H), 4.38-4.00(m, 5H), 3.65-3.30(m, 4H), 2.75- 2.70(m, 2H), 2.35-1.80(m, 16H), 1.40(t, 3H, J = 8.33Hz) 1 H NMR (300 MHz, CD3OD) δ: 7.90 (s, 1 H), 7.60-7.56 (m, 1 H), 7.49-7.46 (m, 1 H), 6.48 (s, 1 H), 4.50-4.45 (m, 1 H) , 4.38-4.00 (m, 5H), 3.65-3.30 (m, 4H), 2.75-2.70 (m, 2H), 2.35-1.80 (m, 16H), 1.40 (t, 3H, J = 8.33 Hz)

실시예 22:Example 22:

(2R)-4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노부타노산(화합물 25)의 합성(2R) -4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) Synthesis of -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminobutanoic acid (compound 25)

a) (2R)-4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노부타노산의 합성a) (2R) -4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrroli Synthesis of diyl) -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminobutanoic acid

실시예 13-d)에서 수득한 화합물(300mg)과 (4R)-4-[(t-부톡시)카보닐아미노] -4-[벤질옥시카보닐]부타노산(330mg)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(450mg)을 수득하였다. 이렇게 수득한 화합물을 실시예 2-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(200mg)을 수득하였다.Compound (300 mg) obtained in Example 13-d) and (4R) -4-[(t-butoxy) carbonylamino] -4- [benzyloxycarbonyl] butanoic acid (330 mg) were prepared in Example 1-. The reaction was carried out in the same manner as in b), to obtain a white foamy compound (450 mg). The compound thus obtained was reacted in the same manner as in Example 2-c) to give the title compound (200 mg) in the form of a white foam.

ES-MS : 568(M+1)+ ES-MS: 568 (M + 1) +

1H NMR(300MHz, CD3OD) δ: 8.00-7.96(m, 1H), 7.70-7.38(m, 2H), 6.50(s, 1H), 4.60-4.10(m, 6H), 3.70-3.40(m, 3H), 2.90-2.80(m, 2H), 2.50-2.35(m, 1H), 2.45-1.80(m, 15H), 1.45(t, 3H, J = 8.3Hz) 1 H NMR (300 MHz, CD 3 OD) δ: 8.00-7.96 (m, 1H), 7.70-7.38 (m, 2H), 6.50 (s, 1H), 4.60-4.10 (m, 6H), 3.70-3.40 ( m, 3H), 2.90-2.80 (m, 2H), 2.50-2.35 (m, 1H), 2.45-1.80 (m, 15H), 1.45 (t, 3H, J = 8.3 Hz)

실시예 23:Example 23:

2-{2-[1-(2-((3S)-3-((2S)-2-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 26)의 합성2- {2- [1- (2-((3S) -3-((2S) -2-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) Synthesis of -pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 26)

a) 2-{2-[1-(2-((3S)-3-((2S)-2-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘의 합성a) 2- {2- [1- (2-((3S) -3-((2S) -2-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-( Synthesis of 2S) -pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine

실시예 13-d)에서 수득한 화합물(300mg)과 (2S)-2-[(t-부톡시)카보닐아미노] -3-[벤질옥시카보닐]프로파노산(330mg)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(350mg)을 수득하였다. 이렇게 수득한 화합물을 실시예1-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(100mg)을 수득하였다.Example 1 Compound (300 mg) and (2S) -2-[(t-butoxy) carbonylamino] -3- [benzyloxycarbonyl] propanoic acid (330 mg) obtained in Example 13-d) were used as Example 1 The reaction was carried out in the same manner as in -b), to obtain a white foamy compound (350 mg). The compound thus obtained was reacted in the same manner as in Example 1-c) to give the title compound (100 mg) in the form of a white foam.

ES-MS : 553(M+1)+ ES-MS: 553 (M + 1) +

1H NMR(300MHz, CD3OD) δ: 7.90(s, 1H), 7.68-7.65(m, 1H), 7.45-7.41(m, 1H), 6.50(s, 1H), 4.50-4.05(m, 5H), 3.80-3.40(m, 4H), 2.97-2.85(m, 2H), 2.62- 2.55(m, 1H), 2.50-2.40(m, 1H), 2.40-1.85(m, 12H), 1.35(t, 3H, J = 7.20Hz) 1 H NMR (300 MHz, CD 3 OD) δ: 7.90 (s, 1 H), 7.68-7.65 (m, 1 H), 7.45-7.41 (m, 1 H), 6.50 (s, 1 H), 4.50-4.05 (m, 5H), 3.80-3.40 (m, 4H), 2.97-2.85 (m, 2H), 2.62- 2.55 (m, 1H), 2.50-2.40 (m, 1H), 2.40-1.85 (m, 12H), 1.35 ( t, 3H, J = 7.20 Hz)

실시예 24:Example 24:

2-{2-[1-(2-((3S)-3-((2R)-2-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 27)의 합성2- {2- [1- (2-((3S) -3-((2R) -2-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) Synthesis of -pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 27)

a) 2-{2-[1-(2-((3S)-3-((2R)-2-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘의 합성a) 2- {2- [1- (2-((3S) -3-((2R) -2-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-( Synthesis of 2S) -pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine

실시예 13-d)에서 수득한 화합물(300mg)과 (2R)-2-[(t-부톡시)카보닐아미노] -3-[벤질옥시카보닐]프로파노산(330mg)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(350mg)을 수득하였다. 이렇게 수득한 화합물을 실시예 1-c)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(120mg)을 수득하였다.Example 1 Compound (300 mg) and (2R) -2-[(t-butoxy) carbonylamino] -3- [benzyloxycarbonyl] propanoic acid (330 mg) obtained in Example 13-d) were used as Example 1 The reaction was carried out in the same manner as in -b), to obtain a white foamy compound (350 mg). The compound thus obtained was reacted in the same manner as in Example 1-c) to obtain the title compound (120 mg) in the form of a white foam.

