CZ2001198A3 - Bispiperidines functioning as antithrombotic agents - Google Patents

Abstract

The present invention relates to compounds of formula I wherein R b, R 2, R 3, Z 2, Z 2 have meaning. These compounds inhibit binding of fibrinogen to Gp Ilb / IIIa platelet receptors and are useful in therapy as antithrombotic drugs.

Description

Technical field

The present invention relates to novel compounds that are inhibitors of fibrinogen binding to Gp IIb / IIIa platelet receptors and which can be used therapeutically as antithrombotic drugs.

BACKGROUND OF THE INVENTION.

During the pathological processes that lead to the formation of thrombus (clot) and then to their growth, platelet aggregation is a key step because it is the source of the severity of this phenomenon. Specifically, the initiation of the thrombus. Ϊ:

particularly in the arterial bloodstream, the intervention of several mutually dependent biochemical reactions induces the aggregation of a progressively increasing platelet count due to the conversion of soluble fibrinogen to the insoluble fibrin of fibrin, increasing the size and weight of the platelets, initially at the original site arterial vascular lesions and then increasingly in the vein lumen.

In this mechanism of platelet aggregation, activation of Gp IIb / IIIa receptors is a source of enhancement of platelet aggregation. Fibrinogen, which can be bound by its two dimers to these receptors, enhances the binding of these platelets and thus induces the formation of a platelet-forming platelet mass at the rupture site of the atheromic plaque.

This mechanism of platelet aggregation is particularly active in all arterial thromboses, whether or not

- appear during intervention cardiology (tansluminal percutaneous angioplasty; stenting), heart surgery (aortic-coronary bypass);

Valve surgery) during acute heart disease (myocardial infarction, unstable angina, acute coronary, syndromes), etc.) or during certain cerebral ischemia or finally during myocardial ischemia, which may complicate antithrombotic treatment.

Thus, reducing or preventing platelet activation in contact with ruptured atherosclerotic plaque is a new and effective therapeutic approach to the treatment of thrombosis, particularly arterial thrombosis, and thus an effective means for preventing acute coronary syndrome including unstable angina and myocardial infarction.

The present invention is so. aimed at providing novel competitive inhibitors of fibrinogen binding to Gp IIb / IIIa receptors, ‘'i'; ’.

The present invention is also directed to providing compounds that can be administered orally, thereby allowing prolonged action and avoiding the risk of bleeding.

SUMMARY OF THE INVENTION

The essence of the invention ^; are compounds of formula (I):

Zý

0 , · 9 · 9 • 9 9 9 9 · 9 9 ' 9 9 9 9 9 · 9 9 . 9 9 9 9 9 9 9 9 9 9 9 9 9-8 w 9 9. • 9

(i) either Ri is selected from;

-C 1 -C 4 alkyl, C 3 -C 12 mono or bicyclic cycloalkyl, C 2 -C 4 alkenyl or C ₂ -C 4 alkynyl groups, these groups being optionally substituted with groups selected from halogens and hydroxyl groups;

- mono-, bi- or tricyclic C6- _C14 aryl groups,

-heteroaryl groups selected from pyridyl, thienyl, furyl, quinolyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups;

phenyl (C1-C4) alkyl and naphthyl (C1-C4) alkyl groups optionally substituted on the aryl ring,

-aryl and heteroaryl groups which are optionally substituted with one or more groups selected independently from halogen, C1-C4 alkyl, trifluoromethyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, C1-C4 alkyloxy, nitro and -COOR groups, CH ₂ -COOR or -O-CH2 COOR, R being a C1-C4 alkyl,

-groups of formula

- C - NR ₄ R ' ₄

II o

wherein R ₄ and R ₄ are selected from C 1 -C 8 alkyl and mono- or polycyclic C 3 -C 12 cycloalkyl groups, wherein these groups are optionally substituted with groups selected from haloogens and a hydroxyl group, R ₁₄ may also be hydrogen, or - alternatively. R 4 and R ₁₄ together form a tetramethylene or pentamethylene group, the latter two groups being optionally substituted by themselves, in particular C 1-4-14 aryl or C 1-4 aryl. (C6-C14) aryl (C1-C4) alkyl;

- groups of formula

5 · • i • « • · • · • · • · · • * · • · 9 •. · · · · ······ · 9 9 0 * • « · - » · · .. • ·

-. —- C - NH- (CH ₂ ) _m -R ₅ · · · · ·

Wherein m = 1 to 4 and R ₅ is selected from phenyl; methoxyphenyl, indole, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuryl groups, and R ₂ is hydrogen, (ii) or R ₁ is hydrogen and R ₂ is selected from the groups of the formula:

-NH-CO-R _6,

- where R 6 is selected from C 1 -C 4 alkoxy, C 3 -C 7

-cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups, ...

groups of the formula:,.

-NH-SO 2 -R 7 '. - 1. ·. where R- is selected from:

r '· /

-C 1 -C 6 alkyl groups optionally substituted by one or more groups selected from halogens, hydroxyl groups and trifluoromethyl groups;

-C2-C5 alkenyl. groups; _t .

mono- or bicyclic C ₃ -C ₁₂ cycloalkyl groups;

mono-, bi- or tricyclic. C6-C14 aryl groups;

heteroaryl groups selected from pyridyl, furyl, thienyl, quinolyl, benzodiaxanyl, benzodioxolyl, isoxazolyl, benzodioxinyl, benzothienyl, thiazolyl, pyrazolyl, benzofuxyl and benzothiazolyl groups;

-phenyl (C1-C4) alkyl and naphthyl (C1-C4) alkyl groups;

$ '4 ·· 9 9 9 9 • ·  9 9 9- 9 9 • 9 9 9 9 · 9 '9 * · 9 • · · 9 P · « 9 , · 9 9 • · • · 99 9 9 9 9 9 · 9 9

and groups of formula:

wherein n = 1, or S and -NH, or 3 and B is selected from -CH ₂ -, O

aryl and heteroaryl groups which are optionally substituted with one or more groups selected independently from halogens, C 1 -C ₄ alkyl, C 3 -C 7 cycloalkyl. trifluoromethyl, C 1 -C ₄ alkylthio, C 1 -C ₄ alkyloxy, C 1 -C 4 alkylsulfonyl, nitro, di ((C 1 -C ₄ ) alkyl) amino, and -GOOR, -CH ₂ COO or -O-CH ₂ -COOR,, wherein R is C 1 -C 4 alkyl, phenyl, naphthyl, and heteroaryl groups selected from thienyl, furyl and pyridyl; iii) R ₃ is selected from hydrogen, C 1 -C ₄ alkyl, and phenyl (C 1 -C ₄ alkyl); -C ₄ ) alkyl groups; ·.

iv) A is selected from -NH-CHR 10 -NH-CHR ₁₀ -CH ₂ - and

s ρ = 1 or 2,

-R 10 is selected from hydrogen and C 1 -C ₄ alkyl and C ₆ -C ₁₄ aryl,

v) and Z 1 and Z ₂ are hydrogen or an amine protecting group, and addition salts thereof with pharmaceutically acceptable acids.

One specific group of compounds of formula (Ia) is represented by compounds of formula (Ia):

in which:

(i) either R-. is selected from

-C1-C4 alkyl, C3 -C12 mono- or bicyclic cycloalkyl, C ₂ -C ₄ alkenyloyých ^ or C 2 ^- C ₄ alkynyl C ♦ '. if groups, and taking these groups. are optionally substituted with groups selected from halogens and hydroxyl groups;

mono-, bi- or tricyclic C6-C14 aryl groups,. /. ...

heteroaryl groups selected from pyridyl, thienyl, furyl, quinolyl, benzodiaxanyl,. benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups;

-phenyl (C1-C4) alkyl and naphthyl (C1-C4) alkyl groups optionally substituted on the aryl ring,

-aryl and heteroaryl groups which are optionally substituted with one or more groups selected independently from halogen, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkyloxy, nitro and - groups COOR, -CH ₂ COOR or -O-CH ₂ -COOR, wherein R 6 is a C 1 -C 4 alkyl group,

-group formula: ·

-7-8 · • ..

-C-NR ₄ R '. ₄ .

wherein R ₄ and R ' ₄ are selected from C 1 -C 8 alkyl ammonium or polycyclic C ₃ -C ₁₂ cycloalkyl groups, wherein these groups are optionally substituted with groups selected from C 1-4 halogen and hydroxyl groups, R' ₄ may also be hydrogen, or alternatively R ₄ and R ' ₄ together form a tetramethylene or pentamethylene group, the latter two groups being optionally substituted by themselves, in particular a C 6 -C ₁₄ aryl or (C 8 -C ₁₄ ) aryl (C 1 -C ₄ ) alkyl radical;

- formula groups:

• -C -NH- (CH _{2) m} -R _fifth In which m = 1 to 4 and R 5 is selected from phenyl, methoxyphenyl, indole, benzodioxolyloy, benzodioxanyl, benzothienyl and benzofuryl groups, and R ₂ is hydrogen, ii) or R 1 is hydrogen and R ₂ is selected from:

'-NH-R ₆ EO ..

wherein R 6 is selected from C 1 -C 4 alkoxy, C 3 -C 7 cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups,.

and groups in the formula:

-NH-SO 2 -R ₇ wherein R ₇ is selected from:

-C 1 -C 5 alkyl groups optionally substituted with one or more groups selected from halogens, hydroxyl groups and trifluoromethyl groups;

mono- or bicyclic C3-C3-2 cycloalkyl groups;

mono-, bi- or tricyclic C6-C14 aryl groups;

heteroaryl groups selected from pyridyl, thienyl, quinolyl, benzodioxanyl, benzodioxolyl, and isoxazyl groups;

-phenyl (C1-C4) alkyl and naphthyl (C1-C4) alkyl groups;

- and groups in which

-aryl and heteroaryl groups which are optionally substituted with one or more groups selected independently from halogen, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylthio, C 1 -C 4 alkyloxy, C 1 -C 4 alkylsulfonyl, nitro, di ( _(Ci-C4) alkyl) amino and groups --COOR, --CH2 --COOR or

-O-CH 2 -COOR, wherein R is a C 1 -C 4 alkyl group, iii), R 3 is selected from hydrogen, C 1 -C 4 alkyl group and '‘phenyl (C 1 -C 4) alkyl group;

iv). and Z 1 and Z ₂ are hydrogen or an amine protecting group, and addition salts thereof with pharmaceutically acceptable acids.

One preferred group of compounds is represented by compounds wherein R 1 = H and R ₂ is a group of formula

-NH-SO 2 -R 7.

Τ3ί

t · '· · • • e · «· • • ·. • • ·· • • ’· • * · · • • 9 '9 9 ^f 9 9 99 9 9 9 · • · • · · • · 4 * · 999

Compounds that are particularly preferred are compounds of this type in which R ₇ is a group selected from naphthyl, substituted naphthyl, biphenyl and phenylthienyl.

Examples of aryl groups include phenyl, anaphthyl, β-naphthyl, fluorenyl and biphenyl.

The C1-C5 alkyl groups may be linear or branched. Examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl.

Monocyclic cycloalkyl groups may be, for example, cyclopentyl or cyclohexyl.

Polycyclic cycloalkyl groups can be, for example, adamantyl, norbornyl and camphoryl groups.

The alkynyl group may be, for example, ethynyl, propargyl and butynyl.

The alkenyl group may be, for example, a vinyl, pentenyl, and allyl group.

The C1-C4 alkoxy groups may similarly be linear or branched. An example is methoxy. ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy groups.

Halogens may be selected from fluorine, chlorine, bromine and iodine.

Amine protecting groups include ethoxycarbonyl, benzyloxycarbonyl, pnitrobenzyloxycarbonyl and t-butoxycarbonyl.

The term "pharmaceutically acceptable acid addition salts" refers to salts which give volné the biological properties of the free base without undesirable

effect. In particular, these salts may be those formed with mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids; acidic metal salts such as disodium orthophosphate and potassium hydrogen sulphate, or with organic acids.

prepared:

The compounds of formula (I) may be

wherein _R and R ₉ are protecting groups, "" I, with an amine of formula or a ₂₎ reacting the acid of formula

(III)

- li

wherein R 5 and R 9 are protecting groups, with an amine of the formula

to form compounds of formula (1b):

(lb)

(b) where appropriate, by converting the group R ₂ to another group · R ₂ ,

ΐ

• i · '4' 4 4 «Í4 4 · · · - ·· '4 4 i 4 4 4 • · · · · 4 ’'·' · . 4 4 4 4 <'4!' 4 4 4 '4 . 4 • i4 4 · 44 · 4 4 ^; · 4 4 4 ·

c) and, optionally, removing the protecting groups.

Compounds of formula (II) may be prepared according to the following reaction scheme (when R 5 and R 8 = Boc):

> N

Scheme 1

Addition salts are obtained in a conventional manner by reacting a compound of formula (I) with a pharmaceutically acceptable acid

In a suitable solvent. Conversely, bases can be obtained from addition salts by reaction with a strong base.

The following examples illustrate the preparation of a compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

A. Preparation of an acid of formula IV

Synthesis of 4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2 {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} butanoic acid (compound 3)

A-1 Synthesis of 4- (4-pyridyl-2- [2- (4-pyridyl) ethyl] butanoic acid dihydrochloride, (compound, 1) ´

To a solution of 4-vinylpyridirium (165 g, 1.49 mol) and diethyl malonate (120 g, 0.75 mol) in 400 mL of ethanol was added sodium (3.5 g, 0.15 mol). The mixture was refluxed for 18 hours. Most of the ethanol was evaporated and the residue was taken up in ether (about 300 mL) and then washed with brine. The solvent was evaporated to give an oil which was refluxed in 400 mL of 12 N hydrochloric acid for 12 hours. The resulting mixture was evaporated to dryness to give a red-brown oil which was taken up in about 1 L of isopropanol and allowed to stand at room temperature. The resulting solution was filtered, washed with isopropanol and acetone and dried under vacuum to give 190 g colored solids.

Yield = 74%

M.p. = 172 ° C '· ^X H-NMR (400 MHz, CD ₃ OD) 5' 2.1 (m, 4H), 2.5 (m, .IH), 3.0 (t, 4H ), 8.0 (d, 4H), 8.7 (d, 4H). '

. · · ·· • '· '· «· ···· 9 » '9 · • '9' 9-9 '9 9 9 • • • · • • • • · · '· · • ·  9 9 9 9

A-2 Synthesis of 4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoic acid dihydrochloride (compound 2)

A mixture of 4- (4-pyridyl) -2- [2- (4-piperidyl) ethyl] butanoic acid dihydrochloride (118 g, 0.344 mol) in 1.5 L of acetic acid was hydrogenated in the presence of 10% palladium on charcoal (10 g) at 100 psi at 60 ° C for 24 hours. The mixture was filtered and evaporated to give an oil which was diluted in ether to give a suspension. The suspension was filtered, washed with ether and dried to give 126 g of a beige solid.

Yield = 104% (contains acetic acid)

M.p. = 180 ° C.

¹ H-NMR (400 MHz, CD ₃ GD): δ 1.35 (m, 8H) -, 1.6 (m, 6H), 2.0 (bd, 4H), 2.3 (m, 1H) 3.0 '(bt, 4H), 3,4' (bd, 4H). .

_. i ', r ^: ·' ΐ ^r ··

A-3 Synthesis of 4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1- (tert-butoxycarbonyl) -4- (piperidyl) ethyl} butanoic acid (Compound 3) _; .

Di-tert-butyl dicarbonate (90 g, 0.413 mol) was added at room temperature to a solution of 4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoic acid dihydrochloride (71.5 g, 0.203 mol) in 300 ml (2.2 mol) of 4 M NaOH and 300 ml of tert-butanol. Stirring was continued for 4 hours. The organic phase was separated and then washed with 1N HCl and water, dried over sodium sulfate and evaporated to give the crude product. Cyclohexane was added and the mixture was allowed to crystallize at about 0 ° C. The product was filtered off, washed with ‘cyclohexane and dried under vacuum to give 71 g of a white solid.

Yield = 73% ·

Mp = 162 ° C

· · · · ' . ·· · • · • · • • · • 9 • · • · • · • ♦ • · · • # · 9 • · '· • • · • · • · ·  · · · • · - · • · 9 9

1 H-NMR (400 MHz, CD 3 OD): δ 1.05 (m, 4H), 1.25 (m, 4H), 1.35 (m, 3H), 1.45 (s, 19H), 1.6 (bd, 6H), 2.25 (m, 1H), 2.88 _; (bt, 4H), 4.05 (bs, 4H). ý.

B Preparation of Compounds of Formula II

B-1 Synthesis of acid

2 - {(4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl] butanoyl) amino} acetic acid

To a solution of 4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl [butanoic acid (18.6 g, 38 mmol) in 150 mL of dichloromethane and ; pyridine (3.1 g, 39.2 mmol) was added at room temperature 2,4,6-trifluoro-1,3,5-triazine (3.6 g, 26.7 mmol). After stirring for 4 hours, water was added. The organic phase was washed with water, dried over sodium sulfate and then filtered. The filtrate was used directly in the next step. * -. ·

The solution was added to a mixture of methyl glycinate hydrochloride (4.9 g, 39 mmol) and diisopropylethylamine (11 g, 8.5, 3 mmol) in 50 mL of dichloromethane. Stirring was continued for 1 hour at room temperature and then 1 N hydrochloric acid was added. The organic phase was washed with water, dried over sodium sulfate and evaporated to an oil which was directly hydrolyzed.

A solution of the above product in 150 mL tetrahydrofuran, 30 mL water and lithium hydroxide monohydrate (4.2 g, 100 mL) was stirred at room temperature for 30 minutes. The organic solvent was evaporated and the residue was taken up in water, acidified to pH 2 and extracted with ethyl acetate. The extracts were washed with water, dried over sodium sulfate and evaporated to give 18.2 g of a white solid.

Ί

* 44 ·· • 4 • · • · »» 4 · 4'4 • • •. · • » • · • 4 4 4 4 44 4 • · 4 • • 4 · '· 4 4 444 • · · • · • ’ 44 44

Yield = 88% (for three necks).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 0, 95-1.65 (m, 36H) ', 2.04 (m, 1H), 2.65 (bt, 4H), 4.0 (bd) 6H), 6.39 (bs, 1H).

Synthesis of B-1 was used to prepare the following compounds:

B-2

3 - [(4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} butanoyl) amino) propanoic acid (compound 5) ethyl 3-aminopropanoate hydrochloride Yield - 86%. .

B-3.

3 - [(4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} butanoyl) amino] 3-methylpropanoic acid (Compound 6 )

Starting material: ethyl 3-aminobutanoate

Yield. = 49% ¹ H-NMR (400 MHz, CDCl 3): δ 1.03 (m, 4H), 1.15 (m, 4H),

1,25 (d, 3H), 1.35 (m, 2H), 1.45 (s, 20H), 1.63 (bd, 6H), 1, 95 (m, IH), 2.55 (dd, 2H), 2.65 (bt, 4H), 4.0 (bs, 4H), 4.35 (m, IH), 6.25 (d, IH).

B-4

3 - [(4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} butanoyl) amino] 3-phenylpropanoic acid (Compound 7) )

Starting material: ethyl 3-amino-3-phenylpropanoate hydrochloride Yield = 68% ¹ H-NMR (400 MHz, CDCl 3): δ 0.9 ~ 1.35 (m, 10H), 1.45 (s,

20H), 1.58 (m, 6H), 2.00 (m, 1H), 2.60 (bq, 4R), 2.90 (dq, 2H), 4.0 (bd, 4H), 5, 45 (q, 1H), 6.78 (d, 1H), 7.25 (m,

5H). -3 · -3 • 9 ··· '9 - ·· ·' «·>

9 9 99 9 9 9 9 9 9 9 9 9 9 99 99 99 9 9 999

B-5

(3R) -1- (4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2 {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl] butanoyl) hexahydro-3-pyridinecarboxylic acid (compound 8)

Starting material: ethyl (R) -nipecotate-L-tartrate

Yield = 66%

C - Preparation of compounds of Formula Ib

Cl - Preparation of compounds of formula Ib (R _: * H, R ₂ = H) ·

1) tert -Butyl 4- (3 - {[1- (1,3-benzodioxol-5-yl) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl) -5- [ 1 (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (compound ¹ 9)

To a solution of 4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- (1- (tert-butoxycarbonyl) -4-piperidyl] ethylbutanoyl) amino] acetic acid (Compound 4) (5.4 g, 10 mmol) in 50 mL of ethyl acetate and N-methylmorpholine (2.2 g, 22 mmol) was added isobutyl chloroformate (1.5 g, 11 mmol). After stirring for 10 minutes, ethyl 3-amino-3- (1,3-benzodioxol-5-yl) propionate hydrochloride (2.8 g, 10 mmol) was added. Stirring was continued at 50 ° C for 2 hours and then 2N hydrochloric acid was added. The organic phase was washed with water, dried over sodium sulphates, evaporated and purified by flash chromatography (dichloromethane / methanol 20/1) to give 6.7 g of a white solid.

