AROMATIC AMIDINE DERIVATIVES USEFUL AS SELECTIVE THROMBIN INHIBITORS

TECHNICAL FIELD

The present invention relates a novel thrombin inhibitor which is effective even when orally administered. More specifically, the present invention relates to an aromatic amidine derivative represented by formula (I) and the salts thereof, which show potent selective inhibitory activity for thrombin-"

in which

R represents a group of formula R _t wherein

R ¹ represents hydrogen, hydroxy, alkyl, alkoxy, alkylcarbonyl, alkylcar- bonyloxy, aralkoxycarbonyl, or a radical of formula (a),

wherein

B represents oxygen or sulfur;

R ¹¹ and R ^l/ independently of one another represent hydrogen, haloalkyl, aJkylcarbonyloxy, dialkylamino, or substituted or unsubstituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring; and g denotes an integer of 0 to 3;

R represents hydrogen, hydroxy, halogen, carboxy, aminocarbonyl, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkylsulfonyl, carboxy¬ alkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, or substituted or unsubstituted arylsulfonyl; 5 R ³ represents hydrogen, halogen, alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, carboxy, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, or a radical of formula (b),

— 0-(CH)h-R ^]3 _(b)

10 R ¹⁴

wherein

R ¹³ and R ^1' independently of one another represent hydrogen, alkyl, or substituted or unsubstituted 3- to 7-membered saturated or unsatu- , ,- rated heterocyclic or carbocyclic ring; and h denotes an integer of 0 to 3;

the group of formula represents a radical selected from

2® the group consisting of indolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydro- naphthyl, indanyl, dihydrobenzofuranyl and dihydrobenzothienyl;

A represents a saturated or unsaturated alkylene group having 2 to 4 carbon atoms, which may have 1 or 2 substituents selected from the group consisting of carboxy, alkyl, hydroxyalkyl, carboxyalkyl, alkyl ^¬ carbonyl, alkoxycarbonyl and alkoxycarbonylalkyl;

W represents a group of formula (c), (d) or (e),

(c) (d) (e)

wherein 35 o, p and q independently of one another denote an integer of 0 to 3,

R", R ⁵ and R ⁶ independently of one another represent hydrogen, hydroxy, carboxy, alkoxycarbonyl, substituted or unsubstituted arylsulfonyl, or substituted or unsubstituted 3- to 7-membered saturated or unsatura¬ ted heterocyclic or carbocyclic ring, or represents a group of formula (f), (g) or (h),

(*) (g) (h)

wherein

R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ independently of one another represent hydrogen, alkyl, alkylsulfonyl, carboxyalkyl, alkylcarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, substituted or unsubsituted arylsulfonyl, substi- tuted or unsubstituted aralkyl, or substituted or unsubsituted 3- to

7-membered saturated or unsaturated heterocyclic or carbocyclic ring;

R ¹⁹ and R ²⁰ independently of one another represent hydrogen, carboxy, aminocarbonyl or alkoxycarbonyl, or represents 3- to 7-memebered saturated or unsaturated heterocyclic or carbocyclic ring which may be fused with one or more 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic rings; and r denotes an integer of 0 to 3;

Y represents hydrogen or a 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring which may be fused with one or more 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic rings and which may be substituted on any atom of the ring with a substituent selected from the group consisting of oxygen, halogen, nitro, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted 3- to 7- membered saturated or unsaturated heterocyclic or carbocyclic ring, and a group of formula (i), (j) and (k),

— NR ²¹ R ²² — O—

(') (i) (k)

wherein

R ²¹ and R ²² independently of one another represent hydrogen, alkyl, alkyl¬ sulfonyl, carboxyalkyl, alkylcarbonyl, alkoxycarbonylalkyl, or sub¬ stituted or unsubstituted arylsulfonyl;

R ²³ and R ²⁴ independently of one another represent hydrogen, carboxy, aminocarbonyl, alkoxycarbonyl, or 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring which may be fused with one or more 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic rings;

R ²⁵ , R ^2e and R ²⁷ independently of one another represent hydrogen, hydroxy, thio, amino, carboxy, aminocarbonyl, alkoxy, alkoxycarbonyl, alkylamino, alkylsulfonylamino, alkenyl, alkoxycarbonylamino, cyclo- alkylamino, alkoxycarbonylalkylam.no, substituted or unsubstituted arylsulfonylamino, or substituted or unsubstituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring; s denotes an integer of 0 to 3; t denotes an integer of 0 to 6; and u denotes an integer of 0 to 8; and n denotes an integer of 0 to 2, provided that when each of g, h, o, p, q, r, s, t and u denotes number of

3 or more, the corresponding alkylene chain may be straight or branched.

The present invention also relates to a process for preparation of the compound of formula (I), and a thrombin inhibitor composition containing the compound of formula (I) as an active component.

BACKGROUND ART

Thrombosis is a pathological process in which platelets aggrega- tion or a fibrin clot occludes a blood vessel. Anticoagulants interfere

with fibrin formation and are used for prophylaxis of thrombosis.

The blood coagulation system involves a number of zymogens (inactive enzymes) that are activated through a cascade of enzymatic reactions. The final step in coagulation is the formation of the fibrin clot from fibrinogen by a trypsin-like serine protease thrombin, which in turn is generated from prothrombin by the action of factor Xa. Accordingly, the blood coagulation enzyme thrombin plays a central role in hemostasis and thrombosis. Thrombin inhibitors are therefore expected to be effective anticoagulants by inhibition of platelets, fibrin formation and fibrin stabilization. It also activates factor V and factor VIII in a positive feed back reaction.

In recent years, numerousthrombin inhibitors have been developed as potential antithrombotic and anticoagulant agents, for example, tripeptide derivatives such as 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 Q. 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 S0 ₄ , Thromb. Haemost., 67, 325 (1992)], Inogatran [HOOC-CH ₂ -(R)Cha-Pic-Nag, where Cha : cyclohexyl- amine, Pic : pipecolic acid and Nag : noragmatine, WO 93/11152, Blood Coag. Fibrinol., 7, 69 (1996)] and CVS- 1123 [(CH ₃ CH ₂ CH ₂ ) ₂ -CHCO- Asp(OCH3)~Pro-Arg, WO 93/15756] and piperidine amide derivatives such as Argatroban [US 4258192, Thromb. Haemost., 18, 13 (1992)] and NAPAP [J. Biol. Chem., 266, 20085 (1991)]. But, they are not necessarily sufficient for practical use in view of oral bioavailability, inhibition selectivity for thrombin over other serine proteases, stability, duration of action and toxicity at the therapeutic dosages.

In view of the above, the present inventors have conducted intensive studies to develop potent thrombin inhibitors which are orally bioavailable, selective in inhibition of thrombin over other serine proteases and sufficient for practical use. As a result of such efforts, we have found that the compound of formula (I) exhibits excellent

thrombin inhibitory activity even when orally administered and has a high selectivity for thrombin in comparison to trypsin, and have thereby completed the present invention.

DISCLOSURE OF THE INVENTION

The present invention relates to an aromatic amidine derivative of formula (I), as defined above, and pharmaceutically acceptable salts thereof.

In addition, the present invention relates to a process for preparation of the compound of formula (I).

The present invention further relates to a thrombin inhibitor composition containing the compound of formula (I) or its pharamceutically acceptable salts as an active component.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound according to the present invention is represented by formula (I) as defined above.

Preferred compound of formula (I) according to the present invention includes those, in which

,NR ¹ NH

R represents a group of formula ~< ^NH 2 or -< NrHF? , , wherein

R ¹ represents hydrogen, hydroxy, Cι-C ₄ alkyl, Ci-C ₄ alkoxy, C ₂ -C ₄ alkyl- carbonyl, C ₂ -Cι alkylcarbonyloxy, or a radical of formula (a),

, . wherein

B represents oxygen or sulfur,

R ¹¹ and R ¹² independently of one another represents hydrogen, C ₁ -C ₄ haloalkyl, C ₂ -Q alkylcarbonyloxy, C ₂ -CG dialkylamino, or substituted or unsubstituted 6-membered carbocyclic ring, and g denotes an integer of 0 to 3;

R ² represents hydrogen, halogen, carboxy, C]-C ₄ alkyl, Cι-G» alkoxy,

Ci-C, hydroxyalkyl, d-C ₄ aminoalkyl, C ₂ -C ₄ alkylcarbonyl, C]-C ₄ alkylsulfonyl, C ₂ -C ₄ carboxyalkyl, C ₂ -C ₄ aminocarbonylalkyl or C ₃ -C ₇ alkoxycarbonylalkyl; R ³ represents hydrogen, halogen, C]-C ₄ alkyl, C1-C4 hydroxyalkyl, C ₂ -C ₄ carboxyalkyl, C3-C7 alkoxycarbonylalkyl, or a radica of formula (b),

-0— (CH)h— — R pi3

(b)

R 14

wherein

R and R independently of one another represent hydrogen or phenyl, and h denotes an integer of 0 to 1;

the group of formula represents a radical selected from the group consisting of indolyl, benzofuranyl, benzothienyl, benzo- imidazolyl and naphthyl;

A represents saturated or unsaturated alkylene group having 2 to 4 carbon atoms, which may have 1 or 2 substituents selected from the group consisting of carboxy, C1-C4 hydroxyalkyl and C ₂ -C ₄ alkoxy¬ carbonyl;

W represents a group of formula (c), (d) or (e),

q—

(c) (d) (e)

wherein o, p and c\ independently of one another denote an integer of 0 to 3, R", R ⁵ and R independently of one another represent hydrogen, hydroxy, carboxy, C ₂ -C,ι alkoxycarbonyl, phenylsulfonyl, or substituted or unsubstituted 3- to 5-membered saturated or unsaturated heterocyclic or carbocyclic ring, or represents a group of formula (f), (g) or (h),

(f) (g) (h)

wherein

R ' , R , R and R independently of one another represent hydrogen, Cι-Cι alkyl, Cι~C ₄ alkylsulfonyl, C ₂ -C ₄ carboxyalkyl, C ₂ -C ₄ alkyl - carbonyl, C ₂ -C ₄ aminocarbonylalkyl, C3-C7 alkoxycarbonylalkyl, or substituted or unsubsituted 3- to 5-membered saturated or unsaturated heterocyclic or carbocyclic ring,

R ¹⁹ and R ²⁰ independently of one another represent hydrogen, carboxy, aminocarbonyl or C ₂ -C ₄ alkoxycarbonyl, or represents 5- to 6- memebered saturated or unsaturated heterocyclic or carbocyclic ring which may be fused with other one or more 5- to 6-membered saturated or unsaturated heterocyclic or carbocyclic ring, and r denotes an integer of 0 to 3;

Y represents hydrogen, or represents 5- to 6-membered saturated or unsaturated heterocyclic or carbocyclic ring which may be fused with other one or more 5- to 6-membered saturated or unsaturated heterocyclic or carbocyclic ring and which can be substituted on any atom of the ring with substituent selected from the group consisting of oxygen, halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl. C1-C4 alkylsulfonyl, phenylsulfonyl, substituted or unsubstituted 3- to 5-membered saturated or unsaturated heterocyclic or carbocyclic ring, and a group of formula (i), (j) and (k),

-NR ²¹ R ²² O—

(i) (!) GO wherein

R r>21 and j r R> ²² : i„ndependently of one another represent hydrogen, Cι-C ₄ alkyl, Cι-Cι alkylsulfonyl, C ₂ -C ₅ carboxyalkyl, C ₂ -C ₅ alkylcarbonyl, C ₃ -C ₇ alkoxycarbonylalkyl or phenylsulfonyl,

R ²³ and R ⁴ independently of one another represent hydrogen, carboxy, aminocarbonyl, C ₂ -C ₄ alkoxycarbonyl, or 3- to 5-membered saturated or unsaturated heterocyclic or carbocyclic ring which may be fused with other one or more 3- to 5-membered saturated or unsaturated heterocyclic or carbocyclic ring,

R , R and R independently of one another represents hydrogen hydroxy, thio, amino, carboxy, aminocarbonyl, Cι-C ₄ alkoxy, C ₂ -C ₄ alkoxycarbonyl, Cι~C ₄ alkylamino, Cι-C ₄ alkylsulfonylamino, C ₂ -Cs alkenyl, C ₂ -C ₄ alkoxycarbonylamino, C3-C6 alkoxycarbonylalkylamino, C3-C6 cycloalkylamino, phenylsulfonylamino, or substituted or unsub¬ stituted 3- to 5-membered saturated or unsaturated heterocyclic or carbocyclic ring, s denotes an integer of 0 to 3, t denotes an integer of 0 to 6, and u denotes an integer of 0 to 8, and n denotes an integer of 0 to 2, provided that when each of g, h, o, p, q, r, s, t and u denotes number of

3 or more, the corresponding alkylene chain may be strainght or branched.

Typical examples of the compound of formula (I) which can be provided by the present invention are listed in the following Table 1.

Table 1.

Table 1. (continued)

Table 1. (continued)

Table 1. (continued)

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Table 1. (continued)

Table 1. (continued)

Specific examples of the paticularly preferred compound of formula (I) according to the present invention are as follows:

3-[[(S)-2-[2- ⁽ 6-amidino-l-ethylindol-2-yl ⁾ ethyl]pyrrolidin-2-yl]methyl]- benzo[b]thiophene-2-carboxamide, 3-[[(S)-2-[2-(6-amidino-l-methylindol-2-yl)ethyl]pyrrolidin- 2-yl]methyl]

- benzo [b] thiophene - 2 -carboxamide, l-ethyl-2-[2-[(S)-l-[2-(3-chlorophenyl)acetyl]pyrrolidin-2-y l]ethyl]indole

- 6 -carboxamidine,

2-[2-[(S)-2-[2-(6-amidino-l-ethylindol-2-yl ⁾ ethyl]pyrrolidinyl]-2-oxoeth -yObenzoic acid,

1 - ethyl -2-[2-[(S)-l- (2 -cy clopentyl - 2 - pheny lacetyl )pyrrolidin - 2 -y l]ethyl] - i ndole - 6 - carboxamidine, l-ethyl-2-[2-[(S)-l-((R ⁾ -2-methylsulfonylamino-2-phenylacetyl)pyrroli- din - 2 - y l]ethyl]indole - 6 - carboxamidine, ethyl 2-[[(R)-2-[2-[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]py rroli- dinyl] - 2 -oxo - 1 -phenyl]ethyl3amino]acetate,

1 -ethyl -2-[2-[(S)-l-[(R)-2-(carbamoylmethylamino)-2-phenylacetyl]py rro lidin - 2 - yl.ethy l]indole - 6 -carboxamidine,

2-[[(R)-2-[2-[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl ]pyrrolidinyl]-2 -oxo-l-phenylethyl]arnino]acetic acid, l -ethyl-2-[2-[(S)-l-(2-cyclopentylacetyl)pyιτoIidin-2-yl]et hyl]indole-6- carboxamidine, ethyl 3-[(S)-2-[2-(6-amidino-l-ethyIindol-2-yl)ethyl]pyrrolidinyl] -2-cyc- lopenty 1 - 3 -oxopropanoate, l-ethyl-2-[2-[(S)-l-(2-cyclohexylacetyl)pyrrolidin-2-yl]ethy l]indole-6- carboxamidine, l-ethyl-2-[2-[(S)-l-(2-cycloproρylaminoacetyl)pyrrolidin-2- yl]ethyl]indole

- 6 - carboxamidine,

1 -ethyl -2-[2-[(S)-l-[2- [cyclopropyKmethylsulf onyl)amino]acetyl]pyrrolidin -2-yl]ethyl]indole-G-carboxamidine, ethyl 2-[[2-[(S)-2-[2-(6-amidino-l-ethylindoI-2-yl)ethyl]ρyrrolid inyl]-2- oxoethyl]cyclopropylamino]acetate, ethyl 2-[[2-[(S)-2-C2-(6-amidino-l-ethylindol-2-yl)ethyl3pyrrolidi nyl]-l- methyl-2-oxoethyl]cyclopropylamino]acetate, 2-[[2-[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]pyrrolidi nyl]-l-methyl

-2-oxoethy0cyclopropylamino]acetic acid, ethyl 4-[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]pyrrolidinyl] -2-cyc- lopropylamino-4-oxobutanoate,

4-[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]pyrrolidin yl]-3-cyclopro- pylamino-4-oxobutanoic acid, l-ethyl-2-[2-[ ⁽ S)-l-((R)-pyrrolidin-2-ylcarbonyl)pyrroIidin-2-yl]ethy l]- indole - 6 - carboxamidine, ethyl 2-[(R)-2-[[(S)-2-[2- ⁽ 6-amidino-l-methylindol-2-yl)ethyl]pyπOlidi- nyl]carbonyl]pyrrolidinyl]acetate, ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]pyrro lidinyl]

- carbony l]pyrrolidinyl] acetate,

2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]py rrolidinyl]carbo -nyl]pyrrolidinyl]acetic acid, 2-t(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yI)ethyl]-(S)- 4-methyl- pyrrolidinyl]carbonyl]pyrrolidinyl]acetic acid, ethyl-2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl ]pyrrolidinyl]

-carbonyl]pyrrolϊdinyl]propionate, ethyl-2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yI)ethyl 3pyrrolidinyI]

- carbony llpyrrolidinyl] butanoate, ethyl-2-[ ⁽ R)-2-[[(S)-2-[2- ⁽ 6-amidino-l-etlιylindol-2-yl)ethyl]pyrrolidinyl]

-carbonyl]pyrrolidinyl] -2 -phenylacetate, l-ethyl-2-[2-[(S)-l-[[(R)-l-(carbamoylmethyl)pynOlidin-2-yl] carbonyl]- pyrrolidin~2-yl]ethyl]indole-6-carboxamidine, l-ethyl-2-[2-[(S)-l-[[(R)-l-[(N-cyclopropylcarbamoyl)methyl] ρyrrolidin-2 -yl]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine, ethyl (S)-2-[2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethy l3pyr- rolidinyl]carbonyl]pyrrolidinyl]acetylamino]propanoate, l-ethyl-2-[2-[(S)-l-[[(R)-l-(l-carbamoyl-3-hydroxypropyl)pyr rolidin-2- yl]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine, 2-[(R ⁾ -2-[[(S) - 2-[2-(6-amidino-l-ethyIindoI-2-yl)ethyl]pyrrolidinyl]car- bony 1] pyrrolidiny 1] - 4 -hydroxy butanoic acid, l-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]ρyrr olidinyl]car- bonyl]pyrrolidinyl]ethane- 1,2-dicarboxylic acid, l-ethyl-2-[2-[(S)-l-[[l-(2-oxo-3-oxolanyl)pyrrolidin-2-yl]ca rbonyl]p}ατo - lidin - 2 - y l]ethyl]indole -6 - carboxamidine,

ethyl 4-[(R)-2-[[(S)-2-[2- ⁽ 6-aιmdino-l-ethylindol-2-yl)ethyl3ρyrrolidinyl3 -carbonyl3pyrrolidinyl]butanoate,

4-t ⁽ R)-2-[[(S ⁾ -2-[2-(6-amidino-l-ethylindol-2-yl)ethyl3pyrrolidinyl3 carbo -nyl3pyrrolidinyl3butanoic acid, ethyl 5-[ ⁽ R)-2-[[(S)-2-[2- ⁽ 6-amidino-l-ethylindol-2-yl)ethyl3ρyrrolidinyl3 -caιbonyl]pyrrolidinyl3pentanoate,

5-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl3py rrolidinyl3carbo -nyl3pyrrolidinyl]pentanoic acid, ethyl 6-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl ⁾ ethyl3pyrrolidinyl] -carbonyl]pyrrolidinyl]hexanoate,

6-[ ⁽ R ⁾ -2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl ⁾ ethyl]pyrrolidinyl]carbo -nyl]pyrrolidinyl]hexanoic acid, l-ethyl-2-[2-[(S)-l-[[ ⁽ R)-l-[2-(methylamino)acety]]pyrrolidin-2-yl]carbo

-nyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine, l-ethyl-2-[2-[ ⁽ S)-l-[[(R)-l-( ⁽ S)-2-aminopropanoyl)pyrrolidin-2-yl]carbo

-nyI]-pyrrolidin-2-yl]ethyl]indole-6-carboxamidine, l-ethyl-2-[2-[(S)-l-[[(R)-l-(2-aminobutanoyl)pyrrolidin-2-yl ]carbonyl]- pyπOlidin-2-yl]ethyl]indole-6-carboxamidine, l-ethyl-2-[2-[(S)-l-[[(R)-l-((S)-2-amino-3-methylbutanoyl)py rrolidin-2 -yl]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine, l-ethyl-2-[2-[(S)-l-[[(R)-l-[(S)-2-(methanesulfonylamino)pro panoyl]pyr- roliώn-2-yl]carbonyl]pyrrolidln-2-yl]ethyl]indole-6-carboxa rnidine, ethyl 4-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]pyrro lidinyl]

-carbonyl]pyrrolidinyl]-(S)-3-amino-4-oxobutanoate, l-ethyl-2-[2-[(S)-l-[[(R)-l-((S)-2-amino-3-carbamoylpropanoy l)pyrroli- din-2-yl]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidi ne,

4-[(R)-2.-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yI)ethyl]p yrrolidinyl]carbo

- ny llpyrrolidinyl] - ( S ) -3 - amino - 4 -oxobutanoic acid, l-ethyl-2-[2-[((S)-l-[[(R)-l-(3-aminopropanoyl)pyrrolidin-2- yl]carbonyl3 -pyrrolidin-2-yllethyl]indole-6-carboxamidine, l-ethyl-2-[2-[(S)-l-[[(R)-l-(3-amino-2-methylpropanoyl)pyrro lidn-2-yl]

- carbony l]pyrrolidin- 2 - yl]ethyl]indole -6 -carboxamidine, l-ethyl-2-[2-[(S)-l-[[(R)-l-(3-aminobutanoyl)pyrrolidin-2-yl ]carbonyl]- pyrrolidin-2-yl]ethyl]indole-6-carboxamidine, l-ethyl-2-[2-[(S)-l-[[(R)-l-[3-[(methanesulfonyl)amino]propa noyl]pyrro-

lidin - 2 - y Ucarbony Upyrrolidin - 2 -y llethy l]indole -6 -carboxamidine, ethyl 4-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]pyπO lidinyl]

-carbonyl]pyrrolidinyl]-(S)-2-amino-4-oxobutanoate, l-ethyl-2-[2-[(S)-l-[[(R)-l-((S)-3-amino-3-caιbamoylpropano yl)pyrroIi- din-2-yl]carbonyl]pyπOlidin-2-yl]ethyl]indole-6-carboxamidi ne,

4-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]py rrolidinyl]carbo

-nyl]pyrrolidinyl]-(S)-2-amino-4-oxobutanoic acid, l -ethyl-2-[2-[(S ⁾ -l-[[l-[(R)-l-[3-carbamoyl-(S ⁾ -3-[(methanesulfonyl)- amino]propanoyl]pyrrolidin-2-yl]caι-bonyl]pyrrolidin-2-yl]e thyl3indole-6- carboxamidine,

4-[(R)-2-[[(S ⁾ -2-[2- ⁽ 6-amidino-l-ethylindol-2-yl)ethyl]pyrrolidinyl]carbo

-nyl]pyrrolidinyl]-(S)-2-[(methanesulfonyl)amino]-4-oxobu tanoϊc acid, l-ethyl-2-[2-[(S)-l -[[(R)-l-(4-aminobutanoyl)pyrrolidin-2-yl]carbonyl]- pyrrolidin-2-yl]ethyl]indole-6-carboxamidine, l-ethyl-2-[2-[(S)-l-[[(R)-l-[(2-piperidinyl)carbonyl3pyrroli din-2-yl]carbo

-nyl]pyπOlidin-2-yl]ethyl]indole-6-carboxamidine,

1 -ethyl -2-[2-[(S)-l-[[(R) -l-(3-piperidinylcarbonyl)pyrrolidin-2-yl]carbo- nyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine, l -ethyl-2-[2-[(S)-l-[[(R)-l-[(4-piperidinyl)carbonyl]pyrrolid in-2-yl]carbo -nyl]pyrrolidin-2-yl]ethyl3indole-6-carboxamidine, l-methyl-2-[2-[(S)-l-[((R)-l-acetylpyrrolidin-2-yl)carbonyl] pyrrolidin-2- yl]ethy 1] indole -6 -carboxamidine, l-ethyl-2-[2-[(S)-l-[((R)-l-acetylpyrrolidin-2-yl)carbonyl]p yrrolidin-2- yl]ethyl]indole -6 -carboxamidine, l-ethyl-2-[2-[(S)-l-[[(R)-l-(2-propylpentanoyl)pyrrolidin-2- yl]carbonyI]

-pyrrolidin-2-yl]ethyl]indole-6-carboxamidine, ethyl 3-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]pyrro lidinyl]

-carbonyl]pyrrolidinyl]-3-oxo-propanoate, l-ethyl-2-[2-[(S)-l-[[(R)-l-(2-carbamoylacetyl)pyrrolidin-2- yl]carbonyl] -pyrrolidin-2-yl]ethyl]iπdole-6-carboxamidine, ethyl 4-[(R)-2-[[(S)-2-[2- ⁽ 6-amidino-l-ethylindoI-2-yl)ethyl]pyrrolidinyl]

-carbonyl]pyrrolidinyl]-4-oxobutanoate,

4-[(R)-2-[[(S)-2-[2- ⁽ 6-amidino-l-ethylindol-2-yl)ethyl]pyrrolidinyl]carbo

- ny πpyrrolidiny 1] - 4 - oxobutanoic acid, l-ethyl-2-[2-[(S)-l-[[(R)-l- ⁽ 3-hydroxybutanoyl)pyrrolidin-2-yl]carbonyl]

- pyrrolidin - 2 - yl]ethyl]indole-6 -carboxamidine,

1 -ethyl -2-[2-[(S) - 1 -[( (R) - 1 -prop-2-enoylpyrrolidin-2-yl)carbonyl]pyrro- lidin-2-yl]ethyl3indole-6-carboxamidine, l -ethyl-2-[2-[(S)-l-[[(R)-l-(methanesulfonyl)pyrroIidin-2-yl] carbonyl]- ρyrroIidin-2-yl]ethyl]indole-6-carboxamidine, l-ethyl-2-[2-[(S)-l-[[(R)-l-(carbamoylmethyl)-5-oxopyrrolidi n-2-yI]car- bonyl]pyrrolidin-2-yI]ethyl]indole-6-carboxamidine, methyl-2-[2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]py rrolidinyl]- carbonyl]piperidinyl]acetate, l-ethyl-2-[2-[ ⁽ S)-l-[(3-piperidinyl)carbonyl]pyrrolidin-2-yl]ethyl]in dole-6 -carboxamidine, ethyl l-[2-[(S)-2-[2-(6-aιmdino-l-ethylindol-2-yl)ethyl]pyπOlidi nyl]-2- oxoethyl]ρyrrolidine-2-carboxylate, ethyl 2-[2-[2-[(S)-l-[((R)-l-acetylpynolidin-2-yl)carbonyl]pyrroli din-2- yl]ethyl]-6-amidinoindolyl]acetate,

2-[2-[(S)-l-[((R)-l-acetylpyrrolidin-2-yl)carbonyl]pyrrol idin-2-yI]ethyl]- 1 - (carbamoylmethyl)indole-6-carboxamidine, and

6-[2-[(S)-l-(2-phenylacetyl)pyrrolidin-2-yl]ethyl]naphtha lene-2-carboχ- amidine.

The compound of formula (I) according to the present invention can form its pharmaceutcially acceptable salt. Such pharmaceutically acceptable salts include acid addition salts produced by acid containing pharmaceutically acceptable anion which can form a non-toxic salt, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., an organic carbonic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid or trifluoroacetc acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., or sulfonic acid such as methansulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naph- thalenesulfonic acid, etc.

The purpose of the present invention is also to provide a process for preparation of the compound of formula (I).

According to the method of the present invention, the compound of formula (I) and its salts can be prepared by a process wherein: (a) an amino-protecting group of a compound of formula (V):

wherein A and n are defined as in formula

(I) and Q represents an amino-protecting group, is removed to obtain a compound of formula (IV):

wherein »2

W, R , A and n are defined as in formula

(I);

(b) the nitrile compound of formula (IV) thereby obtained is reacted with a compound of formula (VT):

(VI)

Y — W -

wherein Y and W are defined as in formula (I) and D represents hydroxy or halogen, to obtain a compound of formula (III):

wherein >2

, R , R , A, Y, W and n are defined as in formula (I);

(c) the compound of foπnula (HI) is reacted with an alcohol compound of formula (VII):

R ^] OH (VH)

wherein R is defined as in formula (I), in the presence of a hydrogen halide to obtain a compound of formula (II):

wherein A, Y, W and n are defined as in

formula (I) and R is a group of formula ¹ wherein R ¹ is defined as in formula (I); and

(d) the compound of formula (II) is reacted with ammonia,

According to the method of the present invention, in step (a) the amino-protecting group Q is removed from the compound of formula (V) to produce the compound of formula (IV).

In the compound of formula (V), a suitable amino-protecting group includes conventional groups for protecting amino radical, particularly, acyl such as carbamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic group or heterocyclic group which are derived from carboxylic, carbonic, sulfonic and carbamic acids. For example, lower alkanoyl, lower alkylsulfonyl, carbamoyl, N-alkyl- carbamoyl, lower alkoxycarbonyl, lower alkenyloxy carbonyl, alkenoyl, aroyl, arenesulfonyl, aralkanoyl, aralkoxycarbonyl, aryloxy alkanoyl, etc. may be mentioned. Particularly preferred amino-protecting group is t-butoxycarbonyl or benzyloxy carbonyl.

The reaction for removing amino-protecting group of step (a) can be carried out by a conventional method, for example, hydrolysis in the presence of an acid (e.g. an organic acid such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid or an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.) or a base (e.g. a hydroxide, hydride, carbonate or bicarbonate of alkali metal or alkaline earth metal such as sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.), reduction by using a combination of a metal (e.g. zinc) or a chrome compound (e.g. chromous chloride) and an organic or inorganic acid (e.g. acetic acid, propionic acid, sulfuric acid, phosphoric acid, etc.) or by using hydrogen in the presence of a catalyst (e.g. a metallic catalyst such as palladium, platinum, nickel, etc.), and the like.

In any case, the reaction can generally be carried out in the presence of a solvent which does not adversely influence the reaction. Examples of the solvent which can preferably be used include water, dichloromethane, alcohols such as methanol, ethanol, etc., tetrahydro- furan, 1,4-dioxane, acetone, or a mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating, preferably at OV to 30 °C .

In the reaction of step (b), the nitrile compound (IV) produced in step (a) is reacted with the compound of formula (VI) to produce the

compound of formula ⁽ HI ⁾ . The reaction of the compound of formula (IV) with the compound of formula (VI) can preferably carried out in the presence of a raction-inert solvent. The solvent which can preferably be used for this purpose includes acetone, 1,4-dioxane, acetonitrile, chloroform, dichloromethane, hexamethylphosphoramide, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylsulfoxide, N,N-dimethylformamide, pyridine, or a mixture thereof.

If necessary, the reaction of step (b) can be carried out in the presence of an acid acceptor. The acid acceptor which can preferably be used for this purpose includes an inorganic base, for example, hydroxide, carbonate or bicarbonate of an alkali metal or an alkaline earth metal such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, etc. or an organic base, for example, triethylamine, trimethylamine, pyridine, N,N- diisopropylethylamine, etc. Particularly, triethylamine or N,N-diisoproyl~ ethylamine is most preferably used as the acid acceptor.

The reaction of step (b) can, if appropriate, be carried out in the presence of a condensing agent. The condensing agent which can preferably be used includes a carbodiimide compound such as N,N- diethylcarbodiimide, l-(3-dimethylaimnopropyI)-3-ethylcarbodiimide hyd¬ rochlonde, N,N-dicyclohexylcarbodiimide, etc.

Although the reaction temperature and time are not critical, the reaction is usually carried out under from cooling to heating for 2 to 24 hours, preferably at 0 <C to 70 ^° C for 4 to 15 hours.

Thereafter, in step (c), the compound of formula (HI) produced in step (b) is reacted with the alcohol compound of formula (VTJ) in the presence of hydrogen halide to produce the compound of formula (II). In this reaction, hydrogen chloride, hydrogen bromide, etc. can be used as hydrogen halide, with hydrogen chloride (HCI) being particularly preferably used. In this reaction, when the alcohol compound of formula (VII) is employed in an excessive amount, it can also be used as a

solvent. If appropriate, this reaction may also be carried out in the presence of a reaction-inert solvent such as chloroform, dichloromethane, benzene, diethyl ether, etc. Although the reaction temperature and time are not critical, the reaction is usually carried out under from cooling to heating for 2 to 48 hours, preferably at 0 ^° C to 30 ^° C for 12 to 24 hours.

In step (d), the compound of formula (III) produced in step (c) is reacted with ammonia to produce the desired compound of formula (I). This reaction is usually carried out in a solvent, for example, Cι-C ₄ alcohol such as ethanol, propanol, etc., aliphatic ether such as diethyl ether, etc., halogenated hydrocarbon such as chloroform, etc., aprotic solvent such as benzene, etc., N,N-dimethylformamide, dimethylsulfoxide, etc., or a mixture thereof. Particularly, Q-Q alcohol solvent such as ethanol is preferably used. Although the reaction temperature and time in this reaction are not critical, the reaction of step (d) is usually carried out under from cooling to heating for 2 to 72 hours, preferably at 0°C to 30 ^° C for 20 to 40 hours.

The compound of formula (I) prepared by the above method according to the present invention can be converted into a salt as mentioned above according to a conventional manner. The compound of formua (I) and its salts thereby produced can be separated and purified by a conventional work-up procedure, for example, column chromato¬ graphy, recrystallization, etc.

All the compound of formula (V) used as the starting material and the compounds of formulas (II), (III) and (IV) produced as the intermediates in the method for preparation of the compound of formula (I) according to the present invention are novel compounds and therefore, encompassed within the scope of the present invention. The compound of formula (V) used as the starting material in the method of the present invention can be prepared by the two method as shown in the following reaction scheme.

In the above reaction scheme,

and n are defined as in formual (I);

X represents hydrogen, alkyl, alkoxycarbonyl or alkoxycarbonylalkyl and in formula (5) two L groups may be same or different; E represents hydrogen or lower alkyl; Q represents an amino-protecting group; X represents halogen; and v denotes an integer of 0 to 2.

The present invention also relates to a thrombin inhibitor composition which contains as an active component a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt together with pharmaceutically acceptable carriers. The composition of the present invention exhibits potent thrombin inhibitory activity and can therefore be used as an agent for prevention and treatment of thrombosis.

The compound of formula (I) according to the present invention is preferable since it is effective even when orally administered.

For clinical purposes, an effective daily dosage of the compound according to the present invention may generally be in the range of 0.1 to 30mg per kg of body weight, and preferably in the range of 0.5 to lOmg per kg of body weight. A dosage suitable for an individual subject can appropriately be determined by a specialist depending on a kind of the compound of formula (I) to be applied, weight, sex, health and nutritional condition of the patient, time and method of administration, excretion rates, a kind of medicines to be administered in combination with the compound of formula (I) and severity of disease.

The compound of the present invention may be administered either orally or by injection, depending on the dosage and the therapeutic effect desired.

Orally administrable solid preparations may be in the form of capsules, tablets, pills, powders and granules, with capsule and tablet preparations being preferable. The tablets and pills can preferably be

applied to enteric coating. The solid dosage form can be prepared by intimately mixing the compound of formula (I) according to the present invention with carriers, for example, one or more inert diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrating agents, binders, etc.

As mentioned above, the compositions containing the compound of formula (I) according to the present invention are characterized by their superior effect even when orally administered. These has been demonstrated through pharmacoldnetic experiments using rats and dogs as the test animals, in which the active compound is shown to be retained in blood for a long time when the composition is orally administered. The compound of the present invention is, therefore, more useful than thrombin inhibitors disclosed in the prior art because it can be effectively used in the form of an oral preparation.

The composition containing the compound of formula (I) according to the present invention can also be formulated in the form of an injectable preparation, for example, as a sterilized injectable aqueous or oily suspension using suitable dispersing agents, wetting agents or suspending agents. Aqueous solvents which can be used for this purpose include water, Ringer's solution or isotonic NaCI solution. Sterilized fixing oils may also be used as a solvent or suspending agent. Non -irritable fixing oils including mono-, di-glycerides can be used for this purpose, and fatty acids such as oleic acid may be used in injectable preparations.

In addition, according to the results of experiment, it has been identified that the compound of formula (I) according to the present invention exhibits potent thrombin inhibitory activity without acute toxicity in mammals, such as rats and dogs.

Although the present invention is specifically illustrated by the following examples, the present invention is not in any manner limited by these examples.

Examnle 1 : Synthesis of l-ethyl-2-r2-((S)-l-beπzvlpvrrolidin-2- yl)ethyl]indole-6-carbonitrile (Compound 1)

a) Synthesis of 4-methyl-3-nitrobeπzenecarbonitrile:

In a 250mS flask, lOg of 4-methylbenzenecarbonitι-ile was dissolved in 30ιn-fi of concentrated sulfuric acid and then cooled to 0°C. 7m£ of nitric acid mixed with lOmt of concentrated sulfuric acid was slowly added thereto over one hour at -2 ^° C to 0 ^° C . The reaction solution was poured into ice water and then stirred. The resulting precipitate was filtered, washed three times with water and then dried. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/ n-hexane(l:3)]. The fractions containing the desired product were combined and then evaporated to obtain 11.2g of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.30(s, 1H), 7.80(d, 1H), 7.53(d, 1H), 2.7(s, 3H)

b) Synthesis of ethyl 3-(4-cyano-2-nitrophenyl)-2-sodiumprop-2-enoate:

To a 500m£ flask, 2.5 lg of sodium and 60m£ of tetrahydrofuran were added and 30m£ of ethanol was then added thereto. The mixture was stirred at room temperature until sodium was completely dissolved. A solution of 14.8m£ of diethyl oxalate in tetrahydrofuran was slowly added thereto and the mixture was stirred for 10 minutes at room temperature. 16g of 4-methyl-3-nitrobenzenecarbonitrile dissolved in tetrahydrofuran was added thereto and the mixture was stirred for 18 hours at room temperature. The reaction solution was evaporated and ether was added to the residue. The resulting precipitate was filtered, washed three times with ether and then dried to obtain 26.4g of the title compound as a brown solid.

c) Synthesis of ethyl 6-cyanoindole-2-carboxylate:

26g of ethyl 3- ⁽ 4-cyano-2-nitrophenyl)-2-sodiumprop-2-enoate

and 59.8g of Zn were introduced into a 500m£ flask and 200m£ of acetic acid was added thereto. The mixture was stirred for 2 hours at room temperature and then for 4 hours at 60~70"C. The reaction solution was evaporated, and the residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:3)]. The fractions containing the desired product were combined and then evaporated to obtain 4.16g of the title compound as a yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.82(m, 2H), 7.42(d, 1H), 7.29(s, 1H), 4.49(m, 2H), 1.47(t, 3H)

d) Synthesis of ethyl 6-cyano-l-ethylindoIe-2-carboxylate:

In a I I flask, 23.5g of ethyl 6-cyanoindole~2-carboxylate was dissolved in 300m£ of dimethylformamide, and 6.6g of 60% NaH was slowly added thereto at 0 ^° C. 17.6m£ of iodoethane was then added thereto at -10~0 ^° C and the mixture was stirred for 2 hours at room temperature. The reaction solution was cooled and, after adding ice, diluted with water and then extracted three times with ethyl acetate. The organic extracts were combined, dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acteate/n-hexane(l:3)L The fractions containing the desired product were combined and then evaporated to obtain 26.2g of the title compound as a yellow solid.

1H NMR(CDC1 ₃ , ppm) : <5 7.77(m, 2H), 7.34(m, 2H), 4.64(m, 2H), 4.42(m, 2H), 1.43(m, 6H)

e) Synthesis of l-ethyl-2-(hydroxymethyl)indole-6-carbonitrile:

In a 1 1 flask, 26.27g of ethyl 6-cyano-l-ethylindole-2-carboxy- late and 0.91g of sodium bicarbonate were dissolved with 300m2 of tetrahydrofuran and then cooled to 0 ^° C. To this mixture was added Cal2

^• H ₂ O and then slowly added NaBH ₄ . The reaction mixture was stirred while slowly warming from 0°C to room temperature with stirring.

After examined by TLC, ice and a catalytic amount of acetic acid were added thereto at 0 ^° C and the mixture was stirred. The reaction solution was evaporated to remove tetrahydrofuran, and the residue was diluted with water and extracted three times with ethyl acetate. The organic extracts were combined, dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:2)]. The fractions containing the desired product were combined and then evaporated to obtain 18.2g of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.63(m, 2H), 7.26(m, 1H), 6.43(s, III), 4.83(s, 211), 4.29(m, 211), 1.41U, 3H)

f) Synthesis of 6-cyano-l-ethylindole-2-methyl triphenylphosphonium bromide:

In a 500ml flask, 18.2g of l-ethyl-2-(hydroxymethyl)indole-6- carbonitrile was dissolved in 200m£ of dichloromethane and then cooled to 0°C . 3.45m<! of PBn was slowly added thereto, and the mixture was stirred for 4 hours at room temperature. dichloromethane was then added and the reaction mixture was washed with aqueous NaaCOs solution, diluted with water and then extracted three times with dichloromethane. The organic extracts were combined, dried over

MgS0 ₄ and then evaporated to obtain 6-cyano-l -ethyl -2-bromomethyl indole. The resulting product was dissolved in 200ml of toluene and 30.9g of triphenylphosphine was added thereto. The mixture was stirred for 10 hours at refluxing temperature and then cooled to room temperature. To this reaction solution was added diethyl ether, and the resulting precipitate was then filtered, washed several times with diethyl ether and dried to obtain 29g of the title compound as a pale brown solid.

g) Synthesis of (S)-methyl pyrrolidine-2-carboxylate:

In a 250ml flask, lOg of L-proline was dissolved in 150ml of methanol, and HCI gas was bubbled therein at 0°C for 2 hours to saturate

the solution. The reaction solution was then stirred for 5 hours at room temperature and evaporated to remove the solvent, thereby obtain 11.2g of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 4.50(m, III), 3.86(s, 3H), 3.52(m, 2H), 2.48(m,

1H), 2.20(m, 3H) MS : 130(M+1)\ 116

h) Synthesis of l-tert-butyl-(S ⁾ -2-(methoxycarbonyl)pyπOlidine carboxy- late:

In a 500ιn£ flask, 11.2g of (S)-methyl pyrrolidine-2-carboxylate was dissolved in 200m2 of dichloromethane and 12ml of triethylamine was added, and the mixture was then stirred for 5 minutes. 20.9g of (Boc)aO dissolved in dichloromethane was added thereto at OV, and the reaction mixture was stirred for 4 hours at room temperature, diluted with water and extracted three times with dichloromethane. The organic extracts were combined, dried over MgS0 ₄ and then evaporated to obtain 19.9g of the title compound as a colorless oil.

Η NMR(MeOH-d ₄ , ppm) : δ 4.20(m, 1H), 3.68(s, 3H), 3.37(m, 211), 2.22 (m, 1H), 1.89(m, 3H), 1.41(m, 9H)

i) Synthesis of l-tert-butyl-(S)-2-formylpyrrolidine carboxylate:

In a 500m(! flask, 9.8g of l-tert-butyl-(S)-2-(methoxycarbonyl)- pyrrolidine carboxylate was dissolved in 200ml of toluene and 85.5ml of DD3AL-H(diisobutylaluminum hydride, l.OM in toluene) was slowly added over 1.5 hour while cooling to -78 ^° C. 15ml of methanol was then added thereto, and the mixture was stirred for 30 minutes at room temperature. To this solution, aqueous solution of Rochell's salt (potassium sodium tartrate tetrahydrate) was added, and the reaction solution was stirred for about one hour at room temperature and then extracted with dichloromethane. The organic extracts were combined, dried over MgSO.i and evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:3)]. The fractions

containing the desired product were combined and then evaporated to obtain 8g of the title compound as a colorless oil.

j) Synthesis of l-tert-butyl-(S ⁾ -2-[2-(6-cyano-l-ethylindol-2-yl)vinyl]- pyrrolidine carboxylate:

In a 500m£ flask, 17.4g of 6-cyano-l-ethylindole-2-methyl triphe- nylphosphonium bromide and 6.6g of l -tert-butyl-(S)-2-foπnylpyrrolidine carboxylate were dissolved in a mixed solvent of tetrahydrofuran/ethanol (1:1), and of l,8-diazabicyclo[5.4.0]undec-7-ene was added thereto. The reaction solution was stirred for 15 hours at room temperature and evaporated to remove the solvent. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:3)]. The fractions containing the desired product were combined and then evaporated to obtain 7.8g of the title compound as a yellow oil.

k) Synthesis of l-tert-butyl-(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]- pyrrolidine carboxylate:

In a 500m2 flask, 13g of l-tert-butyl-(S)-2-[2-(6-cyano-l-ethyl- indol-2-yl)vinyl]pyrroIidine carboxylate was dissolved in 250ml of ethanol, and 4g of 10% palladium on activated carbon was slowly added thereto. Hydrogen gas was bubbled into the reaction solution and the mixture was stirred for 3 hours at room temperature. The reaction solution was filtered through a celite and evaporated to remove the solvent. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:3)]. The fractions containing the desired product were combined and then evaporated to obtain 12g of the title compound as a brown oil.

1H NMR(CDC1 ₃₎ ppm) : δ 7.60(m, 2H), 7.28(m, 1H), 6.36(s, 1H), 4.15(m, 2H), 3.94(m, 1H), 3.72(m, 1H), 3.38(m, 3H), 2.76(t, 2H), 1.46(s, H), 1.39(m, 3H)

1) Synthesis of l-ethyl-2-[2- ⁽⁽ S ⁾ -pyrrolidin-2-yl)ethyl]indole-6-carboni- trile (Compound I-a):

In a 250ml flask, 3.7g of l-tert-butyl-(S)-2-[2-(6-cyano-l~ethyl- indol-2-yl)ethyl]pyrrolidine carboxylate was dissolved in 100m£ of dichloromethane, and 18.2mt of trifluoroacetic acid was slowly added thereto at 0 ^° C . The reaction mixture was stirred for about 2 hours at room temperature, and after adding dichloromethane, then diluted with water and washed three times with saturated aqueous NaHC0 ₃ solution. The aqueous layer was extracted three times with dichloromethane. The organic extracts were combined, dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(3:l)]. The fractions containing the desired product were combined and then evaporated to obtain 2.2g of the title compound as a pale yellow foam.

1H NMR(CDC1 ₃ , ppm) : δ 7.48(m, 211), 7.28(m, III), 6.33(s, 1H), 4.03(m, 2H), 3.58<m, III), 3.27(m, 2H), 2.85(m, 211), 2.35(m, 1H), 2.1 Km,

3H), 2.00(m, 1H), 1.80(m, 1H), 1.27(t, 311)

m) Synthesis of l-ethyl-2-[2-((S)-l-benzylpyrrolidin-2-yl)ethyl]indole -6-carbonitrile:

66mg of the compound I- a obtained in the above I) was dissolved in dichloromethane and then cooled to 0 ^° C. To this solution, 46/4 of triethylamine was added and 38/4 of benzyl chloride was then slowly added. The reaction mixture was stirred for 4 hours at room temperature and then diluted with excess of dichloromethane. The organic layer was washed with water, dried over MgS0 ₄ and filtered under reduced pressure. The filtrate was concentrated and the concentrate was purified with silica gel column chromatography [eluent: dichloromethane/methar 10:1)]. The fractions containing the desired product were combine and evaporated to obtain 39rag of the title compound.

n) Synthesis of l-ethyl-2-[2-((S)-l-benzylpyrrolidin-2-yl)ethyI]indole-6- car boxamidine :

39mg of l -ethyl-2-[2-((S)- l-benzylpyrrolidin-2-yl)ethyl]indole-6-

carbonitrile was dissolved in ethanol and cooled to 0°C . HCI gas was bubbled for 45 minutes into the solution, and the reaction solution was stirred at room temperature overnight and concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethanol and ammonia gas was bubbled into the solution for one hour at 0"C. The reaction solution was stirred overnight at room temperature and then distilled under reduced pressure. The residue was purified with column chromatography [eluent: dichloromethane/methanol(4:l)] on NH-DM1020 silica to obtain 32mg of the title compound a pale yellow solid.

TI NMR(MeOH-d4, ppm) : δ 7.93(s, 1H), 7.66(d, III, J=8.41Hz), 7.44(d, III, J=8.41Hz), 7.34-7.27(m, 5H), 6.40(s, 1H), 4.28(q, 2H), 4.07(d, III), 2.95-2.88(m, 3H), 2.60(m, 1H), 2.31- 1.90(m, 4H), 1.80-1.55 (m, 5H), 1.40(t, 311, J=7.21Hz)

Example 2 : Synthesis of ethyl 2-[(S)-2-[2-(β-amidino- l-methyl- indol-2-yl)ethyl]pyrrolidinyl]-2-phenylacetate (Compound 2)

a) Synthesis of 6-cyano-l-methylindole-2-methyl triphenyl phosphonium bromide:

The reaction was carried out according to the same procedure as Examples 1-a) through 1-f), except that iodomethane was used in place of iodoethane in Example 1-d), to obtain 15g of the title compound as a pale brown solid.

1H NMR(DMSO-de, ppm) : δ 8.00(s, 1H), 7.92(m, 3H), 7.84-7.68(m, 12H), 7.62(d, 1H, J=8.24Hz), 7.35(d, 1H, J=8.24Hz), 6.28(s, 1H), 5.57(d, 2H, J=15.2Hz), 3.19(s, 3H)

b) Synthesis of l-methyl-2-[2-((S ⁾ -pyrrolidin-2-yl)ethyl]-indole-6-carbo -nitrile (Compound I-b):

6-Cyano- l-methylindole-2-methyl triphenylphosphonium bromide obtained in the above a) was reacted according to the same procedure as Example 1-1) to obtain 6.4g of the title compound as a pale yellow foam.