ES-MS : 553(M+1)+ ES-MS: 553 (M + 1) +

1H NMR(300MHz, CD3OD) δ: 7.90(s, 1H), 7.68-7.59(m, 1H), 7.45-7.43(m, 1H), 6.50(s, 1H), 4.50-4.05(m, 5H), 3.80-3.40(m, 4H), 2.97-2.90(m, 2H), 2.62-2.55(m, 1H), 2.50-2.45(m, 1H), 2.40-1.85(m, 12H), 1.35(t, 3H, J= 7.20Hz) 1 H NMR (300 MHz, CD 3 OD) δ: 7.90 (s, 1 H), 7.68-7.59 (m, 1 H), 7.45-7.43 (m, 1 H), 6.50 (s, 1 H), 4.50-4.05 (m, 5H), 3.80-3.40 (m, 4H), 2.97-2.90 (m, 2H), 2.62-2.55 (m, 1H), 2.50-2.45 (m, 1H), 2.40-1.85 (m, 12H), 1.35 ( t, 3H, J = 7.20 Hz)

실시예 25:Example 25:

2-{2-[(2S)-1-(2-((3S,6S)-3-아미노-6-(플루오로메틸)-2-옥소피페리딜)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 28)의 합성2- {2-[(2S) -1- (2-((3S, 6S) -3-amino-6- (fluoromethyl) -2-oxopiperidyl) acetyl) pyrrolidin-2-yl ] Synthesis of ethyl} -1-ethylindole-6-carboxamidine (Compound 28)

a) 메틸 (2S,5S)-5-[(t-부톡시)카보닐아미노]-6-옥소피페리딘-2-카복실레이트의 합성a) Synthesis of methyl (2S, 5S) -5-[(t-butoxy) carbonylamino] -6-oxopiperidine-2-carboxylate

디메틸 (2S,5S)-2,5-디아미노헥산-1,6-디오에이트 디하이드로클로라이드 (500mg, 참조:J. Org. Chem, 1984, 49,2286-2288)을 에탄올과 물(5㎖/5㎖)의 혼합용매에 녹인 후 산화은(I)(464mg)을 가하고 실온에서 30분간 교반하였다. 불용성 고체를 셀라이트를 통해 여과하여 제거하였다. 여액을 감압농축하여 얻은 잔류물을 메틸렌클로라이드(20㎖)에 녹인 후 빙냉하에서 트리에틸아민(0.38㎖)과 t-부틸디카보네이트(516mg)를 가하고 실온에서 18시간 동안 교반하였다. 반응액을 감압농축하여 얻은 잔류물을 메틸렌클로라이드:메탄올=20:1(v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 미황색 거품상의 표제화합물(350mg)을 수득하였다.Dimethyl (2S, 5S) -2,5-diaminohexane-1,6-dioate dihydrochloride (500 mg, see J. Org. Chem, 1984, 49, 2286-2288) in ethanol and water (5 mL / 5 ml) was dissolved in a mixed solvent, and silver oxide (I) (464 mg) was added thereto, followed by stirring at room temperature for 30 minutes. Insoluble solids were removed by filtration through celite. The residue obtained by concentrating the filtrate under reduced pressure was dissolved in methylene chloride (20 mL), and triethylamine (0.38 mL) and t-butyldicarbonate (516 mg) were added under ice cooling, followed by stirring at room temperature for 18 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography using methylene chloride: methanol = 20: 1 (v / v) as an eluent to obtain the title compound (350 mg) as a slightly yellow foam.

1H-NMR(300MHz, CDCl3) δ: 6.23(brs, 1H), 5.45(brs, 1H), 4.14-4.06(m, 2H), 3.78(s, 3H), 2.50-2.43(m, 1H), 2.28-2.12(m, 2H), 1.58-1.52(m, 1H), 1.44(s, 9H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 6.23 (brs, 1H), 5.45 (brs, 1H), 4.14-4.06 (m, 2H), 3.78 (s, 3H), 2.50-2.43 (m, 1H) , 2.28-2.12 (m, 2H), 1.58-1.52 (m, 1H), 1.44 (s, 9H)

b) N-[(3S,6S)-6-(하이드록시메틸)-2-옥소-(3-피페리딜)](t-부톡시)카복스아미드의 합성b) Synthesis of N-[(3S, 6S) -6- (hydroxymethyl) -2-oxo- (3-piperidyl)] (t-butoxy) carboxamide

상기 a)에서 수득한 화합물(450mg)을 무수 THF와 디에틸에테르(3㎖/10㎖)의 혼합용매에 용해시킨 후, 여기에 리튬보로하이드리드(2.0M in THF/0.83㎖)와 리튬 트리에틸보로하이드리드(1.0M in THF/0.17㎖)를 서서히 적가하고 실온에서 2시간 동안 교반하였다. 빙냉하에 메탄올(2㎖)을 서서히 적가한 후 10분간 교반하였다. 반응액을 감압농축하여 얻은 잔류물을 메틸렌클로라이드:메탄올=10:1(v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 흰색 거품상의 표제화합물(160mg)을 수득하였다.The compound (450 mg) obtained in a) was dissolved in a mixed solvent of anhydrous THF and diethyl ether (3 mL / 10 mL), followed by lithium borohydride (2.0 M in THF / 0.83 mL) and lithium. Triethylborohydride (1.0 M in THF / 0.17 mL) was slowly added dropwise and stirred at room temperature for 2 hours. Methanol (2 mL) was slowly added dropwise under ice cooling, followed by stirring for 10 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography using methylene chloride: methanol = 10: 1 (v / v) as an eluent to obtain the title compound (160 mg) as a white foam.

1H-NMR(300MHz, CDCl3) δ: 6.92(brs, 1H), 5.63-5.60(m, 1H), 4.08-4.00(m, 1H), 3.65-3.54(m, 3H), 2.60(brs, 1H), 2.30-2.20(m, 1H), 1.95-1.65(m, 3H), 1.42(s, 9H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 6.92 (brs, 1 H), 5.63-5.60 (m, 1 H), 4.08-4.00 (m, 1 H), 3.65-3.54 (m, 3H), 2.60 (brs, 1H), 2.30-2.20 (m, 1H), 1.95-1.65 (m, 3H), 1.42 (s, 9H)

c) N-[(3S,6S)-6-(플루오로메틸)-2-옥소-(3-피페리딜)](t-부톡시)카복스아미드의 합성c) Synthesis of N-[(3S, 6S) -6- (fluoromethyl) -2-oxo- (3-piperidyl)] (t-butoxy) carboxamide

상기 b)에서 수득한 화합물(160mg)을 메틸렌클로라이드(5㎖)에 녹인 후 빙냉하에서 (디에틸아미노)설퍼트리플루오라이드(0.096㎖)를 가하고 실온에서 24시간 동안 교반하였다. 반응액을 차가운 포화 중탄산나트륨 수용액(10㎖)에 붓고 메틸렌클로라이드로 추출하였다. 유기층을 무수 황산나트륨으로 건조시키고 여과하고감압농축하였다. 수득한 잔류물을 메틸렌클로라이드:메탄올=20:1(v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 갈색 오일상의 표제화합물(50mg)을 수득하였다.The compound (160 mg) obtained in b) was dissolved in methylene chloride (5 mL), and (diethylamino) sulfur trifluoride (0.096 mL) was added under ice cooling, followed by stirring at room temperature for 24 hours. The reaction solution was poured into cold saturated aqueous sodium bicarbonate solution (10 mL) and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography using methylene chloride: methanol = 20: 1 (v / v) as eluent to afford the title compound (50 mg) as a brown oil.