Yield = 88% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.9-1.7 (m, 39H). 2.05 (m,

1 H, 2.6 (bs, 4H), 2.8 (dq, 2 H), 4.0 (m, 8H), 5.3 (q, 1H), 6.55 (t, 1H). 6.75 (m, 3H), 7.55. (d, 1H).

ή. · ♦ · ». »- - - e e · · · · · · · · 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

The method described above was used to prepare the following compounds:

2) tert -Butyl 4- (5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3 - [(2 - ([3-ethoxy-1- (4-isopropylphenyl) -3-oxopropyl] amino) (-2-oxoethyl) amino] carbonyl} pentyl) tetrahydro-1 (2H) pyridinecarboxylate (compound 10)

Starting material: ethyl 3-amino-3- (4-isopropylphenyl) propionate hydrochloride

Yield = 82% ^X H-NMR. (400 MHz, CDC1 _3): δ 0.9 ~ 1.7 (m, 45H), 2.05 (m, IH),

2.6 (bs, 4H); 2.8 (m, 3H), 4.0 (m, 8H), 5.4 (q, 1H), 6.5 (t, 1H), 7.15 · (D, 2H), 7.2 (d, 2H), 7.45 (d, 1H). . - '.

3). tert -Butyl 4- (5- (1- (tert-butoxycarbonyl) -4-piperidyl)] - 3 {[(2 - {[3-ethoxy-1- (4-methoxyphenyl) '- 3-oxopropyl] amino} (2-oxoethyl) amino] carbonyl} pentyl) tetrahydro-1 (2H) pyridinecarboxylate (compound 11).

Starting material: ethyl 3-amino-3- (4-methoxyphenyl) propionate hydrochloride

Yield - 59% ¹ H-NMR (400-MHz, CDCl ₃ ): δ 0.9 ~ 1.7 (m, 39H), 2.05 (m, 1H), 2.6 (bs, 4H.) 2.8 (dq, 2H); 3.75 (s, 3H); 4.0 (m, 8H);

5.38. (q, 1H), 6.55 (t, 1H), 6.85 (d, 2H), 7.2 (d, 2H), 7.45 (d, 1H).

4) tert -Butyl 4- (5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3 - {[(2 - {[3-ethoxy-1- (3,4-dimethoxyphenyl) -3-oxopropyl]] amino} 2-oxoethyl) amino] carbonyl (pentyl) tetrahydro-1 '(2H) pyridinecarboxylate (compound 12)

Starting material: ethyl 3-amino-3- (3,4-dimethoxyphenyl) propionate hydrochloride · ', ‘

Yield = 82%

• *.

5) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -, 4-piperidyl]] - 3 - {[2 - ({3-ethoxy-1- [3- (2-ethoxy-2- oxoethoxy) phenyl] -3-oxopropyl} amino) -2- (oxoethyl) amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridine carboxylate (compound 13)

Starting material: ethyl 3-amino-3- (3- (2-ethoxy-2-oxoethoxy) phenyl) propionate hydrochloride Yield = 61% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.9 ~ 1.7 ( m, 42H), 2.05 (m, 1 H),

2.6 (bs, 4H), 2.8 (dq, 2H), 4.0 (m, 8H), 4.28 (q, 2H), 4.6 (s, 2H), 5.4 (q (1H), 6.5 (t, 1H), 6.8 (dd, 1H), 6.9 (m,

2H), 7.2 (d, 1H), 7.45 (d, 1H).

6) target; Butyl 4- (5- [1- (tert-butoxycarbonyl) -4-piperidyl] -, 3 {[(2 - {[3-ethoxy-1- (3-methoxyphenyl) -3-oxopropyl] amino} - 2-oxoethyl) amino) carbonyl} pentyl) tetrahydro-1 (2H) -pyridinecarboxylate (compound 14).

Starting material: ethyl 3-amino-3- (3-methoxyphenyl) propionate hydrochloride

Yield. =. 78% ¹ H-NMR (400 MHz, CDC1 _3): δ 0 9 ~ 1.7 (m, 39H), 2.05 (m, 1H),

2.6 (bs, 4H), 2.83 (dq, 2H), 3.8 (s, 3H), 4.0 (m, 8H), 5.4 (q, 1H), 6.5. (t: 1H), 6.8 (dd, 1H), 6.85 (m, 2H), 7.2 (t, 1H), 7.45 (d, 1H). '.

7) tert -Butyl 4- {3 - {[1- (2,3-dihydro-1,4-benzodioxin-6-yl) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydr-o1 (2H) -pyridinecarboxylate (Compound 15)

Starting material: ethyl 3-amino-3- (2,3-dihydro-1,4-benzodioxin-6-yl) propionate hydrochloride Yield = 83%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.9-1.7 (m, 39H), 2.05; (III, 1H)

9 · 9 99 9

2.65 (bs, 4H), 2.8 (dq, 2.H), 4.0 (m, 8H), 4.25 (s, 4H), 5.3 (m, 1H), 6.55 (t, 1H), 6.79 (s, 1H), 6.81 (d, 2H), 7.5 (d, 1H).

8) tert -Butyl 4- (5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3 {[(2 - {[3-ethoxy-1- (3-pyridyl) -3-oxopropyl] amino}) -2-oxoethyl) amino] carbonylpentyl) terahydro-1 (2H) pyridinecarboxylate (compound 16)

Starting material: ethyl 3-amino-3- (3-pyridyl) propionate dihydrochloride

Yield = 69%

9) target. Butyl 4- (5- · [1- (tert-butoxycarbonyl) -4-piperidyl] -3 {[(2 - {'[3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} pentyl \ tetrahydro -1 (2H) -.

pyridinecarboxylate (compound 17);

Starting material: ethyl 3-amino-propionate hydrochloride Yield = 69%

¹ H-N1 MR (400MHz, CDC1 ₃ ) : δ 1.05 (m, 4H), 1,2 m (4H) 1,25 (t, 3H), 1.3 (m, 2H), 1.4 (s, 20H) 1.6 (m, 6H), 2.05 - (m, 1H), .2.5 (t, 2H) , 2,6 (bt, 4H), 3.5 (q, 2H), 3.9 (d, 2H), 4.0 (bs, 4H) 4 15 (q, 2H) 6.4 (bt , 1H) , 6, 65 (bt, 1H).

10) »tert -Butyl 4- (5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {[(2 - {, [3-ethoxy-1-methyl-3-oxopropyl] amino} -2betoethyl) (amino) carbonyl} pentyl) tetrahydro-1 (2H) pyridine carboxylate (compound 18)

Starting material: ethyl 3-aminobutanoate hydrochloride Yield = 70% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H), 1.1 ~ 1.35 (m, 13H), 1.4 (s, 19H), 1.55 (m, 6H), 2.05 (m, 1H), 2.5 (m, 2H), 2.6 (bt, 4H), 3.85 ( m, 2H), 4.0 (bs, 4H), 4.1 (q, 2H), 4.3 (m, 1H), 6.4 (t, 1H), 6.75 (d, 1H) .

21 '-

• · «· 9 9 • · • · · · • · «· '· · 'i · • • · * t • • »· • •  · • · • * · «* ' and • ·

11) tert -Butyl 4- (5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {[(2 - {} 3-ethoxy-3-oxo-1-phenethylpropyl] amino} - 2-oxoethyl) amino] carbonyl} pentyl) tetrahydro-1 (2H) pyridinecarboxylate (compound 19)

Starting material: ethyl 3-amino-5-phenylpentanoate hydrochloride Yield = 27% 1 H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H), 1.1 ~ 1.3 (m, 10H) 1.4 (s, 19H), 1.55 (m, 6H), 1.85 (m / 2H), 2.0 (m, 1H), 2.5 (d, 2H), 2.6 ( m., 6H), 3.85 (d, 2H), 4.0 (bs, 4H), 4.1 (q,

2H), 4.25 (m, 1H), 6.25 (t, 1H), 6.6 (d, 1H), 7.1 (m, 3H), 7.2 (t, 2H).

12) Synthesis of tert-butyl 4- {3 - ({[2 - ({1 - [(1-adamantylamino) carbonyl] - (1S) -3-benzyloxy-3-propyl} amino) -2-oxoethyl] amino} carbonyl) -5 - [1 (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (compound 20)

To a solution of 2 - [(4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1- (tert-butoxycarbonyl) -4-piperidylethyl] butanoyl) amino] acetic acid (compound 4) (6.9) g, 11 mmol) in 150 mL of ethyl acetate and N-methylmorpholine (5 g, 49.5 mmol) was added at room temperature. room temperature isobutyl chloroformate (1.7 g, 12.4 mmol). A white suspension was obtained. After stirring for 10 minutes, a solution of benzyl (3S) -3-amino-4- (1-adamantylamino) 4-oxobutanoate trifluoroacetate (6.9 g, 11.2 mmol) in 20 mL of ethyl acetate was added.

Stirring was continued at room temperature for 18 hours. 2N hydrochloric acid was added. The organic phase was washed with water, dried over sodium sulfate and evaporated to give the crude product which was purified by flash chromatography (dichloromethane / methanol 20/1) to give 6.6 g of a beige-colored solid. Yield 68%

The above method was used for the preparation

- 22 of the following compounds:

13) tert -Butyl 4- (3 - ({[2 - ({1 - [[2- (1H-indol-4-yl) ethyl] amino] carbonyl] - (1S) -3-benzyloxy-3-oxo-propyl} amino). -2-oxoethyl] amino} carbonyl) -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (compound 21)

Starting material: trifluoroacetate benzyl. (3S) -3-amino-4- [2 (1H-indol-4-yl) ethylamino] -4-oxobutanoate Yield = 49% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H, 1.25 (m, 6H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.65 (m, 5H) 2.95 (m,

3H), 3.55 (m, 2H), 3.78 (dq, 2H), 4.05 (bs, 4H), 4.8 (m, 1H), 5.05 (s, 2H), 6 3 (t, 1H), 6.8 (t, 1H), 7.0 (d, 1H), 7.1 (t, 1H), 7.2 (m, 2H), 7.35 (m, 6H), 7.6 (d, 1H), 8.2.

(s, 1H). '' \. Butyl 4- (3 - ({[2 - '({1 - [{' (4- j.

methoxyphenethyl) amino] carbonyl] - (1S) -3-benzyldxy-3- (oxopropylamino) -2-oxoethyl] amino) carbonyl) -5- [1, (t-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridine carboxylate (compound 22)

Starting material: trifluoroacetate, benzyl (3S) -3-amino-4 - [(4-methoxyphenethyl) amino] -4-oxobutanoate Yield = 59%

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), 1.25 (m, 6H), 1.45 (s, 20H), 1.6 (m, 6H); 2.05 (m, 1H), 2.65 (m, 7H) , · 3.05 (dd, 1H), 3.4 (m, 2H), 3.75 (s, 3H); 3.85 (d, 2H); 4.05 (bs, 4H), 4.78 (m, 1H), 5.1 (s, 2H), 6.4 (t, 1H), 6.8 (m, 3H) 7.1 (d, 2H), 7.2 (d, 1H), ‘7.4 (m, 5H).

15) tert -Butyl 4- {3 - ({[2 - ({1 - [{(3-phenylpropyl) amino} carbonyl] - (1S) -3-benzyloxy-3-propyl} amino) -2-oxoethyl] amino} carbonyl) -5- [1- 23 -

«» · ». 9 (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (compound 23)

Starting material: benzyl (3S) -3-amino-4 - [(3-phenylpropyl) amino] -4-oxobutanoate trifluoroacetate Yield = 79%

16) tert -Butyl 4- (3 - ({[2 - ({1 - [{(1,3-benzodioxol-5-ylmethyl) amino} carbonyl] - (1S) -3-benzyloxy-3-oxoproyl} amino) 2 oxoethyl] amino} carbonyl) -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) -pyridinecarboxylate (compound 24)

Starting material: benzyl (3S) -3-amino-4 - [(1,3-benzodioxol-5-ylmethyl) amino] -4-oxobutanoate trifluoroacetate Yield = 54% 17) tert -Butyl 4- {3 - ({[2- ({1 - [{(3-.

methoxyphenethyl) amino} carbonyl] - (1S) -3-benzyloxy-3-propyl} amino) -2-oxoethyl] amino} carbonyl) -5- [1- '>

(t-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (compound 25);

Starting material: benzyl trifluoroacetate, (3S) -3-amino-4 - [(3-methoxyphenethyl) amino] -4-oxobutanoate

Yield = 65% ¹ H-NMR · (40 0 MHz, CDCl ₃ ) : δ 0.95 ~ - 1, 25 (m, 7H), 1, 25 ~ 1.5 (m, 22H), 1.6 (m, 6H) · 2.05 (m, 1H) , 65 (m, 3H) , 2 75 (t, 2H), (dd, 1 H) 3, 45 (q, 2 H) , 3 , 8 (with, 3H), 3, 85 (d, 2H), 4.05 (bs, 4H), 4 ', 77 (m, 1H) , 5 , 1 (with, 2H), 6 48 (t, 1H), 6.75 (m, 3H) 6.9 (t, 1 H), 7.4 (m , 6H).

18) tert -Butyl 4- (3 - ({[2 - ({1 - [{(2-hydroxy-1,1-dimethylethyl) amino} carbonyl] - (1S) -3-benzyloxy-3-propyl} amino) -2- oxoethyl] amino} carbonyl) -5- [1 (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (Compound 26) '· ·· · ··

-9 9 9'9 ^; · 5 »· 9 9 9 9

9,999 · ·

9 «« · 9 9 9 9 · ‘· b .9 · 9-9 9 9«

9 9 9 9 9 9 9 9. · 9

Starting material: benzyl trifluoroacetate, (3S) -3-amino-4 - [(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobutanoate Yield = 34% in ¹ H-NMR (400 MHz, CDCl ₃₎ ): δ 1.05 (m, 5H), 1.15 ~ 1.35 (m, 12H), 1.45 (s, 20H), 1.65 (m, 7H), 2.1 (m, 1H) ), 2.62 (m,

6H), 3.08 (dd, 1H), 3.5 (q, 2H), 3.8 (dd, 2H), 4.0 (bs,

4H), 4.8 (m, 1H), 5.1 (s, 2H), 6.8 (s, 1H), 6.9 (t, 1H),

7.8 (m, 6H).

.19) target. Butyl 4- {3 - ({[2 - ({1 - [({1-isopropyl-2-methylpropyl) amino} carbonyl] - (1S) -3-benzyloxy-3-propyl} amino) -2-oxoethyl] amino} carbonyl ) -5- [1 (tert-Butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (Compound 27)

Starting material: benzyl (3S) -3-amino-4 - [(1-isopropyl-2-methylpropyl) amino] -4-oxobutanoate trifluoroacetate,

Yield = 59% 1 H-NMR (400 MHz, CDCl ₃ ): δ 0.9 (m, 9H), 1.0. ~ 1.35 (m, 11H);

1.4 (with, 20H), 1.6 (bs, . 6H) , 1.79 (m, 2H), 2.05 (m, 1H), 2, 65 (m, 6H), 3.1 (dd, 1H) , 3.55 (m, 1H), 3.9 (d, 2H), 4.05 (bs, 5H) 4.82 (m, 1 H), - 5, 15 (dd, 2H) , 6, 3 (t, 1H) , 6.45 (d, 1H), 7.3 (m, 6 H).

20) tert -Butyl 4- {3- (j [2 - ({(1S) -3- (benzyloxy) -3-oxo-1 - [(4-benzylpiperidino) carbonyl] -propyl} amino) -2-oxoethyl] amino} carbonyl ) -5- [1- (tert-Butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) -pyridinecarboxylate (Compound 28)

Starting material: benzyl (3S) -3-amino-4-oxo-4- (4-benzylpiperidino) butanoate trifluoroacetate Yield = 55%

C-2 Preparation of compounds of formula (R = H, R ₂ AH) • • · · · · · • '9 9 9 ·

9.9 9 9,999 9 '· \ ·· *

1). Synthesis of tert-butyl 4 - [(10S) -3- {2- [1 (tert-butoxycarbonyl) -4-piperidyl] ethyl} -10 (ethoxycarbonyl) -4,7,12-trioxo-14-phenyl-13- oxa-5,8,11-triazatetradec-1-yl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 29)

Isdbutyl chloroformate (13 g, 95.2 mmol) was added to a solution of 2 - [(4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1 (tert-butoxycarbonyl)] at room temperature. -4-piperidyl] ethyl (butanoyl) amino] acetic acid (compound 4) (46 g,

85.2 mmol) in 550 mL of ethyl acetate and N-methylmorpholine (19 g, 188 mmol) and a suspension was obtained. After stirring for 20 minutes, ethyl (2S) -3-amino-2 - {[(benzyloxy) carbonyl] amino] propanoate hydrochloride (26.3 g, 86.9 mmol) was added. Stirring was continued for 18 hours at room temperature and the reaction medium was washed with water, 1 N hydrochloric acid and water and then dried over sodium sulfate and evaporated to give a crude product which was purified by flash chromatography (dichloromethane / methanol 20/1). to obtain. 61 g of white solid.

Yield = 91% 1 H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H), 1.15 (m, 4H), 1.25 (m, 5H), - 1.4 (s, 20H), 1.65 (m, 6H), 2.0 (m, 1H), 2.62 (bt, 4H), 3/62 (bs, 2H), 3.85 (m, 2H), 4, 05 (bs, 4H), 4.2 (bt,

2H), 4.4 (m, 1H), 5.08 (s, 2H), 5.95 (d, 1H), 6.4 (bs, 1H), 6.9 (bs, 1H), 7.4 (bs, 5H).

The method described above was used to prepare the following compounds: tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3 ({[2 - ({2- [ (cyclohexylsulfonyl) amino] -3-methoxy-3-propyl-amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 30)

^R 9 9 9 9 9 R '9 9 9 ·

9-9 9 9 9 · 9 · jf® '' - · '· 9, 9 *

Starting material: methyl 3-amino-2 [(cyclohexylsulfonyl) amino] propanoate trifluoroacetate

Yield = 81% 1 H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), 1.1 ~ 1.5 (m, 31H), 1.6 (m, 6H), 1.7 (bd, 1H), 1.85 (bd, 2H), 2.05 (m, 1H), 2.2 (bt, 2H), 2.60 (bt, 4H), 2.85 (m, 1H) 3.55 (m, 1 H), 3.7 (m, 1 H), 3.80 (s, 3 H), 3.95 (m, 2 H), 4.05 (bs, 4 H), 4.2 ( m,

1H), 5.7 (d, 1H), 6.55 (t, 1H), 6.95 (t, 1H).

3) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3 ({. [2 - ({2 - [(isopropylsulfonyl) amino] -3-ethoxy-3-propyl} amino)) -2p oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridine carboxylate (compound -31)

Starting material: 3-ethyl-3-amino-2 [(isopropylsulfonyl) trifluoroacetate ^! amino] propanoate · _v

Yield = 60% '- ¹ ·

NMR (4 00 MHz, CDC1 ₃ ) : δ 1,05. ( M, 4H) , 1,2 (m, 4H) t 1.3 (t, 3H) , 1, 35 (dd, 5H) , 1.45 (s, 21H), 1.6 (m ,. 6H), 2 , 05 (m, . 1H ‘) ' ² ' 65 (bt, 4H) 3.15 (m, 1H), 3.55 (m) 1H), 3 , 75 (m, . 1H) i 3, 95 (t, 2H), 4.05 (bs, 4H), 4.20 (m, 1H), 4 , 25 (q, 2H) r 6 (d, 1 H), 6.45 (t, 1H); H), 6, 85 (t , 1H i) ·

4) tert -Butyl -4- (3 - ({[2 - ((2 - [(1,3-benzothiazol-2ylsulfonyl) amino] -3-ethoxy-3-oxoproyl} amino) -2-oxoethyl] amino) carbonyl) ) -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) -pyridinecarboxylate (Compound 32)

Starting material: ethyl 3-amino-2 - [(1,3-benzothiazol-2-ylsulfonyl) amino] propanoate hydrochloride Yield = 43% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), . 1.15 (t, 3H), 1.20 (m, 4H), 1.3 (m, 2H), 1.45 '(s, 20H), 1.60 (m, 6H), 2.10 ( m, 1H), 2.65 (bt, 4H), 3.70 (m, 1H), 3.80 (m, 1H), 3.95 (d,

^r · · • • • ·· • • · • • •. · • • 9 • '9' • · • »» 4 9 ♦ · • • • · · · • · · • · · • · • • · «

2H), 4.05 (m, 6Η), 4.55 (dd, IH), 6.50 (t _i? 1H), 6. A 85 (bs, 1H), 7.10 (t, 1H), 7.55 (m, 2H), 7.95 (dd, 1H), 8.10 (dd, 1H). .