1H NMWMeOH-d,, ppm) : δ 7.83(s, III), 7.62(d, III, J=8.24Hz), 7.30(d, HI, J=8.24Hz), 6.47(s, 1H), 3.80(s, 3H), 3.64(m, 1H), 3.32(m, 2H), 3.00(m, 2H), 2.41-1.98(m, 5H), 1.80(m, 1H)

5 c) Synthesis of ethyl 2-[(S)-2-[2-(6-cyano-l-methylindol-2-yl)ethyl]- pyrroIidinyl]-2-phenylacetate:

90mg of the compound I-b obtained in the above b) and 86mg of ethyl-2-bromo-2-phenylacetate were treated according to the same ±0 procedure as Example 1-m) to obtain 85mg of the title compound as a pale yellow solid.

d) Synthesis of ethyl 2-[(S)-2-[2- ⁽ 6-amidino-l-methyIindol-2-yl)ethyl]- pyrrolidinyl]-2-phenylacetate:

15

81ιαg of ethyl 2-[(S)-2-[2-(6-cyano-l-methylindol-2-yl)ethyI]- pyιτolidinyl]-2-phenylacetate obtained in the above c) was treated according to the same procedure as Example 1-n) to obtain 19mg of the title compound as a pale yellow solid. 0

1H NMR(MeOH-d ₄ , ppm) : δ 7.82(d, III, J=11.06Hz), 7.52(d, 1H, J=8.1Hz), 7.32(m, 3H), 7.19(m, 3H), 6.10(s, 1H), 4.36(s, 1H), 4.00(m, 2H), 1.95(m, 2H), 1.74-1.45(m, 6H), 1.06(m, 3H)

Example 3 : Synthesis of 2-[(S)-2-r2- ^(β -amidino-l-methylindoI-2- 5 yl)ethyllρyrrolidinyl]-2-ρhenylacetic acid (Compound 3)

13mg of ethyl 2-[(S)-2-[2-(6-amidino-l-methylindol-2-yl)ethylJ- pyrrolidinyl]-2-phenylacetate obtained in Example 2 was dissolved in 5ml of 35% hydrochloric acid solution, and the resulting solution was heated

30 to 60 °C and stirred for 1.5 hours, and then stirred at room temperature overnight. The reaction solvent was removed by distillation under reduced pressure. The residue was purified with column chromato¬ graphy [eluent: dichloromethane/methanol(2:3)] on NH-DM1020 silica. The fractions containing the desired product were combined and then

35 distilled under reduced pressure to obtain 6.2mg of the title compound as a

pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.75(s, III), 7.59-7.51(m, 1H), 7.31-7.20(m, 5H), 6.33(s, III), 4.13(s, 1H), 3.74(s, 3H), 3.61(s, III), 2.98(m, 2H), 2.89(m, 3H), 2.75(m, 2H), 2.40(m, 1H), 2.35-2.05(m, 3H),

1.80-1.77(m, 6H)

Examnlβ 4 : Synthesis of l-methvl-2- r2-r(S)- l-(l-naphthvlmethvl) -pyrrolidin-2-vnethynindoIe-6-carboxamidine (Compound 4)

a) Synthesis of l-methyl-2-[2-[(S)-l-(l-naphthylmethyl)pyrrolidin-2-yl] ethyl]indole-6-carbonitrile:

89mg of the compound I-b obtained in Example 2-b), 127rag of 1-naphthalenemethanol and 148mg of triphenylphosphine were dissolved in chloroform, and 104/4 of DEAD(diethylazodicarboxylate) was slowly added thereto while stirring at room temperature. The mixture was stirred at room temperature overnight and distilled under reduced pressure to remove the solvent. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(l:l)]. The fraction containing the desired product was distilled under reduced pressure to obtain 33mg of the title compound.

b) Synthesis of l-methyl-2-[2-[(S)-l-(l -naphthylmethyl)pyrrolidin-2-yl] -ethyl]indole-6-carboxamide:

30mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain llmg of the title compound as a yellow solid.

1H NMR(MeOH-d4, ppm) : δ 8.20(m, 1H), 7.76(m, 2H), 7.68(d, 1H, J=8.66Hz), 7.52(d, 1H, J=8.21Hz), 7.37-7.22(m, 5H), 6.21(s, 1H), 4.37 (d, 1H), 3.65(m, 1H), 3.55(m, 1H), 2.10-1.90(m, 5H), 1.66-1.61 (m, 6H)

Example 5 : Synthesis of l-methvl-2-r2-r(S)- l-(2-naphthvlmethyl) -pyrrolidin-2-vl1ethyl3indole-β-carboxamidine (Compound 5)

a) Synthesis of 1 -methyl -2-[2-[(S)-l-(2-naphthylmethyl)pyrrolidin-2-yl] -ethyl]indole-6-carbonitrile:

In a 25m£ flask, 70mg of the compound I-b obtained in Example 2-b) and 54mg of 2-naphthalenemethanol were dissolved in 5ml of tetrahydrofuran. To the resulting solution, 105mg of triphenylphosphine was added and 0.08mϋ of DEAD was then added at room temperature. The mixture was stirred for about 40 hours at room temperature and then evaporated to remove the solvent. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/methanol(10:l)]. The fractions containing the desired product were combined and then evaporated to obtain 20mg of the title compound as a pale yellow solid.

1H NMR(MeOH-dι, ppm) : δ 7.81(m, 1H), 7.69(m, 411), 7.52(m, 1H), 7.47 (m, 3H), 7.28(d, 1H), 6.30(s, 1H), 4.14(d, 1H), 3.60(s, 3H), 3.57(d, 1H), 2.99(m, 1H), 2.88(m, 1H), 2.76(m, 1H), 2.63(m, 1H), 2.40(m, 1H), 2.14(m, 2H), 1.79(m, 4H)

b) Synthesis of l-methyl-2-[2-[(S)- l-(2-naphthylmethyl)pyrroIidin-2-yl] -ethyl]indole-6-carboxamidine:

18rag of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain lOmg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ ppm) : δ 7.76-7.62(m, 5H), 7.51(d, 1H), 7.35(m, 4H), 6.24(s, 1H), 4.06(d, III), 3.60(s, 3H), 3.45(d, 1H ⁾ , 2.86(m, 1H),

2.72(m, 2H), 2.53(m, 1H), 2.27(m, 1H), 2.04(m, 2H), 1.69(m, 4H)

Exampl β : Synthesis of l-methyl-2-r2-r(S)-l-(benzo[d11.3- dioxolen-5-yl -methyl )pyrrolidin-2-yl]ethvnindole-6-carboxamidine (Compound 6)

a) Synthesis of l-methyl-2-[2~[(S)-l-(benzo[d]l,3-dioxolen-5-ylmethyl)- pyrrolidin-2-yl]ethyl]indole-6-carbonitrile:

In a 100m£ flask, lOOmg of the compound I-b obtained in Example 2-b) and 66mg of piperonyl alcohol were reacted according to the same procedure as Example 5-a) to obtain 40ιng of the title compound as a pale yellow solid.

^] II NMR(CDC1 ₃ , ppm) : δ 7.56(m, 2H), 7.31(d, III), 6.83(s, 1H), 6.72(m, 211), 6.32(d, III), 5.91(s, 2H), 3.92(d, 1H), 3.69(s, 3H), 3.21(d,

1H), 2.98(m, III), 2.86-2.74(m, 2H), 2.54(m, III), 2.19(m, 1H), 2.03(m, 2H), 1.77(m, 3H), 1.73(m, 1H)

b) Synthesis of l-methyl-2-[2-[(S)-l-(benzo[d]l,3-dioxolen-5-ylmethyl)- pyrτolidin-2-yl]ethyl]indole-6-carboxamidine:

40mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 16mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.89(m, 1H), 7.39(m, 2H), 6.79(s, 1H), 6.69(m, 2H), 6.14(s, 1H), 5.89(s, 211), 3.88(d, 1H), 3.57(s, 3H), 3.11(d, 1H), 2.91(m, 1H), 2.71-2.58(m, 2H), 2.45(m, III), 2.09(m, 1H), 1.98(m, 2H), 1.68(m, 3H), 1.54(m, 1H) MS : 405(M+1)\ 271, 202, 135

Example 7 : Synthesis of methyl 3-[[(S)-2-[2-(6-amidino- l-methyl -indol-2-yl)ethyl]ρyrrolidin-2-yl]methyl1ben2:o[b]thioρhen e-2-carbo -xylate (Compound 7)

a) Synthesis of methyl 3-[[(S)-2-[2-(6-cyano-l-methylindoI-2-yl)ethyl]- pyrrolidin-2-yl]methyI]benzo[b]thiophene-2-carboxylate:

80mg of the compound I-b obtained in Example 2-b) was dissolved in dichloromethane and cooled to 0 ^° C . To this solution, 59/zl of triethyl-

amine was added and llOmg of methyl 3-bromomethylbenzo[b]thiophene- 2 -carboxylate was slowly added. The reaction mixture was stirred for 3.5 hours at room temperature and diluted with excess of dichloromethane. The organic layer was washed with water, dried over MgS0 ₄ and then filtered under reduced pressure. The filtrate was then concentrated. The concentrate was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(l:l)]. The fractions containing the desired product were combined and then evaporated to obtain 80πιg of the title compound as a white solid.

b) Synthesis of methyl 3-[[(S)-2-[2-(6-amidino-l-methylindol-2-yl)ethyl] -pyrrolidin-2-yl]methyl]benzo[b]thiophene-2-carboxylate:

80mg of the compound obtained in the above a) was dissolved in 5 mβ of methanol and cooled to 0 ^° C. HCI gas was bubbled into the solution for 50 minutes and the reaction solution was stirred at room temperature overnight and concentrated under reduced pressure to remove the solvent. The residue was dissolved in 5ml of methanol, and ammonia gas was bubbled for one hour at O'C into the solution. The reaction solution was stirred at room temperature overnight and then distilled under reduced pressure. The residue was purified with column chromatography [eluent: dichloromethane/methanol(4:l)] on NH- DM1020 silica to obtain 22mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 8.13(d, 1H, J=8.06Hz), 7.88(s, 1H), 7.62(d, 1H, J=8.34Hz), 7.47-7.37(m, 3H), 6.30(s, 1H), 4.55(d, 1H, J=12.4Hz), 4.07(d, 1H, J=12.4Hz), 3.83(s, 3H), 3.67(s, 3H), 2.83- 2.67(m, 4H), 2.26(m, 1H), 2 ^{ι r} i-2.05(m, 2H), 1.69-1.57<m. 4H)

Example 8 : Synthesis of 3-[[(b 2-[2-(6-amidiπo-l-ethvIindol-2- yl)ethyl]pyrrolidin-2-yl]methyl]benzo[b]thiophene-2-carbox3� �nide

(Compound 8)

1.46g of the compound I-a obtained in Example 1-1) was treated according to the same procedure as Example 7-a) to obtain 1.38g of the

white solid product, which was then treated according to the same procedure as Example 7-b) to obtain 930mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.95(d, 1H), 7.79(d, III), 7.73(m, 1H), 7.48(d, 1H), 7.33(m, 311), 6.09(s, 1H), 4.22(d, 1H), 3.99(m, 2H), 3.92(d, 1H), 2.85(m, 1H). 2.68-2.61(m, 411), 2.39(m, 1H), 2.15(m, 1H), 1.95<m, 1H), 1.74-1.58(m, 4H), 1.86(t, 3H)

Example 9 : Synthesis of 3-[[(S)-2-[2-(6-amidino- l-methylindoI- 2-yl)ethyl]pyrrolidin-2-yl3methyl1benzo[b]thioρhene-2-carbo xamide (Compound 9)

80mg of 3-[[(S)-[2-(6-cyano-l-methylindol-2-yl)ethyl]pyrrolidin- 2-yl]methyl]benzo[b]thiophene-2-carboxamide was treated according to the same procedure as Example 7-b) to obtain 36mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.90(d, 1H, J=7.5Hz), 7.77(d, 1H, J=7.42Hz), 7.71(s, III), 7.47(d, 1H, J=8.36Hz), 7.33-7.24(m, 3H), 6.10(s, 1H), 4.19(d, III, J=12.99Hz), 4.14(d, 1H, J=7.58Hz), 3.49(s, 1H), 2.85 (m, III), 2.71-2.60(m, 3H), 2.40(m, 1H), 1.92(m, 1H), 1.73-1.58(m, 4H)

Example 10 : Synthesis of l-methyl-2-r2-r(S)- l-[r2-(N-methvI- carbamoyl)benzo[b]thiophen-3-yl]methyl3pyrrolidin-2-yl]ethyl ]indole -6-carboxamidine (Compound 10)

a) Synthesis of N-methyl [3-[[(S)-2-[2-(6-cyano-l-methylindol-2-yD- ethyl]pyrrolidinyl]methyl]benzo[b]thiophen-2-yl]formamide:

Methyl 3-[[<S)-2-[2-(6-cyano-l-methylindol-2-yl)ethyI]pyrrolidi- nyl]methyI]benzo[b]thiophene-2-carboxylate was dissolved in methanol solution of 40% methylamine and then stirred for 2 hours at room temperature. The reaction solution was evaporated to obtain the residue which was then purified with silica gel column chromatography [eluent:

dichloromethane/ethyl acetate(2:l)] to obtain 70mg of the title compound as a white foam.

1H NMR(CDC1 ₃ , ppm) : δ 10.64(d, 1H, J=4.83Hz), 7.88(d, 1H), 7.80(d, 1H), 7.55(d, 2H, J=8.19Hz), 7.40(m, 1H), 7.35-7.31(m, 2H), 6.22(s,

III), 4.18(d, 1H), 3.87(d, 1H), 3.50(s, 3H), 3.02(d, 3H), 2.99(m,

III), 2.77-2.70(m, 3H), 2.45(m, 1H), 2.13(m, 1H), 2.07(m, 1H),

1.85-1.82(m, 2H), 1.68-1.63(m, 2H)

b) Synthesis of l-methyl-2-[2-[(S)-l-[[2-(N-methylcaι-bamoyl)benzo[b]- thiophen-3-yl]methyl]pynoIidin-2-yl]ethyl]indole-6-carboxami dine:

35mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 25mg of the title compound.

1H NMR(CDC1 ₃ , ppm) : δ 10.67(d, HI, J=4.17Hz), 8.08(s, 1H), 7.81-

7.76(m, 2H), 7.49-7.45(m, 2H), 7.37-7.32(m, 2H), 6.10(s, 1H),

4.04(d, III), 3.57(s, 3H), 2.93(d, 311), 2.86(brs, 1H), 2.65(m, 3H), 2.33(m, 1H), 2.20-2.17(m, HI), 2.02-1.96(m, III), 1.77-1.73(m,

2H), 1.58-1.54(m, 2H)

Example 11 : Synthesis of l-methyl-2-r2-r(S)- l-r(4-methoχyphe- nyl)carbonyl1pyrrolidin-2-yl]ethyI]indole-6-carboxamidine (Compound 11)

a) Synthesis of l-methyl-2-[2-[(S)-l-[(4-methoxyphenyl)carbonylj- pyrroIidin-2-yl]ethyl]indole-6-carbonitrile:

70rag of the compound I-b obtained in Example 2-b) and 67mg of p-methoxybenzoic acid were dissolved in dichloromethane, and 119mg of WSCIHCl (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlonde) was added thereto. The reaction mixture was stirred for 2.5 hours at room temperature, and water was added thereto. The reaction solution was extracted two times with dichloromethane. The extracts were

combined, dried over MgS0 ₄ and then concentrated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/ methanol(50:l)] to obtain 78mg of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.54-7.45(m, 211), 7.26(d, 1H), 7.20-7.13(dd, 2H), 6.90-6.80(dd, 2H), 6.39(s, 1H), 4.29-4.18(brs, 1H), 3.78(s, 3H), 3.66(s, 3H), 3.50(t, 211), 2.79(t, 2H), 2.20-2.33(m, 1H), 1.97(m, 3H), 1.74(m, 2H)

b) Synthesis of l-methyl-2-[2-[(S) ^~ l-[(4-methoxyρhenyl)carbonyl]pyrro- lidin - 2- yl]ethyl]indole -6 -carboxamidine:

78mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 26mg of the title compound as a yellowish white solid.

1H NMRdMeOH-dj, ppm) : δ 7.76(s, III), 7.48(d, 1H), 7.06(d, 2H), 6.77(d, 211), 6.33(s, 1H), 4.13-4.05(brs, 1H), 3.65(s, 311), 3.49(s, 3H), 3.54-3.40(m, 2H), 2.82-2.75(m, 2H), 2.25-1.60(m, 6H)

Example 12 : Synthesis of l-methyl-2-[2-[(S)- l-[(3,4-dimethoxy- phenyl)carbonyI]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine (Compound 12)

a) Synthesis of l-methyl-2-[2-[(S)-l-[(3,4-dimethoxyphenyl)carbonyl]- pyrrolidin-2-yl]ethyl]indole-6-carbonitrile:

50mg of the compound I-b obtained in Example 2-b) and 52rag of 3,4-dimthoxybenzoic acid were reacted according to the same procedure as Example 11 -a) to obtain 53mg of the title compound as a white solid.

1H NMR(MeOH-d4, ppm) : δ 7.77(s, 1H), 7.54(d, 1H), 7.25(d, 1H), 7.10(s, 2H), 7.00(d, 1H), 6.50(s, 1H), 4.38-4.25(brs, 1H), 3.83(s, 3H), 3.78(s, 3H), 3.65-3.50(m, 2H), 2.97-2.87(m, 2H), 2.28-1.60(m, 6H)

b) Synthesis of l-methyl-2-[2-[(2S)-l-[(3,4-dimethoxyphenyl)carbonyl]- pyrrolidin-2-yl]ethyl]indole-6-carboxamidine:

42 mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 21mg of the title compound as a yellowish green solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.47-7.40(d, 1H), 7.32-7.20(m, 1H), 7.09(brs, 2H), 6.83-6.81(br, 1H), 6.34(s, 1H), 4.33(brs, III), 3.89(s, 3H), 3.86(s, 311), 3.73(bs, 2H), 3.48(s, 311), 2.79(brs, 2H), 2.22-1.60(m,

611)

Example 13 : Synthesis of l-methyl-2-r2-r(S)- l-(2-phenylace- tyl)pyrrolidin-2-yl]ethyl]indole-6-carboxamidine (Compound 13)

500mg of the compound I-b obtained in Example 2-b) was dissolved in lOmC of dichloromethane, and 460 _/ 4 of triethylamine and 0.35 ml of phenylacetyl chloride were added thereto. The reaction mixture was treated according to the same procedure as Example 1-m) to obtain 430mg of l-methyl-2-[2-[(S)-l-(2-phenylacetyl)pyrrolidin-2-ylJethyl]- indole-6-carbonitrile, which was then treated according to the same procedure as Example 1-n) to obtain 267 mg of the title compound.

1H NMR(MeOH-d ₄ , ppm) : δ 7.92(m, 1H), 7.66(m, 1H), 7.61(m, 1H), 7.36-7.28(m, 5H), 6.46(s, 1H), 4.21(m, 1H), 3.85(s, 3H), 3.77(m,

2H), 3.60(t, 3H, J=6.60Hz), 2.84(m, 2H), 2.27(m, 1H), 1.99-1.82(m, 6H)

Examnle 14 : Synthesis of l-ethyl-2-r2-r(S)- l-<2-phenylacetyl)- pyrrolιdin-2-yl]elhyl]indole-6-carboxamidiπe (Compound 14)

a) Synthesis of l-ethyl-2-[2 ¹ [(2S)-l-(2-phenylacetyl)pyrroIidin-2-yl]- ethyl]indole-6-carbonitrile:

80mg of the compound I-a obtained in Example 1-1) was dissolved

in dichloromethane and then cooled to 0 ^° C. To this solution, 56/4 of triethylamine was added and 53/4 of phenylacetyl chloride was then slowly added. The reaction mixture was stirred for 4 hours at room temperature and then diluted with excess of dichloromethane. The organic layer was washed with water, dried over MgS0 ₄ and filtered under reduced pressure. The filtrate was concentrated. The concentrate was then purified with silica gel column chromatography [eluent: dichloromethane/methanol(10:l)]. The fractions containing the desired product were combined and evaporated to obtain 81mg of the title compound as a pale yellow solid.

b) Synthesis of l-ethyl-2-[2-[(S)-l-(2-phenylacetyl)pyrrolidin-2-yl]ethyl] -indole-6-carboxamidine:

80mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 60mg of the title compound as a pale yellow solid.

1H NMR(MeOH-cU, ppm) : δ 7.81(d, 1H, J=7.15Hz), 7.53(d, 1H, J=8.33 Hz), 7.30(d, 1H, J=8.33Hz), 7.22-7.13(m, 4H), 6.36(s, 1H), 4.14

(m, 311), 3.62(d, 1H), 3.49(m, 2H), 2.73(t, 211, J=8.13Hz), 2.15(m, III), 1.93-1.86(m, 5H), 1.26(t, 3H, J=7.15IIz)

Example 15 : Synthesis of l-ethyl-2-r2-r(S)-l-r2-(3-chlorophenyl) -acetyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine (Compound 15)

70mg of the compound I -a obtained in Example 1-1) and 67mg of

3-chlorophenylacetic acid were treated according to the same procedure as Example 11-a) to obtain 40mg of the pale yellow oily product. 38mg of this product was then treated according to the same procedure as

Example 1-n) to obtain 18mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.84(s, 1H), 7.41(d, 1H, J=8.24Hz), 7.16-7.12(m,

4H), 7.06(m, 1H), 6.27(s, 1H), 4.15-4.10(m, 3H), 3.54(s, 2H), 3.49-3.42(m, 2H), 2.70-2.65(m, 2H), 2.24-2.20(m, 1H), 1.97-1.89

(m, 3H), 1.71-1.63(m, 2H), 1.25(t, 3H, J=7.00Hz)

Example 16 : Synthesis of l-ethyl-2-r2-r(S)-l-r2-(3-hvdroxynhe- nvl)acetvnpyrrolidin-2-vnethvnindole-6-carboxamidine (Compound 16J

a) Synthesis of 2-[3-(l,l,2,2-tetramethyl-l-silapropoxy)ρhenyl]acetic acid:

lg of 3 -hydroxy phenyl acetic acid was dissolved in 10ml of N,N-dimethylfonnamide, and 3.97g of TBDMSC1 (ter-butyl dimethylsilyl chloride) and 2.69g of imidazole were added thereto. The reaction mixture was stirred for 14 hours at room temperature and then for 4 hours at 35 V . The reaction solution was diluted with 150ml of dichloromethane and then washed with saturated saline and 0.7N cold HCI solution. The organic layer was washed again with saturated saline, dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was then dissolved in 20ml of methanol and 8m(! of tetrahydrofuran, and aqueous KaC0 ₃ solution (400mg/8m!) was added thereto. The reaction mixture was stirred for 1.5 hours at room temperature and then concentrated. To the residue was added saturated saline and the reaction solution was acidified with 10% aqueous citric acid solution to pH 4 and extracted with dichloromethane (100ml x 2). The organic layer was washed with saturated saline, dried over sodium sulfate and then filtred. The filtrate was concentrated. The residue was then purified with silica gel column chromatography [eluent: n-hexane/ethyl acetatedU)] to obtain 1.69g of the title compound as a pale yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.02-6.95(m, 1H), 6.73-6.69(m, 1H), 6.59-6.53 (m, 2H), 3.40<s, 2H), 0.79(s, 9H), O.OKs, 6H)

b) Synthesis of l-ethyl-2-[2-[(S)-l-[2~[3-(l,l,2,2-tetramethyl-l-sila- propoxy)phenyl]acetyl]pyrrolidin-2-yl]ethyl]indole-6-carboni trile:

300mg of the compound obtained in the above a) was treated

according to the same procedure as Example 11 -a) to obtain 170mg of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.42-7.36(m, 2H), 7.12-7.09(m, 1H), 7.02-6.97 (m, 1H), 6.71-6.68(m, 1H), 6.61-6.54(m, 2H), 6.23(s, 1H), 4.13 (brs, 1H), 3.95(q, 2H), 3.45(s, 2H), 3.31-3.27(m, 2H), 2.60(t, 2H), 2.20-2.11(m, 1H), 1.81-1.74(m, 3H), 1.57-1.55(m, 2H), 1.18(t, 3H, J=7.20Hz), 0.78(s, 9H), O.OKs, 6H)

c) Synthesis of l-ethyl-2-[2-[(S)-l-[2-(3-hydroxyphenyl)acetyl]pyrroli- din-2-yl]ethyI]indole-6-carbonitrile:

170mg of the compound obtained in the above b) was dissolved in lOmβ of tetrahydrofuran and then cooled to 0°C . To the resulting solution was added 1.65m2 of l.OM tetrabutylammonium fluoride splution, and the mixture was stirred for 45 minutes at the same temperature. After adding saturated saline, the reaction solution was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/ethyl acetate (1:1)] to obtain 120mg of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 8.66(brs, 1H), 7.35-7.29(m, 2H), 7.12-7.07(m, III), 7.00-6.93(m, 2H), 6.60-6.50(m, 2H), 6.13(s, 1H), 4.13(brs, 1H), 3.87(m, 2H), 3.39(s, 2H), 3.31(m, 2H), 2.57-2.54(m, 2H), 2.12-2.09(m, 1H), 1.77-1.74(m, 3H), 1.58-1.43(m, 2H), 1.09(t, 3H)

d) Synthesis of l-ethyl-2-[2-[(S)-l-[2-(3-hydroxyphenyl)acetyl]pyrroli- din-2-yl]ethyl]indole-6-carboxamidine:

70mg of the compound obtained in the above c) was treated according to the same procedure as Example 1-n) to obtain 55mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.80(d, 1H), 7.54(d, 1H), 7.33(dd, 1H, J=8.35Hz, J=1.75Hz), 7.01(t, 1H), 6.60(m, 311), 6.38(s, III), 4.18-4.14(m, 3H),

3.54-3.47(m, 4H), 2.73(t, 2H), 2.17-2.11(m, 1H), 1.92-1.73(m, 5H), 1.27(t, 3H)

Example 17 : Synthesis of l-ethyl-2-r2-[(S)- l-r2-r3-(carhamovl- methnxv ⁾ phenyl1acetyllpyιτoIidm-2- ^y l1ethyl]indole-6-carboxamidine (Compound 18)

a) Synthesis of ethyl 2-[3-[2-[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl] -pyrrolidin - 2 - yl] -2 -oxoethyl]phenoxy]acetate:

58mg ⁽ 0.146 mmole ⁾ of l-ethyl-2-[2-[(S)-l-[2-(3-hydroxyphenyl)- acetyl]pyrrolidin-2-yl]ethyl]indole-6-carbonitrile obtained in Example 16 -c) and 26/4 of ethyl bromoacetate were dissolved in 5ml of dimethylformamide and then cooled to 0 ^° C. After adding NaH, the reaction mixture was stirred for 30 minutes at the same temperature and then for one hour at room temperature. 5m6 of water was added, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate and then filtered. The filtrate was concentrated, and the residue was purified with silica gel column chromatography [eluent: dichloromethane/ ethyl acetate(l:l)] to obtain 53mg of the title compound as a colorless oil.

TI NMR(CDC1 ₃ , ppm) : δ 7.42-7.37(m, 211), 7.13-7.04(m, 2H), 6.76-6.70 (m, 2H), 6.63(m, 1H), 6.24(s, 1H), 4.43(s, 2H), 4.12-4.04(m, 3H), 3.96(m, 2H), 3.46(s, 2H), 3.33(m, 2H), 2.60(t, 2H), 2.21-2.14(m,

1H), 1.82-1.77(m, 3H), 1.58-1.54(m, 2H), 1.19-1.09(m, 6H)

b) Synthesis of l-ethyl-2-[2-[(S)-l-[2-[3~(carbamoylmethoxy)phenyl]- acetyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine:

38mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 18πιg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.81(d, 1H), 7.54(d, HI), 7.32 ⁽ m, 1H), 7.16(t,

1H), 6.83-6.78(m, 3H), 6.38(s, III), 4.37(s, 2H), 4.21-4.13(m, 3H), 3.60(d, 2H), 3.52-3.48(m, 2H), 2.74(t, 211), 2.18-2.13(m, 1H), 1.97-1.86(m, 3H), 1.79-1.75(m, 211), 1.26(t, 3H)

Example 18 : Synthesis of 2-r3-r2-r(S)-2-r2-(6-amidino-l-ethyl- indol-2-vI)ethyl]pyrroIidin-2-yl]-2-oxoethyl]phenoxy]acetic acid (Comooud 19)

7mg of 1 -ethyl -2-[2-(S)-l-[2-[3- (carbamoy lmethoxy )phenyl]acetyl] -pynOlidin-2-yl]ethyl]indole-6-carboxamidine obtained in Example 17 was dissolved in 0.5mfi of acetic acid and linl of 3N HCI solution, and the resulting solution was heated to refluxing temperature and stirred for 3 hours under refluxing. The reaction solution was concentrated to remove the solvent and the residue was then purified with column chromatography [eluent: ethyl acetate/methanoKl:!)] on NH-DM1020 silica to obtain 4mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.78(s, 1H), 7.50(d, 1H, J=7.58Hz), 7.35-7.28(m, Hi), 7.12-7.06(m, 1H), 6.75-6.69(m, 3H), 6.33(s, 1H), 4.24(s, 2H), 4.15-4.06(m, 3H), 3.58-3.47(m, 4H), 2.69-2.65(m, 2H), 2.14-2.09 (m, 1H), 1.94-1.88(m, 3H), 1.80-1.73(m, 2H), 1.22(t, 3H)

Example 19 : Synthesis of l-ethyl-2-r2-[(S)-l-r2-r3-(trifluoro- methyl)phenyl]acetyl]pyιτolidin-2-yl1ethyl]indoIe-6-carpo� �amid'ne (Compound 20)

lOOmg of the compound I-a obtained in Example 1-1) and 120mg of 3-(trifluoromethyl)phenylacetic acid were reacted according to the same procedure as Example 11-a) to obtain 80mg of the product, which was then treated according to the same procedure as Example 1-n) to obtain 34mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.94(m, 1H), 7.65-7.45(m, 6H), 6.46(s, 1H), 4.28(m, 3H), 3.82(m, 1H), 3.64(m, 2H), 2.87(t, 2H), 2.30(m, 1H), 2.05(m, 4H), 1.91-1.82 ⁽ m, 2H), 1.36(m, 3H)

Example 20 : Synthesis of l-ethyl-2-r2-r(S)- l-r2-(2-nitronhe- nyl)acetvnpyrrolidin-2-yl]ethyl]indole-6-carboxamidine (Compound 211

270mg of the compound I-a obtained in Example 1-1) and 250mg of 2-nitrophenylacetic acid were reacted according to the same procedure as Example 11-a) to obtain 180mg of the white solid product. 60mg of the resulting product was then treated according to the same procedure as Example 1-n) to obtain 30mg of the title compound as a pale yellow solid.

TI NMR(MeOH-cL, ppm) : δ 8.00(d, HI), 7.76(m, 1H), 7.54-7.33(m, 5H), 6.31(s, 1H), 4.14(m, 3H), 3.96(m, 2H), 3.61(m, 2H), 2.72(t, 2H), 1.98-1.90(m, 611), 1.80(m, 211), 1.26(t, 3H)

Example 21 : Synthesis of l-ethyl-2-r2-r(S)-l-r2-r2-(methylsul fonylamino)phenyl]acetynpyrrolidin-2-yl]ethyl]indole-6-carbo xami- dine (Compound 22)

HOmg of l-ethyl-2-[2-[(S)- l-[2-(2-nitrophenyl)acetyl]pyrrolidin- 2-yl]ethyl]indole-6-carbonitrile was dissolved in 10ml of ethanol, and 15mg of 10% Pd/C was added thereto. The reaction mixture was stirred for 4 hours in hydrogen atmosphere at room temperature under normal pressure and then filtered under reduced pressure. The filtrate was distilled under reduced pressure and dried to obtain llOmg of the product. To 70 mg of the resulting product thus obtained was added 3ml of pyridine and methanesulfonyl chloride was then slowly added thereto at 0 ^° C. The reaction mixture was stirred for 3 hours at 0 ^o C, and excess of ethyl acetate was added thereto. The organic layer was washed three times with water and IN aciueous HCI solution, dried over sodium sulfate and then filtered under reduced pressure. The filtrate was distilled under reduced pressure. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(l:2)]. The fractions containing the desired product were combined and distilled under reduced pressure to obtain 80mg of the white foamy product. 74mg of the product thereby obtained was treated according to the same procedure as Example

1-n) to obtain 34mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.81 (m, 1H), 7.53(d, 1H), 7.29(m, 2H), 7.16

(m, 211), 7.03(t, 1H), 6.37(s, 1H), 4.19-4.12(m, 3H), 3.75(d, 1H), 3.59(m, 2H), 2.84(s, 3H), 2.74(t, 211, J=8.09Hz), 1.96-1.91(m, 4H),

1.77(m, 2H), 1.25(t, 3H)

Examnle 22 : Synthesis of ethvl 2-r2-r(S)-2-r2-(6-amidino- l- ethylindol-2-yl)ethyl]pyrrolidin-2-vn-2-oxoethvnbenzoate (Compound 23)

a) Synthesis of 2-[2-[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]pyrroli- dinyl]-2-oxoethyl]benzoic acid:

985mg of the compound I-a obtained in Example 1-1) was dissolved in 40ιn£ of ethanol, and 956mg of 75% homophthalic anhydride and 1.05m<! of triethylamine were added thereto. The resulting solution was stirred for one hour at room temperature and distilled under reduced pressure to remove ethanol. To the residue was added water. The mixture was extracted with dichloromethane. The organic layer was then washed with IN-HCl and water, dried over sodium sulfate, and then filtered. The filtrate was distilled under reduced pressure to obtain 1.57g of the title compound as a yellow foamy solid.

1H NMR(CDCI ₃ , ppm) : δ 7.95(dd, 1H, J=7.80Hz, 1.30Hz), 7.50-7.44(m, 211), 7.37-7.34(m, 2H), 7.17-7.25(m, 211), 6.33(s, HI), 4.28(s, 2H), 4.06-3.98(m, 3H), 3.94-3.91(m, 2H), 3.75-3.71(m, 2H), 2.24-2.21 (m, 1H), 2.10-2.05(m, 3H), 1.79-1.72(m, 2H), 1.25-1.21(m, 3H)

b) Synthesis , of ethyl 2-[2-[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)eth- yl]pyrrolidin-2-yl]-2-oxoethyl]benzoate:

150mg of the compound obtained in the above a) was treated according to the same proccedure as Example 1-n) to obtain 50mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.87(dd, 1H, J=7.85Hz, 1.40Hz), 7.76(s, 1H), 7.48(d, HI, J=8.30Hz), 7.39(d, III, J=1.50Hz), 7.30-7.25(m, 2H), 7.18-7.15(m, 1H), 6.32(s, 1H), 4.14-4.09(m, 5H), 3.93(d, 2H, J=7.96Hz), 3.58-3.55(m, 211), 2.74-2.71(m, 2H), 2.14-2.11(m, 1H), 1.96-1.93(m, 3H), 1.83-1.80(m, 2H), 1.19-l.ll(m, 6H)

Example 23 : Synthesis of 2- r2-r ⁽ S ⁾ -2-r2-(β-amidino- l-ethylin- dol-2-yl)ethyl]pyrrolidinyl3-2-oxoethyl]benzoic acid (Compound 24)

150mg of 2-[2-[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]pyrro- lidinyI]-2-oxoethyl]benzoic acid obtained in Example 22-a) was treated according to the same procedure as Example 1-n) to obtain 28mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄₎ ppm) : δ 7.68(s, 1H, J=7.60Hz), 7.62(dd, 1H, J=7.60 Hz, 2.00Hz), 7.43(d, III, J=8.30Hz), 7.22-7.15(m, 4H), 6.37(s, 1H), 4.15-4.10(m, 4H), 3.85(d, 1H, J=15.80Hz), 3.54-3.51(m, 2H), 2.77-2.74(m, 2H), 2.21-2.16(m, 1H), 1.98-1.93(m, 3H), 1.82-1.78 (m, 2H), 1.28-1.22(m, 3H)

ES-MS : 447(M+1) ⁺

Example 24 : Synthesis of l-ethyl-2-[2-[(S)- l-(2-cvclopentyl-2 phenylacetvl)pyrrolidin-2-yl]ethyl]indole-6-rarboχam|dinp (Compound 30)

a) Synthesis of 2-cyclopentyl-2-phenylacetyl chloride:

In a 100ml flask, 0.2g of 2-cyclopentyl-2-phenylacetic acid was introduced and 8mC of thionyl chloride was slowly added thereto at 0°C . The reaction mixture was stirred for 4 hours at 70 "C and then evaporated under reduced pressure to remove the solvent. The residue was dried under reduced pressure to obtain 0.2g of the title compound as a brown oil.

b) Synthesis of l-ethyl-2-[2-[(S)-l-(2-cyclopentyl-2-phenylacetyl)pyrro-

lidin-2-yl]ethyl]indole-6-carbonitrile:

300mg of the compound I-a obtained in Example 1-1) and 30mg of 2-cyclo- pentyl-2-phenylacetyl chloride were treated according to the same procedure as Example 1-m) to obtain 30mg of the title compound as a yellow oil.

³ II NMR(CDC1 ₃ , ppm) : δ 7.53(m, 211), 7.36-7.21(m, 6H), 6.28(s, 1H), 4.33(m, 1H), 4.13(m, 2H), 3.59(m, 1H), 3.38-3.30(m, 2H), 2.64(m, 311), 2.07-1.92(m, 611), 1.62(m, 6H), 1.26(m, 3H), 1.09(m, 2H)

c) Synthesis of l-ethyl-2-[2-[(S)-l-(2-cyclopentyl-2-phenylacetyl)pyrro- lidin-2-yl]ethyl]indole-6-carboxamidine:

26mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-n) to obtain 20mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.03(s, 1H), 7.40-7.18(m, 7H), 6.16(s, 1H), 4.27(m, 1H), 4.10 (m, 2H), 3.55(m, 1H), 3.37-3.28(m, 2H), 2.58(m,

3H), 2.01-1.90(m, 6H), 1.57(m, 611), 1.25(m, 3H), 1.07(m, 2H)

Example 25 : Synthesis of l-ethyl-2-r2-r(S)-l-(2-hvdroχy-2- phenylacetyl)pyrrolidin-2-yl]ethyl]indole-6-carboxamidine (Compound 31)

250mg of the compound I-a obtained in Example 1-1) and 140mg of benzoylformic acid were dissolved in 10ml of dichloromethane, and 358mg of WSCIHCl was then slowly added thereto at 0V. The reaction mixture was stirred at room temperature overnight, and excess of dichloromethane was added thereto. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then filtered under reduced pressure. The filtrate was distilled under reduced pressure. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(2:l)]. The fractions containing the desired

product were combined and distilled under reduced pressure to obtain 83 rag of the product, which was then dissolved in 5mC of methanol, and 16mg of NaBH ₄ was added at room temperature thereto. The mixture was stirred for one hour and then distilled under reduced pressure to remove the reaction solvent. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(l.'l)]. The fractions containing the desired product were combined and then distilled under reduced pressure to obtain 15mg of the white solid product, which was then treated according to the same procedure as Example 1-n) to obtain 7 mg of the title compound as a pale yellow solid.

^] II NMR(MeOH-d4, ppm) : δ 7.81(m, HI), 7.55(d, 1H), 7.34-7.23(m, 6H), 6.41 (s, 1H), 4.23(m, 2H), 4.10(m, III), 3.49(m, 2H), 3.10(m, 1H), 2.78(t, 211), 2.25(m, 1H), 1.91(m, HI), 1.79-1.72(m, 5H), 1.30(t, 3H)

Example 26 : Synthesis of l-methyl-2- r2-r(S)- l- r(R)-2-acetyl- amino-2- ⁽ 4-hvdroxyphenyl ⁾ acetvnpyrrolidin-2-yllethyl]indole-6- carboxamidine (Compound 32)

l.OOg of the compound I-b obtained in Example 2-b) and 1.1 lg of (R)-2-(acetylamino)-2-(4-acetyloxyphenyl)acetic acid were treated accor ^¬ ding to the same procedure as Example 11-a) to obtain 1.67g of 4-[2- [(S)-2-[2-(6-cyano-l-methylindol-2-yl)ethyl]pyrrolidinyl]-(R )-l-acetyla- mino-2-oxoethyl]phenyl acetate. 96mg of the compound thereby obtained was treated according to the same procedure as Example 1-n) to obtain 48mg of the title compound as a pale yellow solid.

1H NMR(MeOH-cU, ppm) : δ 7.80(s, 1H), 7.52<d, 1H, J=8.25Hz), 7.32(d, 1H, J=8.33H^), 7.08 ⁽ d, 2H, J=8.46Hz), 6.62(d, 2H, J=9.42Hz), 6.36

(s, 1H), 4.09(brs, 1H), 3.70(s, 3H), 1.86(s, 3H)

Example 27 : Synthesis of l-ethyl-2-f2-r(S)- l-((R)-2-methyl- sιιlfnpylamino-2-phenylacetyl)ρyrrolidin-2-vnethvnindole- 6-carbox -amidine (Compound 37)

l.OOg of (R)-(-)-2-phenylglycine, 10ml of 1,4-dioxane and 10ml of 2N aqueous NaOH solution were mixed, and 1.73g of (BOO ₂ O was slowly added at 0 ^° C . The reaction mixture was stirred overnight at room temperature and distilled under reduced pressure to remove 1,4-dioxane. To the residue were added 50m£ of water and 5ml of aqueous NH ₄ OH solution. The aqueous layer was washed with dichloromethane, acidified with c-HCl, and then extracted with ethyl acetate. The extract was dried over sodium sulfate and distilled under reduced pressure to obtain 1.6g of liquid (R)-2-[(tert-butoxy)carbonyl- amino]-2-phenyIacetic acid. 507mg of (R)~2-[(tert-butoxy)carbonyl- amino]-2-phenylacetic acid and 450mg of l-ethyl-2-[((S)-pyrrolidin-2- yI)ethyl]indole-6-carbonitrile were then treated according to the same procedure as Example 11-a) to obatin the product, which was then dissolved in dichloromethane. To the resulting solution, 4 ml of trifluoroacetic acid was added. The reaction solution was stirred overnight at room temperature and extracted with excess of dichloromethane. The oragnic layer was neutralized with aqueous

NaHC0 ₃ solution and then extracted with dichloromethane. The extract was dried over MgS0 ₄ and filtered under reduced pressure. The filtrate was then distilled under reduced pressure. The remaining residue was purified with silica gel column chromatography [eluent: dichloromethane/ methanol(10:l)]. The fractions containing the desired product were combined and then distilled under reduced pressure to obtain 290mg of the white solid product. 80mg of the resulting product l-ethyl-2-[2-[(S)-l~ ((R)-2-amino-2-phenylacetyl)pyrrolidin-2-yl]ethyI]indole-6-c arbonitrile was dissolved in 5ml of dichloromethane, and triethylamine (0.299 mmole) and methanesulfonyl chloride (0.299 mmole) were added at 0V thereto. The reaction mixture was stirred for 3 hours at 0°C and excess of dichloromethane was added thereto. The organic layer was washed with water, dried over NazS0 ₄ and then filtered under reduced pressure. The filtrate was evaporated under reduced pressure. The residue was purified with silica gel column chromatography [eluent : n-hexane/ethyl acetate(l:2)] to obtain 90mg of the white foamy solid product. Finally, 70mg of .1 the resulting compound, l-ethyl-2-[2-[(S)- l-((R)-2-methylsulfo-

nylamino-2-phenylacetyl)pyrrolidin-2-yl]ethyl]indole-6-carbo nitrile was treated according to the same procedure as Example 1-n) to obtain 28mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.81(s, 1H), 7.55(d, 1H, J=8.08Hz), 7.37- 7.19(m, 6H ⁾ , 6.39(s, 1H), 5.21(s, HI), 4.23-4.12(m, 3H), 3.62(m, III), 3.12(m, 1H), 2.80(t, 2H), 2.68(s, 3H), 2.25(m, 1H), 1.93(m, 2H), 1.81-1.74(m, 6H), 1.30(t, 3H)

Example 28 : Synthesis of ethvl 2-rr(R)-2-[2- r(S)-2-r2-(β- amidino- 1 -ethyl in.dol-2-yl)etbyl3pyrrolidinvl1-2-oxo- l -phenvllethvn -aminolacetate (Compound 38)

192mg of l-ethyI-2-[2-[(S)-l-((R)-2-amino-2-phenylacetyl)pynO- lidin-2-yl]ethyl]indole-6-carbonitrile obtained in Example 27 and 120mg of ethyl bromoacetate were treated according to the same procedure as Example 1-m) to obtain 129mg of ethyl 2-[[(R)-2-[2-[(S)-2-[2-(6~cyano- l-ethylindol-2-yl)ethyl]ρyrrolidinyl]-2-oxo-l -phenylethyl]amino]acetate. 120mg of the resulting compound was treated according to the same procedure as Example 1-n) to obtain 34mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d4, ppm) : δ 7.81(s, 1H), 7.54(t, 1H), 7.48-7.22(m, 6H), 6.39(s, 1H), 4.52(s, 1H), 4.21(m, 2H), 4.06-4.01(m, 2H), 3.56(m, 2H), 3.05(m, 1H), 2.78(m, 2H), 2.25(m, 1H), 1.80-1.68(m, 7H),

1.29(t, 3H, J=7.10Hz), 1.13(m, 3H)

Example 29 : Synthesis of l-ethyl-2-r2-r(S)- l-r(R)-2-(carba- "loylm ^p thylamino ⁾ -2-phenvlacetvnpvrroIidin-2-vnethvnindole-6- caιjιojςamidin£jC_ompound 39)

129mg of ethyl 2-[[(R)~2-[2-[(S)-2-[2-(6-cyano-l-ethylindol-2- yl)ethyl]pyrrolidinyl]-2-oxo-l-phenyl]ethyl]amino]acetate obtained in Example 28 was treated according to the same procedure as Example l-n) to obtain 40mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.81(s, III), 7.50(m, 1H), 7.34-7.13(m, 6H), 6.39(s, HI), 4.46(s, 1H), 4.21(d, 2H), 4.08(m, III), 3.60(m, 1H), 3.24-2.97(m, 3H), 2.77(t, 2H, J=7.58Hz), 2.30(m, III), 1.92(m, 2H), 1.80-1.68(m, 5H), 1.28(t, 311, J=6.93Hz)

Example 30 : Synthesis of 2-r[(R)-2-r2-r(S)-2-r2-(β-amidino-l- ethylindol-2-yl)ethyl]pyrrolidinvI]-2-oxo-l-pheπylethynamin o1acetic acid (Compound 40)

To 20mg of ethyl 2-[[(R)-2-[2-[(S)-2-[2-(6-amidino-l -ethyl- indol-2-yl)ethyl]pyπOlidinyl]-2-oxo-l-phenyl]ethyl]amino]ac etate obtained in Example 28 was added concentrated HCI solution, and the reaction solution was stirred overnight while heating to 50-55 ^° C and then distilled under reduced pressure to remove the solvent. The residue was purified with column chromatography [eluent: methanol] on NH-DM1020 silica to obtain 14mg of the title compound as a white solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.77(s, 1H), 7.46(t, 1H, J=7.58Hz), 7.36-7.21(m, 6PI), 6.33(s, 1H), 4.51(s, 1H), 4.20-4.08(m, 4H), 3.02(m, 2H), 2.76(t, 311, J=7.90Hz), 2.25(m, 1H), 1.91(m, 2H),

1.77-1.68(m, 5H), 1.26(m, 3H)

Example 31 : Synthesis of l-methyl-2-r2-[(S)-l-(2-cvclopentyl- acetyl)pyrrolidin-2-vI]ethyl]indole-β-carhnxamidiρpi (Compound 42)

a) Synthesis of l-methyl-2-[2-[(S)-l-(2-cyclopenty!acetyl)pyrrolidin-2- yl]ethyl]indole-6-carbonitrile:

lOOmg of the compound I-b obtained in Example 2-b) and 0.055ml of cyclopentylacetic acid were reacted according to the same procedure as Example 11-a) to obtain 32mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.57(m, 2H), 7.29(m, 1H), 6.40(s, 1H), 4.25(d, 1H), 3.71(s, 3H), 3.48(m, 2H), 2.80(t, 2H), 2.28(m, 4H), 1.98(m,

411), 1.88 (m, 2H), 1.75(m, 2H), 1.59(m, 3H), 1.16(m, 2H)

b) Synthesis of l-methyl-2-[2-[(S ⁾ -l-(2-cyclopentylacetyl)pyrrolidin-2- yl]ethyl]indole-6-carboxamidine:

32mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 20mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.95(s, 1H), 7.27(m, 2H), 7.13-6.84(br, 2H), 6.12 (s, 1H), 4.03(m, 1H), 3.56(s, 311), 3.33(m, 211), 2.55(m, 2H), 2.13 (m, 4H), 1.84-1.70(m, 6H), 1.52-1.40(m, 5H), 1.03(m, 2H) ES-MS : 380(M+1) ⁺

Example 32 : Synthesis of l-ethyl-2-r2-r(S)-l-(2 cvclopentyl- acetyl)pyrroIidin-2-vnethvnindole-6-carboxamidine (Compound 43)

a) Synthesis of l-ethyl-2-[2-[(S)-l-(2-cyclopentylacetyl)pyrrolidin-2-yl] -ethyl]indole-6-carbonitrile:

lOOmg of the compound I-a obtained in Example 1-1) and 0.052ml of cyclopentylacetic acid were reacted according to the same procedure as Example 11-a) to obtain 30mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.56(m, 2H), 7.29(m, 1H), 6.40(s, 1H), 4.28(m,

1H), 4.15(m, 2H), 3.50(m, 2H), 2.79(t, 2H), 2.30(m, 4H), 1.98(m,

3H), 1.87(m, 2H), 1.75(m, 2H), 1.59(m, 4H), 1.35(m, 3H), 1.18(m, 2H)

b) Synthesis of l-ethyl-2-[2-[(S)-l-(2-cyclopentylacetyl)pyrrolidin-2-yl] -ethyl]indole-6-carboxamidine:

29mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 19mg of the

title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.06(m, 1H), 7.37(m, 2H), 6.91-6.52(br, 4H), 6.22(s, III), 4.17(m, 3H), 3.43(m, 2H), 2.67(m, 2H), 2.25(m, 4H), 1.94-1.71(m, 7H), 1.56(m, 4H), 1.21(m, 3H), 1.13(m, 2H)

Example 33 : Synthesis of ethvl 3-r(S)-2-r2-(6-amidino-l-ethyl- indol-2-yl)eth ^y l1pyrrolidinyl]-2-cvclopentyl-3-oxoρropanoate (Compound 44)

a) Synthesis of ethyl 3-[(S)-2~[2-(6-cyano-l-ethylindol-2-yl)ethyl]- pyrrolidinyl]-2-cyclopentyl-3-oxopropanoate-'

In a 100ml flask, lg of the compound I-a) obtained in Example

1-1) and lg of α-ethylcarboxylate cyclopentane acetyl chloride were introduced and reacted according to the same procedure as Example 1-n) to obtain 0.5g of the title compound as a pale brown oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.56(m, 211), 7.28(m, 1H), 6.40(m, 1H), 4.31(m,

1H), 4.17(m, 4H), 3.70(m, 1H), 3.59(m, III), 3.30(d, 1H), 2.81(m,

2H), 2.68(m, III), 2.28(m, 1H), 2.02(m, 5H), 1.77(m, 2H), 1.61(m, 511), 1.35(m, 3H), 1.22(m, 3H), 1.09(m, 1H)

b) Synthesis of ethyl 3-[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]- pyrrolidinyl]-2-cyclopentyl-3-oxopropanoate:

0.4g of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 0.31g of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.98(m, 1H), 7.47(m, 1H), 7.33(m, 1H), 6.30(s, 1H), 4.16(m, 5H), 3.69-3.56(m, 2H), 3.30(d, 1H), 2.73(m, 3H), 2.25 (m, 1H), 1.98(m, 5H), 1.72-1.58(m, 7H), 1.31-1.21(m, 6H), 1.03(m, 1H)

ES-MS : 466(M+D ^*

Example 34 : Synthesis of 3-r(S)-2-r2-(β-amidino-l-ethvlindol-2- yl)ethvnpyrrolidinvIl-2-cvclopentvI-3-oχoproρanoic acid (Compound 45J

In a 50ιnl flask, 80mg of ethyl 3-[(S)-2-[2-(6-amidino-l-ethyl- i ndol - 2 - y 1 )ethyl]pyrrolidiny 1] - 2 -cy clopentyl -3 - oxopropanoate obtained in Example 33 was dissolved in 20ml of ethanol, and 10ml of 2N NaOH was added thereto. The reaction mixture was stirred for 10 hours at room temperature, neutralized with 10% aqueous citric acid solution, and then distilled under reduced pressure to remove the solvent. The residue was then purified with column chromatography [eluent: ethyl acetate/methanol (5:1)] on NH -DM1020 silica to obtain 51mg of the title compound as a yellowish white solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.87(s, III), 7.60(d, 1H), 7.38(d, 1H), 6.44(s, III), 4.28(m, 2H), 3.87(m, III), 3.65(m, 1H), 3.19(d, 1H), 2.89(m, 3H), 2.59(m, 1H), 2.24(m, 1H), 2.03(m, 5H), 1.84(m, 4H), 1.59(m, 4H), 1.32(m, 3H)

IR(KBr) : 3420, 2890, 1620 cm ^"1 ES-MS : 439(M+1)\ 462(M+Na)

Example 35 : Synthesis of l-ethyl-2-r2-r(S)-l-(2-cvclohexylacetyl) -pyrrolidin-2-vnethyl]indole-6-carboxamidine (Compound 46)

a) Synthesis of l-ethyl-2-[2-[(S)-l-(2-cyclohexylacetyl)pyrrolidin-2-yl]- ethyl]indole-6-carbonitrile:

lOOmg of the compound I-a obtained in Example 1-1) and 88mg of cyclohexylacetic acid were reacted according to the same procedure as Example 11-a) to obtain 60mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.56(m, 2H), 7.30(m, 1H), 6.40 ⁽ s, 1H ⁾ , 4.28 ⁽ m,

HI), 4.15(m, 2H), 3.47(t, 2H), 2.79(t, 2H), 2.28(m, 1H), 2.17(m, III), 1.99(m, 411), 1.74-1.67(m, 7H), 1.38(m, 4H), 1.26(m, 3H), 0.94(m, 2H)

b) Synthesis of l-ethyl-2-[2-[(S)-l-(2-cyclohexylacetyl)pyrrolidin-2-yI]- ethyl]indole-6-carboxamidine:

50mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 40mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : <5 8.02(s, HI), 7.73-7.54(br, 2H), 7.43(m, 2H), 6.25(s, HI), 4.13(m, 311), 3.48(m, 2H), 2.68(m, 2H), 2.21(m, 1H), 2.13(m, 1H), 1.92(m, 411), 1.69-1.63(m, 711), 1.27(m, 7H), 0.93(m, 2H)

ES-MS : 409(M+1) ⁺

Example 36 : Synthesis of l-ethyl-2-r2-r(S)-ri-(3-phenylpro- panoyDpyrrol idin-2-vπethylJindole~6-carhnxamidiπe (Compound 50)

60mg of the compound I-a obtained in Example 1-1) and 40mg of 3-phenylpropanoic acid were reacted according to the same procedure as Example 11-a) to obtain 55mg of the product, which was then treated according to the same procedure as Example 1-n) to obtain 40mg of the title compound.