1H-NMR(300MHz, CDCl3) δ: 6.23(brs, 1H), 5.46(brs, 1H), 4.48-4.20(m, 2H), 4.07-4.01(m, 1H), 3.76-3.70(m, 1H), 2.07-1.95(m, 1H), 1.80-1.62(m, 3H), 1.42 (s, 9H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 6.23 (brs, 1H), 5.46 (brs, 1H), 4.48-4.20 (m, 2H), 4.07-4.01 (m, 1H), 3.76-3.70 (m, 1H), 2.07-1.95 (m, 1H), 1.80-1.62 (m, 3H), 1.42 (s, 9H)

d) 2-{(3S,6S)-3-[(t-부톡시)카보닐아미노]-6-(플루오로메틸)-2-옥소피페리딜}아세트산의 합성d) Synthesis of 2-{(3S, 6S) -3-[(t-butoxy) carbonylamino] -6- (fluoromethyl) -2-oxopiperidyl} acetic acid

상기 c)에서 수득한 화합물(50mg)을 실시예 1-a)에서와 동일한 방법으로 반응시켜 미황색 거품상의 표제화합물(20mg)을 수득하였다.The compound (50 mg) obtained in c) was reacted in the same manner as in Example 1-a to give the title compound (20 mg) in a slightly yellow foam.

1H-NMR(300MHz, CDCl3) δ: 5.30(brs, 1H), 4.62-4.40(m, 2H), 4.26-4.21(m, 1H), 4.06-3.92(m ,2H), 3.74-3.68(m, 1H), 2.43-2.35(m, 1H), 2.16-1.78(m, 3H), 1.42(s, 9H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 5.30 (brs, 1H), 4.62-4.40 (m, 2H), 4.26-4.21 (m, 1H), 4.06-3.92 (m, 2H), 3.74-3.68 ( m, 1H), 2.43-2.35 (m, 1H), 2.16-1.78 (m, 3H), 1.42 (s, 9H)

e) N-{1-[2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸-(3S,6S)-6-(플루오로메틸)]-2-옥소-(3-피페리딜)}(t-부톡시)카복스아미드의 합성e) N- {1- [2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl- (3S, Synthesis of 6S) -6- (fluoromethyl)]-2-oxo- (3-piperidyl)} (t-butoxy) carboxamide

2-[2-((2S)-피롤리딘-2-일)에틸]-1-에틸인돌-6-카보니트릴(19mg)과 상기 d)에서 수득한 화합물(20mg)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 미황색 오일상의 표제화합물(25mg)을 수득하였다.2- [2-((2S) -pyrrolidin-2-yl) ethyl] -1-ethylindole-6-carbonitrile (19 mg) and the compound obtained in d) (20 mg) were prepared in Example 1-b. In the same manner as in), the title compound (25 mg) was obtained as pale yellow oil.

1H-NMR(300MHz, CDCl3) δ: 7.60-7.52(m, 2H), 7.28-7.24(m, 1H), 6.41-6.36 (m, 1H), 5.30(brs, 1H), 4.70-4.40(m, 2H), 4.31-4.22(m, 2H), 4.16-3.96(m, 4H), 3.84-3.76(m, 1H), 3.56-3.45(m, 2H), 2.82-2.74(m, 2H), 2.40-1.90(m, 6H), 1.82- 1.64(m, 4H), 1.43(s, 9H), 1.37-1.32(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.60-7.52 (m, 2H), 7.28-7.24 (m, 1H), 6.41-6.36 (m, 1H), 5.30 (brs, 1H), 4.70-4.40 ( m, 2H), 4.31-4.22 (m, 2H), 4.16-3.96 (m, 4H), 3.84-3.76 (m, 1H), 3.56-3.45 (m, 2H), 2.82-2.74 (m, 2H), 2.40-1.90 (m, 6H), 1.82- 1.64 (m, 4H), 1.43 (s, 9H), 1.37-1.32 (m, 3H)

f) 2-{2-[(2S)-1-(2-((3S,6S)-3-아미노-6-(플루오로메틸)-2-옥소피페리딜)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘의 합성f) 2- {2-[(2S) -1- (2-((3S, 6S) -3-amino-6- (fluoromethyl) -2-oxopiperidyl) acetyl) pyrrolidine-2 Synthesis of -yl] ethyl} -1-ethylindole-6-carboxamidine

상기 e)에서 수득한 화합물(25mg)을 실시예 1-c)에서와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(3mg)을 수득하였다.Compound (25 mg) obtained in e) was reacted in the same manner as in Example 1-c) to obtain the title compound (3 mg) as a pale yellow solid.

ES-MS : 236(1/2M+1)+, 471(M+1)+ ES-MS: 236 (1 / 2M + 1) + , 471 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.90(s, 1H), 7.64-7.61(m, 1H), 7.42-7.38(m, 1H), 6.46(s, 1H), 4.60-4.10(m, 8H), 4.05-3.96(m, 1H), 3.54-3.48(m, 2H), 2.89- 2.82(m, 2H), 2.26-1.70(m, 10H), 1.42-1.38(m, 3H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.90 (s, 1H), 7.64-7.61 (m, 1H), 7.42-7.38 (m, 1H), 6.46 (s, 1H), 4.60-4.10 (m , 8H), 4.05-3.96 (m, 1H), 3.54-3.48 (m, 2H), 2.89-2.82 (m, 2H), 2.26-1.70 (m, 10H), 1.42-1.38 (m, 3H)

실시예 26:Example 26:

(2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-(6S,3S)-6-(플루오로메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 29)의 합성(2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of ethyl)-(6S, 3S) -6- (fluoromethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 29)

a) (2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-(6S,3S)-6-(플루오로메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산의 합성a) (2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 Synthesis of -oxoethyl)-(6S, 3S) -6- (fluoromethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid

실시예 25-e)에서 수득한 화합물(40mg)을 실시예 2-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(15mg)을 수득하였다. 이것을 다시 실시예 6-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 화합물(15mg)을 수득하였다. 이렇게 수득한 화합물(15mg)을 다시 실시예 2-c)에서와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(3mg)을 수득하였다.Compound (40 mg) obtained in Example 25-e) was reacted in the same manner as in Example 2-a) to give a white foamy compound (15 mg). This was again reacted in the same manner as in Example 6-a) to give a white foamy compound (15 mg). The compound thus obtained (15 mg) was again reacted in the same manner as in Example 2-c) to obtain the title compound (3 mg) as a pale yellow solid.