5) tert -Butyl 4 - [(11S) -3- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} -11- (ethoxycarbonyl) -4,8,13-trioxo-15-phenyl-14-oxa -5,9,12-triazapenadadec-1-yl] tetrahydro-1 (2H) pyridine carboxylate (Compound 33)

Starting material: compound 5 and ethyl (2S) -3-amino-2 - ([(benzyloxy) carbonyl] amino} propanoate hydrochloride Yield = 65% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.0 ( m, 4H), 1.15 (m, 4H), 1.25

(t, 5H) , 1.4 (s, 20H), 1.55 (m, , 6H) 1.9 (m, 1H) 2.3 (bt, 2H), 2, 60 (bq, 4 H), 3.4 (m, 2H) , .3, Δ (t, 2H), 4, 0 (bs, 4 H), 4.2 (q, ^2H), 4.4 (m, 1H) , 05 (with,' 2H), 5.95 (d, 1H), 6.4 (t, 1H) 6.55 (t, 1H), 7.3 (with, 5H).

6) target; Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-pipericlyl] -δ- [3 - ({3-ethoxy-2 - [(2-naphthylsulfinyl) amino] -3-. Oxopropyl} amino) -1-methyl-3-; .

oxopropyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (Compound 34) · ·.

Starting materials: compound 6 and ethyl (2S) -3-amino-2 - [(2-naphthylsulfonyl) amino] propanoate hydrochloride.

Yield. = 75% ¹ H-NMR. (400 MHz, CDCl ₃ ): δ 0.9 '(t, 3H), 1.05 (m, 3H), 1.20' (m, 8H), 1.30. (m, 2H), 1.45 (s, 20H), 1.60 (m, 6H), 1.95 (m, 1H), 2.40 (dq, 2H), 2.65 (bt, 4H) 3.50 (m, 1H), 3.65 (m, 1H), 3.85 (m, 2H), 4.05 (m, 5H), 4.30 (m, 1H), 6.05 ( d, 1H), 6.65 (m, 2H), 7.65 (m, 2H), 7.80 (d, 1H), 7.90 (d, 1H);

1H), 8.00 (d, 2H), 8.40 (s, 1H).

7) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3 ({[3 - ((3-ethoxy-2 - [(2-naphthylsulfonyl) amino] -328-)

t · '· · * 9 9 • '9 9 '· · • »» • «···· ·, · · 9 9 • 9 9 9 9 9 • · • · · • · . · 9 9

oxopropyl} amino) -3-oxo-1-phenylpropyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 35)

Starting materials: compound 7 and ethyl (2S) -3-amino-2 - [(2-naphthylsulfonyl) amino] propanoate hydrochloride Yield = 77% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.95 (t, 3H) 1.00 (m, 4H), 1.10

(m, 4H), 1.30 (m, 2H), 1.45 (s, 20H) 1.60 (m, 6H) 2.05 (m, 1H), 2 ', 65 (bd, 4H) 2.70 (m, 2H) 3.40 (m, 1H) 3.60 (m, 1H), 3, 80 (m, 2H), 4.00 (m, 6H) 5, 40 (m, 1H); 5.85 (d, 1H), , 6.40 (m, 1H), 7.25 (m, 5H), 7.65 (m, 2H), 7.76 (m, 1H), , 7.90 (d, 1H), 7.95 (m, 2H), 8.40 (d, 1H).

8) tert -Butyl 4- [5- [T- (tert-butoxycarbonyl) -4-piperidyl] -3 - {[(3R) -3 - [({3-ethoxy-2 - [(2-naphthylsulfonyl)] amino] -3-oxopropyl} amino) carbonyl] tetrahydro-1 (2H) pyridinyl] carbonyl} pentyl) tetrahydro-1 (2H) pyridinecarboxylate (compound 36)

Starting materials: compound 8 and ethyl (2S) -3-amino-2 - [(2-naphthylsulfonyl) amino] propanoate hydrochloride Yield = 67%.

9) Synthesis of tert-butyl 4- {3 - {[(2 - {[(2S) -2-amino-3-ethoxy-3-propyl] amino} -2-oxo, ethyl) amino] carbonyl} -5- [1] (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridine carboxylate hydrochloride (compound 37)

Tert-Butyl 4 - [(10S) -3- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} -1H- (ethoxycarbonyl) -4,7,12-trioxo-14-phenyl-13 oxa-5,8,11-triazatetradec-1-yl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 29) (60 g, 76.1 mmol), 10% palladium on activated carbon * ('5 g)' in ethanol (400 ml) and ethanol (77 ml) in hydrogen chloride were hydrogenated at room temperature at about 25 psi for 30 minutes. The resulting mixture was filtered and evaporated to give 52 g

- '29

• 9 • 9 9 9 9 9 • · · 9 • ♦ * • · · · • · '' 9 4 '9 • 9 9 • • · ··· . · · • 9 • '4

beige colored solids. . ,

Yield = 99%. ^ - NMR (400 MHz, CDC1 _3): δ '1.0 (m ,. 4H), 1.18 (m, 4H), 1.27 (t, 5H), 1.42 ( s, 20H), 1.58 (m, 6H), 2.0 (m, 1H), 2.6 (bt, 4H), 3.35 (m, 1H), 3.55 (m, 1H) 3.68 (m, 1H), 3.9 (d, 2H), 4.02 (bs, 4H), 4.18 (q, 2H), 6.38 (bt, 1H), 6.72 ( bt, IH)

The method described above was used to prepare the following compounds:

10) Synthesis of tert-butyl 4- {3 - {[(3 - {[(2S) -2-amino-3-ethoxy-3-oxoproyl] amino} -3-oxopropyl) amino] carbonyl} -5- [1 (target) butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate. (compound 38)

Starting material: compound * 33 Yield = 97% ·. \

11) Synthesis of tert-butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3 - ({[2- ({(2S) -3-ethoxy-3-oxo-2 [(phenylsulfonyl) amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 39) tert -Butyl 4- {3 - {[(2- (2S) -2-amino-3-ethoxy- 3-propyl] amino} -2-oxoethyl) amino] carbonyl} -5- [1 (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridine carboxylate (Compound 37) (3.31 g, 4, 8 mmol) was dissolved in 50 mL of dichloromethane containing triethylamine (1.04 g, 5 mmol) and benzenesulfonyl chloride (0.9 g, 5 mmol) was added at about 5 ° C. After two hours at room temperature, water was added. The organic phase was washed with 1N HCl, dried over sodium sulfate and then washed to give the crude product which was purified by flash chromatography (dichloromethane / methanol 15/1) to give 2.8 g of a white solid.

Yield = 74%

-30-.

¹H-NMR (400 MHz, CDC1 _3): δ 1.05 (m, 7H) · 1.25 '(_m, 6H). 1.45 (s, 20H), 1.6 (m, 6H), 2.08 (m, 1H), 2.6 (bs, 4H), 3.5 (m, 1H)., 3.67 ( m, 1H), 4.0 (m, 9H), 6.28 (t, 1H), 6.62. (t, 1H)

7.1 (t, 1H); 7.5 (m, 3H); 7.82 (d, 2H).

The method described above was used to prepare the following compounds:

12) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({(2S) -3-ethoxy-3-oxo-2 - [(1, 3-benzodioxol-5-ylcarbonyl) amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 40)

Starting material: piperonyl chloride

Yield = 74%

13) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({(2S) -3-ethoxy-3-oxo-2- [ (2-naphthylsulfonyl) amino] propyl} amino) -2- ⁽ oxoethyl] amino] carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound - 41) -

Starting material: (2-naphthylsulfonyl chloride)

Yield = 74% 1 H-KMR (400 MHz, CDCl 3): δ 0.95 (t, 3H), 1.05 (m, 4H), 1.2 (m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.63 (bt, 4H), 3.55 (m, .delta.), 3, 7 (m, 1H), 3.9 (q, 2H), 4.0 (m, 7H), 6.3 (bs, 1H), 6.55 (t, 1H), 7.05 (t, 1H) ), 7.65 (m, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 7.95 (d, 2H), 8.4 (s,

1H).

14) tert -Butyl 4- [5 - [[1- (t-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({(2S) -3-ethoxy-3-oxo-2 - [(4) -.

propylphenylsulfonyl) amino] propyl} amino) -2-oxoethyl] amino) carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 42). , ·. '4 · .4 - · ·

4 »

4

• 14 4

Starting material: 4-propylphenylsulfonyl chloride. , '·

Yield = 78% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.95 (t, 3H), 1.05 ~ 1.4 (m, 15H), 1.5 (s, 18H), 65 (m, 1H), 2.15 (m, 1H), 2.65 (bt, 6H), 3.45 (m, 1H), 3.8 (m, 1H), 4.0 (m, 9H) ), 6.0 (d, 1H),

6.55 (t, 1H), 6.9 (t, 1H), 7.35 (d, 2H), 7.75 (d, 2H),

15) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({(2S) -3-ethoxy-3-oxo-2 - [((1) (1'-biphenyl) -4ylsulfonyl) amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 43)

Starting material: 4-biphenylsulfonyl chloride

Yield = 81%. .

¹ H-NMR (4.00 MHz, CDC1 _3): δ'ΐ, '05, (m, 7H), 1.15 (m, 4H).> 1.35 (m, 2H), 1.4 (s, 20H), 1.55 &apos; (m, 6H), 2.05 &apos; (m, 1 &apos;),&lt; 2.6 &gt;

4H), 3.5 (m, 1H), 3.65 (m, 1H), 3.8, 4.1 (m, 1H), 6.25 (bs, 1H), 6.6 (bt) 1H, 7.05 (bt, 1H), 7.4 (m, -3H), 7.55 (d, 2H), 7.65 (d, 2H), 7.85 '(d, 2H).

16) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - (((2S) -3-ethoxy-3-oxo-2 - [(1-naphthylsulfonyl)) amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 44)

Starting material: 1-naphthylsulfonyl chloride

Yield = 92% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.9 (t, 3H), 1.05 (m, 4H), 1.2 (m, 4H), 1.3 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.45 (m, 1H), -3.6 (m, 1H), 3.7.5 (m, 2H), 3.8 (m, 2H), 4.0 (m, 5H), 6.3 (d, 1H), 6.4 (bt, 1H), 6.75 (bt, 1H), 7.5 (t, IH), 7.6 (t, IH), 7.7 (t, IH), 7.9 (d, IH) 8.05 (d, 1H); 8.2 (d, 1H); 8.65 (d, 1H).

Tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({(2S) -3-ethoxy-3-oxo- 2 - [(4 (methylsulfonyl) phenylsulfonyl) amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 45)

Starting material: 4- (methylsulfonyl) phenylsulfonyl chloride Yield = 80% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H), 1.1 (t, 3H), 1.2 (m, 4H), 1.3 (m, 2H), 1.4 (m, 20H), 1.6 (m, 6H), 2.05 (m,

1H), 2.65 (bt, 4H), 3.1 (s, 3H), 3.55 (m, 1H), 3.65 (m,

1H), 3.9 (d, 2H), 4.0 (m, 7H), 6.6 (bt, 2H), 7.05 (bt, 1H), 8.05 (dd, 4H).

18) tert -Butyl-4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({2 - ({(2S) -3-ethoxy-3-oxo-2 - [(2) - ¹ thienylsulfonyl) amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridine carboxylate (compound 46) ·

Starting material: 2-thienylsulfonyl chloride.

Yield = 78 ‘% ·.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H), 1.15 (m, 7H), 1.3 (m, 2H), -1.4 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.55 (m, 1H), 3.7 (m, 1H), 3, 9 (dq, 2H), 4.05 (m, 7H), 6.25 (bs, 1H), 6.55 (bt, 1H), 6.95 (bt, 1H), 7.05 (dd, IH),

7.55 (dd, 2 H).

19) tert -Butyl-4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3 - [({2 - [(. <2S) -2-{[(4-chlorophenyl)] sulfonyl] amino} -3-ethoxy-3-propyl) amino] -2-oxoethyl} amino) carbonyl] pentyl} tetrahydro-1 (2H) pyridine carboxylate (Compound 47)

Starting material: 4-chlorophenylsulfonyl chloride.

Yield = 63%

• · · · • ·· · • · • · • • · 9 · • · • · · 9 • 1 «· _s · ···· • · · • '· • • · • · • · · • ·. • ·. 9 9

¹ H-NMR (400 MHz, CDCl 3): δ 1.05 (m, 4H); 1.15 (t, 3H); 1,2 (m, 4H), 1.3 (m, 2H), 1, Δ (s, 20H), 1.6 (m, 6H) 2.05 (m, 1H), 2.6 (bt, 4H), 3.45 (m, 1H), 3.7 (m, 1H), 4.0 (m, 9H),

6.1 (bd, 1H), 6.45 (bt, 1H), 6.95 (bt, 1H), 7.45 (d, 2H),

7.75 (d, 2 H).

20) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - [({2 - [((2S) -2 - {[(4-fluorophenyl) sulfonyl] amino}) - 3-ethoxy-3-propyl) amino] -2-oxoethyl} amino) carbonyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (compound 48)

Starting material: 4-fluorophenylsulfonyl chloride

Yield = 82% ¹ H-NMR (400 MHz / CDCl ₃ ): δ 1.05 (m, 4H), 1.15 (t, 3H), 1.2 (m, 4H), 1.3 (m 2H, 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.5 (m, 1H); 3.7 (m, 1H); 4.1 (ra, 9H);

6.2 (bs, 1H), 6.55 (bt, 1H), 7.0 (bt, 1H), 7.2 (t, 2H),

7.85 (dd, 2 H).

21.) tert / Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2- (· {(2S) -3-ethoxy-3-oxo-2 - [( 6-methoxy-2-naphthylsulfonyl) aminopropyl (amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 49)

Starting material: 6-methoxy-2-naphthylsulfonyl chloride yýtěžnost ^X = 71% H-NMR (400 MHz, CDC1 _3): δ 0.95 (t, 3H), 1.0 (m, 4H), 1.15

(m, 4H), 1.25 (m, 2H), 1.45 (s, 20H) , 1, 6 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.45 (m, IH), 3.7 (m, IH), 3.75 (q, 2H), 3.9- (s, 3H), 4.0 ' (m, 8H), 6, .05 '(bd, IH), 6, 45 (bt, IH)., 6.75 (bt, 1H), 7.1 (d, 1H), 7.2 (d, IH), 7.75 (m, 3H), 8.25

(s, 1H). .

22) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 34

3 - ({[2 - ({(2S) -3-ethoxy-3-oxo-2-ol)]).

[(mesitylsulfonyl) amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 50)

Starting material: mesitylsulfonyl chloride Yield = 67% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H), 1.10 (t, 3H), 1.20 (m, 4H), 1, 35 (m, 2H), 1.45 (s, 20H), 1.65 (m, 6H), 2.05 (m, 1H), 2.25 (s, 3H), 2.65 (s, 6H) 2.67 (m, 4H), 3.50 (m, 1H), 3.65 (m, 1H), 3.85 ~ 4.15 (m, 9H), 5.90 (d, 1H) 6.40 (bt, 1H), 6.70 (bt, 1H), 6.90 (s, 2H).

23) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({(2S) -3-ethoxy-3-oxo-2 [(butylsulfonyl) (amino) propyl} amino) -2- (oxoethyl) amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 51). , V

Starting material: n-butylsulfonyl chloride ...

Yield = 66% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.9. (t, 3, H), 1.0 (m, 4H), 1.15 (m, 4H), 1.25-1.4 (s, 27H), 1.6 (m, 2.05 (m) 1 H, 2.65 (bt, 4H), 3.0 (t, (m, 1H), 3.9 (t, 2H), 4.05 (bs, 4H), 1H), 6.55 ( bt, 1H), 7.0 (bt, 1H).

³ <ιΙ

6H), 1.75 (m, 2H), 2H), 3.5 (m, 1H), 3.75 4.2 (m, 3H), 5.85 (d, 1H);

24) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({. [2 - ({(2S) -3-ethoxy-3-oxo-2 - [(4-methylphenylsulfonyl) ") (amino) propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound-52) · - Starting material: 4-methylphenylsulfonyl chloride

Yield = 68% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H), 1.15 (t, 3H), 1.2 (m, 4H), - 1.35 ( m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m,

35. - 9 9 ' • · · · · • · · · · • 9 9 ······ • · · · • · · · · · · · IH), 2.4 (s, 3H) 2.65 (bt, 4H) 3.45 (m, 1H) / 3.75 (m, - IH), 3, 85 -4.15 (m, 9H) ), 5, 95 (bd, 1H), 6.5 (bt, 1H), 6.85 (bt, IH), 7.25 (d, 2H). 7.7 (d, 2H).

25) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({(2S) -3-ethoxy-3-oxo-2 - [(3-methylphenylsulfonyl) ") (amino) propyl} amino) -2-oxoethyl] amino) carbonyl) pentyl] tetrahydro-1 (2H) pyridine carboxylate (compound 53)

Starting material: 3-methylphenylsulfonyl chloride Yield = 86% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H), 1.05 (t, 3H), 1.1 (m, 4H) - 1.3 (m, 2H), 1.4 (s, 20H), 1.6 (m, 6H), 2.1 (m,

1H), 2.4 (s, -3H), 2.65 (bt, 4H), 3.4 (m, 1H), 3.75 (m, 1H),

3.85-4.1 (m, 9H), 5.9 (bs, 1H), 6.45 (bt, 1H), 6.8. (bt, 1H), 7.4 (d, 2H), 7.6 (m, 2H)

26) tert -Butyl 4 - [(10S) -3- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} -10- (ethoxycarbonyl) -4,7,12,12-tetraoxo-13-phenyl-12k ^6- thia-5,8,11-triazatridec-1-yl] tetrahydro-1 (2H) -pyridinecarboxylate (Compound 54)

Starting material: 4-benzylsulfonyl chloride

Yield - 49%, ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H), 1.2 (m, 4H), 1.25 (m, 5H), 1.45 (s 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.5 (m, 2H), 3.9 (m, 2H), 4.0 (bs, 4H); 4.2 (q, 2H);

4.3 (q, 2H), 5.75 (bd, 1H), 6.4 (bt, 1H), 6.75 (bt, 1H),

7.55 (m, 5H).

27) tert -Butyl 4 - [(1'OS, 13E) -3- {2- [1- (tert-butoxycarbonyl) 4-piperidinyl] ethyl} -10- (ethoxycarbonyl) -4,7,12,12tetraoxo -14-phenyl-12X- ^6- thia-5,8,11-triaza-13-tetradecen-1-yl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 55)

-. 36 -

• · • ·· « • · ‘ • • • • · • · • ^: · • • · • · • • · , · • · · · • · · • • « • • · • · ··· • ·· • ·

«>

Starting material: - trans- _t -styrene sulfonylphloride _t .

Yield = 57% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.0- (m, 4H), 1.1 ~ 1.2 (m, 7H),

1.3 (m, 2H), 1.45 (m, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.5 (m, 1H) ), 3.8 (m, 1H), 3.85 ~ 4.15 (m, 9H), 5.95 (bs, 1H), 6.5 (bt, 1H), 6.75 (d, 1H) 6.95 (bt, 1 H),

7.35 - 7.5 (m, 6H).

28) tert -Butyl 4 - [(10S) -3- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} -10- (ethoxycarbonyl) -4,7,12,12-tetraoxo-14-phenyl-12A ^with -thia-5,8,11-triazatetradec-1-yl] tetrahydro-1 (2H) -pyridinecarboxylate (Compound 56)

Starting material: hydrogenation product of the compound · 55 'Yield = 96%,

1 H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H),. i, 15 (π, 4H), 1.25

- ´ -t '‘m (m, 5H), 1.4 (s, 20H), 1.55 (m, 6H), 2,0 2.05, (m, 1H)., 2.6 (bt,

4H), 3.0-3.3 (m, 3H), 3.55 (m, 1H), 3.75 (m, 1H), 3.9 (d,

2H) 4.05 (bs, 5H), 4.25 (d, 2H), 6.0 (bs, 1H), 6.55 (bt, 1H);

1H), 7.0 (bt, 1H), 7.1-7.5 (m, 5H). '

29) tert-Butyl 4- [5- [1- (tert-butoxycarbonyl} -4-piperidyl] 3 - {[(2 - {[(2 S) -3-ethoxy-3-oxo-2- ( {[3 (trifluoromethyl) phenyl] sulfonyl} amino) propyl] amino} -2-oxoethyl) amino] carbonyl (pentyl) tetrahydro-1 (2H) pyridinecarboxylate (compound 57)

Starting material: 3-trifluoromethylphenylsulfonyl chloride Yield = 77% 1 H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 7H), 1.15 (m, 4H), 1.25 (m, 2H), 1 4 (s, 20H), 1.55 (m, 6H), 2.05 (m, 1H), 2.55 (bt, 4H), 3.5 (m, 1H), 3.65 (m (1H), 3.85 ~ 4.05 (m, 9H),

6.4 (bs, 1H), 6.55 (bt, 1H), 7.0 (bt, 1H), 7.6 (t, 1H),

7.75 (d, 1 H), 7.95 (d, 1 H), 8.05 (s, 1 H).