1H NMR(CDC1 ₃₎ ppm) : δ 8.08(m, 1H), 7.61 (m, 1H), 7.44(m, 1H), 7.34- 7.17(m, 5H), 6.28(s, 1H), 4.19(m, 3H), 3.36-2.95(m, 2H), 2.92(t, 2H), 2.86(m, 4H), 2.69(m, 2H), 2.54(t, 2H), 2.27(m, 1H), 1.73-1.63 (m, 2H)

Example 37 : Synthesis of l-methyl-2-r2-r(S)-l-((R)-2-aretv1- amino-3-phenylpropanoyl)pyrrolidin-2-vnethvnindole-6-carboxa mi- dine (Compound 53)

l.OOg of the compound I-b obtained in Example 2~b) and l.OOg of (2)-2-acetylamino-3-phenylpropanoic acid were treated according to the same procedure as Example 11-a) to obtain 1.37g of N-[(R)-2-[(S)-2- [2- (6-cyano- 1 -methyIindol-2-yl)ethyl]ρyn-olidinyI] -2-oxo- 1 -benzylethyl] - ethanamide. 78mg of the compound thereby obtained was treated according to the same procedure as Example 1-n) to obtain 32mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : 6 7.79(s, 1H), 7.48(d, 1H), 7.18(d, 1H), 7.14(m, 5H), 6.31(s, III), 4.20-3.90(brs, HI), 3.66(s, 3H), 2.84(s, 3H)

Example 38 ^; Synthesis of l-ethyl-2-r2-r(S)-l-(2-cvcIopropvlami- noacetyl)pyrrolidin-2-vnethvnindole-6-carboxamidine (Compound

511

150mg of the compound I-b obtained in Example 2~b) was reacted with 96mg of chloroacetyl chloride under the same conditions as Example 1-m) to obtain the product, which was then dissolved in N,N-dimethyl- formamide. To the resulting solution were added 50mg of cyclopropyl- amine and KaC0 ₃ . The reaction mixture was stirred overnight at room temperature and extracted with ethyl acetate. The extract was dried over MgS0 ₄ and then filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was then purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane (4:1)] to obtain 120mg of the pale yellow solid product, l-ethyl-2-[2-[(S)-l-(2- cyclopropylaminoacetyl)pyrroIidin-2-yI]ethyl]indole-6-carbon itrile. The product thereby obtained was treated according to the same procedure as Example 1-n) to obtain 45mg of the title compound as a pale yellow solid.

ES-MS : 382(M+1) ⁺

Example 39 : Synthesis of l -ethvl-2-r2-r(S)- l-r2-rcvclopropyl- (methylsulfonyl)amino1acetvnpvrrolidin-2-yllethvnindole-β-c arbox- amidine (Compound 58)

lOOmg of

1 - ethyl -2-[2-[(S)-l- (2 -cyclopropy laminoacety 1 Jpyrrolidin- 2 - yl]ethyl]indole -6-carbonitrile obtained in Example 38 was reacted with 60mg of methanesulfonyl chloride in 2ml of pyridine to obtain 90mg of the product, which was then treated according to the same procedure as Example 1-n) to obtain 55 mg of the title compound as a pale yellow solid.

Example 40 : Synthesis of ethvl 2-IT2-r(S)-2-r2-(β-amidino-l- meth ylindol - 2 -y 1 )ethyl3pyrrolidiny 1] - 2 -oxoeth vHcyclopropylamino] - acetate (Compound 59)

300mg of the compound I-b obtained in Example 2-b) was reacted according to the same procedure as Example 38 to obtain 290mg of 1- methyl -2-[2-[(S)-l-( 2 -cycIopropylaminoacetyDpyrrolidin - 2 - yl]ethyl]indole -6-carbonitrile, which was then reacted with 170mg of ethyl 2-bromo- acetate according to the same procedure as Example 1-m) to obtain 250mg of the yellow solid product. The resulting product was then treated according to the same procedure as Example 1-n) to obtain 85 rag of the title compound as a pale yellow solid.

1H-NMR(MeOH-d ₄ , ppm) : δ 7.80(d, 1H, J=3.28Hz), 7.56-7.51(m, 1H),

7.32(d, 1H, J=8.32Hz), 6.36(s, 1H), 4.08-3.93(m, 5H), 3.71(s, 3H), 3.37-3.34(m, 4H), 2.74-2.61(m, 3H), 2.18-2.11(m, 1H), 1.92(m,

1H), 1.80-1.77(m, 2H), 0.82-0.78(m, 3H), 0.58-0.65(m, 3H), 0.36

(m, 1H)

Example 41 : Svnthsis of ethyl 2-[r2-r(S)-2-r2-(6-amidinn- 1 - methylindol-2-yl)ethyl1pyrrolidinvn-2-oxoethyl]cyclopentvlam inol- acetate (Compound 60)

lOOmg of l-methyl-2-[2-[(S)-l-(2-cycloproρylaminoacetyl)pyrro- lidin-2-yl]ethyl]indole-6-carbonitrile obtained in Example 40 and 60mg of cyclopentylamine were reacted according to the same procedure as

Example 38 to obtain 95mg of the yellow solid product, which was then reacted with ethyl 2 -bromoacetate according to the same procedure as Example 1-m) to obtain 70mg of . the pale yellow solid product. The resulting product was then treated according to the same procedure as Example 38 to obtain 48mg of the title compound as a pale yellow solid.

1H NMR(MeOH-(Li, ppm) : 6 7.80(s, 1H), 7.54-7.51(m, 1H), 7.35-7.31(m,

1H), 6.37(s, 1H), 4.58(m, 2H), 4.38-4.31(m, 1H), 4.08-4.02(m,

211), 3.91(m, 2H), 3.71(s, 3H), 3.65-3.61(m, III), 3.45-3.40(m, 2H), 2.79-2.73(m, 2H), 2.13-2.08(m, 1H), 1.93(m, 3H), 1.80-

1.77(m, 411), 1.57(br, 2H), 1.41(br, 411), 0.82-0.78(m, 3H)

Example 42 : Synthesis of ethyl 2-[T2-r(S)-2-r2-(6-amidino-l- methyli ndol-2-yl)ethyl]pyrrolidinvn-2-oxoethyl]benzy)amino1acetate (Compound 61)

150mg of the compound I-b obtained in Example 2-b) was treated according to the same procedure as Example 1-m) to obtain the product, to which 70mg of ethyl 2-(benzylamino)acetate, lOlmg of KzC0 ₃ and 2.5ml of dimethylformamide were added. The resulting mixture was stirred overnight at room temperature and extracted with ethyl acetate. The extract was dried over MgS0 ₄ and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(4:l)] to obtain 120mg of the pale yellow solid product, which was treated according to the same procedure as Example 1-n) to obtain 45mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d4, opm) : 6 7.77-7.31(m, 4H), 7.28-7.19(m, 4H), 6.37(s, HI). 4.89-4.45(m, 6H), 4.16-3.93(m, 3H), 3.69(d, 3H, J=8.84Hz),

3.44-3.37(m, 2H), 2.81-2.75(m, 2H), 2.18-1.71(m, 6H), 0.82-0.77 (m, 3H)

Example 43 : Synthesis of ethyl 2-rr2-r(S)-2-r2-(6-amidino- l-

ethylindnl-2-vl ⁾ ethvllpvrrolidinvn-2-oxoethvncvclopropvlamino1ace- tate (Compound 62)

a) Synthesis of l-ethyl-2-[2-((S)-l-2-chloroacetylpyrrolidin-2-yl)ethyI]- indole-6-carbonitrile:

300mg of the compound I-a obtained in Example 1-1) and 130mg of chloroacetyl chloride were reacted according to the same procedure as Example 1-m) to obtain 351mg of the title compound.

1H NMR(CDC1 ₃ , ppm) : δ 7.65-7.55(m, 2H), 7.40-7.30(m, 1H), 6.45(s, 1H), 4.40-4.30(m, 1H), 4.25-4.20(q, 211), 4.10(s, 2H), 3.70-3.55(m, 2H), 2.90-2.80(t, 2H), 2.40-2.30(m, 1H), 2.20-1.95(m, 4H), 1.90-1.75 (m, 1H), 1.45-1.35(t, 3H)

b) Synthesis of ethyl 2-[[2-[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]- pyrrolidinyl]-2-oxoethyl]cyclopropylamino]acetate:

351mg of the compound obtained in the above a) was dissolved in dimethylformamide, and 306mg of K2CO3 and 238mg of N-ethylacetato- cyclopropylamine were added. The reaction mixture was stirred overnight at room temperature and extracted with ethyl acetate. The extract was dried over MgS0 ₄ and filtered, and the filtrate was then concentrated under reduced pressure. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(4:l)] to obtain 373mg of the title compound as an oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.65-7.55(m, 2H), 7.30-7.20(m, 1H), 6.50-6.40 (m, 1H), 4.35-4.10(m, 6H), 3.75-3.40(m, 6H), 2.90-2.80(m, 2H), 2.50-2.30(m, HI), 2.20-1.95(m, 1H), 1.45-1.25(m, 1H), 0.95-0.70

(m, 2H), 0.55-0.50(m, 2H)

c) Synthesis of ethyl 2-[[2-[(S)-2-[2-(6-amidino-l-ethylindoI-2-yl)ethyl] -pyrroIidinyl]-2-oxoethyl]cyclopropylamino]acetate:

55 mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-n) to obtain 24mg of the title compound.

1H NMR(CDC1 ₃ , ppm) : δ 7.70(m, 1H), 7.40(m, 1H), 7.20(m, 1H), 6.25(s, HI), 4.55-4.40(d, 1H), 4.20-3.80(m, 511), 3.50-3.10(m, 6H), 2.80- 2.70(m, 211), 2.20- 1.65(m, 6H), 1.20-1.00(m, 6H), 0.75-0.65(m, 4H)

Example 44 : S ^y nthesis of 2-r[2-[(S)-2-r2-(6-amidino- l-ethylin- dol-2-vl ⁾ ethvn ^p vrrolidinvll-2-oxoethvncvclopropylamino1acetic acid (Compound 63)

40mg of ethyl 2-[[2-[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl]pyιτolidinyl]-2-oxoethyl]cyclopropylamino]acetate obtained in Exam¬ ple 43 was dissolved in 50ml of ethanol, and 2ml of 2N NaOH was added thereto. The reaction mixture was stirred for 2 hours and then evaporated under reduced pressure to remove the solvent. The residue was purified with column chromatography [eluent: ethanol] on NH-DM 1020 silica to obtain 25rag of the title compound as a pale yellow solid.

1H NMR(MeOH-d,, ppm) : δ 7.81-7.30(m, 311), 6.37(s, 1H), 4.22-4.04(m, 3H), 3.56-3.43(m, 4H), 3.28(s, 2H), 2.81-2.67(m, 2H), 2.37(m, 1H), 2.23- 1.70(m, 6H), 1.30-1.22(m, 3H), 0.64-0.25(m, 4H) ES-MS : 440(M+1) ^*

Example 45 : Synthesis of ethvl 2-rr2- r(S)-2-r2-(6-amidino-l- ethylindol-2-yl)ethvnpyrrolidinvn- l-methyl-2-oxoethvncvclo-propy

a) Synthesis of ethyl 2-[[2-[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]- pyrrolidinyl] - 1 -methyl- 2 -oxoethyl]cycIopropylamino]acetate:

500mg of l-ethyl-2-[2-((S)-l-2-bromopropanoylpyrroIidin-2-yl)- ethyl]indole-6-carbonitrile and cyclopropylamine were dissolved in dry

N,N-dimethylformamide, and 104mg of NaHC0 ₃ and 20.4mg of KI were added thereto. The reaction mixture was heated under refluxing for one hour and, after water was added, extracted with ethyl acetate. The extract was dried and distilled under reduced pressure. The residue was purified with silica gel colmnn chromatography [eluent: dichloromethane/ methanol(20:l)] to obtain the title compound in a quantitative yield.

b) Synthesis of ethyl 2-[[2-[(S)-2-[2-(6-cyano-l-ethyIindol-2-yl)ethyl]- pyrrolidinyl]- 1 -methyl-2-oxoethyl]cyclopropylamino]acetate:

467mg of ethyl 2-[[2-[ ⁽ S)-2-[2-(6-cyano-l-etiιylindol-2-yl)- ethyl]ρyrrolidinyl]- l-methyl-2-oxoethyl]cyclopropylamino]acetate was dissolved in 15ml of acetonitrile, and diisopropylethylamine and ethyl-2-bromoacetate were added thereto. The reaction mixture was heated to 70°C and stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the residue, which was then purified with silica gel column chromatography [eluent: dichloromethane/methanol(20:l)] to obtain 538mg of the title compound as a pale yellow oil.

1H NMR(CDC1 ₃ , ppm,) : δ 7.79(s, 1H), 7.58(d, 1H, J=8.10IIz), 7.28(d, 1H, J=7.96Hz), 6.45(s, 1H), 4.35-3.90(m, 8H), 3.60-3.40(m, 3H), 2.84 (m, 2H), 2.38-1.70(m, 8H), 1.42-1.13(m, 9H), 0.48(m, 3H),

ES-MS : 465(M+1) ⁺

c) Synthesis of ethyl 2-[[2-[(S)-2-[2-(6-amidino-l-ethyIϊndol-2-yl)ethyl] -pyrrolidinyl] - 1 -methyl -2-oxoethyl]cyclopropylamino]acetate:

500mg of ethyl 2-[[2-[(S)-2-[2-(6-cyano-l-ethyIindol-2-yl)ethyl]- pyrrolidinyl] -l-methyl-2-oxoethyl]cyclopropylamino]acetate obtained in the above b) was treated according to the same procedure as Example 1-n) to obtain 114mg of the title compound.

1H NMR(MeOH-d,, ppm) : δ 7.89(s, 1H), 7.61 (d, 1H, J=8.29Hz), 7.42(d, 1H, J=8.22Hz), 6.44 ⁽ s, 1H), 4.40-3.91(m, 6H), 3.70-3.40(m, 4H),

2.84(m, 211), 2.40-1.70(m, 8H), 1.41(t, 311), 1.23(m, 611), 0.50(m, 3H)

Example 46 : S ^y nthesis of 2-rr2-r(S)-2-r2-(6-amidino-l-ethvlin- dol-2-yl)ethvnpyrrolidinvn-l-methyl-2-oxoethvncyrloprnpylamf nn1 -acetic acid (Compound 65)

32mg of ethyl 2-[[2-[ ⁽ S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyI]- pyrrolidinyl] -l-methyl-2-oxoethyl]cyclopropylamino]acetate was treated according to the same procedure as Example 44 to obtain 27mg of the title compound as a yellowish white solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.82(s, 1H), 7.52(d, 1H), 7.32(d, HI), 6.36(s, III), 4.30-3.80(m, 6H), 3.51-3.12(m, 3H), 2.73(m, 2H), 2.30-1.60

(m, 6H), 1.26(t, 3H), 1.13(m, 3H), 0.62-0.25(m, 4H) ES-MS : 454(M+1) ⁺

Exnmple 47 : Synthesis of ethyl 2-IT2-r(S)-2-r2-(6-amidinn- 1 - ethvlindol-2-yl)ethyl1ρyrrolidinyl]-(lR)- l-methyl-2-oxoethvl]amino] -acetate (Compound 66)

a) Synthesis of N-[2-[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]pyrro- lidinyl] - ( 1R) - 1 -methyl- 2-oxoethyI] (tert-butoxy )f ormamide:

406mg of the compound I-a obtained in Example 1-1) and 316mg of N- (tert-butoxy )carbonyl-D-alanine were reacted according to the same procedure as Example 11-a) to obtain 290mg of the title compound as a white solid.

1H-NMR(CDC1 ₃ , ppm) : δ 7.61-7.54(m, 2H), 7.30(m, 1H), 6.42(s, 1H), 5.37 (d, 1H, J=8.44Hz), 4.47-4.39(m, 1H), 4.20-4.11(m, 3H), 3.74-3.40 (m, 2H), 2.79(t, 2H, J=7.91Hz), 2.39-1.77(m, 6H), 1.43 ⁽ s, 9H), 1.37(t, 3H, J=7.23Hz), 1.25(d, 3H, J=7.13Hz)

b) Synthesis of ethyl 2-[[2-[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]- pyrrolidinyl] - ( 1R) - 1 -methyl~2-oxoethyl]amino]ethanoate:

274mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-1) to obtain the pale yellow solid product, which was then reacted with 0.076ml of ethyl 2-bromoacetate under the same conditions as Example 1-m) to obtain 187 mg of the title compound as a pale yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.62-7.55(m, 211), 7.30(m, 1H), 6.43(s, 1H), 4.26 (brs, HI), 4.21-4.13(m, 4H), 3.50, 3.64(m, 3H), 3.41(d, IHa, J=16.68Hz), 3.25(d, 1Kb, J=16.70Hz), 2.81(t, 2H, J=8.00Hz), 2.41- 1.71(m, 6H), 1.37(t, 311, J=7.21Hz), 1.27-1.23(m, 6H)

c) Synthesis of ethyl 2-[[2-[(S)-2-[2-(6-amidino-l-ethylindoI-2-yl)eth- y l]pyrrolidinyl] - ( 1R) - 1 -methyl -2-oxoethyl]amino]acetate:

183mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-n) to obtain 144mg of the title compound as a pale yellow solid.

^: II NMR(MeOH-d ₄ , ppm) : δ 7.81(s, 1H), 7.60-7.32(m, 2H), 6.40(s, 1H), 4.22-4.01(m, 5H), 3.86-3.72(m, 1H), 3.59-3.27(m, 4H), 2.84-2.68 (m, 2H), 2.26-1.77(m, 6H), 1.30(t, 3H, J=7.13Hz), 1.15-1.06(m, 6H)

IR(KBr) cm ^"1 : 3400, 2970, 1720, 1660, 1625, 1520, 1460

ES-MS : 442(M+lK

Example 48 : Synthesis of 2-[[2-[(S)-2-r2-(6-anrιidino-l-ethyl- indol-2-yl)ethyl]ρyrrolidinyl]-(lR)- l-methyl-2-oxoethynaminn1ar:ftti c acid (Compound 67)

130mg of ethyl 2-[[2-[(S)-2-[2-(6-amidino-l-ethyIindol-2-yl)- ethyl]pyrrolidinyl]-(R)-l-methyl-2-oxoethyl]amino]acetate was treated according to the same procedure as Example 44 to obtain 60mg of the title

compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.76(s, III), 7.57-7.27(m, 2H), 6.35(s, 1H), 4.21-4.06(m, 3H), 3.66-3.40(m, 311), 3.01(s, 2H), 2.82-2.73(m, 211), 2.27-1.71(m, 6H), 1.27(t, 311, J=7.08Hz), 1.13-1.05(m, 3H)

ES-MS : 414(M+1) ⁺

Example 49 : Synthesis of ethvl 2-rr2-r(S)-2- r2-(6-amidino-l- ethylindol-2-yl)ethvnpyrroIidinyl]-( lR)- l-hydroxymethyl-2-oxo- ethyllaminolacetate (Compound 69)

a) Synthesis of N-[2-[[(S)-2-[2- ⁽ 6-Cyano-l-ethylindol-2-yl)ethyl)pyrro- lidinyl] - (R) - 1 - hydroxy methyl - 2 -oxoethyl] -( 1 , 1 -dimethylethyloxy )meth- anamide:

412mg of the compound I-a obtained in Example 1-1) and 348mg of N-(tert-butoxy)carbonyl-D-serine were reacted under the same conditions as Example 11-a) to obtain llOmg of the title compound as a viscous oil.

^! II NMR(CDC1 ₃ , ppm) : δ 7.61-7.54(m, 2H), 7.30(m, 1H), 6.41(s, III), 5.55

(brs, 1H), 4.49(m, 1H), 4.28-4.13(m, 3H), 3.90-3.52(m, 4H),

3.22(brs, 1H), 2.82-2.75(m, 2H), 2.40- 1.77(m, 6H), 1.44(s, 9H), 1.38(t, 3H, J=8.76Hz)

b) Synthesis of ethyl 2-[[2-[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]- pyrrolidinyl] - ( 1R)- 1 -hydroxymethyl-2-oxoethyl]amino]ethanoate:

109mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-1) to obtain the pale yellow solid product, which was then reacted with 0.029ml of ethyl

2 -bromoacetate under the same conditions as Example 1-m) to obtain 20 mg of the title compound as a pale yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.62-7.55(m, 2H), 7.30(m, 1H), 6.41 ⁽ s, 1H), 4.87-4.38(m, 2H), 4.31-4.11(m, 6H), 3.93-3.46 ⁽ m, 4H ⁾ , 2.77 ⁽ m,

2H), 2.38-1.73(m, 6H), 1.40-1.25(m, 6H)

c) Synthesis of ethyl 2-[[2-[(S ⁾ -2-[2-(6-amidino-l-ethylindol-2-yl)ethyl] -pyrrolidinyl] -( 1R) - 1 -hydroxymethyl-2-oxoethyl]amino]acetate:

20mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-n) to obtain lOmg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.70(s, 1H), 7.38(m, 2H), 6.27(s, 1H), 4.21- 4.14(m, 5H), 3.57-3.47(m, 6H), 3.22-2.72(m, 411), 2.29-1.70(m, 611), 1.35(t, 3H, J=7.09Hz), 1.25(t, 311, J=7.14Hz)

ES-MS : 458(M+1) ⁺

Example 50 : Svnthsis of ethyl 4-r(S)-2-r2-(6-amidinn- l-ethyl- indol-2-yl)ethyl]pyrrol idinyl3-3-cyclopropylamino-4-oxobutanoate (Compound 72)

a) Synthesis of N-[2-[(S)-2-[2-(6-cyano-l-etlιylindol-2-yl)ethyl]pyrro- lidinyI]-2-oxoethyl]-N-cycloρropyl(l,l-dimethylethyloxy)met hanamide:

375mg of 2-[2-((S)-l-2-chloroacetylpyπOlidin-2-yl)ethyl]-l- ethyl -indole-6-carbonitrile and 188mg of N-butyloxycarbonylcyclopropylamine were reacted under the same conditions as Example 45-b) to obtain 413rag of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.61-7.53(m, 211), 7.30(m, 1H), 6.36(s, 1H), 4.31 (brs, 1H), 4.15(q, 2H, J=7.28Hz), 3.93(brs, 2H), 3.54-3.37(m, 2H), 2.81-2.76(m, 3H), 2.58-1.75(m, 6H), 1.47(s, 9H), 1.35(t, 3H, J=7.28Hz), 0.75-0.62(m, 4H)

b) Synthesis of ethyl 4-[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]pyr- rolidinyl]-3-[N-cyclopropyl-(l,l-dimethylethyloxy)carbonylam ino]-4- oxobutanoate:

4I3mg of the compound obtained in the above a) was dissolved in 8m£ of tetrahydrofuran and cooled to -78 ^° C . To this solution was slowly added dropwise 0.489ml of 2M LDA (lithium diisopropylamide) solution. The reaction mixture was then stirred for 40 minutes. 0.108ml of ethyl bromoacetate was added dropwise thereto, and the mixture was stirred for 2 hours at -30 ^° C . After 0.5ml of water was added dropwise, the reaction solution was evaporated under reduced pressure, diluted with 150 ml of dichloromethane, washed with 50ιπ! of water, dried over sodium sulfate, and then filtered. The filtrate was evaporated under reduced pressure. The residue was purified with silica gel column chromato¬ graphy [eluent: ethyl acetate/n-hexane(l:l)]. The fractions containing the pure desired product were combined and then evaporated under reduced pressure to obtain 167mg of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.59-7.54(m, 211), 7.29(m, 1H), 6.37(s, HI), 5.11 (brs, III), 4.19-4.09(m, 5H), 3.64-3.33(m, 2H), 3.22-3.12(m, 1H), 2.78(t, 2H, J=8.00Hz), 2.61-2.52(m, HI), 2.36-1.70(m, 7H), 1.47(s, 9H), 1.35(t, 311, J=7.19Hz), 1.23(t, 311, J=7.10Hz), 0.75-0.61(m, 4H)

c) Synthesis of ethyl 4-[(S)-2-[2-(6-amidino-l -ethyIindol-2-yl)ethyl]~ pyrrolidinyl] -3- (cyclopropylamino) -4-oxobutanoate:

165mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-n) to obtain 33mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.77(s, 1H), 7.52-7.30(m, 2H), 6.33(s, 1H), 4.23-4.14(m, 3H), 4.01-3.84(m, 3H), 3.73-3.46(m, 2H), 2.85-2.48 (m, 4H), 2.12- 1.71(m, 7H), 1.29(t, 3H, J=7.14Hz), l.ll-1.05(m,

311), 0.40-0.22(m, 4H) ES-MS : 468(M+l) ^f

Example 51 : Synthesis of 4-[(S)-2-r2-(6-amiHino-l-ethylindol-2- yl)ethyl]ρyrrolidinvn-3-cvclopropylamino-4-oxobutanoic acid

(Compound 73)

26mg of ethyl 4-[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)ethyl]- pyrrolidinyl]-3-cyclopropylamino-4-oxobutanoate was treated according to the same procedure as Example 44 to obtain 16mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.57(s, III), 7.31-7.06(m, 2H), 6.27(s, 1H), 4.22(brs, 1H), 4.13-4.05(m, 211), 3.94-3.82(m, 211), 3.74-3.66(m, 1H), 2.79-2.71(m, 2H), 2.46(m, 211), 2.05-1.82(m, 711), 1.22(t, 3H,

J=7.13Hz), 0.36-0.31(m, 4H)

ES-MS : 440(M+1) ⁺

Example 52 : Synthesis of ethvl 2-r2-r(S)-2-r2-(6-amidinn- 1 - methylindol-2-yl)ethyl]pyrroIidinyI]-N-cvclopentylacetylamin o1 -ace¬ tate (Compound 75)

lOOmg of the compound I-b obtained in Example 2-b) and 98mg of ethyl 2-(2-chloro-N-cyclopentylacetylamino)acetate were reacted under the same conditions as Example 42 to obtain the pale yellow solid product, which was then treated according to the same procedure as

Example 1-n) to obtain 20mg of the title compound as a pale yellow solid.

Η NMR(MeOH-d ₄ , ppm) : δ 7.81-7.32(m, 3H), 6.31(m, 1H), 4.52-4.43(m, 1H), 4.04-3.96(m, 2H), 3.80-3.48(m, 4H), 3.85(s, 3H), 3.11-2.66

(m, 4H), 2.55-1.03(m, 15H), 0.80(t, 3H, J=6.94Hz) ES-MS : 482(M+D ^*

Example 53 : Synthesis of l-methyl-2-[2-[(S)-l- (2-naphthylsulfo- nyl)pyrrolidin-2-yllethvnindoIe-6-carboxamidine (Compound 77)

a) Synthesis of l-methyl-2-[2-[(S)- l-(2-naphthylsulfonyl)pyrrolidin-2- yl]ethyl]indole-6-carbonitrile:

In a 25me flask, 30mg of l-methyl-2-((S)-2-pyrrolidin-2-ylethyl)-

indole-6-carbonitriIe and 36mg of 2-naphthalenesulfonyl chloride were dissolved in 3ml of dichloromethane, and 0.055ml of triethylamine was added at room temperature. The reaction mixture was stirred for 2 hours, diluted with water and then extracted three times with dichloromethane. The extracts were combined, dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:3)]. The fractions containing the pure desired product were combined and then evaporated to obtain 26.9mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.26(s, 1H), 7.88(m, 2H), 7.78(m, 1H), 7.73(d,

III), 7.70(m, 211), 7.64(m, 1H), 7.59(m, HI), 7.34(d, HI), 6.39(s,

HI), 3.79(m, III), 3.74(s, 311), 3.50(m, III), 3.34(m, 1H), 2.93(m,

211), 2.28(m, III), 1.99(m, HI), 1.83(m, 1H), 1.65(m, 2H), 1.58(m, 1H ⁾

b) Synthesis of l -methyl-2-[2-[(S)-l -(2-naphthylsulfonyl)pyrrolidin-2- yl]ethyl]indole-6-carboxamidine:

27mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 14mg of the title compound as a yellowish white solid.

1H NMR(MeOH-d4, ppm) : δ 8.11(s, 1H), 7.89-7.82(m, 3H), 7.64(d, 1H), 7.61-7.44(m, 4H), 7.43(d, 1H), 6.37(s, III), 3.77(s, 3H), 3.63(m,

III), 3.37(m, 1H), 3.25(m, 1H), 2.85(m, 2H), 2.23(m, 1H), 1.91(m,

1H), 1.80(m, 1H), 1.59(m, 2H), 1.36(m, 1H), ES-MS : 461(M+1) ⁺

Example 54 : Synthesis of l-methyl-2-[2-((S)- l-naphthylsulfonyl- pyrrolidin-2-yl)ethyl]indole-6-carhnxamidine (Compound 79)

a) Synthesis of l -methyl-2-[2-((S)-l-naphthylsulfonylpyrrolidin-2-yl)- ethyl]indole-6-carbonitrile:

53 mg of 1-naphthalenesulfonyl chloride was treated according to the same procedure as Example 53 -a) to obtain 55mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.79(d, 1H), 8.12(d, 1H), 7.98(d, 1H), 7.99(d, 1H), 7.54(m, 4H), 7.40(m, 1H), 7.32(m, 1H), 6.25(s, 1H), 3.99(m, 1H), 3.57(s, 3H), 3.47-3.40(m, 2H), 2.74(m, 2H), 2.11(m, 1H), 1.87-1.81(m, 3H), 1.66(m, 211)

b) Synthesis of l-methyl-2-[2-[(S)-l-naphthylsulfonylpyιτolidin-2- yl)- ethyl]indole-6-carboxamidine:

51mg of the compound obtained in the above a) was tretaed according to the same procedure as Example 1-n) to obtain 25mg of the title compound as a yellowish white solid.

1H NMR(MeOH-dι, ppm) : δ 8.77(d, HI), 8.06(m, 211), 7.95(m, 2H), 7.67(d, 1H), 7.58(m, 1H), 7.52-7.40(m, 311), 6.33(s, 1H), 3.94(m, 1H), 3.73(s, 3H), 3.50-3.42(m, 2H), 2.82(m, 2H), 2.14(m, 1H), 1.90(m, 2H), 1.74(m, 2H), 1.64(m, 1H)

Example 55 : Synthesis of l-methyl-2-r2-((S)-l-acetyIpyrrolidin- 2-yl)ethvnindole-6-carboχamidipe (Compound 81)

490mg of l-methyl-2-[2-((S)-l-acetylpyrrolidin-2-yI)ethyl]indole-

6-carbonitrile was treated according to the same procedure as Example 1-n) to obtain 24mg of the title compound.

1H NMR(CDC1 ₃ , ppm) : δ 7.99(s, 1H), 7.33(m, 2H), 6.12(s, 1H), 4.01(bs, III), 3.54(s, 3H), 3.45-3.20(m, 2H), 2.54(bs, 2H), 2.20-1.40(m,

6H), 1.97(s, 3H)

Exampl 5β : Synthesis of l-methyl-2-r2-r(S)-l- (2-phenylsulfonyl -acetyl)pyrrolidin-2-yl1ethyl1indole-6-carhnya^idiπe (Compound 82)

a ⁾ Synthesis of l-methyl-2-[2-[ ⁽ S ⁾ -l-(2-phenylsulfonylacetyl)pyrrolidin- 2-yl]ethyl]indole-6-carbonitrile:

70mg of the compound I-b obtained in Example 2-b) and 81 mg of phenylsulfonylacetic acid were reacted according to the same procedure as

Example 11-a) to obtain 12mg of the title compound as a yellow oil. ^a IT NMR(CDC1 ₃ , ppm) : δ 7.94-7.91 (m, 211), 7.65(d, 1H, J=7.50Hz), 7.57-

7.51(m, 4H ⁾ , 7.29 ⁽ d, 1H), 6.37(s, HI), 4.23-4.10(m, 3H), 3.68(s,

3H), 3.75-3.66(m, 2H ⁾ , 2.80(t, 311, J=8.00Hz), 2.22-1.79(m, 6H)

b) Synthesis of l -methyI-2-[2-[(S ⁾ - l-(2-phenylsulfonylacetyl)pyrrolidin- 2-yl]ethyl]indole-6-carboxamidine:

12mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 4mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.98-7.93(m, 311), 7.74-7.62(m, 4H), 7.47(d, 1H, J=8.30Hz), 6.47(s, 1H), 4.15(bs, 1H), 3.82(s, 3H), 3.66-3.62(m, 211), 3.33(s, 2H), 2.89(t, 2H), 2.20-1.84(m, 6H)

Example 57 : Synthesis of l-ethyl-2- r2-r(S)-l- ((R)-pyrrolidin-2- ylcarbonyl)pyrrolidin-2-yl]ethyl]indole-6-carhpxamidine (Compound

83J

a) Synthesis of tert-butyl-(R)-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]pynOlictinyl]carbonyl]pyιτolidine carboxylate:

17g of l-ethyl-2-[((S)-pyrrolidin-2-yl)ethyl]indole-6-carbonitrile and 17.8g of (R)-N-(tert-butoxycarbonyDproline were dissolved in dichloromethane, and 18.3g of WSCIHCl was added thereto. The reaction mixture was stirred for 2.5 hours at room temperature and, after water was added, extracted two times with dichloromethane. The extracts were combined, dried over MgS0 ₄ and then concentrated. The residue was purified with silica gel column chromatography [eluent:

dichloromethane/methanol(50:l)] to obtain 24g of the title compound as a white foam.

ES-MS : 465(M+1) ⁺

TI NMR(CDC1 ₃ , ppm) : δ 7.60-7.51(m, 2H), 7.32-7.24(m, 1H), 6.41-6.33 (m, 1H), 4.52-4.47(m, 1H), 4.40-4.28(m, 1H), 4.16(q, J=7.20Hz, 2H), 3.79-3.62(m, 2H), 3.50-3.44(m, 2H), 2.83-2.79(m, 2H), 2.15-1.85(m, 10H), 1.43-1.40(m, 9H), 1.35(t, J=7.20Hz, 3H)

b) Synthesis of l-ethyI-2-[2-[(S)-[l-((R)-pyn-olidin-2-yl)carbonyl]pyriO- lidin-2-yl]ethyl]indoIe-6-carbonitrile (Compound II-a):

24g of the compound obtained in the above a) was treated according to the same procedure as Example 1 -1) to obtain llg of the title compound as a white foam.

1H NMR(CDC1 ₃ , ppm) : δ 7.60-7.56(m, 211), 7.31-7.26(m, 1H), 6.43(s, HI), 4.41-4.37(m, HI), 4.20-4.13(m, 3H), 3.64-3.61(m, 1H), 3.41- 3.34(m, 311), 2.81-2.78(m, 2H), 2.43-2.38(m, 2H), 2.17-1.82(m, 8H), 1.38(t, J=7.20Hz, 3H)

c) Synthesis of l-ethyl-2-[2-[(S)-l-((R)-pyrrolidin-2-ylcarbonyl)ρyrro- lidin-2-yl]ethyl]indole-6-carboxamidine:

50mg of the compound II-a obtained in the above b) was treated according to the same procedure as Example 1-n) to obtain 27mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.81(s, 1H), 7.59-7.31(m, 2H), 6.39(s, 1H), 4.21-4.05(m, 3H), 3.68-3.46(m, 3H), 3.10-2.66(m, 4H), 2.27-1.52 (m, 10H), 1.30(t, 3H, J=7.15Hz)

IR(KBr) cm ^"1 : 3480, 1650, 1025

ES-MS : 382(M+1) ⁺

Example 58 : Synthesis of ethyl 2-r(R)-2-rr(S)-2-r2-(fi-amtdino- l-methylindol-2-yl)ethyl3pyrrolidinyl1carbonyl]pyrrolidinyl] acetate

(Compound 84)

a) Synthesis of l-methyl-2-[ ⁽ 2S ⁾ -[l-( ⁽ 2R)-pyrroIidin-2-yl)caι-bonyl]pyr- rolidin-2-yl]ethyl]indole-6-carbonitrile (Compound JQ-b):

300mg of the compound I-b obtained in Example 2-b) was treated according to the same procedure as Examples 57-a) and 57-b) to obtain 200mg of the title compound as a white foam.

1H NMR(CDC1 ₃ , ppm) : δ 7.63(s, III), 7.38(d, 1H), 7.10(d, 1H), 6.30(s, HI ⁾ , 4.25 ⁽ t, 3H), 4.10-4.00(m, 1H), 3.65(s, 311), 3.45-3.20(m, 2H), 2.80-2.70(m, 2H), 2.45-2.30(m, HI), 2.30-2.15(m, III), 2.1- 1.6(m, 1H)

b) Synthesis of methyl 2-[(R)-2-[[(S)-2-[2-(6-cyano-l-methylindol-2-yl) -ethyl]pyrrolidinyl]carbonyl]pyιτolidinyl]acetate:

50.0mg of the compound Il-b obtained in the above a) was dissolved in dichloromethane and then cooled to 0°C. 24 _/ 4 of triethylamine was added thereto, and after 20 minutes, 16/4 of methyl bromoacetate was added dropwise. After 20 minutes, water was added and the reaction solution was extracted two times with dichloromethane. The extracts were combined, dried over MgS0 ₄ and then concentrated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(20:l)] to obtain 28mg of the title compound as a colorless liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.56-7.48(m, 211), 7.32(m, 1H), 6.44(s, 1H), 4.28-4.15(bs, 1H), 3 86(m, 1H), 3.72(s, 3H), 3.67(s, 3H), 3.50(m, 2H), 2.82(m, 4H), 2.ό; -1.60 ⁽ m, 12H)

c) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-methylindol-2- yl)ethyl]ρyrrolidinyl]carbonyl]pyrrolidinyl]acetate:

26mg of the compound obtained in the above b) was dissolved in 15ml of ethanol solution saturated with HCI gas. The reaction solution

was allowed to stand at room temperature for one day and then concentrated under reduced pressure. The remaining HCI was removed for 5 hours by means of a vaccum pump. The dried product was then dissolved in 15ml of ethanol solution saturated with NH ₃ gas. After one day, the reaction solution was concentrated under reduced pressure. The residue was purified with column chromatography [eluent: ethyl acetate/ methanol(l:l)] on NH-DM1020 silica to obtain 12mg of the title compound as a yellowish white solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.94(s, HI), 7.68(d, 1H), 7.47(d, Hi), 6.52(s, HI), 4.30(bs, 1H ⁾ , 3.92(m, HI), 3.80-3.50(m, 711), 3.28(m, III), 3.15-2.90(m, 3H ⁾ , 2.40-1.75(m, 12H), 1.25(t, 3H)

Example 59 : Synthesis of ethyl 2-[(R)-2-r[2-[2-(6-amidino-l- ethylindol-2-yl)ethyl]azetidinyl1carbonyl]pyrrolidinyl1aceta te (Compound 85)

a) Synthesis of methyl (S)-2-azetidine carboxylate:

900mg of azetidine-(S)-2-carboxylic acid was treated according to the same procedure as Example 1-g) to obtain lg of the title compound as a colorless oil.

b) Synthesis of methyl (S)-2-(tert-butoxycarbonyl)-2-azetidine carboxy- late:

lg of the compound obtained in the above a) was treated according to the same procedure as Example 1-h) to obtain 1.8g of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 4.61(m, 1H), 4.02(m, 1H), 3.89(m, 1H), 3.77(s, 3H), 2.50(m, 1H), 2.17(m, 1H), 1.42(s, 9H)

c) Synthesis of tert-butyl (S ⁾ -2-formylazetidine carboxylate:

1.7g of the compound obtained in the above b) was treated according to the same procedure as Example 1-i) to obtain 1.4g of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 4.45(m, HI), 3.92-3.77(m, 211), 3.50(m, 1H),

2.30-2.08(m, 2H), 1.42(s, 9H) ES-MS : 187(M+2) ⁺

d) Synthesis of tert-butyl (S)-2-[2-(6-cyano-l-ethylindol-2-yl)vinyl]aze- tidine carboxylate:

3.8g of 6-cyano-l-ethylindole-2-methyl triphenylphosphonium bromide and 1.3g of tert-butyl (S)-2-formylazetidine carboxylate obtained in the above c) were treated according to the same procedure as Example 1-j) to obtain 1.7g of the title compound as a pale yellow solid.

*II NMR(CDCI ₃ , ppm) : 6 7.60(m, 2H), 7.28(m, 1H), 6.70(s, HI), 6.61(s, HI), 6.55(d, 1H), 4.88(m, 1H), 4.21(q, 2H, J=7.2Hz), 3.92(m, 2H), 2.49(m, 1H), 2.10(m, 1H), 1.43(m, 9H), 1.38(m, 3H)

e) Synthesis of tert-butyl (S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]- azetidine carboxylate:

1.6g of the compound obtained in the above d) was treated according to the same procedure as Example 1-k) to obtain 1.2g of the title compound as a yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.59(m, 2H), 7.28(m, 1H), 6.35(s, 1H), 4.36(m, 1H), 4.14(q, 2H, J=7.2Hz), 3.86(m, 2H), 2.83(m, 2H), 2.33(m, 2H), 2.10(m, 1H), 1.92(m, 1H), 1.46(s, 9H), 1.35(t, 3H, J=7.2Hz)

f) Synthesis of 2-[2-((S)-2-azetidinyl)ethyl]-l-ethylindole-6-carbonitrile:

l.lg of the compound obtained in the above e) was treated according to the same procedure as Example 1-1) to obtain 0.75g of the

title compound as a pale yellow solid.

g) Synthesis of tert-butyl (R)-2-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]azetidinyI]carbonyl]pyrrolidine carboxylate:

730mg of the compound obtained in the above f) was treated according to the same procedure as Example 11-a) to obtain 920mg of the title compound as a yellowish white oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.54(m, 2H), 7.28(m, HI), 6.35(s, HI), 4.54(m, HI), 4.10(m, 311), 3.53(m, HI), 2.93(m, HI), 2.48(m, 1H), 2.30(m, 2H), 2.07(m, 4H), 1.87(m, 2H), 1.44(s, 9H), 1.35(t, 3H, J=7.1Hz)

h) Synthesis of l-etliyl-2-[2-[(S)-l-((R)-pyrrolidin-2-ylcarbonyl)-2-aze- tidinyl]ethyl]indole-6-carbonitrile:

900mg of the compound obtained in the above g) was treated according to the same procedure as Example 1-1) to obtain 660rag of the title compound as a pale yellow solid.

^] II NMR(CDCI ₃ , ppm) : δ 7.56(m, 211), 7.29(m, HI), 6.35(s, 1H), 4.53(m, HI), 4.15(q, 2H, J=7.1Hz), 4.04(m, 1H), 3.63(m, 1H), 3.20(m, HI), 2.88(m, 311), 2.49(m, 2H), 2.02(m, 3H), 1.82(m, 2H), 1.70(m, 1H), 1.36(t, 3H, J=7.1Hz)

i) Synthesis of ethyl 2-[ ⁽ R ⁾ -2-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]azetidinyl]carbonyl]pyrrolidinyl]acetate:

650mg of the compound obtained in the above h) and 0.31ml of ethyl 2 -bromoacetate were treated according to the same procedure as Example 1-m) to obtain 690mg of the title compound as a pale yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.56(m, 2H), 7.29(m, 1H), 6.36(s, 1H), 4.55(m,

1H), 4.16(m, 5H), 3.51 ⁽ m, 2H), 3.20(m, 1H), 2.92-2.75(m, 3H), 2.46(m, 2H), 2.09(m, 2H), 1.92(m, 411), 1.36(t, 3H, J=7.1Hz), 1.25

(m, 3H)

j ⁾ Synthesis of ethyl 2-[ ⁽ 2)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yD- ethyl]azetidinyl]carbonyl]pyιτolidinyl]acetate:

680mg of the compound obtained in the above i) was treated according to the same procedure as Example 1-n) to obtain 90mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.61(m, 1H), 7.53(m, HI), 7.32(m, 1H), 6.33(s, III), 5.08-4.65 ⁽ br, 211 ⁾ , 4.54(m, HI), 4.17(m, 5H), 3.69(m, HI), 3.48(m, 2H), 3.41(m, HI), 3.19(m, HI), 2.88-2.73(m, 3H), 2.45(m, 2H), 2.13(m, 2H), 1.90(m, 4H), 1.36(t, 3H), 1.24(t, 3H) IR(KBr) : 3250, 2900, 1720, 1620, 1460 cm ^{" 1} ES-MS : 454(M+1) ^* , 477(M+Na)

Example 60 : Synthesis of ethyl 2 r(R)-2-rr(S)-2-r2-(6-amidino- l-ethylindol-2-yl)ethvl]nyrrolidinvncarbonyl]pyrrolidinyl]ac etate (Compound 86)

a) Synthesis of methyl 2-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethylindoI-2-yl)- ethyI]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate:

615mg of the compound II-a obtained in Example 57-b) was dissolved in dichloromethane, and 0.39ml of triethylamine was added thereto at room temperature. After 20 minutes, 280mg of methyl bromoacetate was added dropwise thereto. After 20 minutes, water was added and the reaction mixture was extracted three times with dichloromethane. The extracts were combined, dried over MgS0 ₄ and then concentrated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(50:l)] to obtain 406mg of the title compound as a colorless liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.60-7.47(m, 2H), 7.29(s, 1H), 6.44(s, 1H), 4.25 (bs, 1H), 4.20-4.10(m, 2H), 3.83(bs, 1H), 3.67(s, 3H), 3.60-3.43

(m, 2H), 3.25-3.17(m, 1H), 2.88-2.72(m, 3H), 2.38-1.62(m, 12H), 1.36(t, 3H)

b) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindoI-2-yD- ethyl]ρyιτolidinyl]carbonyl]pyrrolidinyl]acetate :

406mg of the compound obtained in the above a) was dissolved in 30ml of ethanol solution saturated with HCI gas. The reaction solution was allowed to stand at room temperature for 2 days and then concentrated under reduced pressure. The remaining HCI was removed for 5 hours by means of a vaccum pump. The dried product was then dissolved in 30ιn6 of ethanol solution saturated with NH ₃ gas. After 2 days, the reaction solution was concentrated under reduced pressure and the residue thereby obtained was purified with column chromatography [eluent: ethyl acetate/methanoKl:!)] on NH-DM1020 silica to obtain 246mg of the title compound as a white foamy solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.88(s, HI), 7.57(d, 1H), 7.40(d, 1H), 6.47(s, 1H), 4.43-4.18(m, 3H), 4.18-4.03(m, 2H), 3.78(m, 1H), 3.74-3.45 (m, 4H), 2.70(m, 211), 2.12-1.60(m, 12H), 1.35(t, 3H), 1.18(t, 3H)

Example 61 : Synthesis of ethyl 2-r(R)-2-fr(S)-2-r2-(6-amidino- l-ethylindol-2-yl)ethyl]piperidyl3carboπyl1pyrrolidinyl1ace tate (Compound 87)

a) Synthesis of tert-butyl (S)-2-(methoxycarbonyl)piperidine carboxylate:

In a 100ml flask, 5g of l-((tert-butyl)oxycarbonyl)piperidine-(S)- 2-carboxylic acid and 3.2g of NaHC0 ₃ were dissolved in 50ml of N,N-dimethylformamide, and 1.8m! of iodomethane was added thereto. The reaction solution was stirred for 8 hours at room temperature. After adding water, the reaction solution was extracted two times with ethyl acetate. The extracts were combined, dried over MgS0 ₄ and evaporated to obtain 4.5g of the title compound as a pale yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 4.94-4.73 ⁽ brs, HI), 3.97(br, 1H), 3.73(s, 3H), 2.95-2.88(br, 1H), 2.21(m, 1H), 1.65(m, 3H), 1.45(br, 9H), 1.25(m, 2H)

b) Synthesis of tert-butyl (S)-2-formylpiperidine carboxylate:

3g of tert-butyl (S)-2-(methoxycarbonyl)piperidine carboxylate obtained in the above a) was treated according to the same procedure as Example 1-i) to obtain 2g of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 9.59(s, HI), 4.58(br, HI), 4.08-3.89(br, 1H), 2.91(br, HI), 2.14(m, III), 1.66(m, 3H), 1.46(br, 9H), 1.25(m, 2H)

c) Synthesis of tert-butyl (S)-2-[2-(6-cyano-l-ethylindol-2-yl)vinyl]- piperidine carboxylate:

4g of 6-cyano-l-ethylindole-2-methyl triphenylphosphonium bromide and 1.9g of tert-butyl (S)-2-formylpiperidinecarboxylate obtained in the above b) were treated according to the same procedure as Example 1-m) to obtain 1.8g of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.60(m, 2H), 7.29(m, 1H), 6.62(m, 1H), 6.43(m, 1H), 6.27(m, 1H), 5.39(m, 1H), 4.18(m, 211), 4.11(m, 1H), 2.99(m, 1H), 1.79(m, 2H), 1.69(m, 2H), 1.48(m, 2H), 1.34(m, 3H), 1.25(m, 9H)

ES-MS : 380(M+1) ⁺

d) Synthesis of tert-butyl (S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]- piperidine carboxylate:

1.5g of the compound obtained in the above c) was treated according to the same procedure as Example 1-n) to obtain 1.5g of the title compound as a brown oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.56(m, 2H), 7.27(m, III), 6.35(s, 1H), 4.41(br,

1H), 4.15(m, 2H), 4.02(m, 1H), 2.68(m, 3H), 2.16(m, 1H), 1.83(m, 1H), 1.67-1.61(br, 6H), 1.45(s, 9H), 1.35(t, 3H, J=7.2Hz)

e) Synthesis of l-ethyl-2-[2-(2-piperidyl)ethyl]indole-6-carbonitrile:

1.5g of the compound obtained in the above d) was treated according to the same procedure as Example 1-1) to obtain l.lg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.47(m, 211), 7.28(m, 1H), 6.3l(s, 1H), 4.63- 4.51(br, 1H), 4.11(q, 2H, J=7.2Hz), 3.18(m, 1H), 2.80(m, 3H), 1.95-1.85(m, 4H), 1.62(m, 1H), 1.40(m, 3H), 1.31(t, 3H, J=7.2Hz) ES-MS : 282(M+1) ⁺

f) Synthesis of tert-butyl (R)-2-[[(2)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]piperidyl]carbonyl]pyrrolidine carboxylate:

l.lg of the compound obtained in the above e) was treated according to the same procedure as Example 11-a) to obtain 860mg of die title compound as a pale brown oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.54(m, 2H), 7.26(m, 1H), 6.33(s, 1H), 4.98(m, 1H), 4.64(m, 1H), 4.16(m, 2H), 3.78(m, 1H), 3.57(m, 1H), 3.47(m, 1H), 3.21(m, 1H), 2.74(m, 2H), 1.88(m, 3H), 1.73-1.64(br, 5H), 1.45(m, 9H), 1.38(m, 3H)

ES-MS : 479(M+1) ⁺

g) Synthesis of l-ethyl-2-[2-[(S)-l-((R)-pyrrolidin-2-ylcarbonyl)-2- piperidyl]ethyl]indole-6-carbonitrile:

670rag of the compound obtained in the above f) was treated according to the same procedure as Example 1-1) to obtain 440mg of the title compound as a pale yellow solid.

h) Synthesis of ethyl 2-[(R ⁾ -2-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)-

ethyl]piperidyl]carbonyl]pyn-olidinyl]acetate:

430mg of the compound obtained in the above g) and 0.19ml of ethyl 2 -bromoacetate were treated according to the same procedure as Example 1-m) to obatin 320mg of the title compound as a pale brown oil.