ES-MS : 293(1/2M+1)+, 586(M+1)+ ES-MS: 293 (1 / 2M + 1) + , 586 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 7.98(s, 1H), 7.67-7.64(m, 1H), 7.40-7.36(m, 1H), 6.42(s, 1H), 4.60-4.15(m, 9H), 4.05-3.98(m, 1H), 3.54-3.48(m, 2H), 2.89-2.70(m, 4H), 2.30-1.68(m, 10H), 1.40-1.35(m, 3H) 1 H-NMR (300 MHz, CD 3 OD) δ: 7.98 (s, 1 H), 7.67-7.64 (m, 1 H), 7.40-7.36 (m, 1 H), 6.42 (s, 1H), 4.60-4.15 (m , 9H), 4.05-3.98 (m, 1H), 3.54-3.48 (m, 2H), 2.89-2.70 (m, 4H), 2.30-1.68 (m, 10H), 1.40-1.35 (m, 3H)

실시예 27:Example 27:

(2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-6-(메톡시메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 30)의 합성(2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Synthesis of ethyl) -6- (methoxymethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 30)

a) (t-부톡시)-N-[6-(메톡시메틸)-2-옥소-(3-피페리딜)]카복스아미드의 합성a) Synthesis of (t-butoxy) -N- [6- (methoxymethyl) -2-oxo- (3-piperidyl)] carboxamide

(t-부톡시)-N-[6-(하이드록시메틸)-2-옥소-(3-피페리딜)]카복스아미드(470mg, 참조:Tetrahedron: Asymmetry,Vol. 8, No. 2, 327-335, 1997)를 아세토니트릴(2㎖)에 녹이고, 빙냉하에서 산화은(I)(0.5g) 및 메틸요오다이드(1.5㎖)를 가한 후 실온에서 하루동안 교반하였다. 불용성 물질을 여과하여 제거하고여액을 감압농축하였다. 잔류물을 메틸렌클로라이드:메탄올=20:1(v/v)을 용출제로 사용하는 실리카겔 칼럼 크로마토그래피로 정제하여 갈색 오일상의 표제화합물 (470mg)을 수득하였다.(t-butoxy) -N- [6- (hydroxymethyl) -2-oxo- (3-piperidyl)] carboxamide (470 mg, see Tetrahedron: Asymmetry, Vol. 8, No. 2, 327-335, 1997) was dissolved in acetonitrile (2 mL), and silver oxide (I) (0.5 g) and methyl iodide (1.5 mL) were added under ice-cooling, followed by stirring at room temperature for one day. Insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methylene chloride: methanol = 20: 1 (v / v) as eluent to afford the title compound (470 mg) as a brown oil.

1H-NMR(300MHz, CDCl3) δ: 6.30(brs, 1H), 5.52(brs, 1H), 4.06-3.98(m, 1H), 3.66-3.60(m, 1H), 3.40-3.26(m, 5H), 2.40-2.30(m, 1H), 2.02-1.92(m, 1H), 1.70- 1.58(m, 2H), 1.40(s, 9H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 6.30 (brs, 1H), 5.52 (brs, 1H), 4.06-3.98 (m, 1H), 3.66-3.60 (m, 1H), 3.40-3.26 (m, 5H), 2.40-2.30 (m, 1H), 2.02-1.92 (m, 1H), 1.70- 1.58 (m, 2H), 1.40 (s, 9H)

b) 2-{3-[(t-부톡시)카보닐아미노]-6-(메톡시메틸)-2-옥소피페리딜}아세트산의 합성b) Synthesis of 2- {3-[(t-butoxy) carbonylamino] -6- (methoxymethyl) -2-oxopiperidyl} acetic acid

상기 a)에서 수득한 화합물(470mg)을 실시예 1-a)에서와 동일한 방법으로 반응시켜 미황색 거품상의 표제화합물(382mg)을 수득하였다.The compound (470 mg) obtained in a) was reacted in the same manner as in Example 1-a to obtain the title compound (382 mg) in a slightly yellow foam.

1H-NMR(300MHz, CD3OD) δ: 4.28-4.18(m, 2H), 3.96-4.10(m, 2H), 3.32(s, 3H), 2.10-1.90(m, 4H), 1.40(s, 9H) 1 H-NMR (300 MHz, CD 3 OD) δ: 4.28-4.18 (m, 2H), 3.96-4.10 (m, 2H), 3.32 (s, 3H), 2.10-1.90 (m, 4H), 1.40 (s , 9H)

c) N-1-[2-(2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-6-(메톡시메틸)-2-옥소-(3-피페리딜))-(t-부톡시)카복스아미드의 합성c) N-1- [2- (2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -6- (meth Synthesis of methoxymethyl) -2-oxo- (3-piperidyl))-(t-butoxy) carboxamide

상기 b)에서 수득한 화합물(382mg)과 2-[2-((2S)-피롤리딘-2-일)에틸]-1-에틸인돌-6-카보니트릴(324mg)을 실시예 1-b)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(371mg)을 수득하였다.The compound (382 mg) obtained in the above b) and 2- [2-((2S) -pyrrolidin-2-yl) ethyl] -1-ethylindole-6-carbonitrile (324 mg) were prepared in Example 1-b. Reaction was carried out in the same manner as in) to obtain the title compound (371 mg) as a white foam.

1H-NMR(300MHz, CDCl3) δ: 7.60-7.50(m, 2H), 7.42-7.38(m, 1H), 6.36(s,1H), 5.32(brs, 1H), 4.40-3.90(m, 5H), 3.74-3.38(m, 6H), 3.30(s, 3H), 2.80- 2.75(m, 2H), 2.38-2.20(m, 2H), 2.15-1.90(m, 6H), 1.82-1.70(m, 2H), 1.40(s, 9H), 1.38-1.32(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.60-7.50 (m, 2H), 7.42-7.38 (m, 1H), 6.36 (s, 1H), 5.32 (brs, 1H), 4.40-3.90 (m, 5H), 3.74-3.38 (m, 6H), 3.30 (s, 3H), 2.80-2.75 (m, 2H), 2.38-2.20 (m, 2H), 2.15-1.90 (m, 6H), 1.82-1.70 ( m, 2H), 1.40 (s, 9H), 1.38-1.32 (m, 3H)

d) 벤질 (2S)-3-{N-[1-(2-((2S)-2-(2-(6-시아노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-6-(메톡시메틸)-2-옥소-(3-피페리딜)]카바모일}-2-[(t-부톡시)카보닐아미노]프로파노에이트의 합성d) benzyl (2S) -3- {N- [1- (2-((2S) -2- (2- (6-cyano-1-ethylindol-2-yl) ethyl) pyrrolidinyl)- Synthesis of 2-oxoethyl) -6- (methoxymethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-[(t-butoxy) carbonylamino] propanoate