«#« · 9 · · β β * β β β β β β β β β β β β β β · · · · ···

30) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {[(2 - {[(2S) -3-ethoxy-2 - ({[3-nitrophenyl] sulfonyl) } amino) -3-oxopropyl] amino} -2- (oxoethyl) amino] carbonyl} pentyl) tetrahydro-Ί (2H) pyridinecarboxylate (compound-58)

Starting material: 3-nitrophenylsulfonyl chloride

Yield = 55% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.0 (m, 4H), 1.15 (t, 3H), 1.2

(m, 4H ·) 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, • 4H) , 3, 65 (m, 2H), 3.9-4.2 ( m, 9H), 6.65 (bt, lH) 7.15 (t, IH) 7 7 t 'r.' (t, 1H), 8.2 (d, 1H), 8.4 (d, 1Ή),, 8-, 7 (s, 1H). . 31) '. target. Butyl 4- [ 5- [l - (target .butoxycarbonyl) - -4-piperidyl] -

3 - {[(2 - {[(2S) '- 3-ethoxy-2 - ({[3-methoxyphenyl] sulfonyl [amino] 3-oxopropyl] amino} oxoethyl) amino] carbonyl} -, pentyl) tetrahydro-1 (2H) pyridinecarboxylate (compound 59) Starting material: 4-methoxyphenylsulfonyl chloride. .

Yield = 55% * 'H-NMR (400 MHz, CDC1 _3): δ, ϊ, Ο (nt, 4H) 1.15 (t, 3H), 1.2 (m, 4H.), 1.35 . (m, 2H), 1/45 (s, 20H), 1.65 (m, 6H), 2.05 (m, 1H), 2.65 (bt, 4H), 3.45 (m, 2H); 1H), 3.75 (m, 1H), 3.85 (s, 3H), 3.9-4.1 (m, 9H), 5.9 (bs, 1H), 6.5 (bt, IH),

6.85 (bt, 1H), 6.95 (d, 2H), 7.75 (d, 2H).

32. tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ([{2 - ({(2S) -3-ethoxy-3-oxo-2 - [( (Quinolylsulfonyl) amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 60).

The starting material 8-chinolinesulfonylchlorid Yield = 55% ¹ H-NMR (400 MHz, 'CDC1 _3): δ 0, -9 (t. 3H), 1.05 (m, 4H), 1.2. (m, 4H), 1.3 (m, 2H), 1.45 (m, 20H), 1.6 (m, 6H), 2.05 (m,

Λ 9 9 9 9 9 9 9 9 9 9999 9 9 9 * i

1 H), 2.65 (bt, 4 H), 3.5 (m, 1 H), 3.65 ~ 4.2 (m, 10 H), 6.35 (bt, 1 H), 6.65 (bt, 1 H) 7.2 (bs, 1H), 7.55 (q, 1H), 7.65 (t, 1H), 8.05 (d, 1H), 8.25 (d, 1H), 8, 35 (d, 1H); 9.05 (d, 1H).

33) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - [((2 - [{(2S) -2 - {[(3,5-dimethyl-4-isoxazolyl)]) sulfonyl] amino} -3-ethoxy-3-oxopropyl) amino] -2-oxoethyl] amino) carbonyl] pentyl} tetrahydro-1 (2H) pyridine carboxylate (Compound 61)

Starting material: 3,5-dimethyl-4-isoxazolylsulfonyl chloride Yield- 81% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), 1.2 (m, 7H), 1.3 (m, 2H), 1.45 (m, 20H), 1.65 (m, 6H), 2.05 (m, 1H), 2.4 (b, 3H), Δ (s, 3H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.7 (m, 1H),

3.85-4.1 (m, 9H), 6.4 (bs, 1H), 6.5-5 / (bt, 1H), 7.0 (bt, 1H). '

34) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - [({2 - [((2S) -2 - {([5- (dimethylamino) -1-naphthyl)] sulfonyl) amino} -3-ethoxy-3-oxopropyl) amino] -2-oxoethyl) amino) carbonyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (compound 62)

Starting material: 5-Dimethylamino-l-naphthylsulfonyl chloride Yield = 73% ^X H-NMR (400 MHz, CDC1 _3): δ 0.9 (t, 3H), 1.15 (m, 4H), 1.3 (m (2H), 1.45 (m, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 2.85 (s, 6H), 3 45 (m, 1H), 3.6 (m, 1H), 3.8 (m, 4H), 3.9-4.1 (m, 5H), 6.15 (bs, 1H), 6, 35 (bt, 1H), 6.6 (bt, 1H)] 7.2 (d, 1H), 7.5 (t, 1H), 7.6 (t, 1H), 8.2 (d) 1 H, 8.25 (d, 1H), 8.55 (d, 1H).

35) target; Butyl 4 - {3 - {[(2 - {[(2S) -2 - ({[2- (acetylamino) -4methyl-1,3-thiazol-5-yl] sulfohyl} amino) -3-ethoxy- 3- 3 9 ^ø 9 9 9 · · »· 9 · 9999

• ·

9

(9-Oxopropyl) amino} -2-oxoethyl) amino] carbonyl} -5- [t- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (Compound 63)

Starting material: 2- (acetylamino) -4-methyl-1,3-thiazol-5-ylsulfonyl chloride Yield = 64% 1 H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), 1.15-1 4 (m, 9H), 1.45 (s, 20H), 1.6 (bd, 6H), 2.1 (m, 1H), 2.3 (s, 3H), 2.45 (s, 3H), 2.65 (bt, 4H), 3.55 (m, 1H), 3.7 (m, 1H), 3.9 -

4.2 (m, 9H), 6.85 (bt, 1H), 7.2 (bt, 1H).

36) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - [({2 - [((2Si-2 - {([3-chloropropyl) sulfonyl) amino})}) (ethoxy-3-oxopropyl) amino] -2-oxoethyl} amino) carbonyl] pentyl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 6.4).

Starting material: 3-chloropropylsulfinyl chloride.

Yield = 68%.

1 H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), 1.2 (m, 4H), 1.35 (m, 5H), 1.45 (s, 20H), 1 6 (m, 6H), 2.05 (m, 1H), 2.3 (m,

2H) 2.65 (bt, 4H), 3.2 (t, 2H), 3.6 (m, 1H), 3.65 (t, 2H),

3.75 (m, 1H); 3.95 (d, 2H). 4.05 (bs, 4H), 4.25 (q, 3H),

6.1 (bd, 1H), 6.6 (bt, 1H), 7.1 (bt, 1H).

37) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - [({2 - [((2S) -2 - {([4-methoxy-1-naphthyl] sulfonyl) (amino) -3-ethoxy-3-oxopropyl) amino] -2-oxoethyl} amino) carbonyl] pentyl} tetrahydro-1 (2H) pyridine carboxylate (compound 65). Starting material: 4-methoxy-1-naphthylsulfonyl chloride, '

Yield = 71% ^X H-NMR (400 MHz, CDC1 _3): δ 0.9 (t, 3H), 1.05 (m, 4H), 1.15 (m, 4H), 1.35 (m, 2.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.65 (bt, 4H), 3.45. (m, 1H), 3.6 (m, 1H), 3.75-4.05; · · · Y · or <· · '* <

4 0 (m, 9Ή), 4.1 (s, 3 H), 6.2 (d, ÍH), 6, 8 (d, 1H), 7.6 (t, ÍH) 8.35 (d, 1H), 8.6. (d, 1H). 38) target .Butyl 4- {5- [1 - (target.

•. * · •. · · · · · ·

3 - [({2 - [((2S) -2 - {([6,7-dimethoxy-2-naphthyl] sulfonyl) amino} 3-ethoxy-3-oxopropyl) amino] -2-oxoethyl} amino) carbonyl] pentyl } tetrahydro-1 (2H) pyridine carboxylate (compound 66)

Starting material: 6,7-dimethoxy-2-naphthylsulfonyl chloride

Yield = 63% ¹ H-NMR (400 MHz, CDCl 3): δ 1.0 (t, 3H), 1.05 (m, 4H), 1.2 (m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.45 (m, 1H), 3, 75 (m, 1H)., 3.8-4., 1 <(m, 15H), 6/0 (d, 1H), 6.5 (bt, 1H), 6.9 (bt, 1H) 7.15 (s, 1H), 7.2 (s, 1H), 7.3 (s, 1H), 7.7 (d, 1H), 7.8 (d, 1H) '; ,. 8.25 (s, 1H). · '. . . /;

39) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3 -, {[(2 - {[(2S) _-2 - ({[2,4-dimethyl] -1,3-thiazol-5 'yl] sulfonyl} amino) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} pentyl] tetrahydro-1 (2H) pyridine carboxylate (Compound 67)

Starting material: 2,4-dimethyl-3 Yield = 54% ^X H-NMR (400 MHz, CDC1 _3): δ 1.05 thiazol-5-ylsulfonyl chloride

m, 4H), 1.2 (m, 7H) 1.35 6H) 2.1 (m, 1H), 2.6 (s, 3.7 (m, 1H), 3.85 ~ 4.15

6.95 (bt, 1H).

(m, 2H), 1.45 (with, 20H), 1.6 (m, 3H) , 2.7. (m, 7H), 3.55 (m, 1H), (m, 9H), 6, 35 (d, ÍH), 6.5 (bt,

yl] sulfonyl} amino) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} pentyl} tetrahydro-1 (2H) 40) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({(2S) -2 - ({[3,5-dimethyl-1H-pyrazole-4-])). 9: Pyridine carboxylate (Compound 68).

Starting material: 3,5-dimethyl-lH-pyrazole-4-ylsulphonyl chloride Yield = 50% ^X H-NMR (400 MHz, CDC1 _3): δ 1.05 (m, 4H), 1.2 (m, 7H) 1.3 (m, 2H), 1.45 (s, 20H), 1.65 (m, 6H), 2.1 (m, 1H), 2.4 (s,

-6H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.7 (m, 1H), 3.9 (bs, 2H),

4.05 (m, 6H), 6.4 (bd, 1H), 6.75 (bt, 1H), 7.15 (bs, 1H), 11.8 (bs, 1H).

41) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - (([2- ((2S) -3-ethoxy-3-oxo-2 - [( 3-pyridylsulfonyl) amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] -tetrahydro-1 (2H) -pyridinecarboxylate (compound 69).

Starting material: 3-pyridylsulfonyl chloride

Yield = 61%

¹ H- ' NMR (400 MH: z, c: DC1 ₃ ) : δ 1, , 05 (m, 4H) 1 15 (t, 4H) , 1,2 (m, 4H) , 1.35 (m, 2H), , 1.45 (m, , 2OH), 1, 65 (m, 6H) · 2.1 (m, IH) / ² ' 7 5 .. 4H) , 3, 6. (m, IH), , 3.7 (m, 1 ,9), 3.9 4.15 (m, 9H) 6.65 (bt, IH) , 6.7 (d, IH), 7.15 (bt, IH) ', 7.45 (q. IH) , 8.15 (dd, IH) , 8.8 (d, IH), 9.05 (s, 1H).

42 ·) target. Butyl 4- (3 - ([(2 - ([(2S) -2 - ((1,3-benzodioxol-5-ylsulfonyl} amino) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl) - 5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) -pyridinecarboxylate (Compound 70)

Starting material: 1,3-benzodioxol-5-ylsulphonyl chloride Yield = .61% · ^X H-NMR (400 MHz, _CDCl3 j η δ 1.05 - (m, 4H), 1: 2 (m, 7H ·) , 1,3

(m, 2H), 1,45- (with, 20H),. 1.65 (m, 7H) 2.1 (m, 1H), 2.65 (bt, 4H), , 3,5 (m, 1H), 3.7 (m , IH), 3.85 ~ 4.1 (m, 9H) 6.05 (d, IH), 6/1 (s, 2H), 6, 55 (bt, 1H), 6.85 (d, 1H), 6.9 (bt, IH), , 7.25 ( d, 1H), 7.4 (d, IH)

43) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {[(2 - {[(2S) -2 - ((2,3-dihydro-1,4- benzodioxin-6ylsulfonyl} amino) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 71)

Starting material: 2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl chloride

Yield - 61% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), .1.2 (m, 7H), 1.35

(m, 2H), 1.45 (with, 20H), 1.65 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.45 (m, 1H), 3.75 (m, 1H), 3.9 ~ 4 1 (m. 9H), 4.3 (dd, 4H) 5; 95 (bs, 1 H), 6.5 (bt, 1 H), 6, 85 (d, 1 H), 6, 95 (d, 1 H), • 7.3 (dd, 1 H), 7 , 35 (d, 1 H). '-

44) tert -Butyl 4- {3 - {[(2 - {[(2S) -2 - ({1-benzothiophen-2-ylsulfonyl} amino) -3-ethoxy-3-oxopropyl] amino} -2- oxoethyl) amino] carbonyl} -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 72)

Starting material i. 1-Benzothiophen-2-ylsulfonyl chloride

Yield = 74%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.95 (t, 3H), 1.05 (m, 4H), 1.2 (m, 4H), 1.3 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.7 (m, 1H); 3.85 (m, 4H); 4.05 (m, 5H); 6.45 (bt, 2H); 6.9 (bt, 1H); 7.5 ( m, 2H), 7.9 (d, 1H), 8.2 (d, 1H), 8.25 (s, 1H).

45) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {[(2 - {[(2S) -2 - ({[2,5-dimethyl-3-furyl] sulfonyl} amino) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} pentyl} tetrahydro-1 (2H) -pyridinecarboxylate (compound 73)

Starting material: 2,5-dimethyl-3-furylsulfonyl chloride

Yield = 78%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), 1.2 (m, 7H), 1.3 · (m, 2H), 1.45 (s, 20H) 1.6 (m, 6H), 2.1. (m, 1H), 2.25 (s> 3H), 2.5 (s, 3H), 2.65 (bt, 4H), 3.45 (m, 1H), 3.75 (m,

1 H), 3.85 ~ 4.15 (m, 9H), 5.9 (bs, 1H), 6.1 (s, 1H), 6.45 (bt, 1H), 6.85 (bt, 1H) ).

46) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {[(2 - {[(2S) -2 - ({[4-cyclohexylphenyl] sulfonyl} amino)) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl) pentyl) tetrahydro-1 (2H) pyridinecarboxylate (compound 74)

Starting material: 4-cyclohexylphenylsulfonyl chloride

Yield ’= 64% - '. '

¹ H-NMR (400 MHz, CDCl 3): δ 1.1 (m, 7H). .1,15 AND) .5 (m, 3OH), 1.6- (m, 6H), 1.8 (m, 6H), 2.1 (m, 1 H), 2.65 (m 1 5H), 3.45 (m, 1H), 3.75 (m, 1H), 3.85 4.15 (m, 9H), 5, 9 (bs, 1H), 6.45 (bt, 1 H), 6.85 (bt, 1 H), 7.35 (d, 2H), 7, 75 (d, 2H).

47) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {[(2 - {[(2S) -3-ethoxy-2 - ({[4-fluoro- (naphthyl) sulfonyl} amino) -3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} pentyl) tetrahydro-1 (2H) pyridinecarboxylate (compound 75)

Starting material: 4-fluoro-1-naphthylsulfonyl chloride Yield = 64% ¹ H-NMR (400 MHz, CDCl 3): δ 0.9 (t, 3H), 1.05 (m, 4H), 1.2 (m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.65 (m, 1H), 3.8 (q, 2H), 3.85 (bd, 2H), 4.05 (* m, 5H) / 6.3 ( bs, 1H, 6.45 (bt, 1H), 6.8 (bt, 1H), 7.2 (t, 1H), 7.7 (t, 1H), 7.75 '(t, 1H), 8.23 (t, 1H), 8.65 (d, 1H).

• ·; · '*, Ί ·

48) target; Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {[(2 - {[(2S) -3-ethoxy-2 - ({[4-chloro-1-]: (naphthyl] sulfonyllamino) -3-oxopropyl] amino} -2- (oxoethyl) amino] carbonyl} pentyl) tetrahydro-1 (2H) pyridinecarboxylate (compound 76)

Starting material: 4-chloro-1-naphthylsulfonyl chloride

Yield = 63%

¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.9 (t, 3H), 1.1 (m, 4H), 1.2 (m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, IH) 2.65 (bt, 4H); 3.5 (m, 1H), 3.6 (m, 1H), 3.8 (q, 2H) 3, 85. (bd, 2H), 3.95-4.15 (m, 5H), 6.4 (bt, 2H), 6.8 (bt, 1H) 7.65 (d, 1H); 7.75 (m, 2H), 8.4 (d, 1 H), 8.7 (d, 1H).

49) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {[(2 - ([(2S) -2 - ({[2,3-dihydro-1-benzofuran) -5-yl] sulfonyl} amino) -3-methoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} pentyl} tetrahydro-1 (2H) pyridinecarboxylate (Compound 77) ·

Starting material: 2,3-dihydro-1-benzofuran-5-ylsulfonyl chloride. Yield = 74% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), 1.2 (m, 7H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.25 (t, 2H), 3.45 (m, 1H), 3, 75 (m, 1H); 3.85-4.1 (m, 9H); 4.65 (t, 2H); 5.8 (d, 1H); 6.45 (bt, 1H); Δ (d, 2H), 7.6 (d, 1H), 7.65 (s, 1H).

50) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({[2S) -3-ethoxy-3-oxo-2 - {[4] - (2-thienyl) phenylsulfonyl] amino} propyl} amino) -2Oxoethyl] amino] carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound, 78)

Starting material: 4- (2-thienyl) -phenylsulfonyl chloride

Yield = 78% @ 1 H-NMR (400 MHz, CDCl3): .delta.1.1 (m, 7H), 1.2 (m, 4H), 1.35-45%

AND

AND'*' · '' »». · «► ’- • · ·. 9 9 < • 9 9 * 9 9 <9 l '· ¹ ''··'' Γ * ’’ · ' 9 9 '9 · · · ·' · ^9: · · · · · A. '. ♦ β- 9 9 · ' 'you • · · ' • · '· , -9, ·· .9 ·

(m, 2H), 1.45 (s, 20H), 1.6 (m _, 4H), 3.5 (m, 1H), 3.75 (m, 1H), 1H); 1.5 (bt, 1H); 6.9- (bt, 1H) ^; s ·

7.7 (d, 2H); 7.85 (d, 2H).

^R &quot; first *.

6H), 2.1 '(m, 1H), 2.65 (bq 3.9 - 4.1 (m, 9H), 6.1. (d, 7.1 (t, 1H); 7.4 (ddý..2H)

^» « «

51.) Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {{2 - {(2S) -3-ethoxy-3-oxo-2 - {[2 - (2-thienyl) phenylsulfonyl] amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 79)

Starting material: 2- (2-thienyl) -phenylsulfonyl chloride

Yield = 63% ^{: 1} H-NMR (400 MHz, CDCl 3): δ 1.05 (m, 4H), 1.2 (m, 7H), 1.3 (m, 2H), 1.45 (s 20H), 1.65 (m, 6H), 2.05 (m, 1H), 2.65 (bt, 4H), 3.5 (m, 2H), 3.8-4. 1 (m, 9HJ, 5.3, d, 1H), -25 (bt, 1H), 6.4 (bt, 1H), 7.15 (t, 1H), 7 5 ^-; (m ,. 4H) 7 6 \ (t,

1H), 8.1 (d, 1H). 'v- ··' '

52) target; Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl} 3 - ({[2 - ({, (2S) -3-ethoxy-3-oxo-2 - {[4- (2-furyl)]) phenylsulfonyl] amino} propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 80)

Starting material: 4- (2-furyl) -phenylsulphonyl chloride Yield = 62% · ^X H-NMR '(400 MHz, CDCl: δ 1.1 (m, 7H), 1.2 (m, 4H), 1 35 (m, 2H), 1.45 (s, 20H), 1.65 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H). Δ (m, 1H), 3.75 (m, 1H), 3.85-4.1 (m, 9H), 6.05 (bs, 1H), 6.5 (bt, 1H), 6, 55 (d, 1H), 7.5 (s, 1H), 7-, 75 (d, 2H), 7-8 '(d, 2H). ....

53) target; Butyl 4- {3 - {[(2 - {[(2S) -2 - ({1-benzofuran-2-ylsulfonyl} amino) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} - 5- [1- (tert-Butoxycarbonyl) -444 piperidyl] pentyl} tetrahydro-1 '(2H) -pyridinecarboxylate (Compound 81)

Starting material: 1-benzofuran-2-ylsulfonyl chloride Yield = 52%

^X H- NMR (400 MH z, CDC1 ₃ ): δ 1 1 (m, 7H), 1.2 · (m, 4H) 1.3 (m, 2H) , 1, 45 (s, 20H) 1.6 (m, 6H), 2.1 (m , IH), 2.65 (bt, 4H) , 3, 65 ( m, 1H), 3.75 (m, 1H), 3.9 - 4.15 (m, 8H) 4.25 (m, IH) , 6, 45 (bt, lH) 6.9 (bt, 1H), 7.35 (m, 2H) 7.48 (t, IH) r 7, 65 (d, 1H) , 7 (d, 1H).

54) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] • 3 - {{2 - ({(2S) -3-ethoxy-3-oxo-2 - [(2-naphthylmethylsulfonyl) (amino) propyl} amino) -2-oxoethyl '] amino} carbonyl) pentyl ·] tetrahydro-1 (2H) -pyridinecarboxylate (compound 82) ·

Starting material: 2-naphthylmethanesulfonyl chloride ',

Yield = 61%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), 1.1 (t, 3H), 1.2 (m, 4H), 1.3 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.65 (bt, 4H), 3.4 (m, 1H), 3 Δ (m, 1H), 3.75-4.1 (m, 9H), 4.4 (q, 2H), 5.7 (bs, 1H), 6.4 (bt, 1H), 6.7 (bt,

1H), 7.5 (m, 3H), 7.8 (m, 4H).