^] II NMR(CDC1 ₃ , ppm) : δ 7.53(m, 211), 7.29(m, HI), 6.36(s, 1H), 4.98(br, 1H), 4.12(m, 511), 3.92(m, 2H), 3.59(m, 211), 3.23(m, 1H), 3.06(m, 1H), 2.79-2.62(m, 411 ⁾ , 2.16(m, 311), 1.91-1.85(br, 5H), 1.28(m, 3H), 1.21(m, 3H)

ES-MS : 465(M+1) ⁺

i) Synthesis of ethyl 2-[ ⁽ R)-2-[[ ⁽ S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl]piperidyl]carbonyl]pynOlidinyl]acetate :

300mg of the compound obtained in the above h) was treated according to the same procedure as Example 1-n) to obtain 60mg of the title compound as a pale yellow solid.

Η NMR(CDC1 ₃ , ppm) : δ 7.88(s, 1H), 7.52(m, 1H), 7.30(m, HI), 6.32(s, 1H), 4.97(br, Hi), 4.14(m, 411), 3.93(m, 111), 3.26(m, 1H), 3.11(m, 1H), 2.74(m, 2H), 2.18(br, 211), 1.86(m, 411), 1.67(br, 6H), 1.33(m, 3H), 1.23(m, 3H) IR(KBr) : 3430, 2900, 1640 cm ^"1 ES-MS : 482(M+1) ⁺

Example 62 : Synthesis of 2-r(R)-2-rr(S)-2-r2-(6-amidino- l- ethylindol-2-yl)ethyl]pvrrolidinyl]carbonyl]pyrrolidinyl]ace tic acid (Compound 88)

720mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate was treated according to the same procedure as Example 44 to obtain 583mg of the title compound as a white solid.

1H NMR(MeOH-d,, ppm) : δ 7.83(s, 1H), 7.55(d, 1H, J=8.34Hz), 7.25(d, III, J=8.36Hz), 6.36(s, HI), 4.25-4.03(m, 3H), 3.62(m, HI), 3.52-3.38(m, 2H), 3.16-3.03(m, 2H), 2.73(m, 2H), 2.37-1.46(m, 1211), 1.24(t, 3H) ES-MS : 440(M+1) ⁺

IR(KBr) : 3200, 1600 cm ^"1

Example 63 : Synthesis of 2-r(R)-2-rr(S)-2-r2-(6-amidino-l- ethvIindol-2-yl)ethynpiperidyl1carbonynpyιτolidinynacetic acid (Compound 89)

In a 50ml flask, 140mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino- l-ethylindol-2-yl)ethyl]piperidyl]carbonyl]pynOlidinyl]aceta te was dissol¬ ved in 10ml of ethanol, and 0.5ml of 2N NaOH was added thereto. The reaction solution was stirred for 3 hours at room temperature and evaporated under reduced pressure to remove the solvent. The residue was purified with column chromatography [eluent: ethyl acetate/methanol (1:1)] on NH-DM1020 silica to obtain 60mg of the title compound as a yellowish white solid.

1H NMR(MeOH-d4, ppm) : δ 7.87(m, III), 7.59(m, 1H), 7.42(m, 1H), 6.42 (m, 1H), 4.25(m, 2H), 3.64(m, 1H), 3.20(m, 1H), 3.15(m, 1H), 2.78(m, 2H), 2.31(m, 2H), 1.91(br, 2H), 1.77-1.68(br, 6H), 1.36(m, 3H) IR(KBr) : 3400, 3000, 1650, 1600 cm ^"1

ES-MS : 454(M+1)\ 476(M+Na), 498(M+2Na)

Example 64 : Synthesis of ethyl 2-r(R)-2-rr(S)-2-r2-(6-amidino- l-ethylindol-2-yl)ethvn-(S)-4-methylpyrrolidinvncarbonvnpvrr olidi -nyllacetate (Compound 97)

a) Synthesis of (R)-4-hydroxy-l-(benzyloxycarbonyl)pyrrolidine-2-carbo- xylic acid:

In a 1 1 flask, 25g of (R)-4-hydroxy-L-proline was dissolved in

350ιn! of 4N-NaOH solution and then cooled to -20°C. To tlie resulting solution was added dropwise 41ml of benzyl chloroformate, and the reaction mixture was stirred for one hour at -20°C. After the reaction is completed, the reaction solution was adjusted to pl-l 4 with 2N aqueous HCI solution and then extracted two times with ethyl acetate. The organic layers were combined, dried over MgS0 ₄ and evaporated to obtain 31.5g of the title compound as a white solid.

b ⁾ Synthesis of ⁽ S)-4-oxo-l-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid:

In a 500ml flask, 37.2g of Cr0 ₃ and a small quantity of ice-water were mixed and 30.8ml of concentrated sulfuric acid was added dropwise thereto. The resulting solution was diluted with water to prepare 140ml of 8N-chromoic acid. In a 2 I flask, 31.5g of the compound obtained in the above a) was dissolved in 800m£ of acetone, and 140ml of 8N-chromoic acid as prepared above was slowly added thereto. The reaction mixture was stirred for 2 hours at room temperature, and methanol was added dropwise to complete the reaction. The resulting precipitate was filtered and the filtrate was evaporated. The resiude was extracted two times with chloroform. The organic layers were combined, dried over MgS0 ₄ and then evaporated to obtain 28.4g of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 10.0(br, 1H), 7.30(s, 5H), 5.15(m. 211), 4.90(m, 1H), 5.95(m, 2H), 2.95(m, 1H), 2.65(m, 1H) ES-MS : 264(M+1) ⁺

c) Synthesis of phenylmethyl (S)-4,4-dimethoxy-2-(methoxycarbonyl)- pyrrolidine carboxylate:

In a 100ml flask, 4.0g of the compound obtained in the above b) was dissolved in 40ml of methanol, and 1.08m2 of thionyl chloride was slowly added thereto at 0V. The reaction mixture was refluxed for 2 hours with stirring. After the reaction was completed, the reaction

solution was evaporated under reduced pressure. The residue was extracted twice with ethyl acetate. The organic layers were combined, dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n~hexane(l:2)]. The fractions containing the desired product were combined and evaporated to obtain 4.2g of the title compound as a colorless liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.30(m, 5H), 5.30-5.0(m, 2H), 4.45(m, 1H), 3.80 (s, 2H), 3.55(m, 3H), 3.15(s, 611), 2.35(m, HI), 2.20(m, 1H) ES-MS : 324(M+lK

d) Synthesis of methyl (S)-4-oxo-l-(benzyloxycarbonyl)pyrrolidine-2- carboxylate:

In a 100ml flask, 3.0g of the compound obtained in the above c) was dissolved in 90ml of acetone and TsOH ^■ H2O was then added. The reaction mixture was refluxed for 2 hours with stirring. After the reaction was completed, the reaction solution was evaporated under reduced pressure, and the residue was extracted twice with ethyl acetate. The organic layers were combined, dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:2)]. The fractions containing the desired product were combined and evaporated to obtain 3.2g of the title compound as a colorless liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.35(m, 5H), 5.20(m, 2H), 4.80(m, 1H), 4.0(s,

2H), 3.80(d, 3H), 2.95(m, 1H), 2.55(dd, 1H, J=18.85Hz, 2.67Hz)

e) Synthesis of methyl (S)-4-methylene-l-(benzyloxycarbonyl)pyrroIidine carboxylate:

In a 100ml flask, lO.Og of methyltriphenylphosphonium bromide was dissolved in 50ml of tetrahydrofuran, and tBuOK was slowly added thereto. The reaction mixture was stirred for 2 hours. 3.1 lg of the

compound obtained in the above d) which was dissolved in a small quantity of tetrahydrofuran was slowly added dropwise, and the mixture was stin-ed for 2 hours. After the reaction was quenched with a small quantity of water, the reaction solution was evaporated under reduced pressure, and the residue was extracted twice with ethyl ether. The organic layers were combined, dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:5)]. The fractions containing the desired product were combined and evaporated to obtain 1.5g of the title compound as a colorless liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.35(br, 511), 5.20(m, 2H), 5.0(br, 2H), 4.55(m,

HI), 4.15(br, 2H), 3.65(d, 311), 3.0(m, III), 2.65(d, 1H, J=16.0Hz) ES-MS : 276(M+1) ⁺

f) Synthesis of methyl (S)-4-methyl-l-[tert-butoxycarbonyl]pyrrolidine- 2 -carboxylate:

1.5g of the compound obtained in the above e) was treated according to the same procedure as Example 1-k) to obtain 540mg of the yellow liquid product, which was then treated according to the same procedure as Example 1-h) to obtain 887mg of the title compound as a yellow liquid.

1H NMR(CDC1 ₃ , ppm) : δ 4.20(m, 2H), 3.70(br, 3H), 3.0(t, 1H, J=10.05Hz), 2.40(m, 1H), 2.20(m, 1H), 1.50-1.30(br, 9H), 1.20(m, 1H), 1.0(br, 3H) ES-MS : 244(M+1) ⁺

g) Synthesis of tert-butyl (S)-2-formyl-(S)-4-methylpyrrolidine carboxy ^¬ late:

880mg of the compound obtained in the above f) was treated according to the same procedure as Example 1-i) to obtain the title compound as a yellow liquid in a quantitative yield.

h) Synthesis of tert-butyl (S)-2-[2-(6-cyano-l-ethylindol-2-yl)vinyl]-(S) -4-methylpyrrolidine carboxylate:

2.85g of 6-cyano-l-ethylindole-2-ethyl triphenylphosphonium bromide obtained in Example 1-f) and the compound obtained in the above g) were treated according to the same procedure as Example 1-j) to obtain 800mg of the title compound as a yellow fluorescent liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.60(m, 2H), 7.25(m, 1H), 6.65(s, HI), 6.60- 6.40(br, 1H), 6.25(dd, Hi, J=15.63Hz, 6.89Hz), 4.40(m, 1H), 4.20

(q, 2H, J=7.24Hz), 4.0-3.45(m, 2H), 2.45-2.10(m, 2H), 1.60-1.30 (m, 12H), 1.25(m, 1H), 1.05(d, 311, J-6.51Hz)

ES-MS : 380(M+l) ^t

i) Synthesis of tert-butyl (S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]-(S) -4-methylpyrrolidine carboxylate:

800mg of the compound obtained in the above h) was treated according to the same procedure as Example 1-k) to obtain 710mg of the title compound as a colorless liquid.

^J II NMR(CDC1 ₃ , ppm) : δ 7.55(m, 2H), 7.25(m, HI), 6.30(s, 1H), 4.15(q, 2H, J=7.24Hz), 3.90-3.60(m, 2H), 2.70(m, 3H), 2.30(m, 2H), 2.10(m, 1H), 1.85(m, 1H), 1.45(s, 9H), 1.35(t, 3H, J=7.24Hz), 1.25 ( _m , 1H), 1.10(d, 3H, J=6.46Hz)

ES-MS : 382(M+D ^*

j) Synthesis of l-ethyl-2-[2-[(S)-((S)-4-methyl)pyrrolidin-2-yl]ethyl]- i ndole - 6 - carbonitrile:

430mg of the compound obtained in the above i) was treated according to the same procedure as Example 1-1) to obtain 401rag of the title compound as a pale yellow solid.

1H NMR(CDCI ₃ , ppm) : δ 7.45(m, 2H), 7.25(m, 1H), 6.25(s, 1H), 4.05(q,

211, J=7.24Hz), 3.60(m, 2H), 3.35(m, 1H), 2.90-2.65(m, 3H), 2.40-2.20(m, 3H), 2.15(m, 1H), 1.25(t, 3H, J=7.24Hz), 1.10(d, 311, J=6.46Hz) ES-MS : 282(M+D ^*

k) Synthesis of tert-butyl (R)-2-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]-(S)-4-methylpyrrolidinyl]carbonyl]pyιτolidine carboxylate:

400mg of the compound obtained in the above j) was treated according to the same procedure as Example 11-a) to obtain 370mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.55(m, 211), 7.25(m, III), 6.30(m, HI), 4.40(m, HI), 4.10(m, 211), 3.60(m, 2H), 3.40(m, 1H), 3.10(m, 1H), 2.80(m, 3H), 2.60-1.80(m, 6H), 1.80-1.10(m, 1311, J=6.46Hz), 1.05(d, 3H,

J=6.46Hz)

ES-MS : 479(M+D ^*

1) Synthesis of l-ethyl-2-[2-[(S)-4-methyl-l-((R)-pyrroIidin-2-ylcarbo- nyl)pyrroIidin-(S)-2-yl]ethyl]indole-6-carbonitrile:

270mg of the compound obtained in the above k) was treated according to the same procedure as Example 1-1) to obtain 220mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.55(m, 2H), 7.25(m, 1H), 6.40(s, 1H), 4.15(q, 2H, J=7.24Hz), 3.80(m, 1H), 3.25(m, 1H), 3.0(m, 2H), 2.80(m, 2H), 2.50(m, 1H), 2.20(m, 2H), 2.0-1.60(m, 4H), 1.50-1.20(m, 4H), 1.05 (d, 3H, J=6.46Hz) ES-MS : 379(M+l) ^f

m) Synthesis of l-ethyl-2-[2-[(S)-4-methyl- l-((R)-ρyrrolidin-2-ylcarbo -nyl)pyrrolidin-(S)-2-yl]ethyl]indole-6-carbonitrile:

150mg of the compound obtained in the above 1) was treated

according to the same procedure as Example 1-m) to obtain 247mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.55(m, 211), 7.25(m, 1H), 6.40(s, 1H), 4.20-4.00 (m, 4H), 3.95-3.75(m, 211), 3.50(q, 2H), 3.20(m, 1H), 3.0-2.70(m,

411), 2.60(m, 1H), 2.35(m, HI), 2.20-1.70(m, 7H), 1.35(t, 3H,

J=7.22Hz), 1.25(m, 411), 1.10(d, 311, J=6.43Hz) ES-MS : 466(M+1) ⁺

n) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl]-(S)-4-methylpyrrolidinyl]carbonyl]ρyrrolidinyl]aceta te :

240mg of the compound obtained in the above m) was treated according to the same procedure as Example 1-n) to obtain 71mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ ) : δ 7.80(s, HI), 7.50(d, HI), 7.40(d, HI), 6.40(s, 1H),

4.30-4.10(m, 4H), 3.90-3.70(m, 211), 3.50(q, 2H), 3.20(m, 1H),

3.0-2.65(m, 411), 2.60(m, 1H), 2.30(m, Hi), 2.20- 1.70(m, 7H), 1.35(t, 3H, J-7.08Hz), 1.25(t, 311, J=7.11Hz), 1.05(d, 311,

J=6.41Hz)

ES-MS : 482(M+lK

IR(KBr) : 3100, 2950, 1750, 1650 cm ^"1

Examnlπ 65 : Synthesis of 2-r(R)-2-rr(S)-2-r2-(6-amidino-l- ethvIindol-2-yl)ethvn-(S ⁾ -4-methvlpvrrolidinvncarbonvnpyrrolidin- yllacetic acid (Compound 98)

42mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl]-(S)-4-methyIpyrrolidinyl]carbonyl]pyrrolidinyl]acetat e obtained in Example 64 was treated according to the same procedure as Example 44 to obtain 27mg of the title compound as a pale yellow solid.

1H NMR(CD ₃ OD, ppm) : δ 7.70(s, 1H), 7.40(d, 1H), 7.20(d, 1H), 6.25(s, HI), 4.20-3.80(m, 311), 3.65(m, 1H), 3.15-2.50(m, 6H), 2.50-1.40

(m, 9H), 1.15(m, 311), 0.95(m, 3H) ES-MS : 454(M+1) ⁺ IR(KBr) : 3200, 2950, 2850, 1650 cm ^"1

Example 66 : S ^y nthesis of ethyl 2-r ⁽ R ⁾ -2-rr(S)-2-f2-(6-amidino l -ethylindol-2-yl)ethvn- ⁽ S ⁾ -4-methoxvnvrrolidinvncarbonvnpvrro- lidinyllacetate (Compound 99)

a) Synthesis of (4R ⁾ -4-hydroxy-l- ⁽ benzyloxycarbonyl)pyrrolidine-(S)-2- carboxy lie acid:

In a 250ml flask, lOg of (R)-4-hydroxypyrrolidine-(S)-2- carboxylic acid and 140ml of 4N NaOH were introduced and cooled to -20 °C, and 17m£ of benzyl chloroformate was slowly added. The reaction solution was stirred for one hour at -20 ^° C and extracted with ethyl ether and water. The ether layer was removed and the aqueous layer was acidified with 2N aqueous HCI solution and then extracted twice with ethyl acetate. The extracts were combined, dried over MgS0 ₄ and then evaporated to obtain 17.3g of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.30(m, 511), 5.17(m, 211), 4.52(m, 111), 4.45(m,

HI), 3.60(m, 2H), 2.24(m, 2H)

b) Synthesis of 4-oxo- l-(benzyloxycarbonyl)pyrrolidine-(S)-2-carboxylic acid:

In a 1 1 flask, 16g of the compound obtained in the above a) was dissolved in 600ml of acetone, and 64ml of 8N chromic acid was then slowly added at -10t:. The reaction mixture was stirred for 4 hours at -10"C , and 40ml of methanol was added thereto. The reaction solution was filtered. To the filtrate was added water, and die mixture was extracted twice with chloroform. The extracts were combined, dried over MgS0 ₄ and evaporated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(10:l)] to obtain 12g of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.34(s, 5H), 5.16(m, 1H), 5.09(m, 1H), 4.69(m,

1H), 3.92(s, 2H), 2.87(m, Hi), 2.64(m, 1H) ES-MS : 264(M+1) ⁺

c) Synthesis of (S)-4-hydroxy-l-(benzyIoxycarbonyl)pyrrolidine-(S)-2- carboxylic acid:

In a 250ml flask, 4.6g of the compound obtained in the above b) was dissolved in 164m6 of methanol, and 2.6g of NaBH ₄ dissolved in 11ml of water was slowly added at -10°C. The reaction solution was stirred for about 2.5 hours at -10 ^° C to OV and then evaporated to remove methanol. About 100ml of 2N aqueous NaOH solution was added to the residue and then stirred for 30 minutes at room temperature. The reaction solution was cooled to 0°C, acidified with hydrochloric acid and then extracted twice with ethyl acetate. The extracts were combined, dried over MgS0 ₄ and evaporated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(3:l)] to obtain 3.2g of the title compound as a yellowish white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.30(m, 511), 6.90(br, HI), 5.12(m, 2H), 4.43(m,

2H), 3.64(m, 1H), 3.54(m, HI), 2.21(br, 2H)

ES-MS : 266(M+1) ⁺

d) Synthesis of (S)-4-methoxy-l-(benzyloxycarbonyl)pyrrolidine-(S)-2- carboxylic acid:

In a 100ml flask, 3g of the compound obtained in the above c) was dissolved in 40ml of tetrahydrofuran, and 0.95g of 60% NaH was slowly added. The reaction solution was stirred for one hour at room temperature, and 1.48ml of iodomethane was added. The reaction mixture was stirred for 3 hours at refluxing temperature and then for 10 hours at room temperature, and evaporated. To the residue was added water, and the mixture was acidified with 2N HCI and extracted twice with dichloromethane. The extracts were combined, dried over MgS0 ₄

and then evaporated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(3:l)] to obtain 3.2g of the title compound as a pale brown oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.31(m, 5H), 5.17(m, 211), 4.46(m, 1H), 3.94(m, 1H), 3.64(m, 211), 3.26(s, 3H), 2.45-2.38(m, 1H), 2.22(m, 1H) ES-MS : 280(M+1)\ 302(M+Na)

e) Synthesis of phenylmethyl (S)-4-methoxy-(S)-2-(methoxycarbonyl)- pyrrolidine carboxylate:

In a 100ml flask, 13ml of methanol was introduced and 0.93ml of thionyl chloride was slowly added thereto at OV . 3.1g of the compound obtained in the above d) which was dissolved in 11ml of methanol was added thereto, and the reaction mixture was stirred for 2 hours at refluxing temperature and then evaporated under reduced pressure. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate (3:1)] to obtain 2.4g of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.31(m, 511), 5.17(m, 2H), 4.45(m, 111), 3.93(m,

HI), 3.72(m, 211), 3.67(s, 3H), 3.25(s, 311), 2.32-2.22(m, 211) ES-MS : 294(M+ D ^*

f) Synthesis of phenylmethyl (S)-2-formyl-(S)-4-methoxypyrrolidine carboxylate:

2.3g of the compound obtained in the above e) was treated according to the same procedure as Example 1-i) to obtain 1.4g of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.33(m, 5H), 5.16(m, 2H), 4.19(m, 1H), 3.92(m, Hi), 3.73(m, HI), 3.52(m, HI), 3.22(s, 311), 2.38(m, 1H), 2.14(m, HI) ES-MS : 264(M+D ^*

g) Synthesis of phenylmethyl (S)-2-[2-(6-cyano-l-ethylindol-2-yl)vinyl] - (S ) -4-methoxypyιτolidine carboxylate:

2.3g of 6-cyano-l-ethylindoIe-2-methyl triphenylphosphonium bromide and 1.2g of phenylmethyl 2-formyl-4-methoxypyrrolidine carbo- xylate were reacted according to the same procedure as Example 1-j) to obtain 1.7g of the title compound as a yellow solid.

^J II NMR(CDC1 ₃ , ppm) : δ 7.58(br, 211), 7.36-7.21(br, 611), 6.64(m, Hi), 6.47(m, HI), 5.14(m, 211), 4.21 (m, HI), 4.00(m, 211), 3.68-3.58(br,

2H), 3.34(s, 311), 2.34(m, 111), 1.23- 1.20(m, 411) ES-MS : 452(M+Na)

h) Synthesis of l-ethyl-2-[2-[ ⁽ S ⁾ - ⁽⁽ S ⁾ -4-methoxy)ρyrrolidin-2-yl]ethyl]- indole-6-carbonitrile:

1.6g of the compound obtained in the above g) was treated according to the same procedure as Example 1 -k) to obtain 500mg of the title compound as a brown oil.

'II NMR(CDC1 ₃ , ppm) : δ 7.58(m, 211), 7.27(m, III), 6.30(s, HI), 4.16(q, 211, J=7.1IIz), 3.91(m, 111), 3.28(s, 311), 3.15(m, 211), 2.92-2.78(m, 411), 2.24(m, 111), 2.02(m, 211), 1.34(t, 311, J=7.1Hz)

ES-MS : 298(M+D ^*

i) Synthesis of tert-butyl ⁽ R ⁾ -2-[[(S)-2-[2-(6-cyano- l-ethylindol-2-yD- ethy 1] - ( S ) -4 -methoxypyrrolidinyl]carbonyl]pyrrolidine carboxylate:

450mg of the compound obtained in the above h) was treated according to the same procedure as Example J l -a) ro obtain 590mg of the title compound as a pale brown oil.

'II NMR(CDC1.,, ppm) : δ 7.55(m, 211), 7.28(m, 111), 6.39(m, Hi), 4.37(m, Hi), 4.16(m, 2H), 4.03(m, III), 3.62(m, 111), 3.32(s, 311), 2.82(m,

211), 2.12- 1.96(br, 411). 1.85 ⁽ m. 211), 1.4()(m, 911), 1.33(m, 311)

j) Synthesis of l-ethyl-2-[2-[(S ⁾ -4-methoxy-l-((R)-ρyιτolidin-2-ylcar- bonyl ⁾ pyιτolidin-(S)-2-yl]ethyl]indole-6-carbonitrile:

580mg of the compound obtained in the above i) was treated according to the same procedure as Example 1-1) to obtain 450mg of the title compound as a pale yellow solid.

1H NMR ⁽ CDC1 ₃ , ppm) : δ 7.56(m, 211), 7.32(m, III), 6.42(s, 111), 4.28(m,

III), 4.15(m, 211), 4.01(m, HI), 3.75(m, Hi), 3.65(m, III), 3.33(s, 311), 3.2HH1, 1H), 2.80 ⁽ m, 211), 2.45(m, 1H), 2.10(m, 211), 1.99-1.79(br, 711), 1.36(m, 311)

k ⁾ Synthesis of ethyl 2-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-cyano-l-ethylindol-2-yl)- ethyl]- ⁽ S ⁾ -4-methoxypyιτolidinyl]carbonyl]pyπOlidinyl]acetate :

440mg of the compound obtained in the above j) and 0.19ιnC of ethyl 2 -bromoacetate were treated according to the same procedure as Example 1-m) to obtain 380mg of the title compound as a pale yellow oil.

ES-MS : 48101+1) ^*

1) Synthesis of ethyl 2-[ ⁽ R)-2-[[(S)-2-[2- ⁽ 6-amidino-l -etlιylindol-2-yl)- ethyl]-(S)-4-methoxypyrrolidinyl]carbonyl]pyπOlidinyl]aceta te:

360mg of the compound obtained in the above k) was treated according to the same procedure as Example 1-n) to obtain 90mg of the title compound as a pale yellow solid.

IR(KBr) : 3300, 3000. 1750, 1640 cm ^"1 ES-MS : 498(M+D ^"

Example 67 : Synthesis of ethvl-2-r(R)-2-rr(S)-2~ [2- (6-amidino- l-ethylindol-2-yl)ethyl]pyrτolidinyl]carhonynpyrrolidinyl]p ropionate (Compound 109)

a) Synthesis of ethyl-2-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]pyiTolidinyl]carbonyl]pyrrolidinyl]propionate:

300mg ⁽ 0.823 mmole ⁾ of l-etlιyl-2-[2-[ ⁽ S ⁾ -l-[((R)-pyrrolidin-2- 5 yl)carbonyl]pyiTolidin-2-yl]ethyl]indole-6-carbonitrile was dissolved in 15 mt of acetonitrile, and 0.29 in £(1.646 mmole) of diisopropylethylamine and 0.22ml .(1.646 mmole) of ethyl 2-bromopropionate were added thereto. The reaction mixture was heated to 70 V , stirred for 4 hours, and then concentrated under reduced pressure. The residue was purified with 10 silica gel column chromatography [eluent: dichloromethane/methanol(20:l)] to obtain 310mg of the title compound as a pale yellow oil.

ES-MS : 464 (M+D ^*

1H NMR(CDC1 ₃ , ppm ⁾ • ^' δ 7.61-7.56 ⁽ m, 211), 7.34-7.28(m, HI), 6.46(s, HI), 1 ₅ 4.31(br, HI), 4.21-4.14(m, 411), 3.80-3.75(m, 1H), 3.61-3.53 ⁽ m,

311), 3.23-3.19(m, HI), 2.86-2.81(m, 311), 2.34-2.31(m, 111), 2.01- 1.77(m, 911), 1.42-1.36(m, 311), 1.32- 1.22(m, 611)

b) Synthesis of ethyl-2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2- 2o yl)ethyl]pyrrolidinyl]carbonyl]pynOlidinyl]propionate:

310mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 220mg of the title compound as a pale yellow foam.

25 ^l H NMR(MeOH-d ₄ , ppm) : δ 7.93-7.89(m, Hi), 7.64-7.58(m, 1H), 7.48- 7.42 ⁽ m, HI), 6.46-6.42 ⁽ m, HI), 4.34-4.30(m, 311), 4.18-4.14(m, 211), 3.91-3.81 ⁽ m, 1H), 3.65-3.61(m, 311), 3.1δ-3.11(m, Hi), 2.88-2.81(m, 311), 2.21-1.85(m, 1011), 1.42-1.27(m, 911)

IR(KBr) : 3300. 2980, 1720. 1680, 1640, 1540 cm ^{' 1}

30

ES-MS : 482(M+1)'

Example 68 : Synthesis of ethyl 2-r(R)-2- [r(S)-2-[2-(6-amidino- l-ethylindol-2-yl)ethyl]pvrrolidinvncarboπyl]ρyrrolidinyl] butanoate _or (Compound 110)

a) Synthesis of ethyl 2-[(R)-2-[[ ⁽ S ⁾ -2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]ρyrrolidinyl]butanoate:

lOOmg of the compound II-a obtained in Example 57-b) and 80 _/ 4 of ethyl 2 -bromoacetate were reacted according to the same procedure as Example 45-b) to obtain 88mg of the title compound.

'Ii NxMR(CDCl ₃ , ppm,) : δ 7.58(m, 211), 7.27(m, HI), 6.40(d, HI), 4.38(m, HI), 4.15(m, 411), 3.69(m, 111), 3.54(m. 211), 3.30-3.10(m, 111), 2.82 ⁽ m, 311 ⁾ , 2.30 ⁽ m, HI), 2.18-1.55(m, 1211), 1.42-1.17(m, 611),

0.89(m, 311)

b) Synthesis of ethyl 2-[ ⁽ R ⁾ -2-[[(S)-2-[2-(6-amidino- l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]butanoate:

88ιng of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 24mg of the title compound.

'II NMR(MeOII-d,, ppm) : δ 8.00-6.24(m, 411), 4.24(m, 5H), 3.64(m, HI), 3.52(m, 211), 3.41 -3.10(m, 311), 2.83(m, 511), 2.31(m, HI), 2.18- 1.54(m, 811), 1.44-1.10(m, 611), 0.84(m, 311)

Example 69 : Synthesis of ethyl 2-r(R)-2-rr(S)-2-r2-(6-amidino- l-ethylindol-2-yl)ethyl3pyrrolidinyl]carbonyl]pyrrolidinyl3h exanoate (Compound 111)

a) Synthesis of ethyl 2-[ ⁽ R ⁾ -2-[[ ⁽ S)-2-[2- ⁽ 6-cyano- l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]hexanoate:

135mg of the compound II-a obtained in Example 57-b) and 155 _/ 4 of ethyl 2 -bromoacetate were reacted according to the same procedure as

Example 45-b) to obtain 112mg of the title compound.

Η NMR(CDC1..„ ppm ) : δ 7.58(m. 211), 7.28(d. III). 6.45 ⁽ d, III, J=

8.20Hz), 4.30-4.00(m, 611), 3.71-3.31(m, 311), 3.25-3.05(m, 111), 2.82(m, 311), 2.45-2.20(m, HI), 2.13-1.55(m, 1111), 1.38-1.12(m, 10H), 0.85(t, 211), 0.75(t, Hi)

5 b) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]hexanoate:

112mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 73mg of the 10 title compound.

^] H NMR(MeOH-d ₄ , ppm) : δ 7.82(s, III), 7.62(d, HI, J=11.71Hz), 7.34(d, HI, J=7.80Hz), 6.46(d, HI, J=11.14IIz), 4.40-4.05(m, 611), 3.75- 3.40(m, 3H), 3.30-3.05(m, HI), 2.99-2.66(m, 311), 2.50-2.30(m, 15 HI), 2.13-1.52(m, 1111), 1.50-1.10(m. 10H), 0.90-0.70(m, 311)

ES-MS : 524(M+l) ^f

Examnle 70 : Synthesis of ethyl-2-[(R)-2-IT(S)-2-r2-(6-ami- dino- l-ethylindol-2-yl)ethyl]pyrrolidinyl]carhonyllpyrrolidinyn-2 - 20 phenylacctate (Compound 112)

a ⁾ Synthesis of ethyl-2-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-cyano-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]-2-phenylacetate:

25 300mg of the compound II-a obtained in Example 57-b) ad 300mg of ethyl 2-bromophenyl acetate were reacted according to the same procedure as Example 45-b) to obtain 300mg of the title compound as a pale yellow foam.

30 'II NMR(CDC1 ₃ , ppm) : δ 7.63-7.57(m. 211), 7.51-7.48(m, 211), 7.34-7.29 ⁽ m, 411 ⁾ , 6.43 ⁽ s, HI ⁾ , 4.65 ⁽ s, HI), 4.24-4.19(m, 3H), 4.11-4.04(m, 311 ⁾ , 3.45-3.41 ⁽ m, 211 ⁾ , 3.06-3.03(m, HI), 2.84-2.71(m, 311), 2.30-2.20(m, 211), 1.98-1.82(m, 811), 1.42(t, J=7.20Hz, 311), 1.08(t, J= 7.10Hz, 311)

Jϋ ES -MS : 526(M+1) '

b) Synthesis of ethyl-2-[ ⁽ R ⁾ -2-[[(S ⁾ -2-[2- ⁽ 6-amidino-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]caι-bonyl]pyrrolidinyl]-2-phenylacetate:

130mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 80mg of the title compound as a pale yellow solid.

1H NMR ⁽ MeOH-d ₄ , ppm ⁾ : δ 8.04-7.95(m, 111), 7.78-7.67(m, 111), 7.50- 7.45(m, 211), 7.31-7.24 ⁽ m, 411), 6.51(m, HI), 4.52(m, 111), 4.37-

10 4.34 ⁽ m, 211), 4.09-4.04 ⁽ m, 311), 3.49-3.44(m, 111), 3.20-3.09(m, 211 ⁾ , 2.98-2.65 ⁽ m, 411 ⁾ , 2.20- 1.75(m, 10H), 1.47- 1.42(m, 311), 1.13-1.06(m, 311)

ES-MS : 544(M+l) ^f

15 Example 71 : Synthesis of ethyl 2-r(R)-2- rr(S)-2-r2-(β-amidino-l - ethylindol-2-yl)ethyl]-pyrrolidinyl]carbonyl1-ρyrrolidinvl3 -2-(3- bromojz4_- methoxyphenvDacetate (Compound 113)

a) Synthesis of ethyl-2-biOmo-2-(3-bromo-4-methoxyphenyl)acetate:

20

4.3g(0.0259 mole) of 4-methoxyphenylacetic acid was dissolved in 10ml of thionyl chloride, and the resulting solution was stirred for 18 hours at 70 ^° C and then cooled to room temperature. To the reaction solution was added 50m£ of carbon tetrachloride and then added 5.54g

25 (0.0331 mole) of N-bromosuccinimide and 5 drops of 48% aqueous IIBr solution. The resulting mixture was stirred for 4 hours at refluxing temperature and filtered to remove the unsoluble materials. 50ml of ethanol was added to the filtrate and the mixture was stirred for 30 minutes and then evaporated under reduced pressure to remove the solvent. The residue was purified with silica gel column

30 chromatography [eluent: ethyl acetate/n-hexane( l:9)] to obtain l.δg of the title compound as a yellow oil.

^] II NMR(CDC1 ₃ , ppm) : δ 7.72(d, J=2.23Hz, Hi), 7.45(dd, HI, J=2.22Hz,

SJ 8.50Hz), 6.93(d, III, J=8.50IIz), 5.28(s,HI), 4.32-4.25 ⁽ m,2H), 3.93

(s, 311), 1.32(t, 311, J=7.00Hz)

b) Synthesis of ethyl 2-[ ⁽ R ⁾ -2-[[ ⁽ S)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]pyιτolidinyl]caι-bonyl]ρyπOlidinyl]-2- ⁽ 3-bromo-4-methoxyphenyI) -acetate:

lOOmg of the compound II-a obtained in Example 57-b) and 80mg of the compound obtained in the above a) were reacted according to the same procedure as Example 1-m) to obtain 170mg of the title compound as a pale yellow foam.

^J II NMR(CDC1 ₃ , ppm) : δ 7.69-7.57(m, 311), 7.40-7.29 ⁽ m, 211), 6.82(m, Hi), 6.44(m, HI), 4.60(m, HI), 4.24-4.21(m, 311), 4.09-3.98(m, 311), 3.78(m, 311), 3.41 -3.37(m, 211), 3.24-3.05(m, 211), 2.81-2.75 (m, 211), 2.21-1.72(m, 1011), 1.4δ-1.39(m, 3H), 1.24-1.08(m, 311)

c) Synthesis of ethyl-2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]caι bonyl]pyπOlidinyl]-2-(3-bromo-4-methoxyplιenyl)- acetate:

170mg of the compound obtained in the above b) was treated according to the same procedure as Example 1 -n) to obtain 70mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.85-7.75(m, 1H), 7.57-7.42(m, 211), 7.33- 7.29(m, 211), 6.96-6.78(m, HI), 6.36-6.33(m, Hi), 4.52(s, 1H), 4.21-4.18(m, 311), 4.04-3.86(m, 311), 3.73(m, 311), 3.22-3.02(m, 211), 2.91-2.78(m, 2H ⁾ , 2.65-2.60(m, 2H), 2.10- 1.65(m, 1011), 1.33- 1.25(m, 311), 1.09-1.00(m, 3H) ES-MS : 653(M+lT

IR(KBr) : 3380, 3020, 1740, 1635, 1540 cm ^{" 1}

Example 72 : Synthesis of l-ethyl-2- r2- r(S)- l-[f(R)- l- (carbamo- ylmethyl)pyrrolidin-2-yl]carbonyl]pyrrolidin-2-yl]ethyl]indo le-β- carboxamidine (Compound 114)

681m ^g of methyl 2-[ ⁽ R ⁾ -2-[[ ⁽ S)-2-[2-(6-cyano-l-ethylindol-2- yl)ethyl]pyrrolidinyl]carbonyl]pyriOlidinyI]acetate was dissolved in 25ιnl of ethanol solution saturated with HCI gas. The resulting solution was allowed to stand for one day at room temperature and then concentrated under reduced pressure. The remaining HCI was removed for 5 hours by means of a vaccum pump- The dried product was dissolved in 25 mP of ethanol solution saturated with NII ₃ gas, and the resulting solution was allowed to stand for 3 days at room temperature and then concentrated. The residue was purified with column chromatography [eluent: ethyl acetate/ethanoldα)] on NH -DM1020 silica to obtain 553mg of the title compound as a colorless solid.

1H NMR(MeOH-dι, ppm) : δ 7.79(s, III), 7.53(d, HI, J=8.42Hz), 7.32(d, 111, J=8.27Hz), 6.40(s, HI), 4.18(m, 311), 3.57(m, III), 3.46(m, 411), 2.84(m, 211), 2.51- 1.7(m, 1211), 1.28(t, 3H)

ES-MS : 439(M+D ^*

Example 73 : Synthesis of l-ethvl-2- r2- r(S)- l-lT(R)- l- r(N-cvclo- propylcarbamoyl)methyl]pyrrolidin-2-yl]carbonyllρyrroli din-2-yl] ^~ _L ethyl]indole-6-carboxamidine (Compound 115)

250mg of the compound II-a obtained in Example 57-b) and 92mg of N-cyclopropyl-2-chloroethanamide were reacted under the same conditions as Example 42 to obtain 125mg of the pale yellow solid product, which was then treated according to the same procedure as Example 1-n) to obtain 93mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.13(d, HI, J=3.75Hz), 7.88(s, Hi), 7.61 -7.38(m, 211), 6.40(s, HI), 4.27-4.13(m, 311), 3.56-3.08(m, 311), 2.90(s, 2H), 2.82U, 211, J=6.91IIz), 2.72-2.65(m, HI ⁾ , 2.50-1.67 ⁽ m, 1211), 1.35

(t, 311, J=7.20Hz), 0.88-0.50(m, 4H) ES-MS : 479(M+l) ^f

Example 74 : Synthesis of ethyl (S )-2-r2-r(R)-2 ^~ rr(S)-2-[2-(6- amidino- l-ethylindol-2-yl)ethvl]pvrrolidinyllcarbonyll ^p jLrroli_diny:l]r

acetvlaminolpropanoate (Compound 116)

250mg of the compound II-a obtained in Example 57-b) and 133mg of ethyl-(S)-2-(2-chloroacetylamino)propa- noate were reacted under the same conditions as Example 42 to obtain 260mg of the pale yellow solid product, which was then treated according to the same procedure as Example 1 -n) to obtain 96mg of the title compound as a pale yellow solid.

ES-MS : 539(M+l) ^f

Example 75 : S ^y nthesis of l-ethyl-2-r2-r(S ⁾ - l-IT(R)-.1 -n -carba¬ moyl -3 -hydroxypropyl)pyrrolidin-2-yl3carbonyl1pyrroIidin-2-vI1- eth y 11indole-6 carboxamidine (Compound 117)

a) Synthesis of l-ethyl-2-[2-[(S)- l -[[(R)-l-(2-oxo-3-oxolanyl)pynOlidin -2-yl]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carbonitrile:

700ιng of the compound II-a obtained in Example 57-b) and 500mg of a -bromo- 7 -butyrolactone were reacted according to the same procedure as Example 45-b) to obtain 650mg of the title compound as a white foam.

^] II NMR(CDC1 ₃ , ppm ⁾ = δ 7.58-7.53 ⁽ m, 211 ⁾ , 7.30-7.26(m, HI), 6.46(s, HI),

4.39-4.34(m, HI), 4.26(br, 1H), 4.21-4.13(m, 311), 3.86-3.63(m, 311), 3.51-3.45(m, 1H), 3.30-3.22(m, 1H), 2.96-2.90(m, HI), 2.83-

2.79(m, 211), 2.39-2.11(m, 411), 2.03-1.96(m, 411), 1.84-1.66(m,

411), 1.35(t, J=7.30IIz, 311)

ES-MS : 449(M+1) ¹

b ⁾ Synthesis of l-etlιyl-2-[2-[ ⁽ S ⁾ - l-[[ ⁽ R ⁾ - J - ' l- _C arbamoyl-3-hydroxy- propyl)pyιτolidin-2-yl]carbonyl]pyrrolidin-2-yl]ethyl]indo le-6-carboχ- amidine:

4δ0mg of the compound obtained in the above a) was treated according Lo the same procedure as Example l ^~ n) to obtain 370mg of the

title compound as a white solid.

1H NMR(MeOH-d4, ppm) : δ 7.85-7.79(m, 211), 7.56-7.52(m, HI), 6.41(m, HI), 4.23-4.18(m, 211), 4.13-4.10(m, HI), 3.64-3.59(m, III), 3.50- 3.31(m, 4H), 3.07-2.87(m, 111), 2.81-2.76(m, 2H), 2.68-2.61(m,

1H), 2.24-2.08(m, 211), 1.92-1.71(m, 1011), 1.30(t, J=7.05Hz, 3H)

ES-MS : 483(M+1) ⁺

IR(KBr) : 3340, 3220, 2980, 1680, 1630, 1540 cm ^"1

Example 76 : S ^y nthesis of 2-r(R)-2-rr(S)-2-r2-(6-amidino-l - ethylindol-2-yl ⁾ eth ^y l3 ^py rrolidin ^y l]carbonvnpyrrolidinyl]-4-hvdroxy- butanoic acid (Compound 118)

250mg of l-ethyl-2-[2-[(S ⁾ -l-[[ ⁽ R)- l-(l-carbamoyl-3-hydroxy- propyl)pyrrolidin-2-yl]carbonyI]pyrrolidin-2-yl]ethyl]indole -6-carboxami- dine was treated according to the same procedure as Example 44 to obtain 180mg of the title compound as a white solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.80-7.74(m, 1H), 7.56-7.48(m, 1H), 7.32- 7.26(m, HI), 6.39-6.34(m, HI), 4.31-4.03(m, 4H), 3.69-3.64(m,

HI), 3.56-3.29(m, 411), 3.04-2.96(m, 1H), 2.78(br, 311), 2.20(br,

HI), 2.01- 1.56(m, 11H), 1.29-1.24(m, 3H) ES-MS : 484(M+D ^* IR(KBr) : 3400, 3000, 1630, 1580 cm ^"1

Example 77 : Synthesis of l-[(R)-2-IT(S)-2-r2-(6-amiHinn- 1 -ethyl -indol-2-yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]ethane- 1.2- dicarboxylic acid (Compound 123)

a) Synthesis of diethyl-2-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]pyrroIidinyl]carbonyl]pyrrolidinyl]butane-l,4-dioate:

230mg(0.525 mmole) of ethyl-2-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethyl

-indol-2-yl)ethyl]pyrrolidinyl]carbonyl]pyrroIidinyl]acet ate was dissol- ved in 15ml of tetrahydrofuran and then cooled to -78°C . 0.79ml of lithium

bis(trimethylsilyl)amide (l.OM solution in tetrahydrofuran) was added dropwise thereto, and the reaction mixture was stirred for 30 minutes. 0.09m!(0.787 mmole) of ethyl bromoacetate diluted with 5ml of tetrahydrofuran was added dropwise thereto, and the resulting mixture was stirred for one hour. After water was added, the reaction solution thereby obtained was extracted with dichloromethane. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(40:l)] to obtain 180mg (Yield : 63.9%) of the title compound as a pale yellow foam.

1H NMR(CDC1 ₃ , ppm) : δ 7.61-7.51(m, 211), 7.27(dd, HI, J=1.30Hz, 8.10Hz), 6.46(s, HI), 4.33(br, HI), 4.21-4.06(m, 611), 3.95-3.91(m, 111), 3.84-3.80(m, HI), 3.67-3.63(m, HI), 3.49-3.45(m, HI), 3.17-3.11(m, 111), 2.99-2.91(m, Hi), 2.82-2.74(m, 311), 2.60-2.55

(m, Hi), 2.38-2.31(m, HI), 2.02-1.95(m, 511), 1.81-1.74(m, 411), 1.38- 1.17(m, 911) ES-MS : 537(M+l) ^f

b) Synthesis of l-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethyIindol-2-yl)ethyl]- pyrrolidinyl]carbonyl]pyrroIidinyl]ethane-l,2-dicarboxylic acid:

400mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 180mg of diethyl 2-[(2)-2-[[(2)-2-[2-(6-amidino-l-ethylindole-2-yl)ethyl]pyrr oIi- dinyl]carbonyl]pyrrolidinyl]butane-l,4-dioate, which was then treated according to the same procedure as Example 44 to obtain 120mg of the title compound as white solid.

1H NMR(MeOH-d ₄ ) : δ 7.79(s, 1H). 7.51-7.47(m, 1H), 7.32-7.29(m, 111), 6.42(s, 1H), 4.57(br, 1H), 4.23-4.19(m, 2H), 3.70(br, 2H), 3.52- 3.48(m, 2H), 2.86-2.74(m, 4H), 2.60-2.54(m, 211), 2.36-2.31(m, 1H), 2.12-2.09(m, 2H), 2.02- 1.92(m, 6H), 1.66-1.61(m, III). 1.33- 1.28(m, 3H) ES-MS : 498(M+D ^*

ffi(KBr) : 3400, 3000, 1630, 1580 cm ^"1

Example 78 : S ^y nthesis of l ethyl-2-r2-r ⁽ S ⁾ -l-rr(R)- l-(2-oxo-3- oxolanvl ^)p vrrolidin-2-yl3carbonyll ^p yrrolidin-2-vnethvnindo1f»-6- r-flrhnvamidine (Compound 125)

130mg(0.269 mmole ⁾ of 2-[(R ⁾ -2-[[(S)-2-[2-(6-amidino-l-ethyl- indol-2-yl ⁾ ethyl]pyrrolidinyl3carbonyl]pyrrolidinyl]-4-hydroxybut anoic acid was dissolved in 5ml of 3N-HC1, and the resulting solution was stirred for 18 hours at room temperature and then evaporated under reduced pressure to remove the solvent. The residue was purified with column chromatography [eluent: ethyl acetate/methanol(3:l) on NH-DM1020 silica to obtain 70mg of the title compound as a white solid.