상기 c)에서 수득한 화합물(371mg)을 실시예 2-a)에서와 동일한 방법으로 반응시켜 미황색 거품상의 화합물(190mg)을 수득하고, 이것을 다시 실시예 6-a)에서와 동일한 방법으로 반응시켜 흰색 거품상의 표제화합물(303mg)을 수득하였다.The compound (371 mg) obtained in c) was reacted in the same manner as in Example 2-a) to obtain a pale yellow foamy compound (190 mg), which was reacted in the same manner as in Example 6-a). The title compound (303 mg) in white foam was obtained.

1H-NMR(300MHz, CDCl3) δ: 7.60-7.48(m, 2H), 7.42-7.36(m, 6H), 6.48-6.38 (m, 1H), 6.36-6.33(m, 1H), 5.80-5.68(m, 1H), 5.20-5.14(m, 2H), 4.57-4.51(m, 1H), 4.40-3.85(m, 6H), 3.66-3.40(m, 5H), 3.32(s, 3H), 2.95-2.86(m, 1H), 2.80- 2.65(m, 3H), 2.40-2.24(m, 2H), 2.10-1.88(m, 6H), 1.80-1.66(m, 2H), 1.42(s, 9H), 1.36-1.32(m, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ: 7.60-7.48 (m, 2H), 7.42-7.36 (m, 6H), 6.48-6.38 (m, 1H), 6.36-6.33 (m, 1H), 5.80- 5.68 (m, 1H), 5.20-5.14 (m, 2H), 4.57-4.51 (m, 1H), 4.40-3.85 (m, 6H), 3.66-3.40 (m, 5H), 3.32 (s, 3H), 2.95-2.86 (m, 1H), 2.80-2.65 (m, 3H), 2.40-2.24 (m, 2H), 2.10-1.88 (m, 6H), 1.80-1.66 (m, 2H), 1.42 (s, 9H ), 1.36-1.32 (m, 3H)

e) (2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-6-(메톡시메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산의 합성e) (2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 Synthesis of -oxoethyl) -6- (methoxymethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid

상기 d)에서 수득한 화합물(303mg)을 실시예 2-c)에서와 동일한 방법으로 반응시켜 미황색 고체상의 표제화합물(90mg)을 수득하였다.The compound (303 mg) obtained in the above d) was reacted in the same manner as in Example 2-c) to give the title compound (90 mg) as a pale yellow solid.

ES-MS : 598(M+1)+ ES-MS: 598 (M + 1) +

1H-NMR(300MHz, CD3OD) δ: 8.05-7.90(m, 1H), 7.65-7.56(m, 1H), 7.48-7.38 (m, 1H), 6.46-6.40(m, 1H), 4.48-4.40(m, 1H), 4.32-4.20(m, 3H), 4.10-3.80(m, 2H), 3.70-3.48(m, 5H), 3.35(s, 3H), 3.15-3.05(m, 2H), 2.88-2.60(m, 4H), 2.40-1.80(m, 10H), 1.40-1.35(m, 3H) 1 H-NMR (300 MHz, CD 3 OD) δ: 8.05-7.90 (m, 1H), 7.65-7.56 (m, 1H), 7.48-7.38 (m, 1H), 6.46-6.40 (m, 1H), 4.48 -4.40 (m, 1H), 4.32-4.20 (m, 3H), 4.10-3.80 (m, 2H), 3.70-3.48 (m, 5H), 3.35 (s, 3H), 3.15-3.05 (m, 2H) , 2.88-2.60 (m, 4H), 2.40-1.80 (m, 10H), 1.40-1.35 (m, 3H)

실험예 1: 트롬빈 및 트립신에 대한 억제활성Experimental Example 1: Inhibitory activity against thrombin and trypsin

50% 메탄올에 용해시킨 각 농도의 본 발명에 따른 화합물 20㎕씩을 마이크로플레이트 웰에 분주한 후, 125mM NaCl, 50mM 트리스 HCl(pH 8.0) 및 2mM 합성기질(N-벤조일-Phe-Val-Arg-p-니트로아닐리드, Sigma B-7632)을 포함하는 반응매질 160㎕를 첨가하였다. 여기에 0.1% 소혈청알부민을 포함하는 인간 트롬빈 용액(5 유니트/㎖, Sigma T-6759, Sigma Co. 제조) 20㎕씩을 가하여 상온에서 반응을 개시한지 20분후에 기질의 가수분해 정도를 405nm에서의 흡광도로 측정하였다. 화합물을 첨가하지 않았을 때의 흡광도 변화를 기준으로하여 1/2의 흡광도 변화를 나타낸 화합물의 농도를 IC50값으로 표시하여 트롬빈 억제활성을 나타내었다.Twenty microliters of the compound according to the present invention at each concentration dissolved in 50% methanol were dispensed into microplate wells, followed by 125 mM NaCl, 50 mM Tris HCl (pH 8.0) and 2 mM synthetic substrate (N-benzoyl-Phe-Val-Arg-). 160 μl of reaction medium containing p-nitroanilide, Sigma B-7632) was added. 20 μl of a human thrombin solution containing 0.1% bovine serum albumin (5 units / ml, manufactured by Sigma T-6759, Sigma Co.) was added thereto, and 20 minutes after the start of the reaction at room temperature, the degree of hydrolysis of the substrate was measured at 405 nm. Absorbance was measured. Based on the change in absorbance when no compound was added, the concentration of the compound exhibiting absorbance change of 1/2 was expressed by IC 50 value, indicating thrombin inhibitory activity.

본 발명에 따른 화합물의 트롬빈 억제활성은 표 2에 나타내었다.The thrombin inhibitory activity of the compounds according to the invention is shown in Table 2.