55) tert -Butyl 4- {5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - {[(2 - {[(2S) -2 - ({[2,3-dihydro-1H-indene] -5-yl] sulfonyl} amino) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} pentyl} tetrahydro-1 (2H) pyridinecarboxylate (compound 83)

Starting material: 5-indanesulfonylchlorid "Yield = 62% ^X H-NMR (400 MHz, CDC1 _3): δ 1.05 (m, 4H), 1.1 (t, 3H), 1.2 (m, 4H ), 1.35 (m, 2H), 1.45 (s, 2H), 1.6 (m, 6H), 2.05 (m, 1H), 2.1 (t, 2H), 2.65 (bt, 4H), 2.95 (t, 4H), 3.45 (m, 1H), 3.75 (m, 1H), 3.85-4.1 (m, 9H), 5.85 (d, 1H), 6.45

(bt, 1H), 6.8 '(bt, 1H), 7.3 (d, 1H), 7.6 (d, 1H), 7.65 (s, 1H).

56) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({(2S) -3-ethoxy-3-oxo-2 - {[(5) (phenyl-2-thienyl) sulfonyl] amino] propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 84)

Starting material: 5-phenyl-2-thiophenesulfonyl chloride

Yield = 60% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), 1.15 (t, 3H), 1.2 (m, -4H), 1.35 (m (2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.65 (bt, 4H), 3.55 (m, 1H), 3 Δ (m, 1H), 3.9 ~ 4.15 (m, 9H), 6.4 (bt, 1H), 6.8 (bt, 1H), 7.25 (d, 1H), 7 4 (m, 3H); 7.55 (m, 3H). .

57) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2 - ({(2S) -3-ethoxy-3-oxo-2 - [( 5,6,7,8-tetrahydro-2-naphthenylsulfonyl) amino] propyl} amino) -2-.

oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridine carboxylate (compound 85)

Starting material: 5,6,7,8-tetrahydro-2-naphthalenesulfonyl chloride

Yield = 12% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (m, 4H), 1.1 (t, 3H), 1.2 (m, 4H), 1.3 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 1.8 (bs, 4H), 2.1 (m, 1H), 2.65 (bt, 4H), 2, Δ (bs, 4H), 3.45 (m,

1H), 3.75 (m, 1H), 3.85 - 4.15 (m, 9H), 5.9 (bs, 1H), 6.5 (bt, 1H), 6.85 (m, 1H); bt, 1H), 7.2 (d, 1H), 7.49 (d, 1H), 7.65 (s, 1H). 58) tert -Butyl 4 - [(10S, Ε3Ε) -3 .- (2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} -10- (ethoxycarbonyl) -4,7,12,12tetraoxo- 12α ⁶ -thia-5,8,11-triaza-13-heptadecene-1448

yl] tetrahydro-1 (2H) -pyridinecarboxylate (Compound 86). .. ··

Starting material: (E) -1-pentenylsulfonyl chloride Yield = 21%. ¹ H-NMR (400 MHz, CDC1 _3): δ 0.9 (t, 3H), 1.05 (m, 4H), 1.2 (m, 4H), 1.27 (t, 3H); 1.30 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.2 (q, 2H), 2.65 (bt) (4H), 3.45. (m,

1Ή) ,. 3.75 (m, 1H), 3.85-4.10 (m, 7H), 4.2 (q, 2H), 5.65 (d, 1H), 6.15 (d, 1H), 6.45 (bt, 1H), 6.75 (dt, 1H), 6.8 '(bt, 1H).

59) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] _: 3 - ({[3 - ({(3S) -3-ethoxy-2 - [(2-naphthylsulfonyl) amino] 3-oxopropyl} amino) -3-oxopropyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) *. pyridine carboxylate (compound 87); , '_

Starting materials: compound 38 and 2-naphthylsulfonyl chloride Yield = 76%.] ·· '_; · .. ·, ''. 1 H-NMR (400 MHz, CDCl ₃ ): δ 0.95 '(t, 3H), 1.05 (m, 4H), 1.2' (m, 4H), 1.30 (m, 2H), 1.45 (s, 20H); 1.6 (m / 6H) / 2.0.

H) · 2.4 (m, 2H), 2.65 (bq, 4H), 3.45 (m, IH) · 3.55 _(m,:

2H), 3.7 (m, 1H), 3.85 (q, 2H), 4.0 (bs, 4H), 4.1 (bs, 1H),

6/0 (bd, 1H), 6.75 (m, 2H), 7.65 (m, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 7.95 (d, 2H), 8.4 (s, 1H).

60) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] phth-3 - ({[3 - ({(3S) -3-ethoxy-3-oxo-2 ^; [( phenylsulfonyl) amino] propyl} amino) -3 (oxopropyl) amino] carbonyl) pentyl] tetrahydro-1 (2H) -.

pyridine carboxylate (compound 88)

Starting materials: Compound 38, and benzeriesulfonyl chloride Yield = 76% 1 H-NMR (400 MHz, CDCl ₃ ):? δ 1.05 (m, 4H), 1.1 (t, 3H), 1.2 (m, 4H), 1.30 (m, 2H), 1.45 (s, 20H), 1, Δ (m, 6H), 2.0 (m, 1H), 2.4 (t, 2H), 2.65 (bt, 4H), 3.4 '(m, 1H), 3.55 (m , 2H),

3.7 (m, 1H), 4.0 (q, 2H), 4 ', 05 (bs, 4H), 5.9 (d, 1H), 6.5 (m, 2H), 7.5 (t, 2H), 7.6 (d, 1H), 7.85 (d, 1H).

61) tert -Butyl 4 - [(1OS) -3- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl) -13- (7,7-dimethyl-2-oxobicyclo [2.2.1] heptl-yl) -10- (ethoxycarbonyl) -4,7,12,12-tetraoxo-12k ^6- thia5,8,11-triazatridec-1-yl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 89)

By the method described for compound 29 starting from ethyl (2S) -3-amino-2 - ({[(7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methyl] sulfonyl) amino) hydrochloride starting material propanoate and compounds 4.

Yield = 78%

NMR (400 MHz, ( EDCI3): δ 0, 90 ( : s, 3H), 1.00 (s, 3H) , 1.05 (m,  4H) , 1.20 (m, 4H), 1.30 (t, 5H), 1.45 (s, 20H), 1.55 '(m,  6H) , 1.95 (t, 3H), 2.05 (im, 2H), 2.15 (t, IH), 2 20 (m, IH) , 2, 40 (m, IH) , 2.65 (bt, '4H) 3.00 (d, 1H ,., 3,: 50 , '(m / 2H) , 3, 80 (m, IH) , 3.95 (dq, 2H) , 4.05 (bs, 4: Hj, 4.2 0 (q,. 2H) , 4, 30 (m, IH) 6.40 (t, IH), 6'50 (d, lH) , 6.70. (t, IH) • 62) Kys élina. (2R) -3 - (2- (4-) [i— ( ; terč.butoxyka rbonyl) -4-

piperidyl] -2 '- {2- [1' (tert-butoxycarbonyl) -4piperidyl] ethyl (butanoyl) amino] acetyl) amino) -2 - [(2-naphthylsulfonyl) amino] propane (compound 90)

Isobutyl chloroformate (3.3 g, 24.2 mmol) was added at room temperature to a solution of 2 - [(4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1-. (butoxycarbonyl) -4-piperidyl] ethyl (butanoyl) amino] acetic acid (compound 4) (10.8 g, 20 mmol) in 200 ml of THE- and N-methylmorpholine (5 g, 4 9.5 mmol). A suspension was obtained. After stirring for 20 minutes at 0 ° C, a mixture of (2R) -3-amino-2 - [(2-naphthylsulfonyl) amino] propanoic acid (8 g, 25 mmol) and water (80 mL) was added.

: · ··· · ··· (ml). Stirring was continued at about 0-5 ° C for 30 ¹ minute and then at room temperature for periods of 18 hours. THF was evaporated and the aqueous solution was acidified to pH 2 with 1 N hydrochloric acid. The mixture was extracted with ether. The extracts were washed with water, dried over sodium sulfate and evaporated to give the crude product which was purified by flash chromatography (dichloromethane / methanol / acetic acid 10 / 0.5 / 0.5) to give 8.3 g of a beige-colored solid.

Yield = 51% ^X H-NMR (400 MHz, CDCl3) ·: δ 1.0 (m, 4H), 1.15 (m, 4H), 1.25

(m, 2H) 1.4 (s, 20H), 1.55 (bd, 6H), 2.1 (m, IH), 2.6 (bq, 4H), 3.6 (m ^,: 1H), 3.75 (m, 1H), 3.8-4.1. (m, 7H), 6.6 (d, 1H), 6.95 (bt 1 H, 7.25 (bt, 1H), 7.6 (m, 2H) 1, 7.85 (t, 2H), 7.95 (t, 2H), 8.45 (s, 1H).

D - Preparation of compounds of formula 1b, via route ₂ : by reacting an acid of formula IV with ¹ amine of formula V.

63) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({[2- ({3-ethoxy-2 - [[2-naphthylsulfonyl) amino] -3-propyl}) amino) -2-oxo-1-phenylethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) pyridinecarboxylate (compound 91)

Ethyl 3 - [(2-amino-2-phenyl-ethanoyl) amino] 2 - [(2-naphthylsulfonyl) amino] propanoate hydrochloride (1.7 g, 3 mmol) and diisopropylethylamine (0.8 g, 6.2 mmol) ) were added to the rotocycle of 4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl] butanoyl fluoride (ref. synthesis B1) at room temperature (1.55 g) , 3 mmol) in 50 mL of dichloromethane. After stirring for 3 hours, water was added. The organic phase was washed with water, dried over sodium sulfate and evaporated to give a crude product which was purified by flash chromatography

51 (dichloromethane / methanol 20-1) gave 1.2 g of a white solid.

Yield = 44%

^X H -NM R (4 00 MHz, CDCl 3): δ 0, 95 (m, 3 H), 1.00 ( m, 4H), 1, 20 May (m, 4H), 1.40 (m, 2H), 1.47 (s, 20H), 1.60 (m, 6H) 2, 05 / (m, ÍH), 2.60 (bd, 4H), 3.50 (m, 1H), 3.58 (m, 1H), 3, 65 (m, ÍH), 3.80 (m, 2H), 3.99 (m, 4H), 5.45 (m, 1H), 5, 75 (dd, ÍH) , 6.40 (dt , ÍH) 6.85 (dd, 1H), 7, 35 (m, 5 H), 7, 52 (m, 2H), 7.75 (d, ÍH), 7.95 (m, 3H), 8.37 (d, 1H).

This method was used to prepare the following compound.

64) tert -Butyl 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] 3 - ({12 - ({3-ethoxy-2 - [(2-naphthylsulfonyl) amino] -3-oxopropyl] amino) 1-methyl-2-.

oxoethyl] amino] carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 92)

Starting material: ethyl 3 - [(2-aminopropanoyl) amino] -2 - [(2-naphthylsulfonyl) amino] propanoate hydrochloride Yield = 71% ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.95 (t, 3H), 1.05 (m, 4H), 1.20

(m, 4H) / 1.30 (d, 5H),. 1.45 (with, 20H), , 1.60 (m, 6H) , 2 , 00 (m ,. 1H) t 2.65 (bs, 4H), 3.50 (m, ÍH), r 3.70 (m, ÍH) , 3 , 88 (m, 2H) t 4.08 (m, 4H), 4.50 (m, ÍH), 6.10 (bd, ÍH) , 6 , 30 (d, ÍH) ! 6, 90 (t, ÍH), 7.65 (m, 2H), 7.80 (d, ÍH), 7, 90 (d, ÍH) ' , 8, 00 (d, 2H), 8.40 (with, ÍH).

Example 1:

Ethyl 3- (1,3-benzodioxol-5-yl) -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-i. Piperidyl) ethyl] butanoyl) hydrochloride (amino) acetyl] amino} propanoate (CRL-42725).

tert -Butyl 4- {3 - {[1- (1,3-benzodioxol-5-yl) -3-ethoxy-3.-propyl] amino] -2-oxoethyl) amino] carbonyl} -5- [1 • 9 <tb> (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) pyridinecarboxylate (compound 9) (3.3 g, 4.35 mmol) was dissolved in 5 ml of dioxane and then 10 ml of a 4 N dioxane-hydrochloric acid solution were added. The mixture was allowed to stir at room temperature for 20 minutes and then dioxane was collected by settling. Ether was added and then settled again and the resulting material was then evaporated to dryness. A white powder was obtained, which was dissolved in about 150 ml of water, and then the solution was filtered and the filtrate was freeze-dried to obtain 2.4 g of a white solid.

Yield = 87%

MS (ES): m / z 559 (Μ ⁺ H) ^* H-NMR (400 MHz, CDC1 _3): δ 1 .1 (m, 7H), 1.25 (m, 6H), 1.45 (m, 4H), 1.75 (m, 4H), 2.15 (m, 1H), 2.75 / (m, 6H), 3.2 (m, 4H), 3.62 (m, -2H), 4.0 (q, 2H), 5.12 (q, 1H), 6.0 (s, 2H), 6.8 '(dd, 2H), 6.95 (s, 1H) .8.1 (t, -1H), 8.4-5. (d, 1H), 8.8 (bs, 2H), 9.1 (bs, 2H). ... _{> r} . ... '. .. '

The method described in Example 1 was used to> prepare the following compounds:

Example 2:

Ethyl 3- [3- (2-ethoxy-2-oxoethoxy) phenyl] -3 {[2- ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] dihydrochloride] amino} propanoate (CRL42640)

Starting material: compound 13

Yield = 92% ¹ H-NMR (400 MHz, CD ₃ OD): δ 1.3 (t, 3H), 1.45 (m, 13H), 1.7%.

(m, 4Hj, 1.95 (m, 4H), 2.35 (m, IH,., 3, O (m, 6H), 3.4 (m, 4H) 3,7,5, (s, 2H), , 3.95 (s, 2H), _r 4.18 (q, .. 2H) , 4.35. (q,. 2H), 4.8 (s, 2H), 5.42 (t, IH), 6,92 (d, IH), 7.05 (m, 2H). 7.35 (t, 1H).

Example 3:

'- 53?

· .., 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 99 999

Ethyl 3- [3- (3-methoxyphenyl)] - 3- [2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] propanoate dihydrochloride (CRL42661) ‘/

Starting material: compound 14

Yield = 93% 1 H-NMR (400 MHz, CD ₃ OD): δ 1.3 (t, 3H), 1.5 (m, 17H), 2.0 (m, 4H), 2.33 (m (1H), 3.0 (m, 6H), 3.4 (m, 4H), 3.9 (s, 3H), 3.98 (s, 2H), 4.2 (m, 2H), 5 42 (t, 1H), 6.95 (m, 2H), 7.05 (bs, 2H), 7.32 (t, 1H).

Example 4:

Ethyl (2S) -2 - [(2-naphthylsulfonyl) amino] - N - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] propanoate · (CRL42968) .

Starting substance: compound 41 · .. ‘

Yield = 100% [a] _D -16.5 (C = 0.97, H ₂ O)

MS (ES): m / z 644 (m + H) ^{+ 1} H-NMR (400 MHz, _DMSO-d): δ 0.85 (t, 3H), 1.1 (m, 4H),

1.25 (m, 6H), 1.45 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H),

2.75 (bq, 4H), 3.2 (m, 5H), 3.3 (m, 1H), 3.6 (m, 4H) _; 3.95 (m, 1H), 7.7 (m, 2H), 7.8 (d, 1H), 8.0-8.2 (m, 5H), 8.4 (s, 1H) 8.55 (d, 1H); 8.85 (bd, 2H); 9.1 (bd, 2H).

Example 5:

3- (1,3-Benzodioxol-5-yl) -3 - {[2- (4 (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] propanoic acid dihydrochloride ( CRL42630)

To a solution of tert-butyl 4- {3 - {[1- (1,3-benzodioxol-5-yl) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} 5- [1- ( tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-54

··. • • • · • · • ·· · · • '· ···· ·· • • · • · · • • · • • · • · · '' · · • · ·· ·

1 (2H) -pyridinecarboxylate (compound 9) (7.6 g, 1.0 mmol) in ml tetrahydrofuran and 20 ml water was added 1 g (23.8 mmol) sodium hydroxide monohydrate. After 4 hours at room temperature, the organic solvent was evaporated. Water was added and the mixture was acidified to pH 2 and then extracted with water and dried over sodium sulfate. The filtrate was evaporated to give 1.3 g of acid.

The acid thus obtained was dissolved in 10 ml of ethyl acetate and 50 ml of a 3 N ethyl acetate solution of hydrochloric acid was added. Stirring was continued at room temperature for 30 minutes. The mixture was separated by standing.

Addition of water (about 200 mL) followed by freeze-drying yielded 4.7 g of a white solid.

Yield = 78%

MS (ES): m / z 531 (M + H) @ ⁺ .

1 H-NMR (400> MHz, CD ₃ OD): δ 1.5 '(m, 12H) 1.95 (m, 4H), 2.25 (m, 1H), 2.75 (bs, 2H) ), 2.9 (m, 4H), 3.3 '(m, 4H), 3.8 (s, 2H), 5.29 (bs, 1H), 5.95 (s, 2H), 6 Δ (d, * 2H), 6.85 (m / 3H). '. /.

The method described in Example -5 was used to prepare the following compounds:

Example 6:

3- (4-Isopropylphenyl) -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl) amino) acetyl] amino] propanoic acid dihydrochloride (CRL42548)

Starting material: compound 10

Yield = 98%

MS-C1: m / z .529 (Μ ⁺ H) ^* H-NMR (400 MHz, CD ₃ OD): δ 1.5 (m, 16H), 1.65 (m, 4H), 1.95 (m, 5H), 2.35 (m, 1H), 3.0 (m, 6H), 3.4 (m, 4H), 3.95 (m, 2H), 5.4 (t 1H, 7.25 (d, 2H), 7.38 (d, 2H).

9 ·. · 9 9 »

9 9 9 9 · * · · ♦! · · · 9

9 9 · 9 9

9 99 ·

55 · 9 · 9 99

9

999 999

Example 7:. '’

3- (4-Methoxyphenyl) -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino [propanoic acid dihydrochloride (CRL42549)

Starting material: compound 11

Yield = 98%

MS-C1: m / z 517 (M + H) ⁺ H-NMR (400MHz, CD ₃ OD): δ 1.5 (m, 14H), 1.95 (m, 4H), 2.16 (m 1 H, 2.9 (dq, 2H), 3.0 (m, 4H), 3.4 (m, 4H), 3.85 (s, 3H), 3.95 (s, 2H), 5 35 (t, 1H), 6.92 (d, 2H), 7.35 (d, 2H).

Example 8:

3- (3,4-Dimethoxyphenyl) -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4- (piperidyl) ethyl) butanoyl} amino) acetyl] dihydrochloride] amino / propane '(CRL42590)' · 7 j

Starting material: compound 12 · '·', '

Yield = 80% - * '‘

MS-C1: m / z: 547 (M + H) ^{+ 1} H-NMR (40 MHz, CD ₃ OD): δ 1.15-1.65 (m, 14H), 1.8 (m,

4H), 2.25 ’(m, 1H), 2.85 (m, 6H), 3.3 (bs, 4H), 3.78 (s,

3H), -.3.8. (s, 3H), 3.85 (m, 2H), 5.25 (t, 1H), 6.85 (d, 2H), 6.95 (d, 1H).

Example 9 :,.

3 - [(3-carboxymethoxy) phenyl] -3 - {[2β {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] aminopropanoic acid dihydrochloride (CRL42639)

Starting material: compound 13

Yield = 79 '%' ^X H-NMR (400 MHz, CD ₃ OD): δ 1.2 - 1.65 (m, 14H), 1.85 (m,

4H), 2.25 (m, 1H), 2.7-3.0 (m, 6H), 3.3 (bs, 4H), 3.78

• · • • • « • • β · 4 4 4 4 • 4 • · • · 4 »· 4 4 4 • ♦ 4 • 4 • 4 * 444 4 « 4 4 · 4 4

(d, 2H), 4.68 (s, 2H), 5.3 (t, 1H), 6.82 (d, 1H), 6.95 (m, 2H), 7.25 (t, 1H); IH).

Example 10:

3- (3-Methoxyphenyl) -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanoic acid dihydrochloride (CRL42660)

Starting material: compound 14

Yield = 81% fe

MS (ES): m / z 517 (M + H) ^{+ 1} H-NMR (400 MHz, CD ₃ OD): δ 1.4 (m, 8H), 1.55 (m, 2H), 1.68 (m, 4H), 1.95 (bs, 4H), 2.3 (m, 1H), 2.9 (dd, 2H), 3.0 (m, 4H), 3.4 (m, 4H) ), 3.86 (s, 3H), 3.95 (s, 2H), 5.4 (m, 1H), 6.9 (m, 1H), 7.0 (m, 2H), 7.3 (t, 1H).