1H NMR(MeOH-d,, ppm) : δ 7.79(s, 1H), 7.54-7.51(m, Hi), 7.34-7.30(m, III), 6.39(s, HI), 4.31-4.20(m, 311), 4.11-4.07(m, 2H), 3.68-3.64 (m, III), 3.58-3.46(m, 411), 2.80-2.75(m, 211), 2.67-2.61(m, HI), 2.30-2.12(m, 311), 1.93-1.87(m, 411), 1.80-1.73(m, 511), 1.31-1.27 (m, 311) ES-MS : 466(M+l) ^f

IR(KBr) : 3400, 3020, 1770, 1640, 1540 cm ^{" 1}

Example 79 : Synthesis of ^' ethyl 4-r(R)-2-IT(S)-2-r2-(6-amidinn- l-ethylindol-2-yl)ethyl3pyrrolidinyl3carbonyl3pyrrolidinyl3b utanoate (Compound 126)

a) Synthesis of ethyl 4-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yD- ethyl]pyrrolidinyl]carbonyl3pyrrolidinyl]butanoate:

400mg of the compound H-a obtained in Example 57-b) and 0.173 ml of ethyl 4-bromobutanoate were reacted according to the same procedure as Example 45-b) to obtain 453mg of the title compound as a viscous oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.59-7.53 ⁽ m, 2H), 7.29(m, 1H), 6.47(s, 1H),

4.32-4.11(m, 3H), 4.05-3.99(m, 2H), 3.61(m, 2H), 3.27-3.18(m, 2H), 2.77(m, 2H), 2.66-1.62(m, 16H), 1.36(t, 3H, J=7.18Hz), 1.17 (t, 3H, J=7.14Hz)

b) Synthesis of ethyl 4-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl3ρyrrolidinyl3carbonyl3pyrrolidinyl]butanoate :

453mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 228mg of the title compound as a pale yellow solid.

^J II NMR(MeOH-d ₄ , ppm) : δ 7.79(s, 1H), 7.56-7.31(m, 211), 6.40(s, HI), 4.21(m, 211), 4.10 ⁽ brs, HI), 3.91-3.80(m, 211), 3.63-3.47(m, 211), 3.08(m, Hi), 2.77(m, 211), 2.52-1.65(m, 1811), 1.30(t, 311, J=7.17 Hz), 1.08-0.97(m, 3H)

IR(KBr) : 3300, 3000, 1740, 1640, 1540, 1480 cm ^{" 1}

ES-MS : 496(M+l) ^f

Example 80 : Synthesis of 4-f(R)-2-rr(S)-2-r2-(6-amidino- l- ethylindol-2-yl)ethyl3pyrrolidinyl3carbonyl3pyrτolidinyl3bu tanoic acid (Compound 127)

122rag of ethyl 4-[ ⁽ R ⁾ -2 ^"" -[[ ⁽ S ⁾ -2-[2-(6-amidino-l-etlιylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]butanoate was treated according to the same procedure as Example 44 to obtain 89mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.79(s, 1H), 7.59-7.28(m, 2H), 6.38(s, 1H), 4.23-4.07(m, 3H), 3.62-3.50(m, 3H), 3.1 Km, HI), 2.77(m, 2H), 2.57-1.61(m, 18H), 1.28(t, 311, J=7.14Hz)

IR(KBr) : 3400, 3000, 1700, 1640, 1540, 1480 cm ^{" 1} ES-MS : 468(M+D ^*

Example 81 : Synthesis of ethyl 5-r(R)-2-lT(S)-2-r2-(e-amirlinn- l-ethylindol-2-yl)eth ^y l3 ^ρy rrolidinyl3carbonyl3pyrrolidinyl3pentaπoate

(Compound 128)

a ⁾ Synthesis of ethyl 5-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-cyano-l-ethylindol-2-yl)- ethyl]pyrrolidinyl3carbonyl]pyrrolidinyl]pentanoate:

138mg of the compound II-a obtained in Example 57-b) and 0.066 ml of ethyl 5-bromovalerate were reacted according to the same procedure as Example 45-b ⁾ to obtain 150mg of the title compound as a brown oil.

1H NMR ⁽ CDC1 ₃ , ppm) : δ 7.62-7.54(m, 2H), 6.46(s, 1H), 4.30-4.04(m, 5H), 3.68-3.51 ⁽ m, 2H ⁾ , 3.27-3.16(m, 211), 2.80(t, 2H, J=7.91Hz), 2.69- 1.59 ⁽ m, 1911), 1.36(t, 311, J=7.20Hz), 1.20(t, 311, J=7.13Hz)

b ⁾ Synthesis of ethyl 5-[ ⁽ R ⁾ -2-[[ ⁽ S)-2-[2- ⁽ 6-amidino- l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]pentanoate:

246mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 48mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.78(s, 2H), 7.54-7.30(m, 211), 6.37(s, HI),

4.22-3.91(m, 511), 3.60-3.47(m, 211), 3.19-3.05(m, 211), 2.81 -2.73

(m, 2H), 2.52-1.37(m7 1911), 1.30(t, 311, J=7.15Hz), 1.05(t, 311,

J=7.88Hz) IR(KBr) : 3100, 2990, 1740, 1670, 1630, 1530, 1470 cm ^{" 1}

ES-MS : 510(M+D ^*

Example 82 ^; Synthesis of 5- r(R)-2-rr(S)-2-r2-(6-amidino- l- ethylindol-2-yl)ethyl3pyrrolidinyl3carbonyl3pyrrolidinyl]pen tanoic acid (Compound 129)

38mg of ethyl 5-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-amidino-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]pentanoate was treated according to the same procedure as Example 44 to obtain 16mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d4, ppm) : δ 7.80(s, 1H), 7.54-7.29(m, 2H), 6.36(s, 1H), 4.27-4.10(m, 3H), 3.65-3.42(m, 2H), 3.19-3.03(m, 2H), 2.82-2.71 (m, 2H), 2.57-1.41(m, 19H), 1.29(t, 3H, J=7.19Hz)

ES-MS : 482(M+D ^*

Example 83 ^; Synthesis of ethyl 6-r(R)-2-rr(S)-2-r2-(fi- _a miHinn-

1 -ethvlindol-2-yl ⁾ ethvn ^p yrrolidinvncarbonvπpyrrolidinvnhexanoate

(Compound 130)

a ⁾ Synthesis of ethyl 6-[(R ⁾ -2-[[(S ⁾ -2-[2-(6-cyaπo-l-ethylindol-2-yl)- ethyl]pyrrolidinyl3carbonyl]pyrrolidinyl]hexanoate:

160mg of the compound II-a obtained in Example 57-b) and 0.086 mi of ethyl 6-bromohexanoate were reacted according to the same procedure as Example 45-b) to obtain 168mg of the title compound as a brown oil.

'II NMR(CDC1 ₃ , ppm) : δ 7.61 -7.54(m, 211), 7.30(m, 111), 6.45(s, 111),

4.27(brs, HI), 4.18-4.04(m, 411), 3.68-3.52(m, 211), 3.26-3.17(m, 2H), 2.80(t, 211, J=7.95Hz), 2.23(t, 211, J=7.45Hz), 2.66-1.25(m, 19H), 1.36(t, 3H, J=7.18Hz), 1.21(t, 3H, J=7.13Hz)

b) Synthesis of ethyl 6-[ ⁽ R ⁾ -2 ^" -[[ ⁽ S)-2-[2-(6-amidino- l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]hexanoate:

161mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 41mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.78 ⁽ s, 211), 7.54-7.30(m, 2H), 6.36(s, 1H), 4.26-3.88(m, 5H), 3.61-3.46(m, 2H), 3.19-3.03(m, 211), 2.81-2.72 (m, 2H), 2.52-1.38 ⁽ m, 2H), 1.18(t, 311, J=7.18Hz), 1.06(t, 3H, J=7.12Hz) IR(KBr) : 3200, 2970, 1730, 1630, 1530, 1470, 1340 cm ^{" 1} ES-MS : 524(M+D ^*

Example 84 : Synthesis of 6-r(R)-2-rr(S)-2-r2-(β-amidiπn- 1 - ethylindol-2-yl)ethvn ^p yrrolidinyl]carbonvn ^p yrrolidinvnhexanoic acid (Compound 131)

30mg of ethyl 6-[(R)-2-[[ ⁽ S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl]pyrrolidinyl3carbonyl3pyrrolidinyl3hexanoate was treated according to the same procedure as Example 44 to obtain 26mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.80(s, 1H), 7.54-7.29(m, 2H), 6.34(s, 1H), 4.27-4.11(m, 311), 3.66-3.45(m, 2H), 3.18-3.04(m, 2H), 2.82-2.71 (m, 211), 2.50-1.17(m, 21H), 1.28(t, 3H, J=7.15Hz)

Example 85 ; Synthesis of ethyl 2-[(R.R)-rr(S)-2-r2-(6-amidino- l-ethylindol-2-yl)ethynpyrτolidinyl1carhonyn-4-methoxypyrro lidinyl lacetate (Compound 135)

a) Synthesis of methyl (R,R)-4-methoxy-l-(tert-butoxycarbonyl)pyrroli- dine-2-carboxylate:

500mg of 4-cis-hydroxy-D-proline was dissolved in 4mC of methanol, and 0.4ml of acetyl chloride was added dropwise at 0°C. 0.14 ml of thionyl chloride was added dropwise at room temperature, and the resulting mixture was heated under refluxing for 2 hours with stirring. The reaction solution was cooled to room temperature and then evaporated under reduced pressure to obtain 704mg of the white solid product, which was then dissolved in 10ml of dichloromethane. To the resulting solution was added dropwise 1.07ml of triethylamine at 0V and then added 930mg of (BOO2O. The reaction mixture was stirred for 2.5 hours at room temperature, diluted with 150ml of dichloromethane, washed with 30ml of 2N-HC1 solution and 30m2 of water, dried over sodium sulfate and then filtered. The filtrate was then evaporated under reduced pressure to obtain 780mg of the brown solid, which was dissolved in 15ml of anhydrous tetrahydrofuran. To the resulting solution was

then added 138mg of NaH, and the mixture was stirred for one hour at room temperature. 0.214ml of methyliodide was slowly added dropwise thereto, and the reaction mixture was heated under refluxing overnight with stirring. After 1ml of water was added dropwise, the reaction solution was evaporated under reduced pressure to obtain the residue, which was then diluted with 150ml of dichloromethane, washed with 50ml of water, dried over sodium sulfate and then filtered. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane( 1:3)3. The fractions containing the desired product were combined and then evaporated to obtain 404mg of the title compound as a viscous oil.

1H NMR(CDC1 ₃ , ppm) : δ 4.46-4.28(m, HI), 3.94(brs, HI), 3.73(s, 3H), 3.63-3.49(m, 2H), 3.30(d, 311, J=9.48Hz), 2.41-2.22(m, 111), 2.11- 1.98(m, 111), 1.44(m, 9H)

b) Synthesis of ⁽ R,R ⁾ -4-methoxy-l-(tert-butoxycarbonyl)pyrroIidine-2- carboxylic acid:

520mg of the compound obtained in the above a) was reacted in the presence of methanol solvent under the same conditions as Example 44 to obtain 480mg of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 4.47-4.34(m, HI), 3.97(brs, 1H), 3.64-3.49(m, 2H), 3.33 ⁽ s, 3H), 2.44-2.10 ⁽ m, 2H), 1.49-1.42(m, 9H)

c) Synthesis of tert-butyl (R,R)-2-[[(S ⁾ -2-[2-(6-cyano-l-ethylindol-2-yl) -ethyl3pyrrolidinyl]carbonyl]-4-methoxypyrrolidine carboxylate:

203mg of the compound I-a obtained in Example 1-1) was reacted with the compound obtained in the above b) according to the same procedure as Example 11-a ⁾ to obtain 212mg of the title compound as a white solid.

1H NMR(CDCI ₃ , ppm) : δ 7.58-7.52 ⁽ m, 2H), 7.30(m, 1H), 6.39(m, 1H), 4.31 (m, 1H), 4.21-4.10 ⁽ m, 2H ⁾ , 3.97-3.40(m, 6H), 3.32(s, 3H), 2.88-

2.76(m, 2H), 2.58-1.67(m, 8H), 1.45-1.40(m, 9H), 1.35(t, 3H, J=7.11Hz)

d) Synthesis of l-ethyl-2-[2-[(S)-l-[((R,R ⁾ -4-methoxypyrrolidin-2-yl)- carbonyl3pyrrolidin- 2 - yl]ethy Uindole -6 -carboni trile-'

210mg of the compound obtained in the above c) was treated according to the same procedure as Example 1-1) to obtain 145mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.59-7.54(m, 2H), 7.29(m, 1H), 6.40(s, 1H), 4.28 (brs, HI), 4.18-4.10(m, 211), 4.04-3.93(m, 2H), 3.67-3.42(m, 2H), 3.31 ⁽ s, 3H), 3.21 ⁽ s, Hi ⁾ , 3.00-2.92(m, 1H), 2.85-2.74(m, 211), 2.43-1.72(m, 911), 1.36(t, 311, J=7.19Hz)

e) Synthesis of ethyl-2-[(R,R ⁾ -[[ ⁽ S)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]-4-methoxypyrrolidin-2-yl]acetat e:

98mg of the compound obtained in the above d) was reacted with 30/4 of ethyl 2 -bromoacetate according to the same procedure as Example 1-m) to obtain 93mg of the title compound as a yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.58-7.53(m, 2H), 7.29(m, 1H), 6.42(s, HI), 4.31

(brs, 1H), 4.20-4.11(m, 4H), 4.08-4.01(m, 211), 3.62-3.50(m. 511),

3.29(s, 3H), 2.82-2.73(m, 3H), 2.35-1.59(m, 8H), 1.35(t, 3H, J=7.24Hz), 1.26(t, 3H, J=7.13Hz)

f) Synthesis of ethyl 2-[(R,R)-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]-4-methoxypyrrolidin-2-yl]acetat e:

93mg of the compound obtained in the above e) was treated according to the same procedure as Example 1-n) to obtain 16mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.83(s, 1H), 7.54-7.31(m, 211), 6.38(s, 1H), 4.21-3.85(m, 7H), 3.58-3.29(m, 5H), 3.18(s, 3H), 2.82-2.73(m,

2H), 2.61(m, 1H), 2.19-1.66(m, 8H), 1.29(t, 3H, J=6.85Hz), 1.17- 1.08(m, 3H) ES-MS : 498(M+D ^*

Example 86 : Synthesis of ethyl-2-r ⁽ R.R ⁾ -rr(S)-2-r2-(6-amidino- 1 -ethylindol-2-vl ⁾ ethvnniperidinvncarbonvn-4-methoxypyrrolidin-2 -yllacetate (Compound 136)

a) Synthesis of (R,R)-4-hydroxy-l-(benzyloxycarbonyl)pyrrolidine-2- carboxy lie acid:

0.81g of (R,R)-4-hydroxypyrroIidine-2-carboxylic acid was treated according to the same procedure as Example 66 -a) to obtain lg of the title compound as a colorless oil.

1H NMR(CDCl3, ppm) : δ 7.31(m, 5H), 5.19(m, 2H), 4.53(m, HI), 4.43(m, HI), 3.60(m, 211), 2.24(m, 211)

b) Synthesis of (R,R)-4-methoxy-l-(benzyloxycarbonyl)pyrrolidine-2- carboxylic acid:

lg of the compound obtained in the above a) was treated according to the same procedure as Example 66-d) to obtain l.lg of the title compound as a pale brown oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.31(m, 5H), 5.16(m, 2H), 4.45(m, 1H), 3.95(m, 1H), 3.64(m, 2H), 3.26(s, 3H), 2.45-2.38(m, Hi), 2.24(m, 1H)

c) Synthesis of phenylmethyl-2-(R,R)-[[(S)-2-[2-(6-cyano-l-ethylindol- 2-yI)ethyl]piperidinyl]carbonyl]-4-methoxyρyrrolidine carboxylate:

0.92g of l-ethyl-2-[2-((S ⁾ -2-piperidyl)ethyl3indole-6-carbonitrile and l.lg of ⁽ R,R ⁾ -4-methoxy-l-(benzyloxycarbonyl ⁾ pyrrolidine-2-carbo- xylic acid were treated according to the same procedure as Example 11-a) to obtain 500mg of the title compound as a yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.56(m, 2H), 7.35(m, 5H), 7.27(m, 1H), 6.33(s, 1H), 5.09(m, 2H), 4.16(m, 1H), 3.95(m, 2H), 3.66(m, 2H), 3.26(m, 3H), 2.32(m, 2H), 1.4l(m, 2H), 1.25(m, 3H)

d) Synthesis of l-ethyl-2-[2-[ ⁽ S)-l-[((R,R)-4-methoxypyrrolidin-2-yl)- carbonyl3ρiperidin-2-yl3ethyl3indole-6-carbonitrile:

480mg of the compound obtained in the above c) was treated according to the same procedure as Example 1-k) to obtain 270mg of the title compound as a pale yellow solid.

e) Synthesis of ethyl 2-[(R,R)-[[(S)-2-[2-(6-cyano-l-ethyIindol-2-yl)- ethyl]piperidinylϊcarbonyl]-4-methoxypyrrolidin-2-yl]acetat e:

250mg of the compound obtained in the above d) and 0.1ml of ethyl

2 -bromoacetate were treated according to the same procedure as Example 1-m) to obtain 200mg of the title compound as a pale yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.78 ⁽ m, 1H), 7.54(m, 111), 7.33(m, 111), 6.31(s, 111), 4.95(br, 1H), 4.12 ⁽ m, 4H), 3.97(m, 2H), 3.72-3.60(m, 2H),

3.28(m, 3H ⁾ , 3.02 ⁽ m, 1H), 2.71(m, 1H), 2.61-2.49(m, 2H), 2.19(m, 111), 1.30(m. 3H), 1.26-1.19(m, 6H)

f) Synthesis of ethyl 2-[ ⁽ R,R ⁾ -[[ ⁽ S ⁾ -2-[2-(6-amidino- l-ethylindol-2-yl)- ethyl]piperidinyl]carbonyl]-4-methoxypyrrolidin-2-yl]acetate :

190mg of the compound obtained in the above e) was treated according to the same procedure as Example 1-n) to obtain 50mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.77(m, 1H), 7.54(m, 111), 7.33(m, 1H), 6.31(s, 1H), 4.95(br, 1H), 4.15(m, 4H), 3.98-3.87(m, 2H), 3.62(m, 2H), 3.28(m, 3H), 3.05(m, 1H), 2.70(m, 1H), 2.77-2.52(m, 2H), 2.18(br, HI), 1.84(m, 2H), 1.67(m, 5H), 1.32(m, 311), 1.24(m, 311) IR(KBr) : 3400, 2920, 1720, 1630, 1460 cm ^"1

Example 87 : Synthesis of l-ethvl-2-r2-r(S)- l -rr(R)-l-(2- hydroxyethyl)pyrrolidin-2-yl3carbonyl3pyrrolidin-2-yl3ethyl3 indole-6 -carboxamidine (Compound 140)

a) Synthesis of l-ethyl-2-[2-[(S)-l-[[(R)-l-(2-hydroxyethyl)pyrrolidin- 2-yl]carbonyl]pynOlidin-2-yl]ethyl]indole-6-carbonitrile:

130mg of the compound II-a obtained in Example 57-b) and 0.1ml of 2-bromoethanol were treated according to the same procedure as Example 45-b) to obtain 140mg of the title compound as a yellow oil.

1H N.Λ1R(CDC1 ₃ , ppm) : 7.50(m, 211), 7.25(s, HI), 6.34(s, HI), 4.20(m, HI), 4.10(t, 311), 3.52(m, 211), 3.37(m, 211), 3.21(m, 211), 2.76(m, 211), 2.44(m, 211), 2.32-1.60(m, 1111), 1.27(t, 3H)

ES-MS : 409(M+l) ^f

b) Synthesis of l-ethyl-2-[2-[(S)-l-[[(R)-l-(2-hydroxyethyl)pyrrolidiπ- 2-yl]caι-bonyl]pynOlidin-2-yl]ethyl]indole-6-carboxamidine:

140mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 45mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d4, ppm) : δ 7.80(s, HI), 7.58(m, 1H), 7.34(s, 1H), 6.83(d, Hi), 4.20(m, III), 4.05(s, 3H), 3.57(m, 211), 3.60(m, 2H), 3.47(m, 2H), 3.20(m, 2H), 2.83(m, 2H), 2.65(m, 2H), 2.40-1.80(m, 11H), 1.37(m, 3H)

ES-MS : 426(M+D ^*

Example 88 : Synthesis of l-ethyl-2-f2-i (S)-l-rr(R)- l-r2-(methyl- amino)acetyl]ρyrrolidin-2-yl]carboπyl3pyrrolidin-2-yl3ethy l3-indole- 6 -carboxamidine (Compound 142)

a) Synthesis of N-[2-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]pynOlidinyl]carbonyl]pyπOlidinyl]-2-oxoethyl]-N-methy l-(tert- butoxy)formamide:

101 mg of the compound II-a obtained in Example 57-b) and 52mg of N- ⁽ tert-butoxycarbonyl ⁾ sarcosine were reacted according to the same procedure as Example 11-a) to obtain 106mg of the title compound as a white solid.

^J II NMR(CDC1 ₃ , ppm ⁾ : δ 7.61-7.52(m, 211), 7.27(m, Hi), 6.34(s, 111), 4.67 (m, HI ⁾ , 4.28-4.12 ⁽ m, 3H), 3.81-3.44(m, 611), 2.88(s, 311), 2.79(t,

211, J=7.90Hz), 2.28-1.73(m, 1011), 1.44(s, 911), 1.35(t, 311, J=7.31Hz)

b) Synthesis of l-eUιyl-2-[2-[ ⁽ S ⁾ -l-[[ ⁽ R)- l-[2-(methylamino)acetyl)pyr- rolidin-2-yl]carbonyl]pyriOlidin-2-yl]ethyl]indole-6-carboxa midine:

103mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 46mg of the title compound as a pale yellow solid.

^] II NMR(MeOH-d ₄ , ppm) : δ 7.81(s, 1H), 7.55-7.31(m, 211), 6.37(s, HI), 4.57(m, HI ⁾ , 4.22-4.08(m, 3H), 3.75-3.47(m, 411), 3.31(s, 211), 2.77(brs, 211), 2.27(s, 311), 2.19-1.77(m, 1011), 1.29(t, 3H, J=7.12Hz) IR(KBr) : 3440, 1640, 1025 cm ^"1 ES-MS : 453(M+l) ^f

Example 89 : Synthesis of l-ethvl-2-r2-r(S)- l-[[(R)- l-((S)-2- aminopropanoyl )pyrrolidin-2 - yl]c bonvl]pyrrolidin-2-yl]ethyl3indole -6 -carboxamidine (Compound 143/

a) Synthesis of N-[ ⁽ lS)-2-[ ⁽ R ⁾ -2-[[(S ⁾ -2-[2-(6-cyano-l-ethylindol-2-yl ⁾ -ethyl]pyriOlidinyl]carbonyl]pyπOlidinyl]- l-methyl-2-oxoethyl]-(tert- butoxy)formamide:

300mg of the compound II-a obtained in Example 57-b) and 187mg of (S)-2-[(tert-butoxy)carbonylamino]propanoic acid were reacted according to the same procedure as Example 11-a) to obtain 210mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.55(m, 2H), 7.24(m, Hi), 6.35(s, HI), 4.57(m, HI), 4.49(m, HI), 4.32(m, HI), 4.13(m, 211), 3.79(m, 211), 3.58- 3.43(br, 211), 2.81(m, 211), 2.12(m, 411), 1.42(m, 9H), 1.35(m, 611)

b) Synthesis of l-ethyl-2-[2-[ ⁽ S)-l-[[(R)-l-((S)-2-aminopropanoyl)- pyιτolidin-2-yl]caι-bonyl]pyπOlidin-2-yl]ethyl]indole-6- carboxamidine:

200mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain lOOmg of the title compound as a yellowish white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.80(m, 1H), 7.38(m, 1H), 7.23(m, Hi), 6.15(m, HI), 4.57(m, 211), 4.13(br, 3H), 3.83(m, 211), 3.66(m, Hi), 3.45(m, 211), 2.71(m, 211), 2.12(m, 3H), 1.97-1.84(br, 6H), 1.25-1.17(m,

611) IR(KBr) : 3420, 3000, 1640 cm ^{" 1} ES-MS : 453(M+D ^f

Example 90 : Synthesis of l-ethyl-2-r2-r(S)-l-rr(R)- l -(2-amino- butanoyl)pyrrolidin-2-yl3carbonyl3pyrrolidin-2-yl3ethyflindo le-6- carhnxamidine (Compound 144)

a) Synthesis of N-[(R)-2-[(S)-2-[2- ⁽ 6-cyano-l-ethylindol-2-yl)ethyl]~ pyrrolidinyl]carbonyl]pyιτolidinyl]-l-ethyl-2-oxoethyl](te rt-butoxy) formamide:

400mg of the compound II-a obtained in Example 57-b) and 270mg of 3- [(tert-butoxy )carbonylamino]butanoic acid were reacted according to the same procedure as Example 11-a) to obtain 350mg of the title

compound as a yellow oil.

b) Synthesis of l-ethyl-2-[2-[(S)-l-[[ ⁽ R ⁾ -l- ⁽ 2-aminobutanoyl)pyrrolidin -2-yl]carbonyl3pyrrolidin-2-yl]ethyl]indole-6-carboxamidine:

340mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 190mg of the title compound as a yellowish white solid.

^: II NMR(CDC1 ₃ , ppm) : δ 7.83(m, HI), 7.32(m, 111), 7.16(m, HI), 6.21(s, HI), 4.60(m, 2H), 4.18(m, 5H), 3.88(m, 211), 3.78(m, 211), 3.64(m, HI), 3.48(m, 511), 2.72(m, 311), 2.16(m, 511), 1.24(m, 511), 0.95(m, 3H) IR(KBr) : 3400, 3000, 1640 cm ^"1 ES-MS : 467(M+l) ^f

Example 91 : Svnthesis of l-ethvl~2-r2-r(S)- l-IT(R)- l-((S)-2- amino-3-me thylbutanoyl)pyrrolidin-2-yl]cabonyl]pyrτolidin-2-yll- ethyl3indole-6-carboxamidine (Compound 145)

a) Synthesis of N-[(lS)-2-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl) -ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]- l-isopropyl-2-oxo-ethyl](tert- butoxy)formamide:

250mg of the compound II-a obtained in Example 57-b) and 298mg of 3 -methyl -(S)- 2- [(tert-butoxy )carbonylamino]butanoic acid were reacted according to the same procedure as Example 11-a) to obtain 300mg of the title compound as a yellowish white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.52(m, 2H), 7.30(m, 111), 6.32(s, 1H), 5.18(m, HI), 4.54(m, 1H), 4.23-4.14(m, 111), 4.15(q, 2H), 3.88(m, 2H), 3.68-3.39(m, 211) 2.82(m, 2H), 2.71 -2.32(m, 10H), 1.38(brs, 9H), 1.34(t, 311), 0.98(m, 3H), 0.85(m, 411)

b) Synthesis of l-ethyl-2-[2-[(S)-l-[[(R)-l -((S)-2-aιmno-3-methylbuta-

noyl)pyrrolidin-2-yl]cabonyl]pynOlidin-2-yl]ethji]-l-ethylin dole-6-car -boxamidine:

140mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 59mg of the title compound as a pale yellowish white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.69(m, 111), 7.42(m, HI), 7.22(m, HI), 6.28(s, HI), 4.58(m, 111), 4.33-4.16(m, 211), 4.11(q, 211), 3.91-3.72(m, 211), 3.58-3.38(m, 2H), 2.73(m, 211), 2.22-1.77(m, 1011), 1.28(t,

311), 0.89(m, 711) ES-MS : 482 ⁽ M+2) ^* IR(KBr) : 2997, 1642, 1543, 1480 cm ^{" 1}

Example 92 : Svnthesis of l-ethyl-2-r2-r(S)-l -IT(R)-l-r(S)-2- (methanesulfoπvlamino)propanoyl3pyrrolidin-2-yπcarbonynpyr rolidin -2-yl]ethyl3indole-6-carboxamidine (Compound 146)

a) Synthesis of l-ethyl-2-[2-[(S)-l-[[(R)-l-((S)-2-aminopropanoyl)pyr- iOlidin-2-yl]caιbonyl]pyιτolidin-2-yl]ethyl]indole-6-carb onitrile:

294mg of N-[(S)-2-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethyIindol-2- yl)ethyl]pyrroIidinyl]carbonyl]pyrrolidinyl]-l-ιnethyI-2-ox oethyl](tert-but- oxy)formamide was treated according to the same procedure as Example 1-1) to obtain 220mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.56(m, 2H), 7.21(m, HI), 6.37(s, IH), 4.58(m, IH), 4.27(m, IH), 4.14(q, 2H), 3.82-3.58(m, 3H), 3.42(m, 211), 2.82 (m, 2H), 2.26-1.78(m, 10H), 1.37(t, 311), 1.21(t, 3H)

b) Synthesis of l-ethyl-2-[2-[(S)-l-[[(R)-l-[(S)-2-(methanesulfonyl- amino)propanoyl]pyrrolidin-2-yl]carbonyl]pyrrolidin-2-yI]eth yl]indole-6 -carbonitrile:

140mg of the compound obtained in the above a) and 20 _/ 4 of

methanesulfonyl chloride were reacted according to the same procedure as Example 1-m ⁾ to obtain 120mg of the title compound as a pale yellow solid.

1H NMR ⁽ CDC1 ₃ , ppm) : δ 7.59 ⁽ m, 211), 7.28(m, HI), 6.41(s, HI), 5.13(m,

HI ⁾ , 4.61 ⁽ m, HI), 4.32(m, HI), 4.14(q, 211), 3.89-3.75(m, 211), 3.55-3.48 ⁽ m, 211 ⁾ , 2.86 ⁽ s, 611), 2.75(m, 211), 2.28-1.74(m, 1011), 1.38(m, 611) ES-MS : 514(M+D ^*

c ⁾ Synthesis of l -eUιyl-2-[2-[ ⁽ S ⁾ - l-[[ ⁽ R ⁾ -l -[ ⁽ S ⁾ -2- ⁽ methanesulfonylami- no ⁾ propanoyl]pyrrolidin-2-yl]carbonyl]pyrrolidin-2-yl]eth yl]indole-6- carboxamidine:

120mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-n) to obtain 61mg of the title compound as a pale yellowish white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.94(m, HI), 7.41(m, HI), 7.23(m, HI), 6.22(s, HI), 4.61 ⁽ m, HI), 4.35(m, HI), 4.18(m, 311), 3.92-3.75(m, 211),

3.50 -3.38(m, 211), 2.86(s, 311), 2.68(m, 211), 2.22-1.71(m. 1011), 1.42(t, 311), 1.24(m, 3H) ES-MS : 53HM+1)' IR(KBr) : 2998, 1643, 1541, 1342 cm ^l

Example 93 : Svnthesis of ethvl 4 r(R)-2-rr(S)-2-r2-(6-amidino- l-ethylindol-2-yl)ethvnpyrrolidinyl1carbonyl1pyrrolidinvn- (S)-3- amino-4-oxobutanoate (Compound 147)

a) Synthesis of phenylmethyl-4-[(R)-2-[[(S)-2 -[2 -(6-cyano-l-ethylindol- 2 -yl)ethyl]pyrrolidinyl]carbonyI]pyrrolidinyl]-(S)-3-[( tert-butoxy )carbo- ny lamino] - 4 -oxobutanoate:

0.6g of the compound II-a obtained in Example 57-b) and 798mg of (S)- 2- [( tert-butoxy )carbonylamino3-3-(benzyloxycarbonyl)propanoic

acid were reacted according to the same procedure as Example 11-a) to obtain l.lg of the title compound as a yellowish white solid.

^] II NMR(CDC1 ₃ , ppm) : δ 7.52(m, 211), 7.35-7.17(m, 611), 6.33(s, HI), 5.26 (m, III), 4.98(m, 211), 4.88 ⁽ m, HI), 4.47(m, HI), 4.12(q, 211), 3.78-

3.39(m, 411), 2.88-2.66(m, 4H), 2.23-1.71(m, 10H), 1.39(brs, 911), 1.29(t, 311) ES-MS : 682(M+Na ^f ), 670(M+1) ⁺

b) Synthesis of ethyl 4-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-amidino- l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyιτolidinyl]-(S )-3-amino-4-oxobutanoate:

l.lg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 250mg of the title compound as a yellowish white solid.

1H NMR(CDCl.ι, ppm) : δ 7.75(m, HI), 7.39(m, III), 7.22(m, HI), 6.27(s, HI), 4.66-4.47(m, HI), 4.27-3.95(m, 611), 3.86-3.37(m, 4H), 2.79- 2.42(m, 411), 2.19- 1.73(m. 1011), 1.31 1.19(m, 611)

ES-MS : 525(M+ l) ^f

IR(KBr) : 3028, 1768, 1647, 1374 cm ^"1

Example 94 : Svnthesis of l -ethvl-2- [2-f(S)- l-[[(R)- l-((S)-2- amino-3-carbamoylpropanoyl)ρyrrolid in-2-yllcarbonvl3pyrrolidin-2- yl3ethyl]indole-6-carboxamidine (Compound 148)

l.lg of phenylmethyl-4-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethylindol- 2-yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]-(S)-3-[(tert- butoxy)carbonyl- amino]-4-oxobutanoate was treated according to the same procedure as Example 1 -n) to obtain lδOmg of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.77(m, III), 7.48(m, HI), 7.32(m, IH), 6.34(s, HI), 4.49(m. HI), 4.22-4.07(m, 3H), 3.92(m, IH), 3.66(m, 211), 3.38(m, 211), 2.71(m, 211), 2.50-2.25(m. 211), 2.22-1.74(m, 1011), 1.30(t, 311)

ES-MS : 496(M+1) '

IR : 3086, 1637, 1367 cm ^{" 1}

Example 95 : Synthesis of 4-rm)^2-[IlSJj^^[2^6^amMniiz _L l^ ethylindol-2-yl ⁾ ethvl1 ^p vrrolidinyl3carbonvllp_yjτolidinχl3-(S)-3- amino-4-oxobutanoic acid (Compou nd 149)

lδOm ^g of ethyl-4-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-amidino l -ethylindol- 2-yl) -ethyl]pyπOlidinyl]carbonyl]pyriOlidinyl3- ⁽ 3S ⁾ -3-amino-4-oxobutanoate and 50m ^g of 2-[2-[ ⁽ S ⁾ -l -[[ ⁽ R ⁾ - l -[ ^{( (} S ⁾ -2-amino-3-carbamoyl)propanoyl]- pyrrolidin-2-yl]carbonyl]pyrrolidin-2-yl]ethyl]- l -ethylindole-6-carboxami -dine were reacted under the same conditions as Example 44 to obtain 145ιng of the title compound as a white solid.

1H NMR(MeOII-d ₁ , ppm) : δ 7.75(m, HI), 7.51(m, HI), 7.30(m, HI), 6.32 (s, HI), 4.56-4.28(m, HI), 4.21-4.08(m, 311), 3.93(m, HI), 3.81- 3.66(m, 211), 3.52-3.2δ(m, 211), 2.76(m, 211), 2.54-2.18(m, 211), 2.12- 1.69(m, 1011), 1.28(t, 311) ES-MS : 498(M+2) ^f IR(KBr) : 1632, 1372 cm '

EjsamDle_M : Svnthesis of l ^~ ethvl-2- r2- r((S ) z±z [[{Rb pronanovDpyrroli din-2-yl]c arbonvl]pyrrolidin- 2-yl]ethyl3 i ndo ler 6 n_ carboxamidine (Compound 155)

a) Synthesis of 2-[2-[(S)- l -[[(R)- l -(3-chloropropanoyl)pyιτolidin-2-yl]- carbonyl]pyrrolidin-2-yl]ethyl]-l-ethylindole-6-carbonitrile :

800mg of the compound II-a obtained in Example 57-b) and 0.475 inf, of 3-chloropropionic acid were reacted according to the same procedure as Example 11-a) to obtain 926mg of the title compound.

Η NMR(CDC1 _:! , ppm) : δ 7.61(s, HI), 7.δ6(d, III, J=8.81Hz), 7.26(d. HI,

J=8.98IIz), 6.37(s, HI), 4.6δ(m, HI), 4.28(m, HI), 4.1δ(q, 211), 3.82 (m, 211), 3.71(m. 411), 3.62-3.40(m, 211), 2.78 ⁽ m, 411), 2.30- 1.78

(m, 1011), 1.33(t, 311)

b) Synthesis of l-ethyl-2-[2-[(S)- l-[[ ⁽ R ⁾ -l-(3-aminopropanoyl)pyπOlidin -2-yl]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carboxaιmdine :

320mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 98mg of the title compound as a pale yellow solid.

^] II NMR(MeOH-d,, ppm) : δ 7.92(s, HI), 7.65(d, III, J=8.25Hz), 7.46(d, III), 6.49(s, HI), 4.40-4.16(m, 311), 3.87(m, HI), 3.78-3.53(m, 411), 2.91(m, 411), 2.89(m, 211), 2.40-1.80(m, 1011), 1.41(t, 311)

Example 97 : Svnthesis of l ethyl-2-[2- r(S)- l- [[(R)- l-(3-amino- 2-methylpropanovl)pyrrolidin-2-yl3carbonyl]pvrrolidin-2-yl3e thyl]- indole-6 -carboxamidine (Compound 156)

a) Synthesis of N-[3-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-cyano-l-ethylindol-2-yI ⁾ etiιyl3 -ethyl3pyrrolidinyl]carbonyl3pyrrolidinyl]-2-methyl-3-oxopro pyl](tert- butoxy)formamide:

430mg of the compound II-a obtained in Example 57-b) and 290mg of 2-methyl-3-[(tert-bιιtoxy)carbonylaιnino]propanoic acid were reacted according to the same procedure as Example 11 -a) to obtain 270mg of the title compound as a yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.57(m, 211), 7.28(m, HI), 6.36(d, HI), 4.62(m, IH), 4.26(m, IH), 4.16(m, 2H), 3.47(m, 211), 3.22(m, 211), 2.79(m, 211), 2.15(m, 3H), 1.93(m, 6H), 1.60(m, 911), 1.27(m, 3H), 1.12(t, 311 ⁾

ES-MS : 5δO(M+l)\ 573(M+Na)

b) Synthesis of l-ethyl-2-[2-[(S)- l-[[(R)- l-(3-amino-2-methylpropano- yl)ρyrrolidin-2-yl]carbonyl]pyrroIidin-2-yl]ethyl]indole-6- carboxamidine

2δ0mg of the compound obtained in the above a) was treated according to the same procedure as Example 1 -n) to obtain lOOmg of the title compound as a pale yellow solid.

1H NMR ⁽ CDC1 ₃ , ppm) : δ 7.89 ⁽ d, HI, J=7.00IIz), 7.32(m, HI), 7.18(m, III), 6.19(d, HI, J=8.70Hz), 4.61(m, HI), 4.14(m, 211), 3.85(m, 311), 3.45(m, 211), 2.69(m, 211), 2.19(m, 611), 1.26(m, 511), 1.07(m, 311), 1.02(m, 311) IR(KBr) : 3420, 1650 cm ^{" 1}

Example 98 : Synthesis of l -ethvl-2-r2- r(S )- l-rr(R)- l-(3-amino- butanovl)pyrrolidin-2-yllcarbonvl3py rrpjidinz 2-yl3ethyl3indole-6- carboxamidine (Compo und 157)

a ⁾ Synthesis of N-[3-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-cyano- l -ethyIindol-2-yl ⁾ ethyl3 -pyrrolidinyl3caι-bonyl3pyπOlidinyl3-l -methyl -3-oxopropyl]( tert-butoxy) formamide:

430mg of the compound II-a obtained in Example 57-b) and 290ιng of 3-[(tert-butoxy)carbonylamino]butanoic acid were reacted according to the same procedure as Example 11 -a) to obtain 260mg of the title compound as a yellow oil.

Η NMR(CDC1 ₃ , ppm) : δ 7.57(m, 211), 7.29(m, III), 6.36(s, HI), 4.62(m, HI), 4.15(t, 211, J=7.20Hz), 4.03(m, HI), 3.69(m, 211), 3.47(m, 311), 2.80(m, 211), 2.57(m, 211), 2.16(m, 311), 1.93(m, 611), 1.43(m, 911), 1.37(m, 311), 1.20(m, 311) ES-MS : 550(M+1) '

b) Synthesis of l -ethyl-2-[2-[(S)-l-[[(R)-l-(3-aminobutanoyl)pyrrolidin- 2-yl]carbonyl]pyrrolidin-2-yI]ethyl]indole-6-carboxamidine:

250mg of the compound obtained in the above a) was treated according to the same procedure as' Example 1 -n) to obtain llOmg ot the

title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.87(m, HI), 7.35(m, IH), 7.20(m, HI), 6.21 (s, HI), 4.60(m, HI), 4.21(m, 411), 3.8δ(m, 211), 2.72(m, 3H), 2.1 Kbr, 611), 1.98(br, 311), 1.21(m, 311), 1.04(m, 311)

IR(KBr) : 3400, 2840, 1650, 1020 cm ^"1

Example 99 : Svnthesis of l-ethyl-2-[2-r(S)- l-rr(R)- l -r3- [(methanesulfonyl)amino]propanoyl3pyrrolidin-2 yl3carbonyllpyrrpli_-_ din - 2 - y 1 le t hyjj indole-6-carboxami d in e_.(C om p QjunxL 158J

a) Synthesis of N-[3-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-cyano-l -ethylindol-2-yl)ethyl] -l)'π-olidinyl]carbony!]pyrrolidinyl]-3-oxopropyl](tert-but oxy)foπnamide

δOOmg of the compound II-a obtained in Example 57-b) and 290mg of 3-[(tert ^~ butoxy)carbonylamino]propanoic acid were reacted according to the same procedure as Example 11-a) to obtain 340mg of the title compound as a yellow oil.

^J II N.\IR ⁽ CDCl:ι, ppm) : δ 7.55(m. 211), 7.26(m, HI), 6.37(s, HI), 4.63(m, IH), 4.28(m,HI), 4.15(t, 211, J=7.20IIz), 3.81(m, HI), 3.66(m, 211), 3.41(m, 611), 2.80(m, 211), 2.52(m, 211), 2.18(m, 411), 1.98(m, 6H), 1.42(m, 911), 1.32(m, 311) ES-MS : 536(M+1)\ 558(M+Na), 574(M+K)

b ⁾ Synthesis of l-ethyl-2-[2-[(S)-l -[[(R)-l -(3-aminopropanoyl)pyrrolidin -2-yl]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carbonitrile:

340mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-1) to obtain 160mg of the title compound as a yellow oil.

c ⁾ Synthesis of l-etlιyl-2-[2-[ ⁽ S ⁾ -l-[[(R)-l-[3- [(methanesulfonyI)amino]- propanoyl]pyrrolidin-2-yl]carbonyl]pyιτolidin-2-yl]ethyl]i ndole-6-carbo-

nitrile:

180mg of the compound obtained in the above b) and 55/4 of methanesulfonyl chloride were reacted according to the same procedure as Example 1-m ⁾ to obtain lOOmg of the title compound as a yellow oil.

^J I1 NMR ⁽ CDC1 _: «, ppm) : δ 7.56(m, 211), 7.25(m, HI), 6.41(s, III), 4.62(m, HI ⁾ , 4.24 ⁽ m, HI ⁾ , 4.18 ⁽ t, 211, J=7.20IIz), 3.75(m, 211), 3.48-3.39(m, 411), 2.87-2.79(m, 411), 2.20(m, 211), 2.01-1.90(br, 711), 1.35(m, 311)

d ⁾ Synthesis of l-ethyl-2-[2-[ ⁽ S)- l -[[ ⁽ R ⁾ - l -[3-[(methane.sulfonyl)amino] -propanoyl3pynOlidin-2-yl]carbonyl]pyiTolidin-2-yl]ethyl3ind ole-6- carboxamidine:

lOOmg of the compound obtained in the above c) was treated according to the same procedure as Example 1-n) to obtain 60mn of the title compound as a yellowish white solid.

1H NMR(CDCl:ι, ppm) : δ 7.69(s, HI), 7.54(m, III), 7.28(m, HI), 6.34(s, HI), 4.60(m, III), 4.21(m, 311), 3.73(m, 211), 3.34(m, 211), 2.83(s, 311), 2.79(m, 211), 2.16(m, 411), 2.02-1.96(br, 411), 1.33(t, 311, J=7.10Hz) IR(KBr) : 3300, 3000, 1640 cm ^J ES-MS : 53KM+ 1)'

Example 100 : Svnthesis of ethvl 4-r(R)-2-[r(S)-2 [2- (6 amidino- l-ethylindol-2-yl)ethyl3 pyrroli dinyl]carbonvπpyrrolidinyl3-(S)-2- amino-4-oxobutanoate (Compound 159)

a) Synthesis of phenylmethyl-4-[(R)-2-[[(S)-2-[2-(6-cyano-l -ethylindol- 2-yl)ethyl]pyrrolidinyl]caι-bonyl]pyπOlidinyl]-(S)-2-[(fe/ f-butoxy)carbo- nylamino] -4 -oxobutanoate:

0.6g of the compound II-a obtained in Example 57-b) and ⁽ ).798g

of (S)-3-[( tert-butoxy )carbonylaιnino]-3-(benzyloxycarbonyl)propanoic acid were reacted according to the same procedure as Example 11-a) to obtain 1.08g of the title compound as a pale yellow solid.

^] II NMR(CDC1 ₃ , ppm) : δ 7.51(m, HI), 7.49(m, III), 7.32-7.04(m, 611), 6.30 (s, HI), 5.67(m, 111), 4.86-4.72(m. 211), 4.59-4.46(m, HI), 4.27- 4.01(m, 311), 3.83-3.58(m, 211). 3.46-3.37(m, 211), 3.09-2.66(m, 411), 2.27-1.69(m, 1011), 1.42(brs, 911), 1.25(t, 311)

ES-MS : 692(M+Na ^f ), 670(M+1) ⁺

b) Synthesis of ethyl 4-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2-(6-amidino- l-ethylindol-2-yl)- ethyl]pyriOlidinyl]carbonyl3pyπ'olidinyl]-(vS)-2-amino-4-ox ohutanoate:

1.08g of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 250mg of the title compound as a pale yellow solid.

'II NMR(CDC1 ₃ , ppm) : δ 7.77(m, HI), 7.44(m, HI), 7.28(m, HI), 6.28(s, III), 4.62(m, HI), 4.21(m, 411), 4.06(q, 211), 3.9()-3.71(m, 211), 3.61 -3.39(m, 211), 2.71(m, 411), 2.28-1.72(m, 1011), 1.32(t, 311),

1.18 ⁽ t, 311)

ES-MS : 52δ(M+l) '

IR(KBr) : 1752, 1648, 1375 cm ^"1

Example 101 : Svnthesis of l-ethvl-2-[2-[(S)- l-fr(R)- l- ((S)-3- amino-3-carbamoylpropanoyl)pyrτolidin-2-yl]carbonyl3pyrroIi din-2 - ynethyl3indole-6-carboxamidine (Compound 160)

1.08g of phenylmethyl 4-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethyl- ) indol-2-yl)ethyl]pyπOlidinyl]carbonyl]pyrrolidinyl] -(S)-[( tert-butoxy )carbo -nylamino]-4-oxobutanoate was treated according to the same procedure as Example 1-n) to obtain 230mg of the title compound as a white solid.

^] II NMR(MeOII-dj) : δ 7.78(m, HI), 7.49(m, HI), 7.28(m, Hi), 6.35(s, HI), 4.53(m. HI), 4.19-4. ⁽⁾ 8(m, 311). 3.76-3.38(m, 511), 2.81-2.42(m,

411), 2.25-1.71(m, 1011), 1.28(t, 311) ES-MS : 496(M+D ^* IR(KBr) : 3098, 1641, 1498, 1365 cm '

Example 102 ^; Svnthesis of 4-r ⁽ R ⁾ -2-rr(S)-2-r2-(6-amidino- 1 - ethylindol-2-yl)ethyl]pyrrolidinyl]qarbonyl3ρ ^j ατplidmyilιdSJ^2z- amino-4-oxobutanoic acid (Compound 161)

170m ^g of ethyl-4-[ ⁽ R ⁾ -2-[[ ⁽ S)-2-[2- (6-amidino-l -ethylindol-2- yl ⁾ ethyl]pyπOlidinyl]carbonyl]pyπOlidinyl]- ⁽ S ⁾ -2-amino-4-oxobutanoate and 130ιn ^g of l-etlιyl-2-[2-[ ⁽ S ⁾ -l-[ ⁽ R ⁾ - l-( ⁽ S ⁾ -3-amino- 3-carbamoylpiO- Iιanoyl)pyriOlidin-2-yl3carbonyl]pyιτolidin-2-yl]ethyl]in dole-6-carboxami- dine were reacted under the same conditions as Example 44 to obtain 170 mg of the title compound as a white solid.

'II NMR(MeOII-d,, ppm) : δ 7.7δ(m, HI), 7.46(m, HI), 7.2δ(m, HI), 6.31 ⁽ s, HI ⁾ , 4.52 ⁽ m, HI ⁾ , 4.18-4.05 ⁽ m, 311), 3.77-3.38(m, 511), 2.89- 2.39(m, 411), 2.29- 1.70(m, 1011), 1.26U, 311) ES-MS : 498(M+2 ^{) *} IR(KBr) : 2980, 1615, 1459, 1381 cm ^{" 1}

Example 103 : Svnthesis _pf 1 ethvl-2- [2 ^~ r(S) ^~ l- |Tl- r(R)- l -r3- carbamoyl-(S)-3- [(methanesulfonyl )amino]propanoyl]pyrrolidin-2-yl 3carbonynpyrrolidin-2-vl3ethyl3indole-6-carboxamidine (Compound 1S2J

a) Synthesis of phenylmethyl 4-[(R)-2-[[(S)-2-[2-(6-cyano-l-ethylindol- 2-yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]-(S)-2-[(tert- butoxy)carbo- ny lamino] -4 -oxobutanoate:

0.3g of the compound II-a obtained in Example 57-b) and 0.346g of (S)-3-[( tert-butoxy )carbonylamino] -3- (benzyloxycarbonyl)propanoic acid were reacted according to the same procedure as Example 11-a) to obtain 0.54g of the title compound as a pale yellow solid.

¹ II-NMR(CDC1 ₃ , ppm ⁾ : δ 7.71(m, HI), 7.49(m, HI), 7.32-7.04(m, 611), 6.30(s, HI), 5.67(m, HI), 4.86-4.72(m, 211), 4.59-4.46(m, IH), 4.27-4.01(m, 311), 3.83-3.58(m, 211), 3.46-3.37(m, 211), 3.09-2.66 (m, 411), 2.27-1.69(m, 1011), 1.42(brs, 911), 1.25(t, 311) y ES-MS : 692(M+Na ^t ), 670(M+1) ⁺

b) Synthesis of phenylmethyl 2-amino-4-[(R)-2-[[(S)-2-[2-(6-cyano-l- ethylindol-2-yl ⁾ ethyl]pyrrolidinyl3carbonyl3pyιτolidinyl]-4-oxobutan oate:

10 0.53g of the compound obtained in the above a) was treated according to the same procedure as Example 1 -1) to obtain 0.40g of the title compound as a pale yellow solid.

¹ II-NMR(CDClj, ppm) : δ 7.58(m, 211), 7.40-7.21 (m, 611), 6.32(s, HI), 5.08 -4.96(m, 211), 4.67-4.48 ⁽ m, HI), 4.28-4.08(m, 311), 3.86-3.67(m, 311), 3.59-3.38(ni, 211), 2.78(m, 411), 2.30-1.76(m, 1011), 1.34(t, 311)

ES-MS : 570(M+1)'

20 c) Synthesis of phenylmethyl 4-[(R) -2-[[(S)-2-[2-(6-cyano-l -ethylindol- 2 \i)ethyl]pyιτolidin\i]carbonyl]pyrrolidinyl] -(S)-2-[(methylsulfonyl)- amino]-4-oxobutanoate:

395 mg of the compound obtained in the above b) and 0.08m£ of 5 methanesulfonyl chloride were reacted according to the same procedure as Example 1-m) to obtain 300mg of the title compound as a pale yellow solid.