실험예 2: 랫트 혈장에서의 트롬빈 시간(thrombin time: TT) 측정Experimental Example 2: Measurement of thrombin time (TT) in rat plasma

하룻밤동안 절식시킨 220±20g (6-7주령)의 S.D.계 수컷 랫트를 사용하여 약물 투여직전에 심장으로부터 채혈하고, 50% PEG400에 용해시킨 본 발명에 따른 화합물을 경구투여한 후 30, 60, 120, 240분째에 채혈하였다. 이 혈액에 0.108M 소듐시트레이트를 9:1의 부피비로 혼합하여 4℃에서 5분간 15,000rpm으로 원심분리하고 혈장만을 취하여 TT 측정 전까지 -20℃에서 보관하였다. TT 측정법은 다음과 같다.After the overnight fasting, 220 ± 20g (6-7 weeks old) SD male rats were bled from the heart immediately before drug administration, and after oral administration of the compound according to the present invention dissolved in 50% PEG400, 30, 60, Blood was collected at 120 and 240 minutes. 0.108M sodium citrate was mixed in the blood at a volume ratio of 9: 1, centrifuged at 15,000 rpm for 5 minutes at 4 ° C, and only plasma was collected and stored at -20 ° C until TT measurement. TT measurement method is as follows.

혈장 50㎕에 오우렌스 완충액(Owren's buffer) 200㎕를 가하고, 희석된 혈장을 혈액응고측정용 바이알에 100㎕씩 분주한 후, 37℃에서 2분간 배양하였다. 이 바이알에 전배양한 20U/㎖의 트롬빈 100㎕를 가하고 응혈이 일어날 때까지의 시간(TT)을 측정하였다. 약물투여 후의 랫트 혈장의 TT와 약물 투여 전의 랫트 혈장의 TT의 비를 구하여 하기 표 2에 나타내었다.200 μl of Owren's buffer was added to 50 μl of plasma, and 100 μl of the diluted plasma was dispensed into a blood coagulation vial, followed by incubation at 37 ° C. for 2 minutes. 100 μl of 20 U / ml pre-cultured thrombin was added to the vial, and the time until the coagulation occurred (TT) was measured. The ratio of TT of rat plasma after drug administration and TT of rat plasma before drug administration is shown in Table 2 below.

실험예 3: 약물동력학적 시험Experimental Example 3: Pharmacokinetic Test

시험방법:Test Methods:

체중 220±20g, SD계의 수컷 랫트를 24시간동안 절식시킨 후 에테르 마취시키고 대퇴부 정맥과 동맥에 카눌레이션(cannulation)한 다음 생리식염수에 용해시킨 실시예 2의 화합물을 정맥주사와 경구투여하였다. 각 시간별로 채혈한 혈액에 즉시 메탄올을 가하여 원심분리(15,000rpm, 5분, 4℃)한 후 상층을 정량적으로 취해 254nm에서 DAD 검출기(Diode Array Detector)를 사용하여 HPLC로 혈액중 약물의 농도를 분석하였다.The male rats of 220 ± 20g body weight and SD system were fasted for 24 hours, and then anesthetized with ether, and then cannulated in the femoral veins and arteries, and then the compound of Example 2 dissolved in physiological saline was orally administered with intravenous injection. Methanol was immediately added to the blood collected for each hour, centrifuged (15,000 rpm, 5 min, 4 ° C), and the upper layer was quantitatively taken. Analyzed.

시험결과:Test result:

실시예 2의 화합물을 정맥 및 경구투여한 후 분석된 시간별 혈중농도를 표 3 및 4에 각각 기록하였으며, 약물동력학적 파라메터를 표 5에 기록하였다. 이들 표에 기재된 결과로부터 알 수 있는 바와 같이, 실시예 2의 화합물은 정맥내 투여했을 때 혈중에서 체내에 빠르게 분포되며 천천히 소실되었다. 또한, 랫트에서 혈중소실 반감기(elimination half-life)는 14분이며, 생물학적 이용률(bioavailabil- ity)은 53.6%로서 매우 우수한 결과를 나타내었다.The hourly blood concentrations analyzed after intravenous and oral administration of the compound of Example 2 were recorded in Tables 3 and 4, respectively, and the pharmacokinetic parameters were recorded in Table 5. As can be seen from the results described in these tables, the compound of Example 2 was rapidly distributed in the body in blood and slowly lost when administered intravenously. In addition, the blood loss half-life (elimination half-life) in the rat was 14 minutes, the bioavailability (bioavailability) was 53.6%, which was very good results.

Claims (10)