Example 11: - '

3- (2,3-Dihydro-1,4-benzodioxin-6-yl) -3 - {[2 - ({4- (4-piperidyl) ethyl] butanoyl} amino) dihydrochloride acetyl] amino} propane * (CRL42718)

Starting material: compound 15

Yield = 84%

MS (ES): m / z 545 (Μ + Η) ^{+ 1} H-NMR (400 MHz, DMSO-d ₆ + D ₂ O): δ 1.1 (m, 4H), 1.25 (m,

6H), 1.4 (m, 4H), 1.7 (m, 4H), 2.15 (m, 1H), 2.6 (t, 2H),

2.75 (m, 4H), 3.15 (bd, 4H), 3.7 (s, 2H), 4.05 (s, 4H), 5.05 (m, 1H), 6.72 (s 1 H, 6.78 (d, 2H).

Example 12: '

3- (3-Pyridyl) -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanoic acid trihydrochloride (CRL42722),.

«· • • • t 0 · • · • • • 9 • • * 9 • 4 ^{* 1} t • * · 4 9 • • • · • · · • 4 . * · β 4 •

Starting material: compound 16 '·'

Yield = 95%

MS (ES): m / z 488 (Μ + H) ^{+ 1} H-NMR (400 MHz, DMSO-d ₆ ): δ 1.1 (m, 4H), 1.25 (m, 6H), 1 4 (m, 4H), 1.65 (m, 4H), 2.15 (m, 1H), 2.85 (m, 4H), 2.9 (bd,

2H), 3.15 (m, 4H), 3.7 (m, 2H), 5.25 (m, 1H), 8.1 (bs, 1H),

8.25 (bs, 2H), 8.65 (d, 1H), 8.85 (bs, 1H), 8.95 (m, 4H), 9.2 (bs, 2H).

Example 13:

3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanoic acid dihydrochloride (CRL43040) 1 ...

Starting material: compound 17

Yield = 100%

MS (ES) m / z 411 (M + H) ^&lt; ^{+ &gt};;_; - Υγ. ' y - '

HH-KMR (400 MHz, DMSO-dg): δ1.1-5 (m, 4H), 1.3 (m, 6H),.

1.45 (m, 4H); 1.75 (bd, 4H); 2.15 (m, 1H); 2.35 (t, 2H);

2.75 (bq, 4H), 3.15 (bd, 4H), 3.25 (σ, 2H), 3.65 '(ο, 2H),

7.9 (t, 1H), 8.15 (t, 1H), 8.85 (bq, 2H), 9.15 (bd, 1H).

Example 14: · /

3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidinyl) ethyl] butanoyl} amino) acetyl] amino} butanoic acid dihydrochloride (CRL43C41). '

Starting material: compound 18;

Yield = 100%.

MS (ES): m / z 425 (M + H) ^{+ 1} H-NMR (400MHz, DMSO-d 6): δ 1.1 (d, 3H), 1.15 (m, 4H), 1.3 . (m, 6H), 1.4 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H) -, 2.25 (q, 1H), 2.45 (q, 1H) 1.75 (bq, 4H), 3.15 (bd, 4H), 3.6 (m, 2H), 4.05 (m, 1H), 7.85 (d, 1H), 8 1 (t, 1H), 8.8 (bq, 2H), 9.1 (bd, 2H).

• • - - 58 • · · · · · · · · · · · · · · · · · · · · · ·. · · · · · · · · · · · ···

Example 15:.

5-Phenyl-3 - {[2 - ({4- (4-piperidyl) ethyl] - [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} pentanoic acid dihydrochloride (CRL43042)

Starting material: compound 19

Yield = 100%

MS (ES): m / z 515 (Μ ⁺ H) ^* H-NMR (400 MHz, DMSO-d₆) δ 1.15 (m, 4H), 1.25 (m, 6H),

1.45 (m, 4H), 1.75 (m, 6H), 2.2 (m, 1H), 2.4 (m, 2H), 2.5 (m, 1H), 2.65 (m) 1H, 2.75 (bq, 4H), 3.15 (bd, 4H), 3.7 (bq, 2H), 4.05 '(m, 1H), 7.2 (m, 3H) 7.25 (t, 2H), 7.95 (d, 1H), 8.2 (t, 1H), 8.8 (bs, 2H), 9.15 (bd, 2H).

Example 16:. . '

(3S) -4- (Itadamantylamino) -4-oxo-3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-) -.

piperidyl) ethyl] butanoyl} amino) acetyl] amino} butane. (CRL42592)

Starting material: Compound 20 Yield = 94% -

MS (ES): m / z 588 (M + H) ^{+ (X} H-NMR (400 MHz, CD ₃ OD): δ 1.25 (m, 10H), 1.5 (m, 4H), 1, Δ (s ', 6H), 1.82 (bd, 4H), 1.9 (bs, 9H), 2.2 (m, 1H), 2.6 (m, 2H)', 2.86 (bt) * 4H), 3.25 (bd, 4H), 3.7 (d, 2H), 4.5 (t,

IH).

Example 17:.

(3S) -4 - {[2- (1H-Indol-4-yl) -ethyl] -amino} -4-oxo-3 - {[2 - ({4- (4-piperidyl) -2- [2 - 4 piperidyl) ethyl] butanoyl} amino) acetyl] amino} butane (CRL42678)

Starting material: compound 21

Yield = 100%

-MS (ES) m / z 597 (M + H) &lt; ⁺ &gt;

- 5.9. (400 MHz, DMSO-d6): δ 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H), 1.75 (m, 4H), 2.2 (m, 1H) 2.55 (m, 2H). 2,7 5 (m, 6H), 3.15 (m, 4H), 3.35 (m, 2H), 3.75 (bs, 2H), 4.6 (m, IH), 6, 98 (t, IH), 7.08 (t, IH), , 7.16 (s,  IH), 7.35 (m, IH), 7.55 (d, IH), 8.1 (d, IH), 8.2 (bs, 2H), 8,9 (bs, 2H), 9.2 (bs, 2H), 10, 9 (bs, IH) •

Example 18:

(3S) -4 - [(4-methoxyphenyl) ethylamino] -4-oxo-3 - {[2 - ({4- (4-piperidyl) ethyl] butanoyl} amino) dihydrochloride acetyl] amino} butane (CRL42694)

Starting material: compound 22

Yield = 97% 1 H-NMR (400 MHz, DMSO-d 6): δ 1.15 (m, 4H), 1.25 (m, 6H),

1.45 (m, 4H), 1.8 (bd, 4H), 2.15 (m, 1H). 2.5 (m, 2H), 2.65 (t, 2H), 2.75 (bd, 4H), 3.15 (bd, 6H), 3.7. (s, 5H), 4.55 (m, 1H), 6.85 (d, 2H), 7.15. (d, 2H) .8.1 (d, 1H). 8.15 (m, 2H), 8.95 (bd, 2H), 9.2 (bd, 2H). '·

Example 19:

(3S) -4- (3-Phenylpropylamino) -4-oxo 3 - {[2 - ((4- (4-piperidyl) ethyl) butanoyl} amino) acetyl] amino dihydrochloride [ butane (CRL42719)

Starting material: compound 23

Yield = 100%.

MS (ES): m / z 572 (M + H) ^{+ 1} H-NMR (400 MHz, DMSO-d 6): δ 1.15. (m, 4H), 1.3 (m, 6H), 1.4 (m, 4H), 1.7 (m, 6H), 2.15 (m, 1H), 2.55 · (m) 2.75 (bd, 4H), 3.05 (m, 2H), 3.2 (bd, 4H), 3.7 (d, 2H), 4.55 (m, 1H), 7.2 (m, 5H), 8.15 (m, 3H), 8.9 (bs / 2H), 9.15 (bs, 2H).

Example 20:

··. • • 9 9 4 9 44 4 = · • • 4 .4 449 4 .4 9 9 4 9 9. • • 9 • · • · <9 4 9 • · 4 • · • ·

(3S) -4 - [(1,3-Benzodioxol-5-ylmethyl) amino] -4-oxo-3 - {[2 - ({4- (4-piperidyl) -2- (2- (4-piperidyl)] -) dihydrochloride ) ethyl] butanoyl} amino) acetyl] amino} butane (CRL42720)

Starting material: compound 24

Yield = 90%

MS ( ESI: m / z 588 (M + H) &lt; + & gt ^{;. 1} H-NMR (400 MHz, 1 'DMSO- -dg): δ 1.15 (m, 4H), 1.3 (m, 6H), 1.4 (m, 4H), 1.7 (m, 4H). 2, 15 (m, 1H), 2.55 (bs, 2H), 2.75 (bd, 4H), 3.15 (d, 4H) ), 3, Δ (d, 2H), 4.15 (d, 2H), 4.6 (m, IH), 5.95 (s, 2H); 7. (d, 1H), 6.8 (s, 1H), 6.81 (d, 1H), 8.2 (m, 2H). 8.55 (t, IH), 8.9 (bs, 2H); 9.15 (bs, 2H).

Example 21:

(3S) -4 - [(3-Methoxyphenyl) amino] -4-oxo-3 - {[2 - ({4- (4-piperidyl) -2- [2- (1,4-piperidyl) ethyl] butanoyl} amino) dihydrochloride) acetyl] amino (butane) (CRL42721).

Starting material: Compound 25.

Yield = 100% * ^; 1 H-NMR (400 MHz, DMSO-d 6): δ 1.15 (m, 4H), 1.3 (m, 6H), 1.4. (m, 4H), 1.7 (m, 4H), 2.15 (m, 1H), 2.5 (m, 4H), 2.7 (m, 4H);

6H.), 3.15 (m, 6H), 3.7 (s, 5H), 4.55 (m, 1H), 6.75 (s, 3H), 7.15 (t, 1H) 8.1 (d, 1H), 8.2 (bs, 2H), 8.9 (bs, 2H), 9.15 (bs, 2H).

Example 22:

(3S) -4 - [(2-Hydroxy-1,1-dimethylethyl) amino] -4-oxo-3 - {[2- ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl]] dihydrochloride ] butanoyl} amino) acetyl] amino} butane (GRL42726) * '' '' '

Starting substance: Compound 26 ·

Yield = 100%

MS (ES): m / z 526 (M + H) ⁺

¹ H-NMR (400 MP Iz, DMSO · -d ₆ ): δ 1.1 (m, 7H) 1.25 (m, 7H), (m, 4H) , 1.7 (m, 4H) 2.15 (m, 1H) H), 2.5 (m, 2H) .6 (m ÍH), 2, 7 (bd, 4H), 3, 1 (bd, 4 H), 3.3 (q, (H), 3.7 (bs, 4.05 (m , (H), 4.45 (m 1H, 4.65 (m, 1H), 8.05 ~ 8 5 (m, 3H), 8, 9 (bs, 2H), 9 16 (bs, 2H) • Ex lad 23:

(3S) -4 - [(1-Isopropyl) -2-methylpropyl) amino] -4-oxo-3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl)]] dihydrochloride ethyl] butanoyl} amino) acetyl] amino} butane (CRL42727)

Starting material :, compound 27

Yield = 89%

MS (ES) m / z 552 (M + H) ^&lt; ⁺ &gt;;

¹ H-NMR (400 MHz, DMSO-d 6): δ 0.8 (m, 9H), 1.15 (m, 11H),

1.25 (m, 4H), 1.85 (m, 6H), 2.15 (m, 1H), 2.6 (m, 1H), 2.75 (m, 4H), 3.15 (m, 4H), 3.4 (m, 4H), 3.7 (m, 2H), 4.55 (m,

1 H), 7.3 (d, 1H), 8.3 (m, 2H), 8.95 (bs, 2H), 9.2 (bs, 2H).

Example 24:

(2S) -2 - {[(Benzyloxy) carboyl] amino} 3 - {[2 - ({4- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino dihydrochloride } Propane (CRL42717)

Starting material: compound 29

Yield = 97% [<x] _D -8 (C = 2.2, H ₂ O)

MS (ES): m / z 560 (M + H) ⁺ 1 H-NMR (400 MHz, DMSO-d ₆ ): δ 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H), 1.75 (m, 4H), 2.15 (m, 4H), 2.8 (bd, 4H), 3.2 (bd, 4H), 3 3 (m, 1H), 3.5 (m, 1H), 3.7 (m, 2H), 4.1 (q,

1 H), 5.05 (s, 2H), 7.35 (m, 4H), 7.55 (d, 1H), 8.05 (s,

1H), 8.15 (s, 1H), 8.9 (bs, 2H), 9.2 (bs, 2H).

** ♦ · · * * * * * * * * φ φ φ φ φ φ φ φ φ φ φ φ

Example 25:

2 - [(1,3-Benzodioxol-5-ylcarbonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- (2- (4-piperidyl) ethyl) butanoyl} amino) acetyl] dihydrochloride amino} propane (CRL42731)

Starting material: Compound 40

Yield = 100%

MS (ES): m / z 574 (M + H) ⁺

¹ H-NM R (4 00 MHz, DM! 3O-d ₆ ): δ 1.15 (m, 4H), 1.25 (m, 6H) r 1.45 (m, 4H), 1, 75, (m, 4H) 2.2 (m, 1H), 2.75 (m, 4H) , 3.2 (bd, 4H), 3.48 ( m, 1H), 3.65 (m, 4H) 4.45 (m, IH) , 6, 1 (s, IH), 7.0 (d, IH) , 7 5 (s, 1H) ), 7.55 (d, 1H) 25 (bd, 2H), 8.65 (d, IH) 8 95 (bs, 2H) 9.2 (bs , 2H).

Example 26: '. '

2 - [[phenylsulfonyl) amino] -3 - {[2 - ({4 (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino (propanoic acid dihydrochloride) CRL42724)

Starting material: compound 39

Yield = 95%

MS-C1: m / z 566 (M) ^{+ 1} H-NMR (400 MHz, DMSO-d 6): δ 1.15 (m, 4H), 1.25 (m, 6H),

1.45 (m, 4H), 1.75 (m, 4H), 2.2 (m, 1H), 2.75 (m, 4H), 3.15 (bd, 4H), 3.25 (m) 1 H, 3.5 (m, 2H), 3.8 (m, 1H), 7.6 (m, 3H), 7.8 (m, 2H), 8.05 (bd, 2H), 8 25 (d, 1H); 9.0 (bd,

2H), 9.25 (bd, 2H).

Example 27:

(2S) -2 - [(2-naphthylsulfonyl) ambno] -3 {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] dihydrochloride .propane (CRL42796) *

Starting material: Compound 41 Yield = 91%

[a] _D -10.1 (C = O , 86, H ₂ O) MS (ES) m / z 616; (M + H) ^{+ 2} Η-ΝΕ [R (400 MHz, DMSO- d ₆ ): δ 1,1 (ra, 4H), 1,25 (m, 6H), 1.45 (m, 4H) 1.7 (m, 4H) , 2.15 (ra, IH), 2.75 (bd, 4H) , 3.2 (bd, 5H), 3.4 (m, IH),  3, 55 (dq, 2H) , 3, 95 (q, IH) , 7, 7 (m, 2H), 7.8 (d, 1H); 8.0 (m, 3H), 8 , 15 (dd, 2H), 8.35 (d, IH), .8,4 (s, 1H), 8.7 (bs, 2H) , 8.95 (bd, 2H)

Example 28:.

2 - {[(4-propylphenyl) sulfonyl] amino} 3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) piperidine]] dihydrochloride.

piperidyl) ethyl] butanoyl} amino) acetyl] amino [propane (CRL42811) ';

Starting material: compound 42 _x '· ”

Yield = 94% ’'

MS (ES): m / z 608 (M + H) ⁺ \ 'IN.

¹ H-NMR (400 MHz, DMSO-d ₅ ): δ '0.85. (t, 3H), 1.15 (m, 4H),

1.25 (m, 6H), 1.35 (m-4H), 1.6 (q, 2H), 1.7 (m, 4H), 2.1 (m, 1H), 2.65 (t, 2H) / 2.75 (m, 4H), 3.15 (m, 4H), 3.25 (m, 1H), 3.5 (m, 2H), 3.8 (m, 1H) 7.35 (d, 2H); 7.65 (d, 2H); 8.0 (t, 1H); 8.05 (m, 1H); 8.1 (d, 1H); Δ (bd, 2H). 9.05 (bd, 2H). Example 29:

(3S) -4-Oxo-4- (4-benzylpiperidino) -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl) dihydrochloride ] amino} butane (CRL42591)

Starting material: compound 28

Yield = 89%

MS (ES): m / z 612 (Μ + H) ^{+ 1} H-NMR (400 MHz, CD ₃ OD): δ 1.3-1.6 (m, 12H), 1.9 (m, 6H) _,

2.26 (m, IH), 2.55. (m, 4H), 2.92 (m, 6H), 3.45 (m, 6H),

3.85 (bd, 2H), 4 (bt, 1H), 4.4 (bd, 1H), 5.2 (bs, 1H), 7.15 (m, -3H), 7.25 (t , 2H).

Example 30:

2 - {([1,1-Biphenyl] -4ylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) dihydrochloride ) acetyl] amino] propane (CRL42913)

Starting material: Compound 43

Yield = 96%.

MS (ES). m / z 642 (Μ + H) ^{+ 1} H-NMR (400 MHz, DMSO-d ₆ ): δ 1.15 (m, 4H), 1.30 (m, 6H),

1.45 (m, 4H); 1.75 (bd, 4H); 2.15 (m, 1H); 2.75 (bq, 4H); 3.20 (bd, 5H); 40 (m, 1H), 3 ', 60 (dq, 2H), 3.9 (m, 1H),

7.45 (t, 1H), 7.5 (t, 2H), 7.75 (d, 2H), 7.85 (s', 4H), 8.05 (bs, 2H), 8.3 (d) (1H), 8.9. (Bq, 2 ') ζ 9 ^ 15 (bq, 25).

Example 31: '

2 - [(1-naphthylsulfonyl) amino] -3 - {[2- ((N- (4-piperidyl) ethyl) butanoyl} amino) acetyl] amino} dihydrochloride Propane (CRL42914)

Starting material: compound 44

Yield = 96%

MS (ES): m / z 616 (M + H) ^{+ 1} H-NMR (400 MHz, DMSO-d _6): δ 1 .05 (m, 4H), 1.2 (m / 6H),

1.4 µm, 4H), 1.7 (bd, 4H), 2.1 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.3 (m, 1H), 3.45 (dq, 2H); 3.85 (q, 1H). 7.65 (m, 3H), 7.95 (m, 2H), 8.05 (d, 1H), 8.1 (d, 1H), 8.2 (d, 1H), 8.5 (d) (1H), 8.65 (d, 1H), 8.75 (bs., 2H), 9 ', 0 (bd,

2H). .

Example 32:

- _ ·, · · ··· · ··

- 65 ~ ···· ♦ · * · · · · · · · · · ·

2 - ({[4 (methylsulfonyl) phenyl] sulfonyl} amino) -3 - {[2 - ((4- (4piperidyl) ethyl) butanoyl} amino) acetyl] amino dihydrochloride [ Propane? (CRL42969)

Starting material: compound 45

Yield = 91%

MS (ES): m / z 644 (M + H) ^{+ 1} H-NMR (400 MHz, _DMSO-d): δ 1.1 (m, 4H), 1.25 (m, 6H), 1, 4 (m, 4H), 1.7 (bd, 4H), 2.1 (m, 1H), 2.7 (bq, 4H), 3.15 (bd, 5H), 3.25 (s, 3H), 3.35 (m, 1H), 3.55 (dq, 2H), 3.9 (m,

1H, 7.95 - 8.1 (m, 6H), 8.55. (d, 1H), 8.8 (bq, 2H), 9.05 (bd, 2H). ‘

Example 33:

2 - [(2-thienylsulfonyl) amino] -3 - {[2 ({4- (4-piperidyl) -2- (2- (4 ', piperidyl) ethyl) butanoyl} amino) acetyl] amino acid dihydrochloride } propane. (CRL42985) '' '.

Starting material: compound 46

Yield = 97%

MS (ES): m / z 572 (M + H) ^{+ 1} H-NMR (400 MHz, DMSO-d 6): δ 1.05 (m, 4H), 1.25 (m, 6H),

1.4 (m, 4H), 1.7 (bd, 4H), 2.15 _: (m, 1H), 2.7 (bq, 4H), 3.15 (bd, 5H), 3.35 ( m, 1H), 3.55 (dq, 2H), 3.85 (q, 1H), 7.15 (dd, 1H), 7.5 (t, 1H), 7.9 (t 1 H, 8.0 (t, 1H), 8.05 (t, 1H), 8.4 (d, 1H), 8.8 (bq, 2H), 9.1 (bd, 2H).