'II-NMR(CDC1 ₃ , ppm) : δ 7.51(m, HI), 7.45(m, HI), 7.39(m, IH), 7.29(m, 0 3IR 7.10(m, 211 ⁾ , 6.31(s, HI), 5.73(m, III), 4.87-4.69(m, 211),

4.63-4.45(m, HI), 4.29-4.06(m, 311), 3.26-3.19(m, HI), 2.96(s, 3H), 2.90-2.67(m, 3H ⁾ , 2.30- 1.79(m, 1011), 1.33(t, 3H)

ES-MS : 670(M+Na'), 648(M+lK

5 d) Synthesis of l-ethyl-2-[2-[(S)-l-[[l-[(R)-l -[3-carbamoyl-(S)-3-

[ ⁽ methanesulfonyl ⁾ amino]propanoyl]pyiTolidin-2-yl3carbonyl]pyrrolidin- 2-yl]ethyl]indole-6-carboxamidine:

300ιng of the compound obtained in the above c) was treated according to the same procedure as Example 1 -n) to obtain 25mg of the title compound as a pale yellow solid.

¹ II-NMR ⁽ MeOII-d ₄ , ppm ⁾ : δ 7.76(m, HI), 7.49(m, HI), 7.28(m, HI), 6.34(s, HI ⁾ , 4.53 ⁽ m, HI ⁾ , 4.25-4.09(m, 411), 3.75-3.38(m, 411), 2.8δ-2.61(m, 411), 2.δ5(s, 311) 2.26- 1.69(m, 1011), 1.28(t, 3H)

ES-MS : 574(M+ D ^* IR(KBr) : 2993, 2385, 1681, 1632, 1472, 1389 cm '

Exam ^p le 104 : Svnthesis of ^JttRh2∑JIlS)s2-zl2≡18-jmidmQ-^ ethvlindol-2-yl)ethvl]pyrrolidinyl]carbonvl]pyrrolidi nyl3 ~(S)-2- I (met hanesulfonyl)amino3-4-oxob u tanoi c_ ac icLXC o jnpoju nd_163 )

6 ⁽⁾ mg of l -ethyl-2-[2-[ ⁽ S ⁾ - l-[[l -[(R ⁾ - l-[3-carbamoyl-(S)-3-

[ ⁽ methanesulfonyl ⁾ amino]propanoyl]pyπOlidin-2-yl]carbonyl]ρyrrolidin-2 -yl ]ethyl]indole-6-carboxamidine obtained in Example 103 was H eated according to the same procedure as Example 44 to obtain Iδmg of the title compound as a pale yellow solid.

¹ II-NMR(MeOII-d.ι, ppm) : δ 7.86(m, HI), 7.δ2(m, HI), 7.34(m, HI), 6.36 ⁽ _s , HI), 4.53(m, IH), 4.28-4.10 ⁽ m, 411), 3.77-3.39(m, 411), 2.87-

2.56(m, 711), 2.24- 1.68(m, 1011), 1.32(t, 311) ES-MS : 575(M+1) ^' IR(KBr) : 2998, 1628, 1468, 1332 cm ^{" 1}

Example 105 ^; Example of l-ethvl-2-[2-[(S)- I -rr(R)-( l-(4-amino - butanovl)nvrrolidin-2-vπcarbonvllpvrrolidin-2-vl3ethvnindol e-6- carboxaiηidϊne (Compound 166)

a ⁾ Synthesis of l-[4-[(R) -2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-cyano-l-ethylindol-2-yl)ethyl] -pyrrolidinyl]carbonyl]pyrrolidinyl]-4-oxobutyl3 ⁽ tert-bιιtoxy ⁾ formamide:

400mg of the compound II-a obtained in Example 57-b) and 270mg of 4- [(tert-butoxy )carbonylamino]butanoic acid were reacted according to the same procedure as Example 11-a) to obtain 360mg of the title 5 compound as a yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.55(m, 211), 7.26(m, 111), 6.37(s, Hi), 4.63(m, HI), 4.28(m, HI), 4.15(t, 211, J=7.20Hz), 3.82(m, HI), 3.66(m, 2H), 3.46(m, 311), 2.80(m, 411), 2.52(m, 211), 2.17(m, 411), 1.91(m, 2H), 10 1.42(m, 911), 1.35(m, 311)

b) Synthesis of l-ethyl-2-[2-[(S)-l-[[(R)- l -(4-aminobutanoyl)pyrrolidin- 2-y]]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine:

15 350mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 170mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , PPm) : δ 7.92(m, HI), 7.34(m, 211), 6.19(s, HI), 4.55(m, 20 HI), 4.16(m, 311), 3.78(m, HI), 3.62(m, 211), 3.41 (m, 3H), 2.62(m,

411), 2.30(m, 2H), 2.07(m, 311), 1.68(m, 411), 1.24(m, 3H) IR(KBr) : 3400, 3000, 1630 cm ^{" 1} ES-MS : 467(M+l) ^t

25 Example 106 : Svnthesis of l-ethvl-2-r2-f(S)- l-ι r(R)- l-[(2- piperidinyl)carbonyl3pyrrolidin-2-.yl3carbonyl]ρyrrolidin-2 -yl3ethyl3- indole-6-carboxamidine (Compound 167)

a) Synthesis of tert-butyl-2-[[(R)-2-[[(S)-2-[2- ⁽ 6-cyano-l-ethylindol- 30 2-yl)ethyl]pyrrolidinyl]carbonyl]pyπOlidinyl]carbonyl]piper idine carbo ^¬ xylate:

400mg of the compound II-a obtained in Example 57-b) and 300mg of l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid were reacted

^• '° according to the same procedure as Example 11-a) to obtain 350mg of the

title compound as a yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.57(ιn, 211), 7.26(m, HI), 6.35(m, 111), 4.66(m, Hi), 4.24(m, HI), 4.14 ⁽ m, 211), 3.87(m, 211), 3.48(m, 211), 2.80(m, 211), 2.15(m, 311), 2.04-1.92(br, 711), 1.46(m, 911), 1.35(t, 311)

b) Synthesis of l-ethyl-2-[2-[(S)- l-[[(R)- l-[(2-piperidyl)carbonyl]pyr- rolidin-2-yl]carbonyI]pyrrolidin-2-yl]ethyI]indole-6-carboxa midine:

330mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 200mg of thr title compound as a yellowish white solid.

'II NMR(CDC1 _:) , ppm) : δ 7.62(m, HI), 7.48(m, HI), 7.21(m, HI), 6.32(m, HI), 4.δ9(ιn, HI), 4.19(m, 411), 3.85(m, 211), 3.71(m, 211), 3.4(m,

311), 3.12(m, 211), 2.76(t, 211), 2.29-2.08(br, 311), 1.81 -1.65(br. 511), 1.39- 1.29 ⁽ br, 511), 1.23 ⁽ m, 311)

IR(KBr) : 3400, 2880, 1640 cm ^{" 1}

ES-MS : 493QI+ 1)'

Example 107 : Synthesis of 1 ethvl -2-r2-KS )- IzIRR) J^(3 - piperidinylcarbonyl)pyrrolidin-2-yl3carbonyl]pyrrolidin-2-vl 3ethvl1 - indolc-Q-carboxamidiπe (Compound J_68J

a) Synthesis of tert-butyl 3-[[(R)-2-[[(S)-2-[2-(6-cyano- l-ethylindol-2- yl)ethyl]pyιτolidinyl]carbonyl]pyrrolidinyl]carbonyl]piper idinecarboxylate:

300mg of the compound II-a obtained in Example 57-b) and 226mg of l -(tert-butoxycarbonyl)piperidine-3-carboxylic acid were reacted according to the same procedure as Example l l-a) to obtain 380mg of the title compound as a yellow oil.

1H NMR(CDCI ₃ , ppm) : δ 7.54(m, 211), 7.24(m, 111), 6.36 ⁽ s, HI), 4.6()(m,

HI), 4.26(m, HI), 4.15(m, 311), 3.84(m, 211), 3.71 ⁽ m, HI), 3.60(m. HI). 3.47(m, HI), 2.80(m, 311), 2.17(m. 211), 2.07- 1.90<br, 411).

1.45(m, 911), 1.35(m, 311) ES-MS : 576(M+1)\ 598(M+Na)

b) Synthesis of l-ethyl-2-[2-[(S)- l-[[(R)-l-(3-i)iperidinylcarbonyl)pyιτo- lidin-2-yl]caιbonyl]pyrrolidin-2-yl]ethyl]indole-6-caι-box amidine:

350mg of the compound obtained in the above a) was treated according to the same procedure as Example 1 -n) to obtain 210mg of the title compound as a yellowish white solid.

IR(KBr) : 3400, 2880, 1640 cm ^{" 1} ES-MS : 493(M+D ^*

Example 108 : Svnthesis of l-ethvl-2-[2-r(S)- l -IT(R)- l-r(4- piperidinvl)carhonvl]pyrrolidin-2-yl1carbonyl]pvrrolidin-2-y l3ethyl3- indole-6-carboxamidi ne (Compound 169)

a) Synthesis of tert-butyl 4-[[(R)-2-[[(S)-2-[2- (6-cyano- l -ethylindol-2- yl)ethyl]pyπOlidinyl]carbonyl]pyrrolidinyl]carbonyflpiperid ine carboxy - late:

300mg of the compound II-a obtained in Example 57-b) and 226mg of l - (tert-butoxycarbonyl ⁾ piperidine-4-carboxyIic acid were reacted according to the same procedure as Example 11-a) to obtain 200mg of the title compound as a yellow oil.

^! II NMR(CDCI _3l ppm) : δ 7.56(m, 211), 7.26(m, III), 6.38(s, HI), 4.54(m, HI), 4.23(m, 111), 4.12(m, 311), 3.80(m, 211), 3.72(m, IH), 3.51(m, 211), 2.79(m, 411), 2.5δ(m, 111), 2.30-2.14(br, 311), 2.01-1.92(br, 611), 1.7δ-1.66(br, 511), 1.44(m. 911). I.32(m, 311)

ES-MS : 576(M+1)\ 598(M+Na)

b) Synthesis of l -ethyl-2-[2-[(S) ^~ l-[[(R)- l-[(4-piperidinyl)carbonyl]~ pyrrolidin-2-yl]carbonyl]pyπOlidin-2-yl]ethyl]indole-6-carb oxamidine:

170mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain lOOmg of the title compound as a yellowish white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.84 ⁽ m, HI), 7.46(m, HI), 7.21(m, 111), 6.2δ(m, HI ⁾ , 4.58 ⁽ m, HI), 4.34(m, 211), 4.16(m, 211), 3.71(m, HI), 3.56(m, 211 ⁾ , 3.12 ⁽ m, HI), 2.63(m, HI), 2.57(m, 311), 2.05(m, 211), 1.99(m, 311), 1.62-1.55(br, 311), 1.25(m, 311) IR(KBr) : 3400, 3000, 1640 cm ^"1 ES-MS : 493(M+1)'

pyrrolidin-2-yl)carbonyJJpyrrolid_i_n-2-yl]ethyl3indole-6-ca rboxami- dine (Compound 170)

a) Synthesis of l -methyI-2-[2-[(S)-l-[((R)- l -acetylpyιτolidin-2-yl)- carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carbonitrile:

90mg of the compound π-b obtained in Example 58-a) was dissolved in dichloromethane and the resulting solution was cooled to -78 ^° C . 182/4 of triethylamine was added thereto and after 20 minutes, 356 /4 of acetyl chloride was added dropwise. After 20 minutes, water was added and the reaction solution was extracted twice with dichloromethane. The extracts were combined, dried over MgSO i amd then concentrated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(20:l)] to obtain 69mg of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.68(s, HI), 7.45(d, HI), 7.14(d, IH), 6.32(s, IH), 4.45(m. HI), 4.09(m, HI), 3.80(s, 311) 3.44(m, 211), 2.70(m, 211),

1.97(s, 311), 2.20-1.65(m, 1211)

b) Synthesis of l -methyl-2-[2-[(S)-l-[((R)- l-acetylpyrroIidin-2-yl)- carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine:

210mg of the compound obtained in the above a) was treated according to the same procedure as Example 1 -n) to obtain 117mg of the title compound as a pale yellow solid.

^J II NMR(MeOII-d ₄ , ppm) : δ 7.88(s, HI), 7.59(d, HI), 7.44(d, HI), 6.46(s, 111), 4.6δ-4.57(m, HI), 4.25-4.15(m, HI), 3.80(s, 311), 3.62(m, 211), 2.88(m, 211), 2.11(s, 311), 2.35- 1.80(m, 1211)

Example 110 : Synthesis of l-ethyl-2- I2-r(S)- l- r((R)- l -acetvl - pyrrolidin-2- ^y l)carbonyl]pyrrolidin-2-ynethyl3indole-β-carboxami- dine (Compound 171)

a) Synthesis of l-ethyl-2-[2-[(S)- l -[ ⁽ (R)-l-acetylpyrrolidin-2-yl)carbo- nyl]pyπOlidin-2-yI]ethyl3indole-6-carbonitrile:

45 mg of the compound π-a obtained in Example 57-b) was dissolved in dichloromethane and the resulting solution was cooled to -78 °C . 34 _/ 4 of triethylamine was added thereto and after 20 minutes, 18 _/ 4 of acetyl chloride was added dropwise. After 20 minutes, water was added and the reaction solution was extracted three times with dichloromethane. The extracts were combined, dried over MgSO i amd then concentrated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(20:l )] to obtain 38mg of the title compound as a white solid.

^! II NMR(CDC1 ₃ , ppm) : δ 7.60-7.48(m. 211), 7.27(s, HI), 6.36(s, III), 4.57 ⁽ t, 111 ⁾ , 4.25 ⁽ bs, HI ⁾ , 4.20-4.08(m, HI), 3.55-3.36(m, 211), 2.80(t, 2H), 2.09(s, 311), 2.40-1.70(m, 12H), 1.34(t, 311)

b) Synthesis of l-ethyl-2-[2-[(S)-l-[((R)-l-acetylpyrrolidin-2-yl)carbo- nyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine:

800mg of the compound obtained in the above a) was dissolved in

30ml of ethanol solution saturated with HCI gas. The resulting solution was allowed to stand for 2 days at room temperature and then

concentrated under reduced pressure. The remaining HCI was removed for 5 hours by means of a vaccum pump. The dried product was then dissolved in 30ιnC of ethanol solution saturated with NII ₃ gas. After 2 days, the resulting solution was concentrated under reduced pressure. The residue was purified with column chromatography [eluent: ethyl acetate/methanoK 1:1)3 on Nil -DM1020 silica to obtain 467mg of the title compound as a white solid.

1H NMR(MeOH-d ,, ppm) : δ 7.92(s, HI), 7.6δ(d, HI), 7.45(d, III), 6.49(s, HI), 4.62 ⁽ t, HI), 4.27 ⁽ m, 311), 3.73-3.48(m, 211), 2.89(t, 211),

2.10(s, 311), 2.30- 1.80(nι, 1211), 1.40(t, 311)

Example 111 : Svnthesis of 3 -ethvl-2- [2-r(S)- l-rr(R)- l-(2-propvl- p.e n tanoyl)pyrrolidin-2-vl3carbonvl3ρyrrolidin-2-vl]ethyllindol e-6- carboxamidine (Compound 173)

a) Synthesis of l-ethyl-2- [2-[(S)- l -[[(R)- l-(2-propylpentanoyl)pyrroli- din-2-yl]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carbo nitrile:

300ιng of the compound II-a obtained in Example 57-b) and 0.257 ml of 2-propylpentaπoic acid were reacted according to the same procedure as Example 11 -a) to obtain 380mg of the title compound.

1H NMR(CDC1 ₃ , ppm) : δ 7.65-7.47(ιn, 211), 7.25(d, IH), 6.35(s, 111), 4.68 (m, IH), 4.24(m, 211), 4.14(q, 211), 3.88(m, IH), 3.73(m, HI), 3.56

(m. 111), 3.41(m, HI), 2.77(m, 2H), 2.5δ(m, IH), 2.37- 1.50(m, 1011), 1.43- 1.17(m, 1111), 0.87(t, 311), 0.79(t, 311)

b) Synthesis of l -ethyl-2-[2-[(S)- l-[[(R)- l -(2-ρroρylpentanoyl)ρyrrolidin - 2 yl]carbonyl]pyrrolidin-2-yl]ethyl]indoIe-6 -carboxamidine:

380mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 268mg of the title compound.

1H NMR(MeOH-dι, ppm) : δ 7.71(s, HI), 7.60(d, HI), 7.25(d, HI), 6.33(s, HI), 4.65(m. HI), 4.21(m, 311), 8.89(m, HI), 3.74(m, HI), 3.60(m, HI), 3.46(m, HI), 2.78(m, 211), 2.54(m. HI), 2.3()-1.50(m, 1211), 1.42-0.92(m, HID, 0.85(t, 311), 0.77(t, 311) ES-MS : 508(M+1)'

Example 112 : Svnthesis of ethvl 3-r(R)-2-rr(S)-2 r2-(6-amidino- lι:ejLhylindol-2-vl)ethyl]pyrrolidinyl]carbonyllpyrrolidiny Il-3-oxopro rjaajnoatt; (Compound 174)

a) Synthesis of methyl 3-[ ⁽ R ⁾ -2-[[ ⁽ S) -2-[2-(6-cyano-l-ethyIindol-2-yI)- ethyl]pyπ"olidinyl]carbonyl]pyιτolidinyl]-3-oxopropanoate :

600mg of the compound II ^~ a obtained in Example 57-b) and 0.353 inP of ethvlsuccinyl chloride were reacted according to the same procedure as Example 1 -m) to obtain 414mς of the title compound.

'II NMR(CDCb, ppm) : δ 7.52(t, 211), 7.22(s, III), 6.32(s, HI), 4.65(m, HI), 4.25(m, HI), 4.16(q, 211), 3.72(m, 511), 3.62(m, 211), 3.42(m, 311), 2.77(m, 211), 2.30- 1.80(m. 1011), 1.34(t, 311)

b) Synthesis of ethyl 3-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yD- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]-3-oxopropanoate:

300mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 97mg of the title compound as a pale yellow solid.

^J II NMR(MeOII-dι, ppm) : δ 7.87(s, Hi), 7.64(d, IH, J=8.40Hz), 7.44(d, HI, J=6.67IIz), 6.49(s, IH), 4.30(m, 311), 4.18(q, 211), 3.82(m, HI),

3.75-3.50(m, 411), 3.00-2.75(m, 211), 2.45-1.75(m, 1211), 1.40(t,

311), 1.20(t, 3H) ES-MS : 496(M+ 1) '

Example 113 : Svnthesis of l-ethvl-2- [2-r(S)~ l -FKR)- l-(2~carba-

c arboxamidine (Compound 175)

300m ^g of methyl 3-[ ⁽ R ⁾ -2-[[ ⁽ S)-2-[2- ⁽ 6-cyano- l-ethylindol-2- yl ⁾ ethyl]pyrroIidinyl3carbonyl3pyriOlidinyl]-3-oxoproρan oate obtained in Example 112-a ⁾ was treated according to the same procedure as Example 1 -n) to obtain 64mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.81(s, HI), 7.48(d, 111), 7.33(d, HI), 6.36(s, HI ⁾ , 4.16 ⁽ m, 311 ⁾ , 3.73 ⁽ m, HI), 3.56(m, 211), 3.45(m, 211), 2.75(m,

211), 2.29-1.50(m, 1211), 1.23(t, 311)

Example 114 : Svnthesis of ethvl 4-r(R)-2-rr(S)-2-r2-(6-amidino- l -ethylindol-2-yl)ethy 1 J pyrrolid inyl3carhonyl3 pyrrolidinyl] -4-oxobuta -noate (Compound 176)

a) Synthesis of ethyl 4-[(R)-2-[[(S)-2-[2-(6-cyano- l-ethyJindol-2-yl)- ethyl]pyιτolidinyl]carbonyl]pyrrolidinyl]-4-oxobutanoate:

30()mg of the compound II-a obtained in Example 57-b) and 250mg of ethyl 3- (chlorocarbonyl)propanoate were reacted according to the same procedure as Example 1 -m) to obtain 380mg of the title compound.

1H NMR(CDC1 ₃ , ppm) : δ 7.82(s, HI), 7.45(d, HI, J=8.22Hz), 7.13(d, HI, J=6.83Hz), 6.32(s, HI), 4.50(m, 111), 4.20-3.90(m, 511), 3.70(m,

111), 3.56(m, Hi), 3.43(m, 211), 2.85-2.34(m, 611), 2.22-1.65(m, 10H), 1.23(t, 311), 1.13(t, 311)

b) Synthesis of ethyl 4-[ ⁽ R)-2-[[(S)-2-[2- ⁽ 6-amidino-l-ethyIindol-2-yl)- ethyl3pyn"olidinyl]carbonyl3pyrrolidinyl] -4 -oxobutanoate:

380mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 117mg of the title compound.

^] II NMR(MeOH-d ₄ , ppm) : δ 7.82(s, HI), 7.50(d, HI), 7.40(d, HI), 6.30(s, HI), 4.50(m, HI), 4.3()-3.80(ιn, 511), 3.67(m, HI), 3.6()-3.30(m, 311), 2.90-2.35(m, 611), 2.20-1.70(m, 1011), 1.30- 1.05(m, 611) ES-MS : 5KKM+1)'

Example 115 : Svnthesis of 4-i (R)-2-rr(S)-2-r2-(6-amidino l- ethyli ndol-2-yl)ethyπpyrrolidinyl3carbonyπpyrrolidinyll^4rpxohu_ ta^ noic acid (Compound 177)

153ιng of ethyl 4-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2-(6-amidino- l-ethylindol-2-yl)- ethyl]pyrrolidinyl3carbonyl]pyrrolidiny]]-4-oxobutanoate obtained in

Example 114 was treated according to the same procedure as Example 44 to obtain 120mg of the title compound as a white foamy solid.

^l ll NMR(CDCl i, ppm) : δ 7.75(s, HI), 7.40(ddd, 211, J=8.28IU 4.60Hz, 1.61Hz), 6.30(s, HI), 4.50(m, HI), 4.10(m, 211), 3.80-3.30(m. δll), 2.90-2.55 (m, 211), 2.5o-1.60(m, 1411), 1.25(t, 311, J=7.14Hz) ES-MS : 482(M+ 1) '

IR(KBr) : 3190, 2950, 1620 cm ^{" 1}

Example 116 : Synthesis of l-ethyl-2-r2-r(S)- ] -IT(R)- l-(3-sulfa- nylpropanoyl)pyrrolidin-2-yl]carbonyl3pyrrolidin-2-vl3ethyl] indole-6 -carboxamidine (Compound 178)

a) Synthesis of l-ethyl-2-[2-[(S)-l-[[(R)- l-(3-sulfanylρropanoyl)ρyrro- lidin-2-yl]carbonyI]pyrrolidin-2-yl]ethyl]indole-6-carbonitr ile:

105mg of the compound II-a obtained in Example 57-b) and 28 _/ 4 of 3-sulfanylpropanoic acid were reacted according to the same procedure as Example 11-a) to obtain 42mg of the title compound as a white solid.

'II NMR(CDC1 ₃ , ppm) : δ 7.61-7.24(m, 3H), 6.37(s, HI), 4.64(m, HI), 4.26 (brs, HI), 4.14(q, 211, J=6.83Hz), 3.88-3.45(m, 411), 2.8()-2.61(m, 611), 2.22-1.79(m, 1011), 2.70(t, 311, J=7.25Hz)

b) Synthesis of l -ethyl-2-[2-[ ⁽ S ⁾ -l -[[ ⁽ R ⁾ -(l-(3-sulfanylpropanoyl)pyrro- lidin-2-yl]carbonyl]pyrroIidin-2-yl]ethyl]indole-6-carboxami dine--

42mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 14mg of the title compound as a pale yellow solid.

1H NMR ⁽ MeOH-d ₄ , ppm) : δ 7.78(s, HI), 7.49-7.29(m, 211), 6.31(s, III), 4.51 ⁽ m, HI ⁾ , 4.19-4.08 ⁽ m, 311), 3.71-3.34(m, 411), 2.82-2.50(m, 611), 2.10-1.71(m, 1011), 1.25(m, 3H)

IR(KBr) : 3400, 3000, 1640, 1480 cm ^{" 1} ES-MS : 470(M+lT

Example 117 : Svnthesis of 1 -ethyl- 2-[2-[(S)- l -[[(R)- l-(3-hvdro- xybutanoyl)pyrrolidin-2-yl3carbonyl]pyrrolidin-2-yl3-ethyl]i ndole-6- carboxamidine (Compound 180)

a) Synthesis of l -ethyl-2-[2-[ ⁽ S ⁾ -l-[[(R)- l -(3-hydroxybutanpyl)pyrroli- din-2-yl]carbonyl]pyπOlidin-2-yl]ethyl]indole-6-carbonitril e:

O.δg of the compound Il-a obtained in Example 57-b) and 0.4m(! of 4-hydroxypentanoic acid were reacted according to the same procedure as Example 1 1-a) to obtain 0.6g of the title compound as a pale yellow solid.

^: II NMR(CDC1 ₃ , ppm) : δ 7.61-7.δl(m, 211), 7.27(m, IH), 6.38(s, HI), 4.66-4.44(m, IH), 4.37-4.14(m, 311). 3.89-3.66(m, 211), 3.59-3.40 (m, 211), 2.83(m, 211), 2.59-2.29(m, 3H), 2.24-1.72(m, 1011), 1.38 (t, 311), 1.22(t, 311)

ES-MS : 473(M+Na'), 45HM+1)'

b) Synthesis of l -ethyl-2-[2-[(S)-l-[[(R)-l-(3-hydroxybutanoyl)pyrroli- din-2-yl]carbonyl]pyιτolidin-2-yl]ethyl]indole-6-carboxami dine

0.6g of the compound obtained in the above a) was treated

according to the same procedure as Example 1-n) to obtain 0.6g of the title compound as a pale yellow solid.

1H NMR(MeOII-d ι, ppm) : δ 7.78 ⁽ m, HI), 7.48(m, HI), 7.29(m, HI), 6.34 (s, HI ⁾ , 4.59-4.35 ⁽ m, HI), 4.29-4.07(m, 311), 3.79-3.41(m, 411), 2.80 ⁽ m, 211), 2.58-2.51(m, 311), 2.11 - 1.78(m, 1011), 1.27(t, 3H), 1.10(t, 311)

ES-MS : 468(M+l) ^f

IR(KBr) : 3167, 2973, 1614, 1508, 1451, 1322 cm '

Example 118 : Svnthesis of l-ethvl-2 J2_- US ) l- [((R)- l-prop-2- -amidine (Compound 182)

320mg of l-etlιyl-2-[2-[ ⁽ S)-l -[[ ⁽ R ⁾ -l-(3-chIoroproρanoyl)ρyrroli- din-2-yl]carbonyl]pyπOlidin-2-yl]ethyI]indole-6-carbonitril e obtained in Example 96-a) was treated according to the same procedure as Example 1-n) to obtain 84mg of the title compound as a pale yellow solid.

^J II NMR(MeOH-d _l , ppm ⁾ : δ 7.96 ⁽ s, HI), 7.64(d, 111, J=8.29Hz), 7.44(d, HI, J=8.38IIz), 6.70 ⁽ q, HI ⁾ , 6.δ ⁽⁾⁽ s, HI), 6.29(d, HI, J=16.85Hz), 5.77(d, HI, J- 12.40Hz), 4.32(m, 311), 3.7()(m, 311), 3.68(m, 211), 3.59(m, 211), 2.9 ⁽ )(m, 211), 2.3δ- 1.80(m, 1211), 1.39(t, 311)

Example 119 : Svnthesis of l-methyl-2 [2- [(S)- l-r[(R)- l- (methane -sulfonyl)ρyrrolidin-2-yl3carbonyl3pyrrol idin-2-yl3ethylJindole-6- carboxamidine (Compound 183)

a) Synthesis of l-methyl-2-[2-[ ⁽ S)-l -[[(R)- l -(methanesulfonyl)pyrrolidin -2-yI]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carbonitrile:

80mg of the compound II-b obtained in Example 58-a) was dissolved in dichloromethane, and the resulting solution was cooled to -78

V . 64/4 of triethylamine was added thereto and, after 20 minutes, 40 _/ 4 of methanesulfonyl chloride was added dropwise. After 20 minutes.

water was added and the reaction solution was extracted two times with dichloromethane. The extracts were combined, dried over MgSOi amd then concentrated. The residue was purified with silica gel column chromatography [eluent: diclιloromethane/methanol(50:l)] to obtain 69ιng of the title compound as a yellowish white solid.

^] II NMR(CDC1 ₃ , ppm) : δ 7.56-7.50(m, 211), 7.32(d, HI), 6.38(s, HI), 4.61 (m, 111), 3.79(bs, 111), 3.70(s, 311), 3.60-3.30(m, 211), 2.98(s, 311), 2.28(m, 211), 2.30-1.70(m, 1211)

b) Synthesis of l -methyl-2-[2-[ ⁽ S ⁾ -l-[[(R)-l-(methanesulfonyl)pyπ-olidin -2- yl]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carboxamidine:

56 mg of the compound obtained in the above a) was dissolved in 15mC of ethanol solution saturated with HCI gas. The resulting solution was allowed to stand for one day at room temperature and then concentrated under reduced pressure. The remaining HCI was removed for 5 hours by means of a vaccum pump. The dried product was then dissolved in 15m t of ethanol solution saturated with NH ₃ gas. After 2 days, the resulting solution was concentrated under reduced pressure. The residue was purified with column chromatography [eluent: dichloro- methane/methanol(3:l)] on NH-DM1020 silica to obtain 41mg of the title compound as a yellowish white solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.03(s, HI), 7.35(m, 211), 6.19(s, 111). 4.δδ(m, 111), 4.14(bs, IH), 3.64(s, 311), 3.43(m, 211), 2.92(s, 311), 2.67(m, 211), 2.30-1.70(m, 1211)

Example 120 : Svnthesis of l-ethyl-2-r2-r(S )- l-IT(R)- l-(methane- sulfonvl)pyrrolidin-2-yl]carbonyl]pyrrolidiπ- 2 yl]ethyl]iπdole-6 car¬ boxamidine (Compound 184)

a) Synthesis of l-ethyI-2-[2-[(S)- l-[[(R)- l-(methanesulfonyI)pyrrolidin- 2-yl]carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carbonitrile:

l.OOg of the compound II-a obtained in Example 57-b) was dissolved in dichloromethane, and the resulting solution was cooled to 0 °C . 0.75mfi of triethylamine was added thereto and after 20 minutes, 0.42 ml of methanesulfonyl chloride was added dropwise. After 20 minutes, water was added and the reaction solution was extracted two times with dichloromethane. The extracts were combined, dried over MgSO.i amd then concentrated. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(50: l)] to obtain 524mg of the title compound as a white solid.

'II NMR(CDC1 ₃ , ppm) : δ 7.48(m, 211), 7.29(d, HI), 6.37(s, HI), 4.57(t, HI), 4.20(bs, HI), 4.10(m, 211), 3.49-3.32(m, 211), 2.99(s, 311), 2.86-2.70(m, 211), 2.30-1.6δ(m, 1211), 1.33(t, 311)

b) Synthesis of l-ethyl-2-[2-[(S)- l -[[(R)- l -(methanesulfonyl)pyrrolidin- 2-yl]carbonyl]pyιτolidin-2-yl]ethyl]indole-6-carboxamidine :

430mg of the compound obtained in the above a) was dissolved in 30mC of ethanol solution saturated with HCI gas. The resulting solution was allowed to stand for two days at room temperature and then concentrated under reduced pressure. The remaining HCI was removed for 5 hours by means of a vaccum pump. The dried product was then dissolved in 80ml of ethanol solution saturated with NI1 ₃ gas. After 3 days, the resulting solution was concentrated under reduced pressure. The residue was purified with column chromatography [eluent: ethyl acetate/methanoK 1:1)3 on NII-DM1020 silica to obtain 184mg of the title compound as an orange solid.

^! II NMR(CDC1 ₃ , ppm) : δ 8.90(bs, Hi), 8.54(bs, HI), 7.35(s, HI), 6.15(s, HI), 4.5δ(s, 111), 4.16(m, IH), 3.70(q, 211), 2.95(s, 311). 2.70(m,

211), 2.30-1.70(m, 1211), 1.18(t, 3H)

Example 121 : Svnthesis of ethvl 2-[(S )-2-rr(S)-2-r2-(6-amidino- l-ethylindol-2-yl)ethyl3pyrrolidinvncarbonyllDvrrolidinyl3ac etate (Compound 186)

a) Synthesis of tert-butyl ⁽ S ⁾ -2-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidine carboxylate:

l.Og of the compound I-a obtained in Example 1-1) and 0.94g of l-(tert-butoxycarbonyl)-L-proline were reacted according to the same procedure as Example 11-a) to obtain 736mg of the title compound.

^] H NMR(CDC1 ₃ , ppm ⁾ : δ 7.61-7.51(m, 211), 7.30(m, HI), 6.38(d, HI, J=9.95Hz), 4.35 ⁽ m, HI), 4.2()-4.05(m, 211), 3.85-3.35(m, 411), 2.80(m, 211), 2.30-1.70(m, HI), 1.50-1.29(m, HID

IR(KBr) : 3400, 3000, 2220, 1700, 1660 cm ^" '

b ⁾ Synthesis of l -ethyl-2-[2-[ ⁽ S ⁾ - l - ^{( (} S ⁾ -pyrroIidin-2-ylcarbonyl)pyrroli- din-2-yl]ethyl]indole-6-carbonitrile:

736mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-1) to obtain 700mg of the title compound.

^] II NMR(CDC1 _:! , ppm) : δ 7.58(s, HI), 7.54(d, HI, J=8.28Hz), 7.28(d, HI, J=8.27Hz), 6.36(s, Hi), 4.5 ⁽⁾ -4.10(m, 1011), 3.70-3.24(m, 411), 2.80 (m, 211), 2.50-1.71(m, 1011), 1.34(t, 311)

c) Synthesis of ethyl 2-[ ⁽ S)-2-[[(S)-2-[2-(6-cyano- l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate:

700mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-m) to obtain 746mg of the title compound.

'II NMR(CDC1 ₃ , ppm) : δ 7.δδ(t, IH), 7.24(d, IH), 6.50(s, IH), 4.31(m, IH), 4.17(m, 411), 3.85(m, Hi), 3.48(m, 311), 3.22(m, IH), 2.82(m, 2H), 2.35-1.60(m, 1011), 1.43- 1.20(m, 6H)

d) Synthesis of ethyl 2-[(S)-2-[[(S)-2-[2-(6-amidino- l-ethylindol-2-yl)-

ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate:

746 mg of the compound obtained in the above c) was treated according to the same procedure as Example 1-n) to obtain 233 mg of the title compound.

^] II NMR(MeOII-d ₄ , ppm) : δ 7.77(s, HI), 7.51(d, HI, J=8.29IIz), 7.32(d, HI, J=8.30Hz), 6.35(s, IH), 4.30-4.12(m, 311), 3.72(m, III), 3.58- 3.10(m, 511), 2.77(m, 211), 2.60(m, III), 2.22 -1.61(m, 1011), 1.27(t, 311), 1.12(t, 3H)

ES-MS : 458(λl+l)'

IR(KBr) : 3200, 1630 cm ^{" 1}

Example 122 : Svnthesis of l ethvl-2-[2-[(S)- l-rr(R)- l-(carbamovI -methvl )-5-oxo-pyrrolidin-2-yl]carbonvl]pyrrolidin -2-yl]ethyl3- indole-6-carboxamidine (Compound 187)

a) Synthesis of l-ethyl-2-[2-[(S ⁾ - l-[(R)-δ-oxopyrro]idin-2-yl)carbonyl]- py rrolidin - 2 - y l]ethyl]indole-6 - carbonitrile:

202mg of the compound I-a obtained in Example 1-1) and 107mg of δ-oxopyrrolidine-(R)-2-carboxylic acid were reacted according to the same procedure as Example 11-a) to obtain 136mg of the title compound as a white solid.

'II NMR(CDC1 ₃ , ppm) : δ 7.61-7.52(m, 211), 7.2δ(m, HI), 6.50(s, III), 6.40 (s, HI). 4.34-4.10(m, 411), 3.58-3.46(m, 211), 2.78(t, 211, J=7.89 Hz), 2.44-1.66(m, 1011), 1.34(t, 311, J=7.20Hz)

b) Synthesis of ethyl 2-[ ⁽ R)-5-[[(S)-2-[2-(6-cyano-l -ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]-2-oxopyrrolidinyl]ethanoate:

160mg of the compound obtained in the above a) and 0.052ml of ethyl bromoacetate were dissolved in 3ml of anhydrous tetrahydrofuran, and 19mg of Nail was added thereto. The reaction mixture was heated

under refluxing for 5 hours with stirring. After 0.5ml of water was added dropwise, the reaction solution was evaporated under reduced pressure. The residue was diluted with lδOml of dichloromethane, washed with 30ml of water, dried over sodium sulfate and then filterd. The filtrate was then evaporated under reduced pressure. The residue was purified with silica gel column chromatography [eluent: dichloro- methane/methanol(40:l)]. The fractions containing the desired product were combined and then evaporated to obtain 141mg of the title compound as a viscous oil.

^] II NMR(CDC1 ₃ , ppm) : δ 7.62-7.f>5(ni, 211), 7.32(m, 111), 6.41(s, HI), 4.69 (m, 211), 4.29-4.11(m, 611), 3.67-3.41(m, 211), 2.79(t, 211, J=7.98Hz), 2.56-1.65(m, 1011), 1.37(t, 311, J=7.21IIz), 1.24(t, 311, J=7.09Hz)

c) Synthesis of l-ethyl-2-r2-[(S)-l-[[(R)- l -(carbamoylmethyl)-5-oxo- pyrrolidin-2-\i]cai-bonyl3pyiTolidin-2-yl]ethyl]indole-6-car boxamidine:

141mg of the compound obtained in the above b) was treated according to the same procedure as Example 1 -n) to obtain 25mg of the title compound as a pale yellow solid.

'II NMR(MeOII-d ₄ , ppm) : δ 7.80(s, HI), 7.58-7.31(m, 211), 6.40(s, HI), 4.59(m. HI), 4.21 -4.14 ⁽ m, 411 ⁾ , 3.64-3.32(m, 311), 2.82-2.73 ⁽ m, 211), 2.37-1.79(m. 1011), 1.30(t, 3H, J=7.15Hz)

ES-MS : 453QI+1) ^*

Example 123 : Svnthesis of 2-[(R)-5-[r(S)-2-ι2-(6-amidino-l- ethylindol-2-yl)ethyl]pyrrolidinyl3carbonyl]-2-oxopyrτolidi nyl3acetic acid (Compound 188)

12mg of l-ethyl-2-[2-[(S)-l -[[(R)- l -(carbamoylmethyl)-5-oxo- pynOlidin-2-yl]carbonyl]pyιτolidin-2-yl]ethyl]indole-6-car boxamidine obtained in Example 122-c) was treated according to the same procedure as Example 44 to obtain 6ιng of the title compound as a pale yellow solid.

^J II NMR(MeOH-d.,, ppm) : δ 7.79(s, HI), 7.54-7.30(m, 211), 6.38(s, HI), 4.34(d, HI, J=17.12Hz), 4.22-4.05 ⁽ m, 311), 3.63-3.34(m, 311), 3.13 (d, HI, J=17.17Hz), 2.81-2.70 ⁽ m, 211), 2.37-1.71(m, 1011), 1.29(t, 311, J=7.15Hz)

ES-MS : 454(M+l) ^f

Example 124 : Svnthesis of l-ethvl-2-r2- [(S)- l-r(2-pjperidvl)- carbonyl3ρyrrolidin-2-yl3ethyl1indole-6-carboxamidine (Compound 18JD

a ⁾ Synthesis of tert-butyl -2-[[ ⁽ S)-[2- ⁽ 6-cyano-l -ethylindol-2-yl)ethyl3- pyrrolidinyl]carbonyl]piperilidine carboxylate-'

1.7g of l-ethyl-2-[[(S)-pyn-olidin-2-yl)ethyl]indole-6-carbonitrile was reacted with 1.75g of l-(tert-butoxycarbonyI)-pipecolinic acid according to the same procedure as Example 11 -a) to obtain 1.17g of the title compound as a pale yellow foam.

^] II NMR(CDC1 ₃ , ppm) : δ 7.63-7.53(m. 211), 7.29-7.26(m, HI), 6.37(s, HI), 4.77(br, IH), 4.31(br, HI), 4.19-4.14(m, 211), 3.93-3.89(m, HI), 3.74-3.70(m, Hi), 3.52-3.48(m, 211), 2.80-2.75(m, 2H), 2.19-2.14 (m, 111), 2.01 - 1.62 ⁽ m, HID, 1.49-1.42(m, 911), 1.35(t, 311, J=7.20Hz)

b) Synthesis of l-ethyl-2-[2-[(S)-l-[(2-piperidyl)carbonyI]pyrrolidin-2- yl]ethyl]indole-6-carboxamidine:

40mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 19mg of the title compound as a white solid.

Η NMR(MeOH-d ₄ , ppm) : δ 7.77(s, IH), 7.52-7.30(m, 2H), 6.33(s, HI), 4.20-4.01(m, 311), 3.56(m, III), 3.47-3.31(m, 211), 3.02-2.50(m, 411), 2.23- 1.04(m, 1211), 1.26(m. 311)

IR(KBr) : 3400, 2980, 1640, 1550, 1480 cm ^{" 1} ES-MS : 396<M+D ^*

ExamBlc_12.5 : Synthesis__of ethvl 2-r2-[f(S)-r2-(6-amidino- l - ethvlindol -2-yl)eth ^y llpyrroiidiar23yJlcaiinmyi3^meji_dinvπ (Compound 190)

a ⁾ Synthesis of ethyl 2-[2-[[ ⁽ S ⁾ -[2- ⁽ 6-cyano-l-ethylindol-2-yl)ethyl3- pyrroIidin-2-yl]carbonyl]piperidinyl]ethanoate:

120m ^g of tert-butyl-2-[[ ⁽ S ⁾ -[2- ⁽ 6-cyano- l -ethylindol-2-yl)ethyl3- pyrrolidinyl]carbonyl]piperidine carboxylate obtained in Example 124-a) was treated according to the same procedure as Example 1-1) to obtain 86 mg of the white solid product, which was then reacted with ethyl 2 -bromoacetate according to the same procedure as Example 1 -m) to obtain 85mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.58(s, III), 7.56- 7.27(m, 211), 6.44(d, HI, J=7.62Hz), 3.71(brs, 211), 3.6()-3.49(m, 211), 3.40-3.28(m, IH),

3.03-2.δ6(m, 411), 2.36-1.65(m, 1211), 1.36(t, 311, J=8.58Hz), 1.27- 1.17(m. 311)

b) Synthesis of ethyl 2-[2-[[ ⁽ S)-[2- ⁽ 6-amidino-l-ethylindol-2-yI)ethyl]- pyrrolidin-2-yl]carbonyl]piperidinyl]ethanoate :

78mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 32mg of the title compound as a pale yellow solid.

'II NMR(MeOII-d,, ppm) : δ 7.79(s, HI). 7.δ6-7.31(m, 211), 6.36(s, HI), 4.27-4.11(m, 311), 4.02-3.83(m, 211), 3.69-3.21(m, 511), 3.94-2.50 (m, 411). 2.22- 1.46 ⁽ m, 12H), 1.29(m, 311), 1.14-1.05(m, 3H)

IR(KBr) : 3400, 2990. 1755, 1690, 1640, 1550, 1485 cm '

ES-MS : 482(M+ D ^*

Example 126 : Svnthesis of ethvl 2-l2-ir(S)-2- r2-(fi-amidinn- l - e thy I i ndol-2-yl)ethyl]piperidinyl1_carbi>nχl1ρJperi dinyl]acetate (Compound 191)

o a) Synthesis of tert-butyl 2-[[(S)-2-[2-(6-cyano-l-ethyIindol-2-yl)ethyl] -piperidinyl]carbonyl3piperidine carboxylate:

600m ^g of l-ethyl-2-[2- ⁽⁽ S ⁾ -piperidinyl)ethyl]indole-6-caι-bonitrile and δOOmg of l-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid were 10 reacted according to the same procedure as Example 11 -a) to obtain 300 mg of the title compound as a yellow oil.

^] II NMR(CDC1 ₃ , ppm) : δ 7.57(m, 211), 7.30(m, 111), 6.35(s, III), 4.95(br, HI), 4.12(m, 211), 3.90(br, III), 3.72(m, III), 2.71 (m, 211), 2.21 (m, 15 HI), 1.84(m, 211), 1.45(m, 911), 1.33(m, 3H)

b) Synthesis of l-ethyl-2-[2-[l-[((S)-2-piperidinyl)carbonyl]-2-piperi- dyl]ethyl]indole-6-carbonitrile:

20 280mg of the compound obtained in the above a) was treated according to the same procedure as Example 1 -1) to obtain 210mg of the title compound as a pale yellow solid.

c ⁾ Synthesis of ethyl 2-[2-[[ ⁽ S ⁾ -2-[2- ⁽ 6-cyano-l -etlιyIindol-2-yI ⁾ etlιyl3- 25 piperidyl]carbonyl]piperidinyl]acetate:

200mg of the compound obtained in the above b) and 0.085ml of ethyl 2 -bromoacetate were reacted according to the same procedure as Example 1 -m) to obtain 120mg of the title compound as a pale yellow oil. 0

TI NMR(CDCI ₃ , ppm) : δ 7.56(m, 211), 7.29(m. IH), 6.38(s, IH), 5.03(br, IH), 4.11 ⁽ m, 411), 3.40(2H), 3.02(m, 211), 2.75(m, IH), 2.60(m, 211), 2.20(m, HI), 1.73(m, 311), 1.32(m, 5H), 1.26(m, 311), 1.17(m, 3H) 5 ES-MS : 479UI+1) ', 501(M+Na)

d) Synthesis of ethyl 2-[2-[[ ⁽ S)-2-[2-(6-amidino-l-ethylindol-2-yD- ethyl]jιiperidinyl]carbonyl]piperidinyl]acetate:

llOmg of the compound obtained in the above c) was treated according to the same procedure as Example 1-n) to obtain 40mg of the title compound as a pale yellow solid.

Η NMR(CDC1 ₃ , ppm ⁾ : δ 7.75(m, HI), 7.56(m, HI), 7.32(m, HI), 6.34(s, HI), δ.OKbr, HI), 4.12(m, 411), 3.46(111), 3.39(m, 211), 3.02(m, 211), 2.7δ(m, HI), 2.59(m, 211), 2.18(m, 111), 1.76(m, 311), 1.67(br,

611), 1.32(m, 511), 1.17(m, 311) IR(KBr) : 3400, 2900, 1610, 1460 cm ^] ES-MS : 497(M+2), 519(M+Na)

Example, 127 : Svnthesis of methvl-2-r2-rr(S)-2-r2-(6-amidino-l- ethylindol-2-yl)ethyl3pyrrolidinyl3carbonyl]piperidinyl3acet ate (Compound 192)

a) Synthesis of methyl-2-[2-[[(S)-2-[2-(6-cyano- l -ethylindol-2-yl)- ethy]]pyrrolidinyl]carbonyl]piperidinyl]acetate:

lg of tert-butyl-2-[[(S)-2-[2- (6-cyano- l -ethylindol-2-yl)ethyl]- pyιτolidinyl]carbonyl]piperidine carboxylate obtained in Example 124-a) was treated according to the same procedure as Example 1-1) to obtain 1 -ethyl -2-[2-[(S)-l -[(2-piperidinyl)carbonyl]pyrrolidin-2-yl]ethyl]indole-6 -carbonitrile, which was then reacted with methyl 2 -bromoacetate according to the same procedure as Example 1-m) to obtain 631mg of the title compound as a pale yellow oil.

ES-MS : 450 ⁽ M- ^» 1) ^'

'II NMR(CDC1 ₃ , ppm) : δ 7.58-7.53(m, 211), 7.3()-7.27(m, HI), 6.46-6.43 (m, IH), 4.35(br, IH), 4.17-4.14(m, 211), 3.67-3.64 ⁽ m, 411), 3.54- 3.48(m, 2H), 3.40-3.32 ⁽ m, IH), 2.98(br, Hi), 2.79 ⁽ br, 211), 2.60- 2.56(m, IH), 2.24-2.21(m, HI), 2.0()-1.98(m, 411), 1.74-1.64(m, 8 II), 1.35(br, 311)

b) Synthesis of methyl-2-[2-[[(S)-2-[2- ⁽ 6-amidino-l-ethyIindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]piperidinyI]acetate:

630mg of the compound obtained in the above a) was treated 5 according to the same procedure as Example 1-n) to obtain 200mg of the title compound as a pale yellow foam.

'II NMR(MeOI-I-dι, ppm) : δ 7.79(s, 111), 7.57-7.51(m, HI), 7.37-7.31(m,

₁₀ HI ⁾ , 6.37 ⁽ s, HI ⁾ , 4.21 -4.18 ⁽ m, 311), 3.62-3.58(m, HI), 3.58-3.54

⁽ m, 311 ⁾ , 3.49-3.45 ⁽ m, 211), 3.29-3.23(m, 211), 2.89-2.85(m, HI),

2.76-2.72(m, 211 ⁾ , 2.51-2.44(m, HI), 2.18-2.05(m, HI), 1.94-1.86

(m, 311 ⁾ , 1.74-1.69(m, 411), 1.55- 1.50(m, 4H), 1.26-1.19(m, 311)

15 Example 128 : Svnthesis of 2-[2-[r(S)-2-r2-(6-amidino-l-ethvl- indol-2-yl)ethyl]pyrro lidinyl3carbonyl]piperidinyl3acetic acid (Compound 193)

30mg of methyl-2-[2-[[(S)-2-[2- (6-amidino-l-ethylindol-2-yl)- 20 ethyl]pyrrolidinyl]caι-bonyl]piperidinyl]acetate obtained in Example 127-b) was treated according to the same procedure as Example 44 to obtain 17 mg of the title compound as a pale yellow solid.

ES-MS : 454(M+D ^* 95 1H NMR(MeOH-d ₄ , ppm) : δ 7.80-7.78(m, IH), 7.55-7.50(m, III), 7.35- 7.31(m, HI), 6.37 ⁽ s, HI), 4.22-4.18(m, 3H), 3.75-3.69(m, HI), 3.61-3.δ0(m, 2H), 2.99-2.91(m, 311), 2.78-2.75(m, 2H), 2.47-2.42 (m, 111), 2.12-1.5δ(m, 1211), 1.25-1.19(m, 3H)

IR(KBr) : 3420, 2980, 1580 cm ^{" 1}

30

Example 129 : Svnthesis of l-ethyl-2-[2-[(S)- l-[(3-piperidinvl)- carbonyl]ρyrrolidin-2-yl]ethyl3indole-6-carboxamidine (Compound 194)

OJ a) Synthesis of tert-butyl 3-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)ethyl]

-pyrrolidinyl]carbonyl]piperidine carboxylate:

130mg of the compound I-a obtained in Example 1-1) and 1 - [(tert-butoxy ⁾ carbonyl]piperidine-3-carboxylic acid were reacted according to the same procedure as Example 11-a) to obtain 76mg of the title compound as a white solid.