하기 화학식 (1)의 화합물, 그의 약제학적으로 허용되는 염 및 입체화학적 이성체:Compounds of formula (1), pharmaceutically acceptable salts and stereochemical isomers thereof: (1) (One) 상기식에서In the above formula A 는 C1-C4-알킬, 할로게노-C1-C4-알킬, C1-C4-알콕시-C1-C4-알킬, 하이드록시-C1-C4-알킬에 의해 치환될 수 있는 C2-C6-알킬렌을 나타내고,A is substituted by C 1 -C 4 -alkyl, halogeno-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl C 2 -C 6 -alkylene, which may be R1은 수소원자를 나타내거나, C1-C4-알킬 또는 페닐에 의해 치환될 수 있는 C1-C4-알킬을 나타내며,R 1 is represents a hydrogen atom, or, C 1 -C 4 - represents an alkyl, - C 1 -C 4 optionally substituted with alkyl or phenyl R2및 R3는 각각 독립적으로 수소원자를 나타내거나, 각각 카복시, 할로겐, 카바모일, 아미노, 메틸설포닐아미노, C1-C4-알킬아미노, 디(C1-C4-알킬)아미노, 하이드록시, C1-C4-알콕시카보닐 또는 C1-C4-알콕시카바모일에 의해 일치환되거나 다치환될 수 있는 C1-C4-알킬 또는 C1-C5-알카노일을 나타낸다.R 2 and R 3 each independently represent a hydrogen atom or each represents carboxy, halogen, carbamoyl, amino, methylsulfonylamino, C 1 -C 4 -alkylamino, di (C 1 -C 4 -alkyl) amino C 1 -C 4 -alkyl or C 1 -C 5 -alkanoyl which may be mono- or polysubstituted by hydroxy, C 1 -C 4 -alkoxycarbonyl or C 1 -C 4 -alkoxycarbamoyl Indicates. 제1항에 있어서, A 가 메틸, 에틸, 플루오로메틸, 메톡시메틸 또는 하이드록시메틸에 의해 치환될 수 있는 에틸렌, 프로필렌 또는 부틸렌을 나타내는 화합물A compound according to claim 1 wherein A represents ethylene, propylene or butylene, which may be substituted by methyl, ethyl, fluoromethyl, methoxymethyl or hydroxymethyl 제1항에 있어서, R1이 수소원자, 메틸, 이소프로필 또는 벤질을 나타내는 화합물.A compound according to claim 1, wherein R 1 represents a hydrogen atom, methyl, isopropyl or benzyl. 제1항에 있어서, R2및 R3가 각각 독립적으로 수소원자, 메틸, 에틸, 3-카복시프로필, 카복시메틸, 3-아미노-3-카복시-프로파노일, 3-카바모일-3-아미노-프로파노일, 4-아미노-4-카복시-부티릴, 4-카바모일-4-아미노-부티릴, 3-메틸설포닐아미노-3-카복시-프로파노일, 3-디에틸아미노-3-카복시-프로파노일, 3-하이드록시-3-카복시-프로파노일 또는 3-카바모일-2-아미노-프로파노일을 나타내는 화합물.The compound of claim 1, wherein R 2 and R 3 are each independently hydrogen atom, methyl, ethyl, 3-carboxypropyl, carboxymethyl, 3-amino-3-carboxy-propanoyl, 3-carbamoyl-3-amino -Propanoyl, 4-amino-4-carboxy-butyryl, 4-carbamoyl-4-amino-butyryl, 3-methylsulfonylamino-3-carboxy-propanoyl, 3-diethylamino-3 Carboxy-propanoyl, 3-hydroxy-3-carboxy-propanoyl or 3-carbamoyl-2-amino-propanoyl. 제1항에 있어서,The method of claim 1, 2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소아자퍼하이드로에피닐)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 1);2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxoazahydrohydropinyl) acetyl) pyrrolidin-2-yl] ethyl} -1-ethylindole -6-carboxamidine (Compound 1); 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노산(화합물 2);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} butanoic acid (Compound 2); 2-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}아세트산(화합물 3);2-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} acetic acid (compound 3); 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-메틸-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노산(화합물 4);4-{[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -1-methyl-2 -Oxoethyl) -2-oxoazahydrohydroepin-3-yl] amino} butanoic acid (Compound 4); 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]에틸아미노}부타노산(화합물 5);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] ethylamino} butanoic acid (Compound 5); (2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]카바모일}-2-아미노프로파노산(화합물 6);(2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] carbamoyl} -2-aminopropanoic acid (compound 6); 2-{2-[(2S)-1-(2-((3S)-3-아미노-2-옥소피롤리디닐)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 7);2- {2-[(2S) -1- (2-((3S) -3-amino-2-oxopyrrolidinyl) acetyl) pyrrolidin-2-yl] ethyl} -1-ethylindole-6 Carboxamidine (compound 7); 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]아미노}부타노산(화합물 8);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] amino} butanoic acid (compound 8); (2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]카바모일}-2-아미노프로파노산(화합물 9);(2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] carbamoyl} -2-aminopropanoic acid (compound 9); 2-{2-[(2S)-1-((2S)-2-((3S)-3-아미노-2-옥소피롤리디닐)-3-메틸부타노일)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 10);2- {2-[(2S) -1-((2S) -2-((3S) -3-amino-2-oxopyrrolidinyl) -3-methylbutanoyl) pyrrolidin-2-yl] Ethyl} -1-ethylindole-6-carboxamidine (compound 10); 4-{[(3S)-1-((1S)-2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-1-(이소프로필)-2-옥소에틸)-2-옥소피롤리딘-3-일]아미노}부타노산(화합물 11);4-{[(3S) -1-((1S) -2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -1 -(Isopropyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] amino} butanoic acid (Compound 11); 2-{[(3S)-1-((1S)-2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소-1-벤질에틸)-2-옥소피롤리딘-3-일]아미노}아세트산(화합물 12);2-{[(3S) -1-((1S) -2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2 -Oxo-1-benzylethyl) -2-oxopyrrolidin-3-yl] amino} acetic acid (compound 12); 2-{2-[1-(2-((3S)-3-아미노-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 13);2- {2- [1- (2-((3S) -3-Amino-2-oxopiperidyl) acetyl)-(2S) -pyrrolidin-2-yl] ethyl} -1-ethylindole- 6-carboxamidine (Compound 13); 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-3-피페리딜]아미노}부타노산(화합물 14);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo-3-piperidyl] amino} butanoic acid (Compound 14); 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노프로파노산(화합물 15);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminopropanoic acid (compound 15); 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]-N-에틸카바모일}-(2S)-2-아미노프로파노산(화합물 16);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)]-N-ethylcarbamoyl}-(2S) -2-aminopropanoic acid (compound 16); 2-{2-[1-(2-((3S)-3-((3S)-3-아미노-3-카바모일-N-에틸프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 17);2- (2- [1- (2-((3S) -3-((3S) -3-amino-3-carbamoyl-N-ethylpropanoylamino) -2-oxopiperidyl) acetyl) -(2S) -pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 17); (2R)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 18);(2R) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 18); 2-{2-[1-(2-((3S)-3-((3R)-3-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 19);2- {2- [1- (2-((3S) -3-((3R) -3-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) -Pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 19); 4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노부타노산(화합물 20);4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminobutanoic acid (compound 20); 2-{2-[1-(2-((3S)-3-((4S)-4-아미노-4-카바모일부타노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 21);2- {2- [1- (2-((3S) -3-((4S) -4-amino-4-carbamoylbutanoylamino) -2-oxopiperidyl) acetyl)-(2S)- Pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 21); 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-[(메틸설포닐)아미노]프로파노산(화합물 22);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-[(methylsulfonyl) amino] propanoic acid (compound 22); 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-(디에틸아미노)프로파노산(화합물 23);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2- (diethylamino) propanoic acid (compound 23); 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-하이드록시프로파노산(화합물 