Example 34:

2 - {[(4-chlorophenyl) sulfonyl] amino} 3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino [propanoic acid dihydrochloride (CRL42986). '

Starting material: Compound 47

- 66 _in · - · ··. 9: 9 9

99 9 9 99 99 9 9 9 9 9. 9 9 9 9

999 999 99 · ·· 9 · 9

Yield = 92.% MS (ES) m / z 600 (M &lt; + &gt;) H) ^{+ 1} H-NMR (4 00 MHz, DMSO- d ₆ ): δ 1.1 (m (m, 4H) 1.7 (bd, 4H). 2.1 (m, lH) 5H), 3.3 (m, 1H), 3.55 ’(Dq, 2H), 3 7.75 (d, 2H), 8.05 (m, 2H), 8.35 (< 9.1 (bd, 2H).

4H), 1.25 (m, 6H), 1.4 2.7 (bq, 4H), 3.15 (bd 8 (q, 1 H), 7.6 (d, 2H),

(1H), 8.85 (bq, 2H),

Example 35:

2 - {[(4-Fluorophenyl) sulfonyl] amino} 3 - {[2 - ({'4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] dihydrochloride amino} propane (CRL42999)

Starting material: Compound 48. _Λ ....

Yield = 97%

MS (ES): m / z 584 (M + H) +. @ ¹ H-NMR (400 MHz, DMSO-d6): .delta. 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H), 1.75 (bd, 4H) 2.15. (m, 1H), 2.75 '(bq, 4H). 3.2 (bd, 5H), 3.35 (m, 1H), 3.6 (dq, 2H), 3 ', -35' (m, 1H), δ. 7.4 (t, 2H), 7.85 (dd ,; 2Ή), 8.05 (m, 2H), 8.30 (d, 1H), 8.8 . (bq,  2H) , · 9, Ί (bd, ’ 2H).

Example 36:

(2S) -2 - {[(6-methoxy-2-naphthyl) sulfonyl] amino} -3 - {[2 - ({4- (4-piperidyl) ethyl] -2- [2- (4-piperidyl) ethyl] butanoyl} dihydrochloride} amino) acetyl] amino} propanoic acid dihydrochloride (CRL43000) Starting material: compound 49 Yield = 90% [a] _D -10 JC = 1, H ₂ O)

MS (ES): m / z 646 (Μ + Η) ⁺ , ¹ H-NMR (400 MHz, DMSO-d 6): δ (m, 4H), 1.7 (bd, 4H), 2.15 ( bd, 5H), 3.35 (m, 1H), 3.6

1.1 (m, 4H), 1.25 (m, 6K), 1.4 (m, 1H), 2.75 (bq, 4H), 3.2 · (dq, 2H), 3.85 (m, IH), 3/9 (s,

67 -,. • · · • • · ·. • · 4 4 4 • 4 · '· ·' 4 4 4 4 4.4 4 4 4 4 4 4 4 '4 3H), 7.3 (d, AA) , 7.45 (s, 1H), 7.75 (d, . 1H), 8.0 (d, IH) 8.05 (m, 3H); 25 (d, 1H), 8.3 (s, 1H), 8.8 (bq, 2 H, 9.1 (bd, 2 H).

• ·

Example 37:.

2 - [(mesitylsulfonyl) amino] -3 - {[2 ({4- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanoic acid dihydrochloride (CRL43031) '*

Starting material: Compound 50 Yield = 98%

MS (ES): m / z 608- (Μ + H) ^{+ 1} H-NMR (400 MHz, DMSO-d 6): δ 1.15 (m, 4H)., 1.3 (m, 6H) -1.4 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H), 2.25 (s, 3H), 2.55 (s, 6H), 2, 75 (bq, 4H), 3.2 (bd / 5H), 3.35 (m, 1H), 3.55 (dq, 2H), 3.8 (σ, 1H), 7.0 (s, 2K), .8, C. (m, 3K), 8.85 (bq, 2H);

9.15 (bd, 2H).

Example 38: ',

(2S) -2 - [(Butylsulfonyl) amino] -3 ('[2 - ({4- (N-piperidyl) -2- [2- (4', 4'-piperidyl) ethyl] ethyl) butanoyl) dihydrochloride (amino) acetyl] amino} propane (CRL43032)) Starting material: compound 51

Yield = 90%.

/ -. [α] _D 7-10.5 (C = 1, H ₂ O). MS (ES): m / z 546 (M + H) ⁺ t ^{+ 1} H-NMR (400 MHz, DMSO-d6): δ 0.9 (t, 3H), 1.15 (m, 4H) gb ^at 1.25-1.5 (m, 12H), 1.6-1.75 (m, 6H), 2.15 (m, 1H), 2.75. (bq, 4H). 3.0 (m, 2H), 3.15 (bd, 4H), 3.25 ( _m , 1H), 3.45 ( _m , 1H), 3.7 (dq, 2H), 3.95 (m, 1H), 7.6, (d, 1H), 8.05 (t, 1H, 1H), 8.15 (t, 1H), 8.85 (bq, 2H); M / z (bd, 2H).

Example 39:. '

2 - {[(4-methylphenyl) sulfonyl] amino} 3 - {[2 - ({4- (4-piperidyl) -2- (2- (4-piperidyl) ethyl) butanoyllamino) acetyl] amino} propanoic acid dihydrochloride (CRL43033 )

Starting material: Compound 52

Yield = 87%

MS (ES): m / z 580 (Μ ⁺ H) ^* H-NMR (400 MHz, DMSO-d₆) δ 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.4 (s, 3H),

2.75 (bq, 4H), 3.15 (bd, 5H), 3.35 (m, 1H), 3.55 (dq, 2H), 3.8 (q, 1H), 7.35 (d 1 H, 7.7 (d, 2H), 8.0 (t, 1H), 8.05 (t, 1H), 8.1 (d, 1H), 8.8 (bq, 2H), 9.1 (bd, 2 H).

Example 40:

2 - {[(3-methylphenyl) sulfonyl] amino} 3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanoic acid dihydrochloride (CRL43043)

Starting material: Compound 53

Yield = 99%

MS (ES): m / z 580 (Μ ⁺ H) ^* H-NMR (400 MHz, DMSO-d₆) δ .: 1.1 (m, 4H), 1.25 (m, 6H), 1, 4 (m, 4H), 1.7 (bd, 4H), 2.1 (m, 1H), 2.35 (s, 3H), 2.7 (bq, 4H), 3.15 ' (bd, 5H), 3.3 (m, 1H), 3.5 (dq, 2H), 3.8 (m, 1H), 7.4 (m, 2H), 7.55 (m, 2H) ), 8.0 (m, 2H), 8.15 (d, 1H), 8.8 (bq, 2H), 9.1 (bd, 2H).

Example-41:

2 - [(Benzylsulfonyl) amino] -3 - {[2 ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanoic acid dihydrochloride (CRL43055) • Default Compound 54 Yield = 99%

MS (ES): m / z 580 (Μ + H) ^{+ 1} H-NMR (400 MHz, DMSO-d 6): δ 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H),

3.15 (bd, 4H), 3.35 (m, 1H), 3.45 (m, 1H), 3.7 (d, 2H), 3.95 (m, 1H), 4.35 (s) (2H), 7.35 (m, 5H), 7.6 (d, 1H), 8.1 (t, 1H), 8.15 (t, 1H), 8.85 (bq, 2H), 9 1 (bd, 2H).

Example 42:

2 - ({[(E) -2-phenylethenyl] sulfonyl) amino) -3 - {[2- ({4 - '(4-piperidyl) -2- [2 (4-piperidyl) ethyl] butanoyl]] dihydrochloride } amino) acetyl] amino} propane (CRL43057)

Starting material: compound Yield = 100%

MS (ES): m / z 592 (M + H) ^{+ 1} H-NMR (400 MHz, DMSO-d6): δ

1.45 (m, 4H), 1.75 (bd, 4H), 3.15 (bd, 4H) , 3.3 (m, · IH) (m, IH), 7.15 (d, l.H), 7.35 2H), 7.9 (d, IH), 8.1 ( m, 2P

1.15 (m, 4H), 1.3 (m / 6H),

2.15 (m, 1H), 2.75 (bq, 4H),

3.45 (m, 1H), 3.65 (m, 2H), 3.9 (d, 1H), 7.4? (M, 3H), 7?, 7 (m, 1H);

8.9 '(bq, 2H), 9.15 (bd, 2H).

Example 43:

2 - [(2-Phenethylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] propanoic acid dihydrochloride (CRL43056)

Starting material: Compound 56

Yield = 96%

MS (ES): m / z 594 (Μ ⁺ H) ^* H-NMR (400 MHz, DMSO-d₆) δ 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H), 1, 7 (bd, 4H), 2.15 (m, IH), 2, 75 (bq, 4 H), 2.95 (m, IH), 3, 1 (m, IH), 3.15 (bd, 5H), 3, Δ (m, 2H), 3.5 (m, IH), 3.7 (m, 2H), 4.05 '(m, 1H), 7 , 3 (rr 1, 5H), 7.8 (d, IH); 8.1 (m, 2H) , 8.9 (bq, 2H), 9.15 (bd, [0100] 2H ) ·

• • · • • e • · • · • «A and • • · and a and a • • · · • aaa a and a • • a • and a and a • · · • a • • ·

Example 44:

2 - ({[3- (trifluoromethyl) phenyl] sulfonyl} amino) -3 - {[2 - ((4- (4piperidyl) ethyl) butanoyl} amino) acetyl] aminopropanoic acid dihydrochloride (CRL43058)

Starting material: Compound 57

Yield = 93%

MS (ES): m / z 634 (Μ + H) ^{+ 1} H-NMR (400 MHz, DMSO-d 6): δ 1.15 (m, 4H), 1.3 (m, 6H), 1, 4 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.2 (bd, 5H), 3.4 (m, 1H) ), 3.6 (dq, 2H), 3.95 (m, 1H), 7.85 (t, 1H), 8.0 (d, 1H), 8.05 (m, 4H), 8.6 (t, 1H); 8.85 (bq, 2H);

9.1 (bd, 2 H).

Example 45:

2 - {[(3-nitrophenyl) sulfonyl] amino} 3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] propanoic acid dihydrochloride ( CRL43059)

Starting material: compound 58

Yield = 90%

MS (ES): m / z 611 (M + H) &lt; + &gt; (400 MHz, DMSO-d _6): δ 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, (4H),

3.2 (bd, 5H), 3.35 (m, 1H), 3.6 (dq, 2H), 3.9 (m, 1H), 7.9 (t, 1H), 8.1 (m, 2H), 8.2 (d, 1H), 8.45 (dd, 1H), 8.55 (s, 1H), 8.75 (d, 1H), 8.85 (bq, 2H), 9 1 (bd, 2H).

Example 46:

2 - {[(4-Methoxyphenyl) sulfonyl] amino} -3 - {[2 - ((4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] propanoic acid dihydrochloride · * · 99 9

9 9 9 9 ·· ((C (C · C4 (CRL43060)

Starting material: Compound 59

Yield = 95%

MS (ES): m / z 596 (Μ ⁺ H) ^* H-NMR (400 MHz, DMSO-d _6): δ 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1 H), 2.75 (bq, 4H), 3.2 (bd, 5H), 3.35 (m, 1H), 3.6 (dq, 2H), 3.8 (m, 1H), 3.85 (with, 3H), 7.1 (d, 2H) ), 7.7 (d, 2H), 8.05 (m, 3H), 8.85 (bq, F.  2H), (bd, 2H).

Example 47:

2 - [(8-quinolinylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] propanoic acid trihydrochloride (CRL43061) . 1

Starting material: Compound 60

Yield = 100%

MS (ES): m / z 617 (M + H) ^{@ +} Y ^{@ 1} H-NMR (400 MHz, DMSO-d _6): δ 1.15 (m, 4HJ, 1.25 (m, 6H), '

1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H),

3.2 (bd, 4H), 3.35 (m, 2H), 3.55 (dq, 2H), 4.25 (m, 1H),

7.75 (m, 3H), 8.0 (t, 1H), 8.1 (t, 1H), 8.3 (m, 2H), 8.6 (d, 1H), 8.9 (bd) 2 H, 9.1 (m, 1H), 9 (bd, 2H).

Example 48:

2 - {[(3,5-Dimethyl-4-isoxazolyl) sulfonyl] amino] -3 - {[2 - ((4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl) butanoyl)] dihydrochloride} amino) acetyl] amino] propane (CRL43068) '

Starting material: Compound 61

Yield = 85%

MS (ES): m / z 585 (M + H) ^{+ 1} H-NMR (400MHz, DMSO-d ₆ ): δ 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H); 1.75 (bd, 4H); 2.15 (m, 1H); 2.35 (s, 3H); * '· »., · · ·' · 4 '9 9 9 4.

- / Ζ. , '4 4' 4 4 '

.. · * · 4 '* · · ··· 9 9 ·, · ¹ · 9 4 4 4 4 4 t) 9 _t · »··· 4f>> 99 494

2.6 (s, 3H), 2.75 (bq, 4H), 3.2- (bd, 5H), 3.4 (m, 1H), 3.6 (dq, 2H), 3, 85 (m, 1H); 8.1 (t, 2H); 8.6 (d, 1H); 8.9 (bq,

2H), 9.15 (bd, 2H). ’

Example 49:

T. 2 - ({[5- (dimethylamino) -1-naphthyl) sulfonyl} amino) -3 - {[2 - ({4- (4-piperidyl) ethyl] butanoyl} hydrochloride amino) acetyl] amino) propane (CRL43069)

Starting material: compound 62

Yield = 100%

MS (ES) m / z, 659 (M + H) &lt; + & gt ^{;. 1} H-NMR. (4 00 MHz, DMSO-d6): δ 1.1 (m, 4H), 1.3 (m, 7H) , 1.45 (m, 4H) 1.7 (bd, 4H), 2.15 (m, 1H). 1H), 2.75 (bq , · 4Η), 3.2 (bs, 11H) , 3.35 ( m, 2H), 3.5 (q, 1H) , 3,9- (q, 1H) < ⁷ ' 75. (q. 2H), 7.9 (bs, 1 H) 7.95 (t, 1H), '' 8, 'O 5, (t _,? , ÍHj , .8,7 ( dd ·, ' 2H), 8.9 (bq, 2H) 9.15 (bd, 2H). ·. -

Example 50:. . ,: ‘

2 - ({[2- (Acetylamino) -4-methyl-1,3-thiazol-5-yl] sulfonyl} amino) -3 - {[2 - ({4- (4-piperidyl) -2- [ 2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propane (CRL43070)

Starting material: Compound 63

Yield = 100%

MS (ES): m / z 644 (Μ + H) ^{+ 1} H-NMR (400MHz, DMSO-d 6): δ 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H), 1.75 (bd, 4H) , 2.15 (m‘), 1H) .2.2 (s, 3Ή), 2.45 (with, 3Ή), 2.8 (bq, 4H), 3.2 (bd, 5H), 3.4 (m, 1H), 3.6 (dq, 2H), 3.9 (m, 1 H), 8 ,! (m, 2H) , 45 (d, 1H), 8.88 '(bq. 2H), 9.1 (bd, 2H).

Example-51:

2 - {[(3-chloropropyl) sulfonyl] amino} dihydrochloride

3 - {[-2- ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino) propane (CRL43078)

Starting material: Compound 64

Yield = 100%

MS (ES): m / z 566 (Μ + H) ^{+ 1} H-NMR (400 MHz, DMSO-d ₆ ): δ 1.15 (m, 4H), 1.25 (m, 6H),

1.45 (m, 4H), 1.75 (bd, 4H) 2.15 (m, 3H); 2.75 (bq, 4H); 3.15 (m, 7H), 3.45 (m, IH), 3.65 (m, 2H); 3.75 (t, 2H); 3, 95 (m, IH), 7.75 (d, IH), 8.1 (m, 2H), 8.8 (bq, 2H), 9.1 (bd, 2H)

Example 52:.

2 - {[(4-methoxy-1-naphthyl) sulfonyl] amino} -3 - {'[2- (4- {4-piperidyl) -2- (2- (4-piperidyl) ethyl] dihydrochloride butanoyl} amino) acetyl] amino (propane γ (CRL43079)).

Starting material: compound 65 '

Yield = 95% ·

MS (ES) m / z 646 (M + H) &lt; + & gt ^;. (m, 4H) 1.3 (m, 6H) ¹ H-NMR (400 MHz, DMSO-d 6):? δ 1,15 1.45 (m, 4H); 1.7 (bd, 4H) , 2,1 ( m, 1H), 2.75 (bq, 4H) 3.15 (bd, 5H); 3.3 (m, 1H) , 3.45 (dq, 2H), 3.8 (m, 1H) 4.05 (s, 3H); 7.1 (d, 2H); 7.60 ( t, 1H), 7.7 ( t, 1H), 7.9 (t; 1H) δ, 8.0 (t, 1H), 8.1 (d, 2H) 8.3 (d, 1H) , 8, .35 (d, 1H), 8.6 (d, 1H), 8.85 (bs , 2H), 9.1 (bs, 2H).  '.

Example 53:

2 - {[(6,7-Dimethoxy-2-naphthyl) sulfonyl] amino} -3 - {[2 - ({4- (4-piperidyl) ethyl] butanoyl} dihydrochloride} amino) acetyl] amino} propane (CRL43080) ·

Starting material: compound 66

Yield = 86%. ··

- 74 ♦ · .1 *

<· •.

· É * * * * * * * * * * * *

MS (ES): m / z 676 (Μ + H) ^{+ 1} H-NMR (400 MHz, DMSO-d ₆ ): δ 1.15 (m, 4H), 1.3 (m, 6H),

1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.35 (m 1 H, 3.55 (dq, 2H), 3.85 (m, 1H), 3.9 (s, 3H), 3.92 (s, 3H), 7.45 (s, 1H), 7 55 (s, 1H), 7.65 (d, 1H), 7.9 (d, 1H), 8.05 (bs, 2H), 8.20 (d, 1H), 8.25 (s, 1H), 1H), 8.85 (bq, 2H), 9.1 (bd, 2H).

Example 54:

2 - {[(2,4-Dimethyl-1,3-thiazol-5-yl) sulfonyl] amino} -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl)]] dihydrochloride ethyl] butanoyl} amino) acetyl] amino} propane (CRL43120)

Starting material: Compound 67

Yield = 94%

MS (ES): m / z 601 (M + H) ⁺ . ·.

¹ H-NMR (400 MHz, DMSO-d 6): δ 1.15. (m, 4H), 1.3 (m, 6H);

1.45 (m, 4H), 1.75 (bd, 4H), 2.15 '(m, 1H), 2.5 (s, 3H),

2.65 (s, 3H), 2.75 (bq, 4H), 3.2 (bd, 5H), 3.4 (m, 1H), 3.6 (dq, 2H), 3.9 (q 1 H, 8.1 (m, 2H), 8.7 (d, 1H), 8.9 (bq, 2H), 9.15 (bd, 2H).

Example 55:.

2 - {[(3,5-Dimethyl-1H-pyrazol-4'yl) sulfonyl] amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4- piperidyl) ethyl] butanoyl} amino) acetyl] amino} propane (CRL43121)

Starting material: Compound 68 Yield = 98%

MS (ES): m / z 584 (M_ ⁺ H) ^* H-NMR (400 MHz, DMSO-d _6): δ 1.15 (m, 4H), 1.25 (m, 6H),

1.4 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H), 2.3 (s, 6H), 2.75 (bq, 4H), 3.15 (bd) (5H), 3.3 (m, 1H), 3.6 (dq, 2H), 3.75 (m, 1H), 7.8 (d, 1H), 8.0 (bt, 1H), 8 1 (bt, 1H), 8.8 (bq,?)

, · ·. 9 ♦ 9 '· · 99 9' 9 9 9 9 9 9 · 9 9 .9 9 9 · · * 9 · '9999999 «9

9 9 9 rt 9 9 9

999 t »t 9-9 '# · Λ 99 9

2H), 9.15 (bd, 2H). > '' · \

Example 56:

2 - [(3-pyridylsulfonyl) amino] 3 - {[2 ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanoic acid dihydrochloride (CRL43122)

Starting material: compound 69

Yield = 69%.

MS (ES): m / z 567 (Μ ⁺ H) ^* H-NMR (400 MHz, DMSO-d₆): δ 1.1 (m, 4H), 1.3 (m, 6H), 1.45

(m, 4H), 1.7 (bd, 4H), 2.15 (m, IH), 2, 75 (bd, 4H), 3.15 (bd, 5H), 3.45 (m, 1Ή), 3.55 (dq , 2H) , 3/9 5 (q, 1H), 7.75 (t, 1H), 8.15. (bd, 2H), 8.35 (d, IH), 8,7 5 (d, IH),. 8.9 (bd, IH), 8'95 (bd (2H), 9.0 (with, IH.) ', 9.2 ' (bd / · 2H),

Example 57:. · '..', ', ·.,'

2 - [(1-, 3-Benzodioxol-5'-ylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4'-piperidyl)] dihydrochloride) ethyl] butanoyl} amino) acetyl] amino} propane (CRL'43123) '

Starting material: Compound 70

Yield = 91%

MS (ES): m / z 610 (Μ ⁺ H) ^* H-NMR (400 MHz, DMSO-d₆): δ 1.1 (m, _ 4H), 1.25 (m, 6H), 1 4 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.3 (m, 1H), 3.6 (dq, 2H), 3.75 (m, 1H), 6.1 (d, 2H), 7.0 (d, 1H), 7.2 (s, 1H). 7.25. (d, 1H), 8.05 (m, 3H), 8.75 (bd, 2H), 9.05 (bd, 2H).