1H NMR(CDCJ ₃ , ppm) : δ 7.60-7.29(m, 311), 6.40(d, HI, J=3.62Hz), 4.28- 4.02 ⁽ m, 511), 3.71-3.42 ⁽ m, 211), 2.77(m, 411), 2.53-1.59(m, 1111), 1.46(s, 911), 1.38(t, 311, J=7.10Hz)

b) Synthesis of l-ethyl-2-[2-[ ⁽ S)- l-[(3-piperidinyl)carbonyl]pyrrolidin-2- yl]ethyl]indole-6 -carboxamidine:

71mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 35 mg of the title compound as a pale yellow solid.

¹ H-NMR(MeOH-d ₄ , ppm) : δ 7.80(s, HI), 7.54-7.31(m, 211), 6.36(s, IH), 4.22-4.02(m, 311), 3.52(m, 211), 2.92 2.28(m, 611), 2.18-1.41(m,

1111) IR(KBr) : 3380, 2990, 1630, 1540, 1480 cm ^{" 1} ES-MS : 396(M+1)'

5 Example 130 : Svnthesis of l-ethyl-2- [2-r(S )- l-i (4-piperidmyl)- carbonyllpyrrolidin-2-yl3ethyl3indole-6-carboxamidine (Compound 135)

a) Synthesis of tert-butyl 4-[[(S)-2-[2-(6-cyano-l-ethylindol-2-yl)- 0 ethyl]pyrrolidinyl]carbonyl]piperidine carboxylate:

148mg of the compound I-a obtained in Example 1-1) and 1- [(tert-butoxy)carbonyl]piperidine-4-carboxylic acid were reacted accor ^¬ ding to the same procedure as Example 11 -a) to obtain 63mg of the title ° compound as a white solid.

'II NMR(CDC1 ₃ , ppm) : δ 7.58-7.24(m, 311), 6.39(s, HI), 4.30-3.95(m, 511), 3.54(m, 211), 2.89-2.68(m, 411), 2.52-1.58(m, HID, 1.46(s, 911), 1.36(t, 311, J=7.25Hz)

b) Synthesis of l-ethyl-2-[2-[(S)- l-[(4-piperidinyl)cm-bonyl]pyrrolidin- 2-yl]ethyl]indole-6-carboxamidine:

59mg of the compound obtained in the above a) was treated according to the same procedure as Example 1 -n) to obtain 26mg of the title compound as a pale yellow solid.

^λ II NMR(MeOH-d,, ppm ⁾ : δ 7.81-7.32(m, 311), 6.37(s, HI), 4.24-4.06(m, 411), 3.53(m, 211), 3.00-2.53(m, 711), 2.18-1.50(m, 911) IR(KBr) : 3300, 2980, 1620, 1530, 1470 cm ^l ES-MS : 396(M+D ^*

Example 131 : Svnthesis of ethvl l-[2-[(S)-2-[2-(6-amidino- l- ethylindol-2-yl)ethyl]pyrrolidinyl3-2-oxoethyl3pyrrolidine-2 -carbo- xylate (Compound 196)

a ⁾ Synthesis of ethyl l -[2- [ ⁽ S ⁾ -2-[2-(6-cyano- l -ethylindol-2-yl)ethyl3- pyrrolidinyl]-2-oxoethyl]pyrrolidϊne-2-carboxylate:

109mg of l-ethyl-2-[2-[(S)-l-(2-chloroacetyl)ρyrrolidin-2-yl]ethyl]

-indole-6-carbonitriIe was treated according to the same procedure as Example 45-b) to obtain 133mg of the title compound as a viscous brown oil.

Η NMR(CDC1 ₃ , ppm) : δ 7.61 -7.54( -n, 2IΪ), 7.32(m, IH). 6.41(s, HI), 4.20-4.13(m, 511), 3.61(dd, J=I4.52IIz, 6.38IIz), 3.50(m, 2H), 3.33 (t, HI, J= 15.46Hz ⁾ , 3.12 ⁽ brs, HI), 2.83-2.74(m, 211), 2.38- 1.70(m, HID, 1.36(t, 311, J=7.17Hz), 1.24(t, 311, J=6.7HIz)

b) Synthesis of ethyl l-[2-[(S )-2-[2-(6-amidino-l -ethylindol-2-yl)ethyl]

-pyrrolidinyl] -2-oxoethyl]pyrrolidine-2-carboxylate:

130mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 35mg of the title compound as a pale yellow solid.

^] II NMR ⁽ MeOH-d ₄ , ppm) : δ 7.78(s, HI), 7.52-7.30(m, 211), 6.36(s, HI), 4.21-3.97(m, 511), 3.56-3.27(m, 511), 3.01(m, HI), 2.83-2.74(m, 211 ⁾ , 2.56- 1.72 ⁽ m, HID, 1.29(t, 311, J=7.12Hz), 1.08(t, 311, J=7.04Hz)

IR(KBr) : 3350, 2980, 1730, 1620, 1520, 1460, 1160 cm ^{" 1}

ES-MS : 468(M+l) ^f

Example 132 : Synthesis of l - [2-[(S)-2-f2- (6-amidino- l -ethvI- indol-2-yl)ethvl]pvrrolidinyl]-2-oxoethyl3ρvrrolidine-2-car boxylic acid (Compound 197)

22mg ethyl l-[2-[(S)-2-[2-(6-amidino- l-ethylindol-2-yl)ethyl]- pyrrolidinyl]- 2-oxoethyl]pyiTolidine-2-carboxylate was treated according to the same procedure as Example 44 to obtain 15mg of the title compound as a pale yellow solid.

'II NMR(MeOH-d.ι, ppm) : δ 7.88-7.32 ⁽ m. 311), 6.42-6.33(m, 111), 4.25- 4.18(m, 311), 3.50-3.08(m, 511), 3.00-2.86(m, HI), 2.76(m, 211), 2.47-1.51(m, HID, 1.28(t, 3D, J=7.20Hz)

IR(KBr) : 3350, 2960, 1700, 1650, 1450 cm ^{" 1} ES-MS : 4400M+1T

Example 133 : Synthesis of ethvl 1-T2 -[(S)-2-[2-(6- amidino- 1- ethylindol- 2 -vl)ethyl3ρyrrolidinyl] -2-oxoethyl]piperidine- 2-carboxy late (Compound 198)

a) Synthesis of ethyl l -[2-[(S)-2-[2-(6-cyano- l -ethylindol-2- yl ⁾ ethyl3- pyrrolidinyl]-2-oxoethyl]piperidine-2-carboxylate:

112ιπg of l-ethyl-2-[2-[(S)-l-(2-chloroacetyl)pyπOlidin-2-yl]ethyl] -indole-6-carbonitrile was treated according to the same procedure as Example 45-b) to obtain 140mg of the title compound as a viscous brown oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.61-7.54(m, 211), 7.30(m, HI), 6.41(d, HI, J=3.07IIz), 4.28-4.13(m, 511), 3.73-3.30(m, 411), 3.19(t, IH), 3.03- 2.95(m, HI), 2.79(t, 211, J=7.98Hz), 2.64-1.60(m, 1311), 1.36U, 311, J=7.22Hz), 1.29-1.23(m, 311)

b) Synthesis of ethyl l -[2-[ ⁽ S ⁾ -2-[2- ⁽ 6-amidino-l-ethylindol-2-yl ⁾ ethyl3 -pyrrolidinyl] -2-oxoethyl]piperidine-2-carboxylate:

136ιπg of the compound obtained in the above a) was treated according to the same procedure as Example 1 -n) to obtain 43mg of the title compound as a pale yellow solid.

'II NMR(MeOH-d ₄ , ppm) : δ 7.77(s, HI), 7.53-7.30(m, 211), 6.35(s, HI), 4.21-4.02(m, 511), 3.59-3.03(m, 511), 2.96-2.88(m, HI), 2.79-2.69 (m, 211), 2.4δ-1.37(m, 1311), 1.29(t, 311, J=7.13IIz), 1.18- 1.13(m,

311)

IR(KBr) : 3300, 2960, 1730, 1620, 1520, 1460, 1180 cm ^l

Example 134 : Svnthesis of l-[2-[(S)-2-[2- (6-amidino- l-ethyl- indol-2-yl)ethyl3pyrroIidinyl3-2-oxoethyl3piperidine-2-carbo xylic acid (Compound 199)

27mg of ethyl l-[2-[(S ⁾ -2-[2-(6-amidino- l-ethylindol-2-yl)ethyl3- pyrrolidinyl]- 2 -oxoethyl]piperidine-2 -carboxylate was treated according to the same procedure as Example 44 to obtain 14mg of the title compound as a pale yellow solid.

'II NMR(MeOH-d ₄ , ppm) : δ 7.71(s, HI), 7.55-7.27(m, 211), 6.29(s, HI), 4.20-4.06(m. 311), 3.61-3.35(m, 311), 3.41 (d. HI, J= 14.55Hz), 2.82

⁽ d, HI, J=14.65Hz), 2.93-2.64(m, 311), 2.28- 1.50(m, 1311), 1.27- 1.19(m, 311) ES-MS : 454(M+l) ^f

Example 135 : Svnthesis of ethyl 2-[2-[2-r(S)- i r((R)- l -acetvl- acetate (Compound 222)

a ⁾ Synthesis of 2- ⁽ hydroxymethyl)indole-6-carbonitrile:

lOg of ethyl 6-cyanoindole-2-carboxylate was treated according to the same procedure as Example 1-e) to obtain 6.8g of the title compound as a vellow solid.

'II NMR(MeOH-d,, ppm) : δ 7.63(s, 111), 7.52(d, HI), 7.15(m, III), 6.38(s, HI), 4.67(s, 211)

b) Synthesis of tert-butyl (vS)-2-[2-(6-cyanoindol-2-yl)vinyl]pyrrolidine carboxylate:

lg of 2-(hydroxymethyl)indole-6-carbonitrile was treated accor¬ ding to the same procedure as Examples 1-f) and 1-m) to obtain 800mg of the title compound as a yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.47(m, 2H), 7.24(m, HI), 6.33(s, HI), 4.40(m, HI), 3.36(m, 211), 2.15-1.70(m, 611), 1.47(m, 9H)

c) Synthesis of tert-butyl (S)-2-[2-(6-cyanoindol-2-yl)ethyl]pyrrolidine carboxylate:

800mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-k) to obtain 620mg of the title compound as a yellow oil.

Η NMR(CDC1 ₃ , ppm) : δ 7.66(s. IH), 7.5()(t, HI), 7.20(m, HI), 6.21(s,

HI), 3.92(m, 111), 3.32(m, 211), 2.80(m, 211), 2.1- 1.7(m, 611), 1.6- 1.35(m, 911)

d) Synthesis of ethyl 2-[6-cyano-2-[2-[(S)-l-[(tert-butoxy)carbonyl]- pyrrolidin-2-yl]ethyl]indolyl]acetate:

620mg of the compound obtained in the above c) and 0.3ml of ethyl 2 -bromoacetate were reacted with Nail in the presence of N,N-dimethyl- formamide to obtain 850ιng of the title compound as a brown oil.

10

^] II NMR(CDC!:,, ppm) : δ 7.60(s, HI), 7.51(s, HI), 7.36(d, HI), 6.46(s, HI), 4.84(s, 211), 4.32-4.20(m, 211), 3.98(m, HI), 3.43-3.27(m, 211), 2.80-2.65(m, 211), 1.95-1.67(m, 611), 1.60-1.42(m, 911), 1.37-1.23 (m, 311)

15 e) Synthesis of ethyl 2-[6-cyano-2-[2-[(S) ^~ l-[[(R) -l -[(tert-butoxy)- carbonyl]pyπOlidin-2-yI]carbonyl]jjyrrolidin-2-yl]ethyl]ind olyl]acetate:

800mg of the compound obtained in the above d) was treated 20 according to the same procedure as Examples 1-1) and 11-a) to obtain 340mg of the title compound as a pale yellow solid.

^] II NMR(MeOH-d,,, ppm) : δ 7.63(s, III), 7.50(d, HI), 7.20(d, HI), 6.42(m, HI), 4.68(s, 2H), 4.30-4.20(m, HI), 4.10(m, 211), 3.67-3.57(m, HI), 25 3.51(m, 211), 3.32(m, 211 ⁾ , 2.10-1.60(m, 211), 1.36-1.25(m, 911),

1.10(m, 3H)

f) Synthesis of ethyl 2-[2-[2-[(S)- l-[((R)-l-acetylpyrrolidin-2-yl)car- bonyl]pyrrolidin-2-yl]ethyl]-6-cyanoindolyl]acetate:

30

300mg of the compound obtained in the above e) was treated according to the same procedure as Examples 1-1) and 1-m) to obtain 180mg of the title compound as a yellow solid.

' 3K5 i 'H NMR(CDC1 ₃ , ppm) : δ 7.60(m, HI), 7.50(s, III), 7.34(m, HI), 6.47(s,

HI ⁾ . 4.86(m, 211), 4.35-4.17(m, 311), 3.89(m, HI), 3.70(m, 211), 3.54(m, 211), 2.30-1.90(m, 911), 1.35(m, 611)

g ⁾ Synthesis of ethyl 2-[2-[2-[(S)-l-[((R)-l-acetylpyrrolidin-2-yl)carbo- nyl]pyrrolidin-2-yl]ethyl]-6-amidinoindolyl]acetate:

150mg of the compound obtained in the above f) was treated according to the same procedure as Example 1-n) to obtain 80mg of the title compound as a pale yellow solid.

^] II NMR(CDC1 _:! , ppm) : δ 7.50(m, 211), 6.32(s, III), 4.97(s, 211), 4.65(m, HI), 4.15(m, 311), 3.86(m, HI), 3.68(m, 211), 3.39(m, 211), 2.70(m, 211), 2.19- 1.82(m, 1211), 1.22(m, 311)

ES-MS : 482(M+lT

Example 136 : Synthesis of 2-[2-[(S)- l -[((R)- l -acetylpyrrolidin-

2-vl)carbonyl3pyrrolidin-2-yl3ethyl]- l- (carbamovlmethyl)indole-6- carboxamidine (Compound 224)

somg of ethyl 2-[2-[2-[(S)-l -[((R)- l -acetylpyιτolidin-2-yl)- carbonyl]pyιτolidin-2-yl3ethyl3-6-cyanoindolyl]acetate obtained in Example 135-g) was treated according to the same procedure as Example 1 -n) to obtain 3()mg of the title compound as a yellowish white solid.

1H NMR(MeOH-d ₄ , ppm) : δ 7.74(s, HI), 7.59(m, HI), 7.36(m, III), 6.39(s, III), 4.87(s, 211), 4.59(m, HI), 4.29(m, HI), 3.73(m, 311), 2.7δ(m, 2H), 2.21(m, 2H), 2.09(s, 311), 2.0 ⁽ )- 1.89(m, 911) ES-MS : 453(M+1)'

0 Examule 137 : Svnthesis of 2-[2-T2-r(S)- l-[((R)- l-ncetvlpyrro- lidin-2-yl)carbonyllpyrrolidin-2-yl]ethyl3-6-amidinoindolyl3 acetic acid (Compound 225)

4()mg of ethyl 2-[2-[2-[(S)- l-[((R)- l -acetylpyrrolidin-2-yl)- ° carbonyl]pyrrolidin-2-yl]ethyl]-6-amidinoindolyl]acetate obtained in

Example 135 was treated according to the same procedure as Example 44 to obtain 15mg of the title compound as a white solid.

'II NMR(MeOH-d ,+CDCIi, ppm) : δ 7.46(m, 211), 7.28(m, IH), 6.37(s, HI), 4.64 ⁽ s, 211), 4.53(s, HI), 4.19(br, HI), 3.79(m, HI), 3.64(m, 311),

2.75(m, 211), 2.17(m, 3D), 2.03(s, 311), 2.01-1.78(m, 711), 1.28(m, 211) ES-MS : 45HM+D ^*

0 Example 138 : Svnthesis of ethvl 2-[(R)-2-r[(S)-2-r2-(5 amidino- l -methylindol-2-vl)ethyl3pyrrolidinvl3carbonyllpyrrj?ljdinyj3 acetate_ (Compound 242)

a) Synthesis of ethyl 5-bromoindole-2-carboxylate: 5

In a 500ml flask, 14g of 4-bromophenylhydrazine hydrochloride was dissolved in 170ιnl of ethanol, and 1.2ml of sulfuric acid and 8.5ml of ethyl pyruvate were added. The reaction mixture was stirred for about 2 hours at room temperature and evaporated under reduced pressure to 0 dryness. To the residue was added 23ml of polyphosphoric acid, and the resulting solution was then stirred for 2 hours at 100°C - 110 ^° C . After water was added, the reaction solution was neutralized with saturated aqueous NaIIC0 ₃ solution and then extratced two times with ethyl acetate. The extracts were combined, dried over MgSOi and then 5 evaporated. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(9:l)] to obtain lOg of the title compound as a brown solid.

'II NMR(CDC1 ₃ , ppm) : δ 9.03(br, HI), 7.82(s, HI), 7.41(m, HI), 7.31(m, 0 HI), 7.14 ⁽ s, HI ⁾ , 4.40 ⁽ q, 211, J=7JHz), 1.4) ⁽ t, 311, J=7.JHz)

b) Synthesis of ethyl 5-bromo-l -methylindole-2-carboxylate:

4.5g of the compound obtained in the above a) and 2.1ml of : iodomethane were reacted according to the same procedure as Example

1-d) to obtain 5.9g of the title compound as a yellow oil.

c) Synthesis of ethyl 5-cyano- l-methylindole-2-carboxylate:

In a 500ml flask, 8.7g of the compound obtained in the above b) was dissolved in 430ιπl of l-methylpyrrolidin-2-one, and 4.1g of CuCN was added thereto. The reaction mixture was stirred for 14 hours at 190 ^° C -20() ^° C, cooled to room temperature and then filtered. To the filtrate was added water, and the reaction solution was extracted two times with chloroform. The extracts were combined, dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(3:l)] to obtain 6.5g of the title compound as a brown solid.

d) Synthesis of l -methyl-2-(hydroxymethyl)indole-5-carbonitrile:

6g of the compound obtained in the above c) was treated according to the same procedure as Example 1-e) to obtain 2.4g of the title compound as a yellowish white solid.

'II NMR(CDC1 ₃ , ppm) : δ 7.90(s, 111), 7.42(m, HI), 7.33(m, HI), 6.53(s,

HI), 4.83(s, 211). 3.84(s, 311) IR(KBr) : 3250, 2200, 1600, 1480 cm ^{" 1}

e) Synthesis of (5-cyano- l-methyl-2-indolyl)methyltriphenylphosphonium bromide:

2.4g of the compound obtained in the above d) was treated according to the same procedure as Example 1 -f) to obtain 5.3g of the title compound as a pale pink solid.

Η NMR(MeOH-d ₄ , ppm) : δ 7.82(m, 3H), 7.62(m, 15H), 6.26(m, IH), 5.19 (d, 211), 3.08(s, 3H)

f) Synthesis of tert-butyl ⁽ S)-2-[2- (5-cyano- l-methylindol-2-yl)vinyl]-

pyrrolidine carboxylate:

5g of the compound obtained in the above e) was treated according to the same procedure as Example 1-j) to obtain 1.6g of the title compound as a yellow oil.

g) Synthesis of tert-butyl (S)-2-[2-(5-cyano-l-methylindol-2-yl)ethyl]- pyrrolidine carboxylate:

1.4g of the compound obtained in the above f) was treated according to the same procedure as Example 1-k) to obtain 1.3g of the title compound as a yellow oil.

h) Synthesis of l-methyI-2-((S)-2-pyrrolidin-2-ylethyl)indole-5-carboni- trile:

1.2g of the compound obtained in the above g) was treated according to the same procedure as Example 1-1) to obtain 710mg of the title compound as a yellow oil.

^] II NMR(CDC1,, ppm) : δ 7.82(s, HI), 7.3δ(m, III), 7.26(m, III), C.32(s, HI), 3.66(s, 3D), 3.19(m, Hi), 3.06(m, 211), 2.97(m, HI), 2.81(m, 211), 1.94(m, 511)

i) Synthesis of tert-butyl (R)-2-[[(S)-2-[2-(5-cyano-l-methylindol-2- yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidine carboxylate:

700mg of the compound obtained in the above h) was treated according to the same procedure as Example 11-a) to obtain lg of the title compound a _Λ a yellow oil.

^J II NMR(CDC1 ₃ , ppm) : δ 7.85(m, HI), 7.36(m, IH), 7.27(m, IH), 6.34(s, Hi), 4.1 Km, HI), 3.80(m, HI), 3.68(s, 311), 3.61 (m, 2H), 3.43(m, 311). 2.82(m, 211), 2.16-1.87(m, 911), 1.42(s, 911)

j) Synthesis of l-ιnethyl-2-[2-[(S ⁾ - l- ^{( (} R ⁾ -pyπOlidin-2-ylcarbonyl)pyιτo- lidin-2-yl]ethyl]indole-5-carbo nitrile:

lg of the compound obtained in the above i) was treated according to the same procedure as Example 1-1) to obtain 730mg of the title compound as a yellow oil.

k ⁾ Synthesis of methyl 2-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2-(5-cyano- l-ethylindol-2-yl)- etlιyl]pyrrolidinyl]carbonyl]pyπOlidinyl]acetate:

720mg of the compound obtained in the above j) and 0.35ml of ethyl 2 -bromoacetate were reacted according to the same procedure as Example 1 -m) to obtain 680mg of the title compound as a pale yellow oil.

'II NMR(CDCL;, ppm) : δ 7.87(s, HI), 7.44(m, III), 7.29(m, HI), 6.40(s, HI), 4.23(m, HI), 4.12(m, 211), 3.87(m, III), 3.72(s, 311), 3.53(m, 211), 3.22(m, HI), 2.82(m, 311), 2.01 -1.89(m, 911), 1.22(t, 311, J=7.1Hz ⁾

1) Synthesis of ethyl 2-[ ⁽ R)-2-[[(S) -2-[2- (5-nmidino-l -methylindol-2- yl)ethyl]ρyrrolidinyl]carbonyl]pyπOlidinyl]acetate:

670mg of the compound obtained in the above k) was treated according to the same procedure as Example 1-n) to obtain 200g of the title compound as a yellowish white solid.

Η NMR(CDC1 ₃ , ppm) : δ 7.98(s, 111), 7.49(m, HI), 7.30(m, 111), 6.56(s, HI), 4.70-4.39(br, 211), 4.28(m, 111), 4.12(q, 211), 3.81(m, HI), 3.66(s, 3H), 3.60(m, 211), 3.29(m, HI), 2.77(m, 311), 2.35(m, IH), 2.17(m, 111), 2.00- 1.78(m, 911), 1.24(t, 311)

IR(KBr) : 3300, 2900, 1720, 1620 cm ^] ES-MS : 454(M+ 1) \ 476(M+Na)

Example 139 : Svnthesis of ethyl 2-[(R)-2- ri(S)-2-[(S)-2-(5- amidjno- 1 - ethy Ijndol -2 - V 1 )ethy Upyrrolidinv ilcarbonv Hpyrrolidiny 1] -

acetate (Compound 243)

a) Synthesis of ethyl 5-bromo- l-ethylindole-2-carboxylate:

4.5g of ethyl 5-bromoindole-2-carboxylate and 2.7ιπ? of iodoethane were reacted according to the same procedure as Example 1-d) to obtain 5.2g of the title compound as a yellow oil.

b) Synthesis of ethyl 5-cyano- l-ethylindole-2-carboxylate:

In a 500m! flask, 7.7g of the compound obtained in the above a) was dissolved in 360ml of l-methylpyrrolidin-2-one, and 3.5g of CuCN was added thereto. The reaction mixture was stirred for 14 hours at 19() ^° C' -200°C, cooled to room temperature and then filtered. To the filtrate was added water, and the reaction solution was extracted two times with chloroform. The extracts were combined, dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(3:l)] to obtain 5.4g of the title compound as a brown solid.

c) Svnthesis of l -ethvI-2-(hvdiOxvmethvl)indole-5-carbonitrile:

δg of the compound obtained in the above b) was treated according to the same procedure as Example 1-e) to obtain 2.9g of the title compound as a yellowish white solid.

^J II NMR(CDC1 ₃ , ppm) : δ 7.91(s, 111), 7.44(m, HI), 7.38(m, Hi), 6.52(s, HI), 4.83(s, 211), 4.32(q, 211, J=7.2I!z), 1.42(t, 311, J=7.2Hz)

IR(KBr) : 3450, 2200, 1600, 1480 cm ^"

d) Synthesis of (5-cyano-l-ethyl-2-indolyl)methyltriphenylphosphonium bromide:

2.8g of the compound obtained in the above c) was treated according to the same procedure as Example 1 -f) to obtain 6g of the title

compound as a pale pink solid.

1H NMR ⁽ MeOH-d ₄ , ppm) : δ 7.92(m, 3H), 7.74(m, 15H), 6.29(m, Hi), 3.78 ⁽ q, 2H, J=7.1Hz), 3.33(m, 2H), 1.12(t, 3H, J=7.1Hz)

e ⁾ Synthesis of tert-butyl ⁽ S ⁾ -2-[2-(5-cyano- l-ethylindol-2-yl)vinyl]- pyrrolidine carboxylate:

5g of the compound obtained in' the above d) was treated according to the same procedure as Example 1-j) to obtain 1.7g of the title compound as a yellow oil.

f) Synthesis of tert-butyl ⁽ S)-2-[2- (5-cyaπo-l-ethyIindoI-2-yl)ethyl]- pyrrolidine carboxylate:

1.6g of the compound obtained in the above e) was treated according to the same procedure as Example 1 -k) to obtain l.δg of the title compound as a yellow oil.

^r H NMR(CDC1 ₃ , ppm) : δ 7.85(s, HI), 7.38(m, HI), 7.26(m, IH), 6.35(s, HI), 4.14(q, 211, J=7.2Hz), 3.95(br, 111), 3.37(m, 211), 2.7δ(m, 211), 1.92-1.76(m, 611), 1.47(s, 911), 1.3δ(t, 311, J=7.2Hz)

g) Synthesis of l-ethyl-2-((S)-2-pyrrolidin-2-ylethyl)indole-δ-carboni- trile:

1.4g of the compound obtained in the above f) was treated according to the same procedure as Example 1-1) to obtain 940mg of the title compound as a yellow oil.

h) Synthesis of tert-butyl (R)-2-[[(S)-2-[2-(5-cyano-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidine carboxylate:

930mg of the compound obtained in the above g) was treated according to the same procedure as Example 11-a) to obtain 960mg of the

title compound as a yellow oil.

³ H NMR(CDC1 ₃ , ppm) : δ 7.85(m, IH), 7.35(m, IH), 7.28(m, IH), 6.36(s, IH), 4.15(m, 3H), 3.80(m, IH), 3.62(m, 2H), 3.43(m, 3H), 2.79(m, 2H), 2.11-1.85(m, 9H), 1.42(s, 9H)

i) Synthesis of l-ethyl-2-[2-[(S)-l -((R)-pyrrolidin-2-ylcarbonyl)pyrro- lidin-2-yl]ethyl]indole-δ-carbonitrile:

960mg of the compound obtained in the above h) was treated according to the same procedure as Example 1-1) to obtain 6δ0mg of the title compound as a yellow oil.

j) Synthesis of ethyl 2-[ ⁽ R)-2-[[(S)-2-[2-(5-cyano-l-ethylindol-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate:

640mg of the compound obtained in the above i) and 0.3ml of ethyl 2 -bromoacetate were reacted according to the same procedure as Example 1 -m) to obtain 6δ0mg of the title compound as a pale yellow oil.

'II NMR(CDC1 ₃ , ppm) : δ 7.80(s, HI), 7.38(m, HI), 7.28(m, HI), 6.40(s, HI), 4.27(m, HI), 4.13(m, 411), 3.87(m, HI), 3.56(m, 211), 3.22(m, HI), 2.78(m, 311), 2.02-1.86(m, 911), 1.3δ(t, 311, J=7.1Hz), 1.22(t, 311, J-7.1Hz)

k) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(5-amidino-l-ethylindol-2-yl)- ethyI]pyrrolidinyl]carbonyl]pyrrolidinyI]acetate:

630mg of the compound obtained in the above j) was treated according to the same procedure as Example 1-n) to obtain 150mg of the title compound as a yellowish white solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.15(s, IH), 7.55(m, IH), 7.30(m, IH), 6.71 (s,

IH), 6.10-5.80(br, 211), 4.38(m, IH), 4.11(m, 4H), 3.73(m, IH), 3.44(m, 2H ⁾ , 3.38(m, IH), 2.72(m, 311), 2.45(m, IH), 2.20(m, 111),

1.99-1.70(m, 9H), 1.26(m, 6H) IR(KBr) : 3200, 3000, 1740, 1620 cm ^"1 ES-MS : 468(M+1) ⁺

Example 140 : Synthesis of 6-[2-[(S)- l- (2-phenylacetyl )pyrroli- din-2-yl3ethvl3na ^p hthalene-2-carhoχa,φidi"f ^> (Compound 244)

lg of 7-cyanonaphthalene-3-methyltriphenylphosphonium bromide and 390mg of (S)-l -(t-butoxycarbonyl)-2-pyrrolidinal were dissolved in a mixed solvent of 15ml of tetrahydrofuran and 15ml of ethanol, and 360 _/ 4 of DBU (l,8-diazabicyclo[5.4.0]undec-7ene) was added at room tempera¬ ture. The reaction solution was stirred overnight at room temperature and distilled under reduced pressure to remove the solvent. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(3:l)]. The fractions containing the desired product were combined and distilled under reduced prssure to obtain the product, tert-butyl (S)-2-[2-(6-cyano-2-naphthyl)vinyl]pyrrolidine carbo ^¬ xylate. 410mg of this product thus obtained was dissolved in lδmC of ethanol and then hydrogenated in the presence of δOmg of Pd/C(10% w/w) for 2 hours under normal pressure with stirring. The reaction solution was filtered under reduced pressure to remove Pd/C, and the filtrate was distilled under reduced pressure and dried under reduced pressure. The residue was dissolved in 10ml of dichloromethane, and 8ml of trifluoroacetic acid was added. The mixture thereby obtaned was stirred overnight at room temperature, and excess of dichloromethane was added thereto. The organic layer was separated, washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then filtered under reduced pressure. The filtrate was distilled under reduced pressure to obtain 320mg of the oily product, 6-((S)-2-pyrrolidin-2- ylethyl)naphthalene-2-carbonitrile. 85mg of the resulting oily product was then treated according to the same procedure as Example 1-m) to obtain 50mg of the compound 6-[2-[(S)- l-(2-phenylacetyl)pyrrolidin- 2-yl]ethyl)naphthalene-2-carbonitrile, which was then treated according to the same procedure as Example 1-n) to obtain 30mg of the title compound as a vellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 8.20(d, IH), 7.83(m, 2H), 7.68(m, 2H), 7.37 (d, IH), 7.21-7.12(m, 5H), 6.98(d, IH), 6.76(d, IH), 4.05(m, IH), 3.59(m, 2H), 3.37(m, 4H), 2.70(t, 2H), 2.15(m, IH), 1.93-1.79(m, 7H), 1.70(m, IH)

Example 141 : Svnthesis of methvl 2-r(R)-2-rr(S)-2-r2-(6-ami- dino-2-πaphth ^y l ⁾ ethyl3pyrτolidinyllcarbonyl3pyrrolidinyl1acetate

(Compound 245)

a) Synthesis of methyl 2-[(R)-2-[[(S)-2-[2-(6-cyano-2-naphthyl)ethyl] -pyrrolidinyl]carbonyl]pyrrolidinyl]acetate:

250mg of 6-((S)-2-pyrrolidin-2-ylethyl)naphthalene-2-carbonitrile was treated according to the same procedure as Example 11-a) to obtain 256mg of tert-butyl (R)-2-[[(S)-2-[2-(6-cyano-2-naphthyl)ethyl3pyrro- lidinyl3carbonyl]pyrrolidine carboxylate. IδOmg of the compound thereby obtained was reacted according to the same procedure as Example 1-1) to obtain 134mg of 6-[2-[(S)-l-((R)-pyrrolidin-2-ylcarbonyl)pyrrolidin-2-yl] -eth\i]naphthalene-2-carbonitrile. Thereafter, 130mg of the compound thus obtained was treated according to the same procedure as Example 1 -m) to obtain 129mg of the title compound as a yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.17(s, Hi), 7.92- 7.79(m, 211), 7.73(s, HI), 7.50 (m, 2H), 4.19(bs, IH)

b ⁾ Synthesis of methyl 2-[ ⁽ R)-2-[[(S)-2-[2-(6-amidino-2-naphthyl)- ethyl]pyrroIidinyl3carbonyl3p}'rrolidinyl3acetate:

124mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-n) to obtain 48mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d ₄ , ppm) : δ 8.35(s, IH), 7.95(m, 2H), 7.89(m, 211), 7.54(d,

HI, J=11.73Hz), 4.20-4.00(m, 3H), 3.79(m, IH), 3.62(m, 2H), 3.46 ⁽ d, 2H, J=19.11Hz), 3.20 ⁽ m, Hi), 3.00(m, IH), 2.98-2.70(m, 3H),

2.33-1.70(m, 11H)

ES-MS : 45HM+D ^*

Evamnle 142 : Synthesis of 7- [2-r(S)- l-(2-phenylacetyl)pyrro- lidin-2-yl3ethyl3naρhthalene-2-carhoxamjdine (Compound 246)

a) Synthesis of tert-butyl (S)-2-(2-(7-cyano-2-naphthyl)vinyl)pyrrolidine carboxylate:

5.6g of 7-cyanonaphthalene-2-ιnethyltriphenylphosphonium bro¬ mide was reacted according to the same procedure as Example 1-j) to obtain 2.9g of the title compound.

1H NMR(CDC1 ₃ , ppm) : δ 8.24-7.54(m, 611), 6.55(bs, HI), 6.30(bs, IH), 4.δl(bd, IH), 3.49(s, 211), 2.17- 1.82(m, 411), 1.83- 1.26(m, 911)

b) Synthesis of 7-((S)-2-pyrrolidin-2-ylethyl)naphthalene-2-carbonitrile:

2.9g of the compound obtained in the above a) was treated according to the same procedure as Example 1-k) to obtain 2.7g of the product, which was then treated according to the same procedure as Example 1-1) to obtain 1.6g of the title compound as a yellow oil.

³ I1 NMR(CDC1 ₃ , ppm) : δ 7.79(s, HI), 7.76(d, Hi, J=8.46Hz), 7.68(d, III, J=8.42Hz), 7.54-7.48(t, 2H), 7.37(d, IH, J=8.43Hz), 3.49(t, Hi),

3.26(m, 2H), 2.91-2.82(m, 2H), 2.30- 1.68(m, 611) ES-MS : 25HM+D ^*

c) Synthesis of 7-[2-[(S)- l-(2-phenylacetyl)pyrrolidin-2-yl]ethyl]naph- thalene-2-carbonitrile:

445mg of the compound obtained in the above b) and 0.47m! of phenyl acetvlchloride were reacted according to the same procedure as Example 1-m) to obtain 298mg of the title compound.

1H NMR(CDCl3, ppm) : δ 8.14(s, HI), 7.86-7.78(q, 2H), 7.67(s, IH), 7.55- 7.δl(m, 2H), 7.32-6.92(m, 5H), 4.21(m, IH), 3.64(s, IH), 3.46(m, 2H), 2.80(t, 2H, J=8.16Hz), 2.33(m, IH), 2.04-1.59(m, 5H)

d) Synthesis of 7-[2-[ ⁽ S)-l- ⁽ 2-phenylacetyl)pyrrolidin-2-'l]ethyl]naph- thalene-2 -carboxamidine:

270mg of the compound obtained in the above c) was treated according to the same procedure as Example 1 -n) to obtain 128mg of the title compound as a pale yellow solid.

^] I1 NMR(MeOH-d ₄ , ppm) : δ S.08(s, IH), 7.77-7.61(m, 411), 7.34-7.32(d, IH, J=8.38Hz), 7.20-7.13(m, 311), 6.94(m, IH), 6.73(d, HI), 4.08 (bs, Hi), 3.56(s, 211), 3.45-3.30(m, 211), 2.67(t, 2H), 2.20-1.50(m, 6H)

ES-MS : 386(M+D ^*

Example 143 : Svnthesis of ethyl 2-r(R)-2-r[(S)-2-ι 2 (7-amidino- 2-naphthyl )ethyl3pyrτolidinyl3carbonyl3pyrrolidinyl3acetate (Compound 247)

a) Synthesis of 7-[2-[(S)- l-((R)-pyrrolidin-2-ylcarbonyl)pyrrolidin- 2-yl]ethyl]naphthalene-2-carbo nitrile:

4δ0rag of 7-((S)-2-pyrrolidin-2-ylethyl)naphthalene-2-carbonitrile obtained in Example 142-b) was treated according to the same procedure as Example 11-a) to obtain 643mg of tert-butyl (R)-2-[[(S)-2-[2- ( 7 - cyano - 2 - naphthy 1 )ethy l]pyrrolidinyl] carbony l]pyrrolidine carboxylate, which was tiien treated according to the same procedure as Example 1-1) to obtain 472mg of the title compound as a brown oil.

1H NMR(CDC1 ₃ , ppm) : δ 8.17(s, IH), 7.90(d, IH, J=8.83Hz), 7.79(d, IH, J=8.49Hz), 7.73(s, IH), 7.49(d, 2H), 4.35(t, IH), 4.02(m, IH), 3.52(m, IH), 3.32(m, 211), 2.76(m, 2H), 2.36(m, IH), 2.23(m, IH), ^• 2.10-1.80(m, 8H), 1.74-1.60(m, IH)

ES-MS : 348(M+1) ^*

b) Synthesis of ethyl 2-[ ⁽ R ⁾ -2-[[ ⁽ S ⁾ -2-[2-(7-cyano-2-naphthyl)ethyl]- pyrrolidinyl]carbonyl]pyrrolidinyl]acetate:

δ72m ^g of the compound obtained in the above a) was treated according to the same procedure as Example 1-m) to obtain 700mg of the title compound as a yellow solid.

1H NMR ⁽ CDC1 ₃ , ppm ⁾ : δ 8.18 ⁽ s, IH), 7.90-7.70(m, 311), 7.50(m, 2H), 4.01 ⁽ m, 2H ⁾ , 3.89 ⁽ m, HI ⁾ , 3.67(m, 111), 3.54-3.12(m, 5H). 3.0δ(m, IH ⁾ , 2.92 ⁽ m, IH ⁾ , 2.73(m, 211), 2.20- l.δ0(m, 1011), 1.06(t, 3H) ES-MS : 434<M+ ir, 456(M+Na)

c) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(7-amidino-2-naphthyl)ethyl]- pyrrolidinyl]carbonyl]p'rrolidin'l]acetate:

6δ0mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-n) to obtain 148mg of the title compound as a pale yellow solid.

^] H NMR(MeOH-d ₄ , ppm) : δ 8.08(s, HI), 7.78-7.76(m, 411), 7.34(m,lII), 4.00(m, 2H), 3.90 ⁽ m, HI), 3.6δ(m, HI), 3.57-3.15(m, 411), 3.07(m, 111), 2.88(m, HI), 2.65(m, 211), 2.17- 1.50(m, 1011), 1.07(t, 3H) ES-MS : 451(M+1)\ 474(M+Na)

IR(KBr) : 3200, 1220 cm ^{" 1}

Example 144 : Synthesis of 2- r2- r(S)- l-(2-phenvIacetyl)pyrrolidin- 2-yl3ethyllbenzorblfuran-5-carboxamidine (Compound 248)

a) Synthesis of ethyl 2- ⁽ 4-bromo-2-formylphenoxy)acetate:

In a 1 £ flask, 30g of 5-bromosalicyl aldehyde was stirred in δOO m£ of acetone solvent at room temperature, and then 26.8g of K2CO;) was slowly added thereto. After the mixture thereby obtained was stirred for

30 minutes, 21.5m! of ethyl bromoacetate was slowly added dropwise thereto and the reaction mixture was refluxed for 2 hours with stirring. After the reaction was completed, the reaction solution was evaporated. To the residue was added dichloromethane and the resulting precipitate was filtered ^' and washed two times with water. The organic layers were combined, dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:3)]. The fractions containing the desired product were combined and then evaporated to obtain 43g of the title compound as a yellow liquid.

1H NMR(CDCb, ppm) : δ 10.45(s, HI ^" ), 7.95(d, IH, J=2.59Hz), 7.60(dd, IH, J=8.79Hz, 2.61Hz), 6.75(d, III, J=8.62Hz), 4.75(s, 2H), 4.20(q, 211, J=7.14Hz), 1.25(t, 311, J=7.15Hz) ES-MS : 288 ⁽ M+1) ⁴

b) Synthesis of ethyl 5-bromobenzo[d]furan-2-carboxylate:

In a I f flask, 2.96g of Na was slowly added to 250m! of ethanol solvent, and this mixture was stirred for 30 minutes. 42g of the compound obtained in the above a) was slowly added dropwise thereto at room temperature. The reaction solution was stirred for 2 hours and then evaporated under reduced pressure. The residue was extracted two times with ethyl acetate. The combined organic layer was dried over MgS0 ₄ and then evaporated to obtain 11.7g of the title compound as a yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.80(s, HI), 7.45(m, 2H), 4.40(q, 2H, J=7.13Hz), 1.40(t, 3H, J=7.13Hz) ES-MS : 270(M+D ^*

c) Synthesis of ethyl 5-cyanobenzo[d]furan-2-carboxylate:

In a 250π4 flask, 24.7g of the compound obtained in the above b) was dissolved in 100π4 of N-methylpyrrolidinone, and 16.53g of CuCN

and 1.48g of CuS0 ₄ catalyst were added thereto. The reaction mixture was refluxed for one hour at 200-220 ^° C with stirring. The reaction solution was then stirred for 30 minutes at room temperature. After excessive amount of water was added, the reaction solution was stirred and then filtered. The residue was washed three times with ethyl acetate. The orgamc layers were combined, dried over MgS0 ₄ and then evaporated under reduced pressure. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:5)]. The fractions containing the desired product" ¹ were combined and then evaporated to obtain 6.39g of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.05(s, πi), ^" 7.70(m, 2H), 7.55(s, HI), 4.4δ(q, 211,

J=7.10Hz), 1.45(t, 311, J=7.12IIz) ES-MS : 216(M+ 1) ^'

d) Synthesis of 2-(hydroxymethyl)benzo[b]furan-5-carbonitrile:

6.39g of the compound obtained in the above c) was treated according to the same procedure as Example 1-e) to obtain a s ^' toichiometric amount of the title compound as a white solid.

³ H NMR(CDC1 ₃ , ppm) : δ 8.0(s, HI), 7.60(s, 211), 6.7δ(s, IH), 4.80(s, IH),

4.6δ(s, IH) ES-MS : Ϊ74(M+1)'

e) Synthesis of benzo[b]furan-5-carbonitrile-2-methyltriphenylphospho- nium bromide:

5.34g of the compound obtained in the above d) was treated according to the same procedure as Example 1-f) to obtain 14.8g of the title compound as a white solid.

1H NMR(CDCls, ppm) : δ 7.95-7.60(m, 16H), 7.45(m, IH), 7.25(m, 211), 6.05(d, 2H)

f) Synthesis of tert-butyl (S)~2-[2-(5-cyanobenzo[d]furan-2-yl)vinyI]- pyrrolidine carboxylate:

11.8g of the compound obtained in the above e) was treated according to the same procedure as Example 1-j) to obtain 3.99g of the title compound as a fluorescent yellow liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.80(s, IH), 7.45(m, 2H), 6.55(s, IH), 6.50-6.10 (m, 2H), 4.45(m, IH), 3.45(br, 211), 2.0- 1.70(m, 4H), 1.40(br, 9H)

g) Synthesis of tert-butyl (S)-2-[2-(δ-cyanobenzo[d]furan-2-yl)ethyl]- pyrrolidine carboxylate:

2.09g of the compound obtained in the above f) was treated according to the same procedure as Example 1-k) to obtain 1.75g of the title compound as a colorless liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.80(s, IH), 7.4δ(m, 211), 6.50(s, HI), 3.90(m, HI), 3.40(m, 211), 2.80(m, 211), 2.30-1.60(m, 611), 1.40(br, 911)

h) Synthesis of 2-((S)-2-pyrrolidin-2-ylethyl)benzo[b]furan-δ-carboni- trile:

1.55g of the compound obtained in the above g) was treated according to the same procedme as Example 1-1) to obtain a stoichiometric amount of the title compound as a colorless foamy solid.

^] H NMR(CDC1 ₃ , ppm) : δ 9.30(br, IH), 7.75(s, IH), 7.40(m, 2H), 3.50(m,

IH), 3.25(m, 2H), 2.90(m, 2H), 2.3δ-1.80(m, 4H), 1.70(m, IH) ES-MS : 241(M+1) ⁺

i) Synthesis of l-((S)-2- ⁽ 2-(5-ethynylbenzo[d]furan-2-yl)ethyl)pyrrolidi- nyl)-2-phenylethan-l-one:

220mg of 2-((S)-2-pyrrolidin-2-ylethyl)benzo[b]furan-5-carbo- nitrile obtained in the above h) and 180mg of phenylacetyl chloride were reacted according to the same procedure as Example 1-m) to obtain 200mg of the title compound as a colorless liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.80(s, 2H), 7.45(m, 211), 7.25(m, 5H), 6.55(s, IH), 4.25 ⁽ m, IH), 3.65(m, 2H), 3.45(m, 211), 2.80(m, 2H), 2.30(m, IH), 2.10-1.80(m, 3H), 1.70(m, 2H)

ES-MS : 358(M+1) ⁺

j ⁾ Synthesis of 2-[2-[ ⁽ S)-l- ⁽ 2-phenylacetyl)pyrrolidin-2-yl]eth\i]benzo- [b]f uran - 5 - carboxamidine:

190mg of the compound obtained in the above i) was treated according to the same procedure as Example 1-n) to obtain 180mg of the title compound as a colorless foamy solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.70( s, IH), 7.55-7.10(m, 711), 6.50(s, 111), 4.25 (m, HI), 3.65(s, 2H), 3.4δ(m, HI), 2.80(t, 211, J=7.80Hz), 2.30(m, Hi), 2.10- 1.80(m, 311), 1.70(m, 211)

ES-MS : 376(M+D ^* IR(KBr) : 3300, 2950, 2800, 1650 cm ^"1

Example 145 : Svnthesis of 2-[2-r(S)- l-(2-phenylacetyl)pyrro- lidin-2-yl1vinyl3benzo[b3ιuran~5-carboxamidine (Compound 249)

a) Synthesis of 2-(2-pyrrolidin-(S)-ylvinyl)benzo[b3furan-5-carbonitrile:

490mg of tert-butyl (S)-2-[2~(5-cyanobenzo[d]furan-2-yl)vinyl]- pyrrolidine carboxylate obtained in Example 144-f) was treated according to the same procedure as Example 1-1) to obtain a stoichiometric amount of the title compound as a colorless solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.75(m, IH), 7.45(m, 2H), 6.65-6.30(m, 3H), 4.10(m, IH), 3.35-3.15(m, 211), 2.40-1.75(m, 4H)

ES-MS : 239(M+1) ⁺

b) Synthesis of 2-[2-[(S)-l-(2-phenylacetyl)pyrrolidin-2-yl]vinyl]benzo- [b]f uran - 5 -carbonitrile:

450mg of the compound obtained in the above a) and 0.3mfi of phenylacetyl chloride were reacted according to the same procedure as Example 1-m) to obtain 344mg of the title compound as a colorless foamy solid.

1H NMR(CDCl3, ppm) : δ 7.75(m, IH), 7.45(m, 2H), 7.40-7.15(m, 5H), 6.65-6.20(m, 3H), 4.75(m, ΪH), 3.80-3.40(m, 4H), 2.25- 1.75(m, 4H)

ES-MS : 357(M+1) ⁺

c) Synthesis of 2-[2-[(S)-l - (2-phenylacetyl)pyrrolidin-2-yl]vinyl]benzo- [b]furan-δ-carboxamidine:

223mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-n) to obtain 190mg of the title compound as a colorless foamy solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.75(m, 211), 7.60-7.0(m, 711), 6.70-6.20(m, 311), 5.20-4.80(br, 3H), 3.75-3.40(m, 411), 2.25- 1.75(m, 411) ES-MS : 374<M+D ^*

IR(KBr) : 3200, 2950, 2850, 1650 cm ^"1

Example 146 : Synthesis of ethyl 2-r(R)-2-rr(S)-2-[2-(5-amidino- benzord3furan-2-yl)ethyl3pyrrolidinyl3carbonyl3pyrrolidinyl3 acetate (Compound 250)

a) Synthesis of tert-butyl (R)-2-[[(S)-2-[2-(δ-cyanobenzo[d]furan-2-yl)- ethyl]pyrroIidinyl]carbonyl3ρyrrolidine carboxylate:

447mg of 2-( ⁽ S)-2-pyrrolidin-2-ylethyl)benzo[b3furan-5-carbonitrile

obtained in Example 144-h was treated according to the same procedure as Example 11-a) to obtain 370mg of the title compound as a colorless foamy solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.80(m, IH), 7.40(m, 211), 6.55(d, IH), 4.40(m, IH ⁾ , 4.20 ⁽ m, IH), 3.85-3.30(m, 4H), 2.85(m, 2H), 2.45-1.60(m, 10H), 1.40(br, 9H) ES-MS : 438(M+D ^*

b ⁾ Synthesis of 2-[2-[ ⁽ S ⁾ -l- ⁽⁽ R ⁾ -ρyrrolidin-2-ylcarbonyl ⁾ pyrrolidin-2-yl3 -ethyl]benzo[b3furan-δ-carbonitrile:

240mg of the compound obtained in the above a) was treated according to the same procedure as Example 1-1) to obtain 200mg of the title compound as a pale yellow foamy solid.