24);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-hydroxypropanoic acid (compound 24); (2R)-4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노부타노산(화합물 25);(2R) -4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminobutanoic acid (compound 25); 2-{2-[1-(2-((3S)-3-((2S)-2-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 26);2- {2- [1- (2-((3S) -3-((2S) -2-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) -Pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 26); 2-{2-[1-(2-((3S)-3-((2R)-2-아미노-3-카바모일프로파노일아미노)-2-옥소피페리딜)아세틸)-(2S)-피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 27);2- {2- [1- (2-((3S) -3-((2R) -2-amino-3-carbamoylpropanoylamino) -2-oxopiperidyl) acetyl)-(2S) -Pyrrolidin-2-yl] ethyl} -1-ethylindole-6-carboxamidine (Compound 27); 2-{2-[(2S)-1-(2-((3S,6S)-3-아미노-6-(플루오로메틸)-2-옥소피페리딜)아세틸)피롤리딘-2-일]에틸}-1-에틸인돌-6-카복스아미딘(화합물 28);2- {2-[(2S) -1- (2-((3S, 6S) -3-amino-6- (fluoromethyl) -2-oxopiperidyl) acetyl) pyrrolidin-2-yl ] Ethyl} -1-ethylindole-6-carboxamidine (Compound 28); (2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-(6S,3S)-6-(플루오로메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 29); 및(2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl)-(6S, 3S) -6- (fluoromethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 29); And (2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-6-(메톡시메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 30)으로 구성된 그룹중에서 선택된 화합물.(2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -6- (methoxymethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 30). 제5항에 있어서,The method of claim 5, 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]아미노}부타노산(화합물 2);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] amino} butanoic acid (Compound 2); 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]에틸아미노}부타노산(화합물 5);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] ethylamino} butanoic acid (Compound 5); (2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소아자퍼하이드로에핀-3-일]카바모일}-2-아미노프로파노산(화합물 6);(2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxoazahydrohydropin-3-yl] carbamoyl} -2-aminopropanoic acid (compound 6); (2S)-3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소피롤리딘-3-일]카바모일}-2-아미노프로파노산(화합물 9);(2S) -3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxopyrrolidin-3-yl] carbamoyl} -2-aminopropanoic acid (compound 9); 4-{[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-3-피페리딜]아미노}부타노산(화합물 14);4-{((3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo-3-piperidyl] amino} butanoic acid (Compound 14); 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노프로파노산(화합물 15);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminopropanoic acid (compound 15); 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]-N-에틸카바모일}-(2S)-2-아미노프로파노산(화합물 16);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)]-N-ethylcarbamoyl}-(2S) -2-aminopropanoic acid (compound 16); 4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-아미노부타노산(화합물 20);4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-aminobutanoic acid (compound 20); 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-(디에틸아미노)프로파노산(화합물 23);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2- (diethylamino) propanoic acid (compound 23); 3-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-(2S)-2-하이드록시프로파노산(화합물 24);3- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -2-oxo- (3-piperidyl)] carbamoyl}-(2S) -2-hydroxypropanoic acid (compound 24); (2R)-4-{N-[(3S)-1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노부타노산(화합물 25);(2R) -4- {N-[(3S) -1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxoethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminobutanoic acid (compound 25); (2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-(6S,3S)-6-(플루오로메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 29); 및(2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl)-(6S, 3S) -6- (fluoromethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 29); And (2S)-3-{N-[1-(2-((2S)-2-(2-(6-아미디노-1-에틸인돌-2-일)에틸)피롤리디닐)-2-옥소에틸)-6-(메톡시메틸)-2-옥소-(3-피페리딜)]카바모일}-2-아미노프로파노산(화합물 30)으로 구성된 그룹중에서 선택된 화합물.(2S) -3- {N- [1- (2-((2S) -2- (2- (6-amidino-1-ethylindol-2-yl) ethyl) pyrrolidinyl) -2-oxo Ethyl) -6- (methoxymethyl) -2-oxo- (3-piperidyl)] carbamoyl} -2-aminopropanoic acid (compound 30). 활성성분으로서 유효량의 제1항에 따르는 화학식 (1)의 화합물, 그의 약제학적으로 허용되는 염 또는 입체화학적 이성체와 약제학적으로 허용되는 담체를 함유하는 트롬빈 억제제 조성물.A thrombin inhibitor composition comprising as an active ingredient an effective amount of a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt or stereochemical isomer thereof and a pharmaceutically acceptable carrier. 제7항에 있어서, 혈전증 예방 및 치료제로서 사용하기 위한 트롬빈 억제제 조성물.8. The thrombin inhibitor composition according to claim 7, for use as an agent for preventing and treating thrombosis. 제7항에 있어서, 경구투여용 제제로 제형화된 트롬빈 억제제 조성물.8. The thrombin inhibitor composition according to claim 7, formulated as a formulation for oral administration. (a) 하기 화학식 (6)의 화합물을 하기 화학식 (5)의 화합물과 축합반응시켜 하기 화학식 (4)의 화합물을 수득한 다음, 화학식 (4)의 화합물을 탈보호기화시켜 하기 화학식 (3)의 화합물을 수득하고, 생성된 화학식 (3) 화합물의 시아노 그룹을 아미디노 그룹으로 전환시켜 하기 화학식 (1a)의 화합물을 수득하거나;(a) Condensation reaction of a compound of formula (6) with a compound of formula (5) to yield a compound of formula (4), followed by deprotection of a compound of formula (4) Obtaining a compound of and converting the cyano group of the resulting compound of formula (3) to an amidino group to obtain a compound of formula (1a); (b) 화학식 (3)의 화합물을 하기 화학식 (7)의 화합물 및 하기 화학식 (8)의 화합물 중에서 선택된 어느 하나 또는 둘다와 커플링반응시켜 하기 화학식 (2)의 화합물을 수득한 다음, 생성된 화학식 (2) 화합물의 시아노 그룹을 아미디노 그룹으로 전환시켜 하기 화학식 (1b)의 화합물을 수득하거나;(b) coupling the compound of formula (3) with either or both of the compound of formula (7) and the compound of formula (8) to obtain a compound of formula (2) Converting the cyano group of the compound of formula (2) to an amidino group to obtain a compound of formula (1b); (c) 필요에 따라 화학식 (1b)의 화합물을 가수분해시켜 카복시 그룹을 함유하는 화학식 (1)의 화합물을 수득함을 특징으로 하여 제1항에 정의된 화학식 (1)의 화합물, 그의 염 또는 이성체를 제조하는 방법:(c) a compound of formula (1) as defined in claim 1, a salt thereof, characterized in that the compound of formula (1b) is hydrolyzed to obtain a compound of formula (1) containing a carboxy group, if necessary How to prepare isomers: (6) (6) (5) (5) (4) (4) (3) (3) (1a) (1a) R2'-X (7)R 2 '-X (7) R3'-X (8)R 3 '-X (8) (2) (2) (1b) (1b) 상기식에서In the above formula A 및 R1은 제1항에서 정의한 바와 같고,A and R 1 are as defined in claim 1, P 는 아미노 보호기를 나타내며,P represents an amino protecting group, R2'및 R3'는 각각 독립적으로 수소를 제외한 R2및 R3를 나타내고, 여기에서 R2및 R3는 제1항에서 정의한 바와 같으며,R 2 ' and R 3' each independently represent R 2 and R 3 excluding hydrogen, wherein R 2 and R 3 are as defined in claim 1, X 는 반응성 이탈기를 나타내고,X represents a reactive leaving group, m 및 n 은 각각 독립적으로 0 또는 1 의 정수를 나타내며,m and n each independently represent an integer of 0 or 1, p 는 2-(m+n)의 정수를 나타낸다.p represents the integer of 2- (m + n).
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