'II NMR(CDC1 ₃ , ppm) : δ 7.75(s, III), 7.40(m, 211), 6.55(s, HI), 4.55(m, HI), 4.1δ(m, 111), 3.60(m, IH), 3.40(m, 311), 2.7δ(m, 211), 2.45(m, IH), 2.25(m, IH), 2.15-1.70(m, 811)

c) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(5-cyanobenzo[d]furan-2-yl)- ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate:

203mg of the compound obtained in the above b) was treated according to the same procedure as Example 1-m) to obtain 248mg of the title compound as a pale yellow liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.80(s, IH), 7.45(m, 2H), 6.65(s, IH), 4.30-4.0 (m, 3H), 3.85(m, IH), 3.65-3.v35(m, 411), 3.20(m, IH), 2.80(m, 3H), 2.30(m, IH), 2.15(m, IH), 2.10-1.60(m, 8H), 1.25(t, 3H, J=7.14Hz)

d) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(5-amidinobenzo[d]furan-2-yl)- ethyl3pyrrolidinyl3carbonyl]pyrrolidinyl]acetate :

200mg of the compound obtained in the above c) was treated

according to the same procedure .as Example 1-n) to obtain lOOmg of the title compound as a pale yellowish white foamy solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.90(s, IH), 7.50(m, 2H), 6.65(s, IH), 4.45(m, IH), 4.20-3.95(m, 4H), 3.65(m, IH), 3.50(m, IH), 3.35(m, IH), 3.15 ⁽ m, IH), 2.80(m, IH), 2.45(m, IH), 2.25(m, IH), 2.10-1.70(m, 9H), 1.15(t, 3H, J=7.10Hz)

ES-MS : 44HM+D ^*

IR(KBr) : 3200, 2950, 1750, 1670 cm ^{" 1} 0

Example 147 : Synthesis of ethyl 2-[(R)-2-rr(S)-2-r2-(6-amidino- benzo[d3furan-2-yl)ethyl3ρyrrolidinyl3carbonyl3pyrrolidinyl ]acetate (Compound 251) and 2-r2-r(S)- l -rr(R)- l-(carbamoylmethyl)pyrro- lidin-2-yl3carbonyl3pyrτolidin-2-yl3ethyl3benzorb3furan-6-c arboxa- 5 midine

a) Synthesis of 3-bromo-l-(2-bromoprop-2-enyloxy)benzene:

In a 1 £ flask, 25g of 5-bromophenol was stirred in 250m! of o dimethylformamide at room temperature, and 39.9g of K2C0 ₃ was slowly added thereto. After the mixture thereby obtained was stirred for 30 minutes, 22.4ml of 2,3-dibromopropene was slowly added dropwise thereto and the reaction mixture was refluxed for 2 hours with stirring. After the reaction was completed, excessive amount of water was added to the 5 reaction solution, which was tiien extracted three times with ether. The combined organic layer was dried over MgS0 ₄ and then evaporated.

The residue was purified with silica gel column chromatography [eluent: hexane]. The fractions containing the desired product were combined and then evaporated to obtain 37. lg of the title compound as a yellow 0 liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.10(m, 3H), 6.82(m, IH). 5.96(s, IH), 5.68(s, IH), 4.60(s, 2H)

5 b) Synthesis of 5-bromo-2-(2-bromoprop-2-enyl)phenol:

In a 500π4 flask, 240m£ of lN-BBr ₃ was slowly added over one hour to 37g of the compound obtained in the above a) in 250π4 of CS ₂ solvent, and this mixture was then stirred for 6 hours. The reaction was quenched with 5N HCI at OV . The reaction solution was evaporated under reduced pressure and extracted two times with ether. The combined organic layer was dried over MgS0 ₄ and then evaporated to obtain 24. Og of the title compound as a yellow oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.10-6.90(m, 3H)„ ^> S.55(d, IH, J=1.40Hz), 5.50(d, IH, J = 1.60Hz), δ.0δ(s, IH), 3.70(s, 2H)

c) Synthesis of 6-bromo-2-methylbeήzo[b]furan:

In a 250n4 flask, 24. Og of the compound obtained in the above b) was dissolved in 50m? of ethanol at room temperature, and 200mf of 2M NaOEt was slowly added dropwise thereto. The reaction solution was refluxed for 5 hours with stirring and then evaporated under reduced pressure. The residue was extracted three times with ethyl acetate. The combined organic layer was dried over MgS0 ₄ and then evaporated under reduced pressure. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:30)]. The fractions containing the desired product were combined and then evaporated to obtain 11.3g of the title compound as a pale yellow liquid.

^] H NMR(CDC1 ₃ , ppm) : δ 7.75(s, III), 7.30(s, 211), 6.30(s, 111), 2.40(s, 311)

d) Synthesis of 2-methylbenzo[b]furan-6-carbonitrile:

11.3g of the compound obtained in the above c) was treated according to the same procedure as Example 144-c) to obtain 381mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.69(s, 111), 7.50(ddd, 211, J=24.96Hz, 8.02Hz, 1.04Hz), 6.45(s, IH), 2.50(s, 2H)

e) Synthesis of 2-(bromomethyI)benzo[b]furan-6-carbonitrile:

380mg of the compond obtained in the above d) was dissolved in 100π4 of carbon tetrachloride, and 472mg of NBS (N-bromosuccinimide) was added thereto. The reaction solution was refluxed for 6 hours with stirring and then evaporated under reduced pressure. The residue was then extracted three times with ethyl acetate. The combined oragnic layer was dried over MgS0 ₄ and evaporated under reduced pressure. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/ n-hexane(D7)3. The fractions containing the desired product were combined and then evaporated to obtain 520mg of the title compound as a pale yellow solid.

^J H NMR(CDC1 ₃ , ppm) : δ 7.75(s, IH), 7.55(m, 211), 6.80(s, IH), 4.60(s, 211)

f) Synthesis of benzo[b3furan-6-carbonitrile-2-methyl-triphenylρhospho- nium bromide:

520mg of the compound obtained in the above e) was treated according to the same procedure as Example 1-f) to obtain 770mg of the title compound as a pale yellow solid.

1H NMR(CDC1 ₃₎ ppm) : δ 7.90-7.35(m, 1911), 6.10(d, 2H)

g) Synthesis of tert-butyl ⁽ S ⁾ -2-[2- ⁽ 5-cyanobenzo[d3furan-2-yl)vinyl3- pyrrolidine carboxylate:

770mg of the compound obtained in the above f) was treated according to the same procedure as Example 1-j) to obtain 308mg of the title compound as a fluorescent yellow liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.70 ⁽ m, IH), 7.50(m, 2H), 6.70-6.20(m, 3H), 4.50 (m, IH), 3.45(br, 2H), 2.25-1.70(m, 411), 1.40(br, 9H)

h) Synthesis of 2-((2S)-2-pyrrolidin-2-ylethyl)benzo[b3furan-6-carboni-

trile:

308mg of the compound obtained in the above g) was treated according to the same procedure as Example 1-k) to obtain 270rag of the yellow liquid product, which was then treated according to the same procedure as Example 1-1) to obtain 229mg of the title compound as a yellow liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.61(s, IH), 7.45(dd, 2H, J=23.51Hz, 8.02Hz), 0 6.50(s, IH), 3.50(m, IH), 3.30(m, 2H), 2.92(m, 2H), 2.49-1.88(m,

511), 1.71(m, IH) ES-MS : 24HM+D ^*

i) Synthesis of tert-butyl (R)-2-[[(S)-2-[2-(6-cyanobenzo[d]furan-2-yl)- 5 ethyl]pyrrolidinyl]carbonyl]pyrrolidine carboxylate:

228mg of 2-((S)-2-pyrrolidin-2-ylethyl)benzo[b]furan-6-carbonit- rile obtained in the above h) was treated according to the same procedure as Example 11-a) to obtain 167mg of the title compound as a yellowish o white foamy solid.

^] II NMR(CDC1 ₃ , ppm) : δ 7.80( m, HI), 7.4ϋ(m, 211), 6.5δ(d, IH), 4.40(m, IH), 4.20(m, IH), 3.85-3.30(m, 411), 2.8δ(m, 211), 2.4δ- 1.60(m, 10H), 1.40(br, 9H) 5 j) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(6-cyanobenzo[d]furan-2-yl)- ethyl3pyrrolidinyl3carbonyl3pyrrolidinyl3acetate:

167mg of the compound obtained in the above i) was treated _Q according to the same procedure as Example 1-1) to obtain lOOmg of the white foamy product, which was then reacted with ethyl 2 -bromoacetate according to the same procedure as Example 1-m) to obtain 60mg of the title compound as a white foamy solid.

5 1H NMR(CDC1 ₃ , ppm) : δ 7.75(s, HI), 7.55(m, 2H), 6.80(s, IH), 4.30-4.0

(m, 3H), 3.85(m, IH), 3.50(m, 2H), 3.20(m, IH), 2.80(m, 3H), 2.40-1.60(m, 12H), 1.25(t, 3H, J=7.14Hz)

k) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidinobenzo[d3furan-2-yl)- ethyl3pyrrolidinyl3carbonyl3pyrrolidinyl3acetate :

60mg of the compound obtained in • the above j) was treated according to the same procedure as Example 1-n) to obtain 4.2mg of the title compound as a white foamy solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.65(s, IH), 7.45(m, 2H), 6.60(s, III), 5.05(br, 3H), 4.30-4.0(m, 311), 3.8δ(m^ IH), 3.50(m, 4H), 3.20(m, HI), 2.80 (m, 311), 2.40-1.60(m, 10H), 1.47(t, 3H, J=7.14Hz) ES-MS : 442(M+2) ^*

1) Synthesis of 2-[2-[(S)-l-[[(R)- l-(carbamoylmethyl)pyrrolidin-2-yl]- carbonyl3pyrrolidin-2-yl3ethyl3benzo[b3furan-6-carboxamidine :

60mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-cyanobenzo[d3furan-2-yl)- ethyl3pyrrolidinyl3carbonyl3ρyrrolidinyl]acetate obtained in the above j) was treated according to the same procedure as Example 1-n) to obtain 3.2mg of the title compound as a yellow foamy solid.

1H NMR(CD ₃ OD, ppm) : δ 7.75(s, IH), 7.50(m, 211), 6.55(s, HI), 4.05(m, HI), 3.60-3.2δ(m, 3H), 3.10(m, IH), 3.0-2.60(m, 3H), 2.40(m, HI),

2.15(m, IH), 2.15-1.55(m, 10H) ES-MS : 413(M+2) ⁺

Example 14R ^; Synthesis of ethyl 2-r(R)-2-rr(S)-2-r2-(6-amidino- 3-methyIbenzofd1furan-2-yl)ethyπpyrrolidinyπcarbonyllpyrro Iidinyl) -acetate (Compound 252)

a) Synthesis of l-(4-bromo-2-hydroxyphenyl)ethan-l-one:

In a 1 i flask, 25g of 5-bromoanisole was stirred in 250m£ of CS2

solvent at 0 ^° C , and 12.4mC of acetyl chloride was added and 53.5g of AICI3 was slowly added portionwise thereto. After the addition was completed, the reaction solution was refluxed for one hour with stirring. The reaction was quenched with 2N HCI. Excessive amount of water was added and the reaction solution was extracted three times with ethyl acetate. The combined organic layer was dried over MgS0 ₄ and then evaporated. The residue was purified with silica gel column chromato¬ graphy [eluent: ethyl acetate/n-hexane( 1:10)3. The fractions containing the desired product were combined and then ^s evaporated to obtain 7.68g of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 12.3(s, 111), 7.57(d, IH, J=8.56Hz), 7.17(d, IH, J=1.92Hz), 7.04(dd, IH, J=8.49Hz, 1.98Hz)

ES-MS : 237(M+D ^*

b) Synthesis of ethyl 2-(5-bromo-2-acetylphenoxy)acetate:

7.68g of the compound obtained in the above a) was treated in acetone solvent according to the same procedure as Example 42 to obtain 3.58g of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.65(d, HI, J=8.34IIz), 7.20(dd, HI, J=8.32Hz, 1.76Hz), 6.95(d, HI, J=1.64Hz), 4.70(s, 2H), 4.25(q, 211, J=7.15 Hz), 2.65(s, 3H), 1.35(t, 3H, J=7.11Hz)

c) Synthesis of ethyl 6-bromo-3-methylbenzo[d]furan-2-carboxylate:

3.58g of the compound obtained in the above b) was treated according to the same procedure as Example 144-b) to obtain 1.26g of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.70(s, III), 7.40(m, 2H), 4.40(q, 2H, J=7.13Hz),

2.50(s, 3H), 1.40(t, 3H, J=7.13Hz) ES-MS : 283(M+1) ⁺

d) Synthesis of ethyl 6-cyano-3-methylbenzo[d]furan-2-carboxylate:

7.52g of the compound obtained in the above c) was treated according to the same procedure as Example 144-c) to obtain 790mg of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.85(s, IH), 7.70(d. HI, J=8.24Hz), 7.55(dd, IH, J=8.15Hz, 1.26Hz), 4.45(q, 2H, J=7.14Hz), 2.60(s, 3H), 1.45(t, 3H, J=7.12Hz) ES-MS : 230(M+1) ⁺

e) Synthesis of 2-(hydroxymethyl)-3-methylbenzo[b]furan-6-carbonitrile:

789mg of tlie compound obtained in the above d) was treated according to the same procedure as Example 1-e) to obtain 459mg of the title compound as a yellow solid.

1H NMR(CDC1 ₃ , ppm) : <5 7.75(s, IH), 7.55(d, IH, J=7.96Hz), 7.40(d, HI, J=8.03Hz), 4.60(s, 2H), 2.15(s, 3H)

f) Synthesis of benzo[b]furan-6-carbonitrile-2-methyl-triphenylphospho- nium bromide:

459mg of the compound obtained in the above e) was treated according to the same procedure as Example 1-f) to obtain 855mg of the title compound as a yellow solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.95-7.35(m, 18H), 5.85(d, 2H), 2.25(s, 3H)

g) Synthesis of tert-butyl (S)-2-[2-(6-cyano-3-methylbenzo[d]furan-2- yl)vinyl]pyrrolidine carboxylate:

850mg of the compound obtained in the above f) was treated according to the same procedure as Example 1-j) to obtain 344mg of the title compound as a fluorescent yellow liquid.

1H NMR(CDCl3, ppm) : δ 7.65(s, IH), 7.45(m, 2H), 6.40(br, 2H), 4.50(m, IH), 3.45(br, 2H), 2.25(s, 3H), 2.05-1.70(m, 4H), 1.40(br, 9H)

h) Synthesis of 3-methjd-2- ⁽⁽ S)-2-pyrrolidin-2-ylethyl)benzo[b]furan- 6-carbonitrile:

344mg of the compound obtained in . the above g) was treated according to the same procedure as Example 1-k) to obtain 340mg of the colorless liquid product, which was then ti"eated according to the same procedure as Example 1-1 to obtain 187mg of the title compound as a colorless liquid.

1H NMR(CDC1 ₃ , ppm) : δ 7.55(s, HI), 7.40(s, 2H), 3.50(m, IH), 3.25(m, 211), 2.85(m, 2H ⁾ , 2.35- 1.85(m, 811), 1.6δ(m, IH)

i) Synthesis of 3-methyl-2-[2-[(S)- l - ((R)-pyrrolidin-2-ylcarbonyl)pyrro- lidin-2-yl]ethyl]benzo[b]furan-6-carbonitrile:

185mg of the compound obtained in the above h) was treated according to the same procedure as Example 11-a) to obtain 161mg of the colorless foamy solid product, which was then treated according to the same procedure as Example 1-1) to obtain lOOmg of the title compound as a colorless foamy solid.

j) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(6-cyano-3-methylberιzo[d]- f uran - 2 - y 1 )ethy l]pyrrolidinyl3carbony l3py rrolidiny llacetate :

lOOmg of the compound obtained in ^he above i) was treated according to the same procedure as Example i- m) to obtain 61mg of the title compound as a colorless foamy solid.

^] H NMR(CDC1 ₃ , ppm) : δ 7.65(s, IH), 7.45(s, 2H), 4.20-4.0(m, 3H), 3.90 (m, IH), 3.50(m, 2H), 3.15(m, IH), 2.80(m, 3H), 2.15(s, 311), 2.10- 1.60(m, 12H), 1.20(t, 3H, J=7.19Hz)

k) Synthesis of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-3-methylbenzo[d] -furan-2-yl)etiιyl3pyrrolidinyl]carbonyl3pyrrolidinyl3aceta te:

60mg of the compound obtained in the above j) was treated according to the same procedure as Example 1-n) to obtain 2.9mg of the title compound as a colorless foamy solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.65(m, IH), 7.45(m, 2H), 4.80(br, 3H), 4.20-4.0 (m, 3H), 3.85(m, IH), 3.50(m, 4H), 3.15(m, IH), 2.80(m, 3H), 2.15(s, 3H), 2.10-1.60(m, 10H), 1.20(t, 3H, J=7.19Hz)

ES-MS : 456<M+2) ⁴

Eχampl^ 149 ' Synthesis of 2-f2-[(S)-l-(2-phenylacetyl)pyrrolidin- 2-yllethyl3benzorb3thiophene-5-carhnxamidiπe (Compound 253)

a) Synthesis of 5-bromo-2-((dimethylamino)thioxomethoxy)benzaldehyde:

In a 500m£ flask, 35.6g of 5-bromosalicyl aldehyde was dissolved in 150m! of acetone, and 29.38g of anhydrous potassium carbonate was added. Thereafter, 21.9g of N,N-dimethylthiocarbamoyl chloride was slowly added, and the reaction solution thereby obtained was then stirred for 2 hours, poured into ice -water and then stirred. The resulting precipitate was filtered and washed three times with water. The filtered solid product was dried and then recrystallized from ethyl acetate/ n-hexane(l:3) solvent system to obtain 42.3g of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 10.03 ⁽ s, IH), 8.01(m, IH), 7.72(m, IH), 7.02(m, IH), 3.47(s, 3H), 3.42(s, 3H) ES-MS : 311(M+Na ⁺ ), 289(M+1) ⁺

b ⁾ Synthesis of N,N-dimethyl ⁽ 4-bromo-2-formylphenylthio)formamide:

In a 100m£ flask, 42.3g of 5-bromo-2-((dimethylamino)thioxome- thoxy)benzaldehyde was introduced, melted for 10 minutes in oil bath at

210-220 ^° C and then dissolved in 30m? of toluene. After 100m? of methanol was added, the resulting precipitate was filtered, washed several times with n-hexane and then dried to obtain 12.3g of the title compound as a white solid.

1H-NMR ⁽ CDC1 ₃ , ppm) : δ 10.25(s, IH), 8.13(m, IH), 7.70(m, IH), 7.31 (m,

IH), 3.15(s, 3H), 3.03(s, 3H) Mass : 311(M+Na ⁺ ), 289(M+1) ⁴

c ⁾ Synthesis of l- ⁽ 5-bromobenzo[b]thiophen-2-yl)ethan-l -one:

In a 100m? flask, 12.3g of N,N-dimethyl(4-bromo-2-formylphenyl- thio)formamide was dissolved in 35m? of methyl orthoformate, and 0.6g of p-toluenesulfonate was added. The reaction solution was stirred for 50 minutes at refluxing temperature and then cooled, and saturated NaIIC0 ₃ solution was added. The organic layer was then extracted three times with benzene. After the extract was evaporated to remove the solvent, the residue was dissolved in 60m? of methanol, and 20m? of 2N~NaOH was added thereto. The reaction solution was refluxed under nitrogen atmosphere for one hour, cooled, adjusted to pH 1 with concentrated hydrochloric acid, and then extracted with benzene. After the solvent was removed from the extract, the residue was dissolved in 13m? of acetone. To the resulting solution was slowly added 3.5g of chloroacetone at room temperature. 1.3g of anhydrous potassium carbonate and 90m? of acetone were slowly added thereto. The reaction solution was stirred for 30 minutes at room temperature, refluxed again for 30 minutes, cooled and then filtered to remove the unsoluble material. The filtrate was evaporated and then purified with silica gel column chromatography [elue : ethyl acetate'n-hexaneQ^)}. The fractions containing the desire product were imbined and then evaporated to obtain 1.66g of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.03(m, IH), 7.85(s, IH), 7.75(m, IH), 7.54(m, IH), 2.66(s, 3H)

d) Synthesis of 5-bromobenzo[b]thiophene-2-carboxylic acid:

1.25m? of bromine was slowly added to 10m? of 5N aqueous NaOH solution with stirring and the resulting solution was cooled to -5 ^° C -0°C.

5 At the same temperature, a solution of 1.66g of l-(5-bromobenzo[b]- thiophene-2-yl)ethan-l-one in 15m? of 1,4-dioxane was slowly added thereto. The reaction solution was stirred for 30 minutes at room temperature and then for 30 minutes at 50 "C, cooled, poured into ice- water and then adjusted to pH 2 with concentrated hydrochloric acid. _j 0 The resulting precipitate was filtered, washed several times with water, dried and then purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane( 1:2)3. Tlie fractions containing the desired product were combined and evaporated to obtain 1.42g of the title compound as a white solid.

15

Η NMR(CDC1 ₃ , ppm) : δ 8.03(m, HI), 7.92(s, 111), 7.76(m, HI), 7.50(m, 111)

e) Synthesis of ethyl 5-bromobenzo[b3thiophene-2-carboxylate: 0

In a 100m? flask, 1.42g of 5-bromobenzo[b]thiophene-2-carboxylic acid and 25m? of methanol were introduced and then stirred. The resulting suspension was cooled in ice bath and 0.6m? of thionyl chloride was slowly added thereto. The reaction solution was refluxed for one 5 hour and then cooled. After 1.1m? of thionyl chloride was added, the reaction solution was refluxed for further 2 hours, cooled and then adjusted to pH 9 with saturated NaHC0 ₃ solution. The resulting precipitate was filtered, dried and then purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane( 1:3)3. The fractions _Q containing the desired product were combined and then evaporated to obtain 1.3g of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : 6 8.01(m, IH), 7.96(s, HI), 7.73(m, IH), 7.54(m, IH), 4.41(q, 2H, J=7.0Hz), 1.42(t, 3H, J=7.0Hz) 5

f) Synthesis of ethyl 5-cyanobenzo[b3thioρhene-2-carboxylate:

In a 50m? flask, 1.3g of 5-bromobenzo[b3thiophene-2-carboxylate and 1.02g of CuCN were introduced and 20m? of N-methyl-2-pyrroIidone was then added thereto. The mixture was stirred and the resulting suspension was refluxed under nitrogen atmosphere for 2 hours at 200 °C.

The reaction solution was cooled, poured- into ice- water, vigorously stirred and then filtered to remove the unsoluble material. The filtrate was then extracted with ethyl acetate. The extract was evaporated to remove the solvent, and the residue was then purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:3)]. The fractions containing the desired product were combined and evaporated to obtain 330mg of the title compound as a white solid.

^] H NMR(CDC1 ₃ , ppm) : δ 8.21(m, HI), 8.09(s, HI), 7.97(m, HI), 7.70(m, HI), 4.45(q, 211, J=7.0Hz), 1.43(t, 311, J=7.0IIz)

g) Synthesis of 2-(hydroxymethyl)benzo[b]thiophene-5-carbonitrile:

220mg of the compound obtained in the above f) was treated according to the same procedure as Example 1-e) to obtain 120mg of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.03(m, IH), 7.90(m, IH), 7.51 (m, HI), 7.26(s, IH), 4.97(s, 2H)

h) Synthesis of (5-cyanobenzo[b]thioρhen-2-yl)methyltriphenylphospho- nium bromide:

120mg of the compound obtained in the above g) was treated according to the same procedure as Example 1-f) to obtain 21δmg of the title compound as a yellowish white solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.09-7.27(m, 19H), 6.70(s, 2H)

i) Synthesis of tert-butyl ⁽ S)-2-[2-(5-cyanobenzo[b]thiophen-2-yl)vinyl3-

pyrrolϊdine carboxylate:

211mg of (5-cyanobenzo[b3thiophen-2-yl)methyltriphenylphospho- nium bromide obtained in the above h) was reacted according to the same procedure as Example 1-j) to obtain 150mg of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.01(m, IH), 7.81(m, IH), 7.48(m, IH), 7.14(s, IH), 6.69-6.49(m, IH), 6.13-6.05(m> IH), 4.57-4.32(m, IH), 3.42 (m, 2H), 2.38- 1.73(m, 4H), L48(brs, 9H)

ES-MS : 377(M+Na ^* ), 355<M+1) ⁺

j) Synthesis of tert-butyl ⁽ S)-[2- ⁽ 5-cyanobenzo[b3thiophen-2-yl)ethyl3- pyrrolidine carboxylate:

155mg of the compound obtained in the above i) was treated according to the same procedure as Example 1-k) to obtain 130mg of the title compound as a white solid.

^H NMR(CDC1 ₃ , ppm) : δ 7.93(m, IH), 7.82(m, HI), 7.41 (m, IH), 7.08(s, IH), 3.90(brs, HI), 3.52-3.27(m, 211), 2.89(m, 211), 2.35-1.65(m, 6H), 1.41(brs, 911)

ES-MS : 379(M+Na ^< ), 357(M+D ^*

k ⁾ Synthesis of 2-( ⁽ S)-2-pyrrolidin-2-ylethyl)benzo[b3thiophene-5-carbo- nitrile:

128mg of the compound obtained in the above j) was treated according to the same procedure as Example 1-1) to obtain 72 rag of the title compound as a white solid.

1 ⁾ Synthesis of 2-[2-[ ⁽ S)-l- ⁽ 2-phe ^ή ylacetyl)pyrroIidin-2-yl3ethyl3ben2:o- [b3thiophene-5-carbonitrile:

72mg of the compound obtained in the above k) and phenylacetyl chloride were reacted according to the same procedure as Example 1-m)

to obtain 55mg of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 7.94(m, IH), 7.80(m, IH), 7.43(m, IH), 7.36-7.23 (m, 5H), 7.11(s, IH), 4.22(m, IH), 3.66(m, 2H), 3.48(m, 2H), 2.93(m, 2H), 2.39- 1.75(m, 6H)

ES-MS : 397(M+Na ⁺ ), 375(M+1) ⁺

m ⁾ Synthesis of 2-[2-[ ⁽ S)-l- ⁽ 2-phenylacetyl)pyrrolidin-2-yl]ethyl3- benzo -[b]thiophene-5-carboxamidine:

55mg of the compound obtained in the above 1) was treated according to the same procedure as ^Example 1-n) to obtain 45mg of the title compound as a white solid.

^] II NMR(CDC1 ₃ , ppm) : δ 7.91(m, 111), 7.75(m, IH), 7.46(m, IH), 7.32-7.13 (m, 511), 7.07(s, 111), 4.23(m, HI), 3.66-3.58(m, 211), 3.48(m, 211), 2.89(m, 2H), 2.38- 1.75(m, 611) ES-MS : 392<M+lK IR(KBr) : 3079, 2954, 1613 cm ^"1

Exampl 150 ; Synthesis of 3-methoxy-2-[2-[(S)- l- (2-phenyl- acetyl)ρyrrolidin-2-yl]ethyl3benzo[b]thioρhene-6-carboxami dinp (Compound 255)

a) Synthesis of prop-2-enyl 3-nitro-4-(prop-2-enoxycarbonyl)benzoate:

In a 500m? flask, 25g of 2-nitrobenzene- l,4-dicarboxylic acid and 21.88g of NaHC0 ₃ were dissolved in 150m? of N,N-dimethylformamide. To the resulting solution was slowly added 25.6m? of allyl bromide. The reaction solution was stirred for 3 hours at 50 ^° C, cooled, adjusted to pH 6 with 2N-HC1 and then extracted three times with ethyl acetate. The combined extract was dried and then purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane( 1:3)3. The fractions containing the desired product were combined and then evaporated to obtain 34g of the title compound as a pale yellow liquid.

1H NMR(CDCl3, ppm) : δ 8.61(m, IH), 8.33(m, IH), 7.82(m, IH), 6.14-5.94

(m, 2H), 5.49-5.32(m, 4H), 4.92-4.86(m, 4H) ES-MS : 314(M+Na ⁺ )

b) Synthesis of methyl 3-hydroxy-6-(prop-2-enyloxycarbonyl)benzo[b]- thiophene- 2-carboxylate:

In a 500m? flask, 34g of the compound obtained in the above a) and 15.66m? of methyl thioglycolate were dissolved in 150m? of N,N-dimethylformamide. The resulting solution was cooled in ice-bath and lithium hydroxide was added portionwise thereto. The reaction solution was stirred for 30 minutes under ice-bath and then for 2 hours at room temperature, poured into ice-water, treated with concentrated hydrochloric acid and then extracted three times with ethyl acetate. The combined extract was dried and purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane( 1:7)3. The fractions containing the desired product were combined and then evaporated to obtain 13. lg of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 10.08(s, 111), 8.52(s, HI), 8.09-7.98(m, 211), 6.12-6.01(m, IH), 5.49-5.33(m, 211), 4.89(m, 211), 3.97(s, 3D) ES-MS : 315(M+Na ^< ), 293(M+1) ⁺

c) Synthesis of 3-hydroxy-2-(methoxycarbonyl)benzo[b3thiophene-6-car- boxy lie acid:

In a 500m? flask, 22.8g of the compound obtained in the above b) and 32.8g of dimedone were dissolved in 150m? of tetrahydrofuran, and 4.5g of tetrakis ⁽ triphenylρhosphine)palladium [Pd(PPh ₃ ) ₄ 3 was added thereto. The reaction solution was stirred for 3 hours at room temperature. The resulting precipitate was filtered, washed several times with ethyl acetate and then dried in air to obtain 18.2g of the title compound as a white solid.

1H NMR ⁽ DMSO-de, ppm) : δ 8.56(s, IH), 8.01-7.91(m, 211), 3.87(s, 3H)

d) Synthesis of methyl 6-carbamoyl-3-hydroxybenzo[b3thiophene-2-cabo- xylate:

In a 100m? flask, 18.2g of the compound obtained in the above c) was dissolved in 40m? of thionyl chloride. The resulting solution was refluxed for 30 minutes, cooled and then distilled under reduced pressure to remove thionyl chloride. The remaining thionyl chloride was removed for 5 hours by means of a vaccum pump. To the dried product was slowly added 40m? of NH ₄ OH at 0V . The ^s reaction solution was stirred for 4 hours at room temperature, and the resulting precipitate was filtered, washed several times with ethji acetate and then dried to obtain 17.5g of the title compound as a white solid.

1H NMR(DMSO-d6, ppm) : δ 8.17(s, HI), 7.98(brs, 111), 7.79-7.69(m, 211), 7.30(brs, IH), 3.69(s, 3H)

e) Synthesis of methyl 6-cyano-3-hydroxybenzo[b]thiophene-2-caboxylate

In a 500m? flask, 17.5g of the compound obtained in the above d) was dissolved in 50m? of tetrahydrofuran, and a solution of 54.8g of triphenylphosphine in 100m? of carbon tetrachloride was slowly added. The reaction solution was stirred for 30 minutes at room temperature and then for one day at 60 V, cooled and filtered to remove the unsoluble material. The filtrate was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane( 1:3)3. The fractions containing the desired product were combined and evaporated to obtain 457mg of the title compound as a pale pink solid.

1H NMR(CDC1 ₃ , ppm) : δ 10.14(s, IH), 8.06-7.99 ⁽ m, 2H), 7.62(m, IH), 3.99(s, 3H)

ES-MS : 489(2M+Na ⁺ ), 256(M+Na ⁺ )

f) Synthesis of methyl 6-cyano-3-methoxybenzo[b]thiophene-2-carboxy- late:

In a 50m? flask, 227mg of the compound obtained in the above e) was dissolved in 10m? of N,N-dimethylformamide, and 47mg of NaH was added thereto at O'C . To this mixture was slowly added 0.15m? of methyliodide. The reaction solution was stirred for 4 hours at 60 V and ice- water was then added. This solution was extracted three times with dichloromethane. The extract was dried and purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(l:3)3. The fractions containing the desired product were combined and evaporated to obtain 153mg of the title compound as a white solid.

1H NMR ⁽ CDCl3, Ppm ⁾ : δ 8.08(m, IH), 7.95(m, IH), 7.59(m, HI), 4.22(s,

311), 3.97(s, 3H) ES-MS : 270 ⁽ M+Na ^* )

g) Syntliesis of 2-(hydroxymethyl)-3-methoxybenzo[b3thiophene-6-carbo- nitrile:

260mg of the compound obtained in the above f) was treated according to the same procedure as Example 1-e) to obtain 176mg of the title compound as a white solid.

Η NMR ⁽ CDC1 ₃ , ppm) : δ 8.06(m, 111), 7.79(m, IH), 7.58(m, IH), 4.97(s,

2H), 4.01 (s, 311) ES-MS : 461(2M+Na ^* ), 242(M+Na ⁺ )

h) Synthesis of (6-cyano~3-methoxybenzo[b3thiophen-2-yl)methyltriphe- nylphosphonium bromide:

176rag of the compound obtained in the above g) was treated according to the same procedure as Example 1-f) to obtain 340mg of the title compound as a white solid.

1H NMR ⁽ CDCl3, ppm) : δ 7.91-7.52(m, 18H), 5.89(m, 2H), 3.89(s, 311)

i ⁾ Synthesis of tert-butyl ⁽ S)-[2-(6-cyano-3-methoxybenzo[b]thiophen- 2-yl)vinyl3pyrrolidine carboxylate:

335rag of ⁽ 6-cyano-3-methoxybenzo[b]thiophen-2-yl)methyltriphe- nylphosphonium bromide obtained in the above h) was treated according to the same procedure as Example 1-j) to obtain 230mg of the title compound as a white solid.

1H ^« NMR(CDC1 ₃ , ppm) : δ 8.00(m, IH), 7.76(m, IH), 7.57(m, IH), 6.78(m, IH), 6.10-5.77 ⁽ m, IH), 4.96(m, IH), 3.95(s, 3H), 3.48(m, 2H), 2.38-1.74(m, 4H), 1.42(m, 9H)

j) Synthesis of tert-butyl ⁽ S)-[2- ⁽ 6-cyano-3-methoxybenzo[b]thiophen-2- yl)ethyl]pyrrolidine carboxylate:

230mg of the compound obtained in the above i) was treated according to the same procedure as Example 1-k) to obtain 233mg of the title compound as a white solid.

1H NMR(CDC1 ₃ , ppm) : δ 8.01 (m, IH), 7.72(m, HI), 7.51(m, HI), 3.92(s, 311), 3.δ7-3.28(m, 311), 2.86(m, 211), 2.28-1.66(m, 611), 1.43(m, 9H) ES-MS : 409(M+Na ^* )

k) Synthesis of 3-methoxy-2-[((S)-2-pyrrolidin-2-yl)ethyl]benzo[b]thio- phene-6-carbonitrile:

230mg of the compound obtained in the above j) was treated according to the same procedure as Example 1-1) to obtain 39mg of the title compound as a colorless oil.

1H NMR(CDC1 ₃ , ppm) : δ 7.97(m, IH), 7.71(m, IH), 7.55(m, IH), 3.90(s, 3H), 3.58(m, IH), 3.47-3.29(m, 211), 3.08(m, 2H), 2.50-1.80(m, 6H)

ES-MS : 287(M+1) ⁴

1) Synthesis of 3-methoxy-2-[2-[(S)-l-(2-phenylacetyl)pyrrolidin-2-yl]- ethyl]benzo[b3thiophene-6-carbonitrile:

39mg of the compound obtained in the above k) and phenylacetyl cloride were reacted according to the same procedure as Example 1-m) to obtain 18mg of the title compound as a colorless oil.

1H NMR(CDCl3, ppm) : δ 7.98(m, IH), 7.68(m, IH), 7.48(m, IH), 7.23(m, 5H), 4.24(m, IH), 3.89(s, 3H), 3.65(m, 2H), 3.47(m, 2H), 2.88(m, 2H), 2.32-1.65(m, 6H) ES-MS : 427(M+Na ⁴ ), 405(M+1) ⁺

m) Synthesis of 3-methoxy-2-[2-[(S)-l-(2-phenylacetyl)pyrrolidin-2-yl]~ ethyl]benzo[b]thiophene-6-carboxamidine:

18mg of the compound obtained in the above 1) was treated according to the same procedure as Example 1-n) to obtain lOmg of the title compound as a pale yellow solid.

^] 1I NMR(CDCl3) : δ 7.97(m, HI), 7.68-7.52(m, 211), 7.26-6.98(m, 511), 4.16 (m, HI), 3.87(s, 311), 3.65(m, 211), 3.44(m, 211), 2.87(m, 211),

2.26-1.58(m, 6H) ES-MS : 422<M+1)' IR(KBr) : 2992, 1612, 1460 cm ^{" 1}

Example 151 : Svnthesis of N-methyl r3-fT(S)-2-r2-r6-nmino- (mpt.hv1aminn ⁾ methyl3- l-methvIindol-2-yl1ethyl3pyrτolidinyl3methyl] -benzo[b3thiophen-2-yl]formamide (Compound 258)

68mg of l-methyl-2-[2-[ ⁽ S)-l-[[2-(N-methylcarbamoyl)benzo[b3- thiophene -3 - yl]methy l]py rrolidin - 2 - y 13ethy l]indole - 6- carboxamidine obtained in Example 10 was dissolved in 10m? of 40% methylamine methanol solution and then stirred overnight at room temperature. The reaction solution was distilled under reduced pressure to remove the reaction solvent and the residue was purified with column chromato¬ graphy [eluent: dichloromethane/methanol(10:l)3 on NH-DM1020 silica. The fractions containing the desired product were combined and distilled under reduced pressure to obtain 52rag of the title compound as a pale

yellow solid.

1H NMR ⁽ MeOH-d4, ppm) : δ 7.91(d, IH), 7.84(d, IH, J=6.54Hz), 7.67(s,

IH), 7.52 ⁽ d, IH), 7.39-7.31(m, 3H), 6.15(s, IH), 4.12(d, IH), 3.83(d, IH), 3.62(s, 3H), 3.05(s, 3H), 2.99(s, IH), 2.85(m, IH),

2.77-2.70(m, 2H), 2.41(m, IH), 2.19(m, IH), 2.05(m, IH),

1.79-1.58(m, 4H)

Exam ^p le 152 : Svnthesis of l - r ⁽ S ⁾ -2-r2-(6- I(hvdroxyimino)amino- methyll- l-ethylindol-2-vnethvn ^p yrrolidinvn-2-nhenylethan- l-one (Compound 260)

190mg of l-ethyl-2-[2-[ ⁽ S)-l-(2-phenylacetyl)pyrrolidin-2-yl]- ethyl]indole-6-carbonitrile obtained in Example 14-a) was dissolved in methanol. 103mg of hydroxylamine hydrochloride and 210mg of sodimri carbonate were added and the reaction solution was refluxed overnight with stirring. After water was added, the reaction solution was extracted two times with dichloromethane. The extract was dried over MgS0 ₄ and distilled under reduced pressure. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol (20: 1)] to obtain llmg of the title compound.

1H NMR(MeOH-d ₄ ) : δ 7.52(s, IH), 7.34(d, 111, J=8.38Hz), 7.27-6.80(m, 6H), 6.18(s, IH), 4.08(m, 3H), 3.60(d, 2H, J=5.36Hz), 3.44(m, 211), 2.66(t, 2H, J=8.00Hz), 2.13(m, IH), 1.92-1.60(m, 6H), 1.21(t, 3H,

J= 7.15Hz)

ES-MS : 419(M+1)\ 441(M+Na)

FΛamnlft 153 : Synthesis of ethyl 2-r(R)-2-r[(S)-2-[2-r6-r(hvd- roxvimino ⁾ arη _ι jnomethyl1- l-ethylindol-2-yl3ethyl]pyrrolidinyl3carbo- nyl]pyrrolidinyl]acetate (Compound 261)

480mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-cyano- l-ethylindol-2-yl)- ethyl3pyrrolidinyl]carbonyl3pyrrolidinyl3acetate obtained in Example 60-a) was dissolved in methanol. 304mg of hydroxylamine hydrochloride and

695mg of sodium carbonate were added and the reaction solution was refluxed overnight with stirring. After water was added, the reaction solution was extracted two times with dichloromethane. The extract was dried over MgS0 ₄ and distilled under reduced pressure. The residue was purified with silica gel column chromatography [eluent: dichloro- methane/methanol(20:l)3 to obtain 27mg of the title compound.

1H NMR(MeOH-cU, ppm) : δ 7.53(s, IH), 7.35(d, IH, J=8.25Hz), 7.21(d, III, J=4.43Hz), 6.21(s, IH), 4.11(m, ^N 3H), 3.99(m, 2H), 3.68(t, IH), 3.49(m, 2H), 3.34(d, 2H, J=18.9Hz), 3.12(m, IH), 2.68(m, 2H),

2.25-1.60(m, 11H), 1.25(t, 3H), 1.10(t, 311)

Example 154 : Svnthesis of ethyl 2-r(R)-2-[r(S)-2-r2-fl-ethvI- 6-[(acetylamino ⁾ iminomethyl1indol-2-yl3ethyl3ρyrrolidinyl]carbonyl3 -nyrrolidinvnacetate (Compound 265)

52mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl3pyrrolidinyl3carbonyl3pyrrolidinyl]acetate obtained in Example 60 was dissolved in dry dichloromethane. To the resulting solution was added 31μ? of triethylamine, and the mixture was cooled to -7812. After 16μ? of acetyl chloride was added, the reaction solution was stirred for 3 hours and warmed to room temperature. Water was added and the mixture was extracted with dichloromethane. The extract was dried over MgS0 ₄ and evaporated under reduced pressure to remove the solvent. The residue was purified with silica gel column chromato- graphy [eluent: ethyl acetate/methanol(50:l)3 to obtain 7mg of the title compound as a pale yellow solid.

1H NMR(MeOH-d4, ppm) : δ 7.72(s, IH), 7.44(d, IH, J=8.00Hz), 7.29(d, IH, J=8.27Hz), 6.28(s, IH), 4.17(m, 3H), 4.02(m, 2H), 3.70(m, IH), 3.49(m, 4H), 3.33(d, 2H, J=20.26Hz), 3.09(m, IH), 2.75(m, 2H), 2.64(m, IH), 2.30-1.60(m, 8H), 1.25(t, 3H), 1.19(s, 311), 1.07(t, 3H)

Example 155 : Svnthesis of N-rri-ethyl-2-ι 2-r(S)- l-(2-phenyl- acetyl)pyrrolidin-2-yl]ethyl3indol-6-vniminomethvnethoxyform amide (Compound 266)

170mg of l-ethyl-2-[2-[(S)-l-(2-phenylacetyl)pyrrolidin-2-yl3- ethyl3indole-6-carboxamidine obtained in Example 14 was dissolved in dichloromethane. 90/il of triethylamine and- 70mg of ethyl chloroformate were added at OV . The reaction solution was stirred for one hour at room temperature and distilled under rediiced pressure to remove the reaction solvent. The residue was purified with column chromatography [eluent: ethyl acetate] on NH-DM1020 silica. The fractions containing the desired product were combined and distilled under reduced pressure to obtain HOmg of the title compound as a white solid.

1H NMR(MeOH-d ₄ , ppm) : δ 8.34(s, 111), 7.49(d, 111), 7.42(m, IH), 7.38- 7.22(m, 5H), 6.36(s, HI), 4.34-4.22(m, 611), 3.66(s, 211), 3.50(m, 311), 2.77(m, 2H), 2.33(m, III), 1.98(m, 511), 1.74(m, 3D), 1.37(m, 611)

Example 156 : Svnthesis of ethyl 2-[(R)-2- [[(S)-2-r2-[l-ethyl- 6-[(ethoxycarbopylamino)iminomethyl1indol-2-yl3ethyl3pyrroli dinyl3- carbonyl3pyrrolidinyl3acetate (Compound 267)

200mg of ethyl 2-[ ⁽ R)-2-[[(S)-2-[2-(6-amidino- l-ethylindol-2-yl3- ethyl3pyrrolidinyl3carbonyl3pyrrolidinyl]acetate obtained in Example 60 was dissolved in dichloromethane and then cooled to 0°C. 119 μt of triethylamine was added and after 30 minutes, 49μi of ethyl chlorocarbo- nate was added. After one hour, water was added to the reaction solution, which was then extracted two times with dichloromethane. The combined extract was dried over MgS0 ₄ and then concentrated. The residue was subjected to column chromatography [eluent: ethyl acetate] on NH-DM1020 silica to obtain 124mg of the title compound.

1H NMR(MeOH-d4, ppm) : δ 8.03(s, IH), 7.20(s, IH), 6.40(s, IH), 4.35- 4.05(m, 7H), 3.81 ⁽ q, IH), 3.74-3.34(m, 4H), 3.25(m, HI), 2.85(m,

2H), 2.77(m, IH), 2.40-1.70(m, 10H), 1.35(m, 6H), 1.22(m, 3H)

Example 157 : Svnthesis of ethyl 2-r(R)-2-rr(S)-2-r2-ri-ethyl- 6-riminor(methvlethoxy)carbonylamino1methvnindol-2-yllethvnp yr- rolidinyllcarbonvnpyrrolidinyllacetate (Compound 270)

200mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl3pyrroIidinyl3carbonyl3pyrrolidinyl]acetate obtained in Example 60 was reacted with 67μd, of isobutylchloroformate according to the same procedure as Example 154 to obtain 195mg of the title compound.

1H NMR(MeOH-d ₄ , ppm) : δ 7.91(s, IH), 7.42(m, 2H), 6.32(s, IH), 4.18(m, 3H), 3.75(d, 211, J=6.66Hz), 3.67(t, HI), 3.50(m, 3H), 3.30(d, 211), 3.08(m, IH), 2.74(m, 211), 2.62(q, 111), 2.30-1.60(m, 1211), 1.28(t, 3H), 1.08(t, 311), 0.92(d, 6H)

Example 158 : Svnthesis of ethyl 2-I(R)-2-rr(S)-2-r2-[6- rr(trichloromethoxy)carbonylamino]iminomethyl3- l-ethyIindol-2-yl]- ethynpyrrolidinyncarbonyl]pyrrolidinyl3acetate (Compound 272)

lOOmg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2- yI)ethyl3ρyrrolidinyl3carbonyl]pyrrolidinyl3acetate obtained in Example 60 was reacted with 35μt of trichloroethylcliloroformate treated according to the same procedure as Example 154 to obtain 92mg of the title compound.

1H NMR(MeOH-d ₄ , ppm) : δ 7.97(s, IH), 7.46(m, 211), 6.29(s, IH), 4.81 (s, 2H), 4.18(m, 3H), 3.67(t, IH), 3.57-3.05(m, 7H), 2.76(m, 2H), 2.64(q, IH), 2.30-1.60(m, 10H), 1.27(t, 3H), 1.07(t, 3H)

Example 159 : Svnthesis of ethyl 2-r(R)-2-rr(S)-2-r2-ri-ethyl- 6-πmiino(pibenylcarbonvlamino ⁾ methvπindol-2-yl3ethvnpvrτolidinvn- carbonyl1pyrτolidinyDacetate (Compound 273)

60mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-l-ethylindol-2-yl)- ethyl3pyrroUdinyl3carbonyl3pyrrolidinyl3acetate obtained in Example 60 was

reacted with 24μl of benzylchloroformate according to the same procedure as Example 154 to obtain 64mg of the title compound.

1H NMR(MeOH-d ₄ , ppm) : δ 8.10-6.60(m, 8H), 6.30(s, IH), 4.16(m, 3H), 4.00(m, 2H), 3.65(m, IH), 3.49(m, 2H), 3.34(d, 2H, J= 19.08Hz),

3.11(m, IH), 2.75(m, 211), 2.66(q, IH), 2.40-1.60(m, 10H), 1.26(t, 3H), l.lHt, 3H) ES-MS : 588<M+D ^*

Test 1 : Inhibitory activity for thrombin and trypsin

20μ? of each compound of the present invention was dissolved in 50% methanol in various concentrations and then added to each well of a microplate, to each of which 160μ£ of the reaction medium containing 125mM NaCI, 50mM Tris-HCl (pH 8.0) and 2mM synthetic substrate (N-benzoyl-Phe-Val-Arg-ρ-nitroaniIide, Sigma B-7632) were added. 20 μl of human thrombin solution (5 units/mC, Sigma T-6759, manufactured by Sigma Co.) containing 0.1% bovine serum albumin was added to each well to initiate the enzymatic reaction. After 20 minutes, the hydrolysis of substrate was determined by measuring the absorbance at 405πm. The concentration of the test compound showing half the change of the absorbance in the well that did not contain the test compound was represented as IC50 value. The selectivity index was calculated by dividing the IC50 value for trypsin by the IC50 value for thrombin. The tlirombin inhibitory activity and the trypsin inliibitory activity for the compound of the present invention are shown in the following Table 2.

Table 2. Inhibitory activity for thrombin and trypsin

Table 2. (continued)

Table 2. (continued)

Table 2. (continued)

Test 2 : Measurement of the thrombin time (TT) in rat plasma

SD male rats weighing 220±20g which had fasted overnight were used as experimental animals. Blood taken from the hearts of the experimental animals just before administration of the test compound and at 30, 60, 120 and 240 minutes after oral administration of the test compound was mixed with 0.108M sodium citrate in the ratio of 9:1. The mixtures thereby obtained were centrifuged at 15,000rpm for 5 minutes at 4°C to separate the plasma, which was stored at -20 ^° C until the TT was measured by means of the method described below.

200 μl of Owren's buffer was added to 50 μl of the plasma and 100 μl of the diluted plasma thereby obtained was injected into the vial of a coagulometer and then incubated for 2 minutes at 37 ^° C . To each vial was added lOOμl of thrombin at a concentration of 20U/m?, which had prewarmed at 37 °C, to measure the time (TT) until clotting occurred.

The ratio of the TT in rat plasma after administration of the test compound to the TT in rat plasma before administration of the test compound was calculated. The TT ratios for the compounds of the present invention are shown in the following Table 3.

Table 3. Plasma TT ratio after admimstration to rat

Test 3 : Pharmacokinetic test

Test method :

S.D. male rats weighing 200±20g which had fasted overnight were subjected to cannulation at their femoral veins and arteries.

Compound 88 prepared in Example 62 was dissolved in physiological saline and then administered to the rats both by intravenous injection and oral administration. Blood was taken at prescribed intervals of time and then immediately mixed with methanol The mixture was centrifuged (15,000rpm, 5 min., 4 ^C C ) to obtain quantitative amount of the supernatant which was then subjected to HPLC in Diode Array Detector at 254nm to analyse the concentration of the test compound in the blood.

Test results :

The blood concentrations of compound 88 according to the present invention analysed after intravenous injection and oral administration are shown in the following Tables 4 and 5, and the pharmacoldnetic parameter is described in the following Table 6. As can be seen from the experimental results shown in these tables, when compound 88 of the present invention was administered via intravenous injection, it was rapidly distributed in the body and slowly disappeared. In rats, compound 88 of the present invention exhibited a good result, i.e. an elimination half-time of 64 minutes and a bioavailability of 32.6%.

Table 4. Blood concentration of the compound 88 of example 62 following intravenous injection of lOmg/kg in rats

Time Blood concentration (βg/ml) (h) Rat-1 Rat- 2 Rat-3 Rat-4 Rat- 5 Mean SE

0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

0.033 11.186 25.999 23.841 28.971 18.505 21.700 1.975

0.083 8.793 11.984 10.776 14.222 11.623 11.480 0.658

0.250 2.707 4.629 3.531 5.982 3.895 4.149 0.484

^! 0.500 0.816 1.963 1.685 2.939 1.516 1.784 0.284

1.000 0.784 0.773 0.577 ~ 1.204 0.535 0.775 0.137

2.000 0.204 0.098 0.000 0.424 0.162 0.178 0.081

4.000 0.000 0.000 0.000 0.121 0.055 0.035 0.026

6.000 0.000 o.ooo ! 0.000 0.090 0.051 0.028 0.020

24.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

Table δ. Blood concentration of the compound 88 of example 62 following oral administration of lOOmg/kg in rats

Table 6. Pharmacokinetic parameters of the compound 88 of Example 62 in rats

Parameter Mean ± error

Elimination Half-life (hr) 1.07 ±0.27

Bioavailability (%) 32.62 ±7.69