Example 58: ·

2 - [(2,3-dihydro-1,4-benzodioxin-6ylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) ethyl] -2- [2- (4-piperidyl) ethyl] butanoyl] dihydrochloride (amino) acetyl] amino} propane

- 7 6 • * 9 · '· · ·. · · · ·: ·:: 9::::::::::::::: »· <* - 9 · 9 · · ··· ··· · · <; «· ···

LIS (CRL43124)

Starting material: compound

Yield = 91%

MS (ES): m / z 624 (Μ + H) ^{+ 1} H-NMR (400 MHz, DMSO-d ₆ ): δ 1.1 (m, 4H), 1.3 (m, 6H), 1, 4 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.3 (m, 1H) ), 3.6 (dq, 2H), 3.75 (q, 1H), 4.3 (dd,

2H), 6.95 (d, 1H), 7.2 (d, 1H), 7.22 (s, 1H), 8.05 (m, 3H),

8.85 (bq, 2H); 9.1 (bd, 2H).

Example 59:

2 - [(1-Benzothiophen-2-ylsulfonyl) amino] -3 - {[2 - ((4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino acid dihydrochloride } propane (CRL43125) ''.> - '

Starting material: Compound 72

Yield = 99%. - / ·

MS (ES): mlz 622 (M + H) ⁺ -. '· / .. *' ^X H-NMR (400 MHz, DMSO-d₆) δ ϊ, 1 (m, 4H), 1.25 (m ,. 6H) _S 1.4

(m, ... 4H), 1.7 '(bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H) 3.15 (bd; 5H) 3.3 (m, 1H), 3.45 (dq, 2H), 3.9 (q, 1H), 7 , 5 (m, 2H) 8.0 (m, 2H) 8.1 (d, 1H), 8.2 (d, 1H) , 8.45 (s, ÍH), 8.55 (d, (H), .8,9 (bq, 2H), 9.15 (bd, 2H).

Example 60:

2 - ([(2,5-Dimethyl-3-furyl) sulfonyl] amino} -3 - {[2 - ((4- (4-piperidyl) ethyl) butanoyl} amino) dihydrochloride acetyl] amino [propane (CRL43131). ·

Starting material: Compound 73.

Yield = 99%

MS (ES): m / z 584 (M + H) ^{+ 1} H-NMR (400 MHz, DMSO-d 6): δ 1.15 (m, 4H), 1.3 (m, 6H), ·

1.45 * (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.25 (s, 3H),

• ai • « • • · »· ·· ' • • • 9 9 • 9 • · · · • · te « • »· • • • · ·. ♦ • · · • • • • ·

2.4 (s, 3H), 2.75 (bq, 4H), 3.2 (bd, 5H), 3.35 (m, 1H), 3.6 (dq, 2H), 3, Δ (m, 1H), 6.2 (s, 1H), 8.05 (m, 3H), 8.8 (bq, 2H), 9.05 (bd, 2H).

Example 61:

2 - {[(4-Cyclohexylphenyl) sulfonyl] amino) -3 - {[2 - ({4- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino dihydrochloride } Propane (CRL43132)

Starting material: compound 74

Yield = 94%.

MS ( ES): m / z 648 (M + H) ^{+ 1} H-NMR (400 MHz, _'DMSO-d6 0: δ 1.0 ~ 1.5 (m, 19H) , 1.75 (m, 8H), 2.15 (m, 1H), 2.6 (bt, 1H), 2.75 (bq, 4-H) , 3.2 (bd, 5H), 3.35 (m, 1H), 3.5 (dq, 2H), 3.8 iq / IH) 7.15 (dr 2H), 7.7 (d, 2H); 7.98 (t, 1H), 8.04. (', IH) 8, i '(d , IH 8.8 (bq, 2H) 9.05 (bd, 2H) • - · '

Example 62: ·

2 - {[(4-fluoro-1-naphthyl) sulfonyl] amino}} - 3 - {[2- ({4- (4-piperidyl) ethyl] butanoyl} amino) acetyl dihydrochloride ] amino} propane (CRL43133)

Starting material: Compound 75

Yield = 90%

MS (ES): m / z 634 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.1 (m, 4H), 1.25 (m, 6H), 1.4 (m, 4H), 1.7 (bd, 4H), 2.1 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.3 (m, 1H), 3.5 (dq, 2H) , 3.85 (q,  IH) 7.5 (t, 1H), 7.8 (m, 2H), 8.0 (m, 2H), 8.15 (m, 2H) , 65 (d, 1Η) _ς 8.7 (d, 1H); 8.8 (bq, 2H); 9.05 (bd, 1H); 2H).

Example 63:

2 - {[(4-chloro-1778) acid dihydrochloride

• » • • · • ¹ • · • • • • • »· • · ’ « • • • • · • · . ·  · · · • • 9 • • • β · «· · t · · * • · • · ·

naphthyl) sulfonyl] amino} -1-] [2 - ({4- (4-piperidyl) -2- (2- (4 *, piperidyl) ethyl] butanoyl} amino) acetyl] amino} propane (CRL43134)

Starting material: Compound 76

Yield = 91%

MS (ES): m / z 650 (Μ + H) ^{+ X} H-NMR (400 MHz, DMSO-d₆): δ 1.1 (m, 4H), 1.25 (m, 6H), 1, 4 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.35 (m, 1H), 3.5 (dq, 2H), 3.85 (q, 1H), 7.85 (m, 3H), 8.0 (m, 2H), 8.1 (t, 1H), 8, 75 (m, 4H) .9D (bd, 2H).

Example 64:

2 - [(2,3-Dihydro-1-benzofuran-5-ylsulfonyl) amino] -3 - {(2 - ({4- (4-piperidyl) ethyl) butanoyl] dihydrochloride } amino) acetyl] amino} propane (CRL43142)

Starting substance: Compound · 77 -,. Recovery = 94%? MS (ES): m / z 608 (M + H) &lt; + &gt;

^r H NMR ((400 MHz, DMSO-d₆) δ 1 .1 (m, 4H) · 1.25 (m, 6H), 1.4

(m, 4H), 1.7 (bd, 4H) > 2.15 (m, TH), 2.75 (bq, 4H), 3.2 (m, 7H), 3.3 (m, IH), 3.6 (dq, 2H), 3.75 (q, 1H), 4.65 (t, 2H) 6, 9 (d, IH) 7.52 (d, 1H), 7.6 (s, 1H), 8.0 (, d, IH) , 8.05 (t, 1H), 8.10 (t, 1H), 8.85 (bq, 2H), 9.1 (bd, 2H).

Example 65:

2 - ({[4- (2-Thienyl) phenyl] sulfonyl} amino) 3 - {[2 - ({4- (4-piperidyl) ethyl] butanoyl} amino) dihydrochloride acetyl] amino (propane (CRL43143) ''

Starting material: compound 78

Yield = 66%

MS (ES) m / z 648 (M + H) &lt; + & gt ^;.

- 79. ¹ H-NMR (400 MHz, DMSO-d 6) δ 1.1 (m; 4H), 1.25 (m, 6H), ·

1.35 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.1 (bd, 5H), 3.3 ( m, 1H), 3.55 (dq, 2H), 3.85 (m, 1H), 7.2 (bs, 1H), 7.65 (bs, 2H), 7.75 (dd, 4H) 8.05 (m, 2H); 8.30 (d, 1H); 8.85 (bq, 2H); 9.1 (bd, 2H).

Example 66:

2 - ({[2- (2-Thienyl) phenyl] sulfonyl} amino) 3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl)) ethyl] dihydrochloride] butanoyl} amino) acetyl] amino} propane (CRL43144)

Starting material: compound 7 9

Yield = 97%

MS (ES): m / z 648 (Μ + H) ⁺ / H-NMR (400 MHz, DMSO · d _6): δ-1 .1 (m, 4H), 1.25 (m, 6H) 1.4 (m, 4H), 1.7 (bd, -4H), 2.1 (m, 1H),. 2.75 / (bq, 4H), 3 / 15- (bd, 4H), 3.3 (m, 1H), 3.35 (rh _of 1H), 3.65. (dq) 2H), 3.8 (q, 1H), 7.1 (t, 1H), 7.35 (d, J), 7.5 (d, 2H). 7.6 (m, 3H), 7.85 (d, 1H), 8.0 (d, 1H), 8.1 (m, 2H), 8.8 (bq, 2H), 9.1 (bd) 2H).

Example 67:

2 - ({[4- (2-Furyl) phenyl] sulfonyl} amino) -3 - {[2 - ((4- (4-piperidyl) ethyl) butanoyl) dihydrochloride} amino) acetyl] amino} propane (CRL43146).

Starting material: Compound 80

Yield = 84%

MS (ES): m / z 632 (M + H) ^{+ 1} H-NMR (400 MHz, DMSO-d ₆ ): δ 1.1 (m, 4H), 1.25 (m, 6H),

1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.2 (bd, 5H), 3.35 (m 1H, 3.6 (dq, 2H), 3.85 (q, 1H), 6.7 (d, 1H), 7.2. (d, 1H), 7.8 (d, 2H), 7.85 '(m, 3H), 8.1 (m,

2H), 8.25 (d, 1H), 8.85 (bq, 2H), 9.1 (bd, 2H).

'i' - ·

Example 68:

2 - [(1-Benzofuran-2-ylsulfonyl) amino] -3 - {[2 - ((4- (4-piperidyl) ethyl) butanoyl} amino) acetyl dihydrochloride ] amino] propane (CRL43147)

Starting material: Compound 81

Yield = 94%

MS (ES): m / z 606 (M + H) ^{+ 1} H-NMR (400MHz, DMSO-d 6): δ 1.1 (m, 4H), 1.2 (m, 6H), 1.4

(m, 4H.),. 1.75 (bd, 4H) 2.15 (m, IH) , 2, 75 (bq, 4H) 3.15 (bd, 5H), 3.5 (m, IH), 3.55 (dq, 2H) , 4, 05 / (m, 1H), 7.4 (t, IH), 7.5 (m, 2H), 7.7 (d, 1H) , 75 (d, IH) 8.05 (bs, 2H); 8.8 (bd, 3H), 9.1 (bd, 2H).

Example 69:

2 - {[(2'-naphthylmethyl) sulfonyl] amino} -3 - {[2 - ({4- (4-piperidyl) ethyl] butanoyl} amino) acetyl dihydrochloride ] amino} propane (CRL43158)

Starting material: Compound 82 ^'r

Yield - 8 8%

MS. (ES): m / z 630 (M + H) ^{+ 1} H-NMR (400 MHz, DMSO-d 6): δ 1.2 (m, 7H), 1.45 (m, 4H), 1.7

(m, 4H), ' 2.15 (m, 1H), 2.75 (bq, 4H), 3.1 (bd, 4H), 3.4 (m, 2H), 3.7 (d, 2H), 4.05 (q, 1H), 4.5 (with, 2H), 7.55 (d _r 2H) 7.65 (d, 1H), 7.95 (m, 4H), 8.05 (t, IH) , 8.1 (t, 1H), 8.6 (bq, 2H), 8.85 (bd, 2H).

Example 70:

2 - [(2,3-Dihydro-1H-inden-5-ylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) dihydrochloride dihydrochloride ) acetyl] amino} propane (CRL43159) • - 31 -

Výchozí · Starting substance :. Compound 83 .1- * * '’

Yield = 94% · ''

MS (ES): m / z 606 (M + H) ^{+ 1} H-NMR (400MHz, DMSO-d 6): δ 1.15 (m, 4H), 1.25 (m, 6H),

1.4 (m, 4H) 1.7 (bd, 4H), 2.05 (m, 2H), 2.15 (m, 1H), 2.75 (bq, 4H), 2, 9 (t, 4 H), 3.15 (bd, 5H); 3.35 (m, 1H) , 3,5 (dq, 2H), 3 Δ (q, 1H) 7.4 (d, 1H); 7.55 (d, 1H); 7.6 (s, 1H), 8.0 (m, 4H), 8.75 . (bq, 2H), 9.0 (bd, 2H).

Example 71:

2 - {[(5-phenyl-2-thienyl)) sulfonyl] amino} -3 - {[2 - ({4- (4-piperidyl) ethyl] butanoyl} amino) acetyl dihydrochloride ] aminopropane (CRL43160) '

Starting material: Compound 84 in

Yield = 97%. ', \. . ''^L; ·

MS (ES): m / z 648 ([+] -) ⁺ -, 1 '/ ··'. · .. ·· '

1 H-NMR (400 MHz, DMSO-d 6): δ 1.1 (m, 4H), 1.25 (m, 6H), 1.4 (m, 4H), 1.7 (bd, 4H) 2, 15 (m, 1H), 2.75 (bc, 4H), 3.15 (bd, 5H), 3.4 (m, 1H), 3.6 (dq, 2H), 3.95 (q, 1H), 7.4 '(m, 3H), 7.55 (s, 2H), 7.75 (d, 2H), 8.05 (bs, 2H), 8.55' (d,

1H), 8.85 (bq, 2H), 9.1 (bd, 2H) ’

Example 72:.

2 - [(5,6,6,7,8-tetrahydro-2-naphthalenyisulfonyl) amino] 3 - {[2 - ([4- (4-piperidyl) ethyl] butanoyl} amino] dihydrochloride Acetyl] aminopropane (CRL43161).

Starting material: Compound 85 - Yield - 97%

MS. (ES): m / z = 620. (M + H) ⁺ .

@ 1 H-NMR (400 MHz, DMSO-d6): .delta.1.1. (m, 4H), 1.25 (m, 6H),

1.45 (m, 4H), 1.75 (bs, 8H), 2.15 (m, 1H), 2.75 (bs, 8H), 3.2 (bd, 5H), 3.35 (m) , 1H), 3.55 (dq, 2H), 3.8 (q, 1H), 7.2 »99 * ·· '* - · 9' · * · · '·' · 9 *. (D, 1H), 7.45 (d, 2H), 8.0 (m, 3H), 8.75. (bq, 2H)., 9.0 (bd,

2H). · '· _T ^: '

Example 73:

2 - {[(E) -1-pentenylsulfonyl] amino} 3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] dihydrochloride Propane (CRL43176)

Starting material: Compound 86

Yield = 93%

MS (ES): m / z 558 (M + H) ^{+ 1} H-NMR (400 MHz, DMSO-d 6): δ 0.9 (t, 3H), 1.15 (m, 4H),

1,25 (m, 6H), 1.45 (m, 6H), 1.75 (bd, 4h; 1, 2.15 (q, 3H), 2.75 (bq, _4H) , 3.2 (bd, 5H) of 3.4 ~ 3, 75 (m, 4H) 6.3 (d, ÍH), 6, 5 (dt, ÍH), 7.65 (d, MH), • 8.0 (t, (IH) 8, 1, (t of · 1Η) ζ 8.75 (bq, 2H) , 9.0 (bd, 2H) •

Example 74: '· · ·

2 - [(Cyclohexylsulfonyl) amino] -3 ([2 - ({4- (4-piperidyl) -2- [2- (4- 'piperidyl) ethyl] butanoyl} amino) acid] amino} propanoic acid dihydrochloride' ( CRL43190)

Starting material: compound 30

Yield = 93%.

MS (ES): m / z -572 (M + H) ₊ , ¹ H-NMR (400 MHz, DMSO-d 6): δ 1.05 -1.40 (m, 15H), 1.45 ( m, 4H), 1.60 (bd, 1H), 1.75 (m, 6H), 2.0-2.25 (m, 3H) _, 2.75 (bq, 4H), 2.85 (m) (1H), 3.15 (bd, 4H), 3.25 (m, 1H), 3.45 (m, 1H), 3.70 (m, 2H), 3.95 (m, 1H), 7 Δ (d, 1H), 8.10 (m, 2H), 8.85 (bd, 2H), 9.1 (bd, 2H).

Example 75:

2 - [(isopropylsulfonyl) amino] -3 - {[2 ({4- (4-piperidyl) -2- [2- (4- 83)]], ··; 9 · · ·· · '·..' · · · '·· · · · • _»r», ·,. · ····' 9 · · ·

9 ·· ··· »· ·. 'Piperidyl) ethyl] butanoyl} amino) acetyllamino} propane (CRL43191)'

Starting material: compound 31

Yield = 97%

MS (ES): m / z 532 (M + H) ⁺ Ή NMR (400 MHz, DMSO-d _6): δ 1.1 ~ 1.35 (m, 16H), 1.45 (m, 4H 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.1 (m, 1H), 3.2 (bd, 4H), 3.3 (m, 1H), 3.45 (m, 1H), 3.70 (m, 2H), 3.95 (m, 1H), 7.5 (d, 1H), 8.05 (t, 1H) 8.10 (t, 1H), 8.8 (bq, 2H), 9.05 (bd, 2H).

Example 76:

2 - [(1,3-benzothiazol-2-ylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] propanoic acid dihydrochloride ,. (CRL43194) · - '-. 'V

Starting material: Compound 32 '' '. '

Yield = 98%> '' '... *' '.

MS (ES): m / z 623 (Μ + H) ⁺ 1 H-NMR (400 MHz, DMSO-d ₆ ) δ 1.15 (m,: 4Ή), 1, 30 (m, 6Ή), 1.45 (m, 4H), 1.70 (m, 4H), 2.15 (m, ÍH), 2.75 (bd, 4H), 3.15 (bd, 4H); 3.25 (m, 1H), 3.60 (m, 3H), 4.20 (q, 1H), 7.70 (m, 2H), 8.05 (bd, 2H), 8.20 (d, ÍH), 8.30 (d, 1H), 8.90 (bd, 2H); 9.20 (bd, 2H), 9.25 (d , ÍH) ý

Example 77:

(2S) -2 - {[(Benzyloxy) carbonyl] amino} -3 - {[3 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) propanoyl] dihydrochloride amino} propane (CRL43022)

Starting material: compound 33

Yield = 88%

MS (ES): m / z 574 (Μ ⁺ H) ^* H-NMR (400 MHz, DMSO-d _6): δ 1.10 (m, 4H), 1.25 (m, 6H),

8.4 1.45 (m, 4H), 1.75 (bd, 4H), 2.05 (m, 1H) / 2.25 (r, 2H),. 2.75 (bq, 4H), 3.15 (bd, 6H), 3.3 (m, 1H), 3.45 (m, 1H),

4.1 (m, 1H), 5.05 (s, 2H), 7.35 (s, 5H), 7.55 (d, 1H), 7.95 (t, 1H), 8.15 (t 1H, 8.95 (bq, 2H), 9.15 (bs, 2H).

Example 78:

2 - [(2-naphthylsulfonyl) amino] -3 - {[3 ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) propanoyl] amino} propanoic acid dihydrochloride (CRL43021)

Starting material: Compound 87

Yield = 84%

MS (ES): m / z 630 (M + H) ⁺

¹ H-NMR ( 400 MHz, DMSO-d _6): No i 1.05 (m, 4H) 1.25 (m, 6H); 1.40 (m, 4H), 1.75 (bd, 4H) , 2.05 (m , - 3H 2.75 '(bq, 4H); 3.15 (m, 7H), 3.3 (m, 1H); 3.95 (q, IH), 7/7 (m, 2 H), 7.8 (d, IH) 7.9 (t, 1H), 8.05 (d, IH) 8/1 (m, 3H), 8.3 (d, 1H), 8.4 (s, 1H), 9.0 (bd, 2H), 9.25  (bd , 2H). Example 79:

2 - [(phenylsulfonyl) amino] -3 - {[3- ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) propanoyl] amino] propanoic acid dihydrochloride (CRL43145)

Starting material: Compound 88

Yield = 86%

MS (ES) m / z 580 (Μ + H) ^{+ 1} H-NMR (400 MHz, DMSO-d ₆ ): δ 1.05 (m, 4H), 1.25 (m, 6H),

1.40 (m, 4Ή), 1.70 (bd, 4H), 2.05 (m, 1H), 2.1 (q, 2H),

2.75 (bq, 4H), 3.15 (m, 1H), 3.30 (m, 1H), 3.85 (q, 1H) / 7.55 (m, 3H), 7.8 (d 1.5) / 7.9 (t, 1H) 8.1 (t, 1H) / 8.25 (d, 1H), 8.9 (bd, 2H), 9.10 (bd, 2H).

Example 80:.

2 - [(2-Naphthylsulfonyl) amino] -3 - {[3 ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) butanoyl] amino} propanoic acid dihydrochloride (CRL43195 )

Starting material: compound 34

Yield = 100%

MS (ES): m / z 644 (Μ + H) ^{+ 1} H-NMR (400 MHz, DMSO-d ₆ ): δ 0.9 (d, 3H), 1.05 (m, 4H), 1, 25 (m, 6H), 1.40 (m, 4H), 1.70 (m, 4H), 1.95 (m, 1H), 2.00 (m, 1H), 2.15 (dd, 1H), 2.75 (bq, 4H), 3.05 (m, 1H),

3.20. (bd, 4H), 3 ', 35 (m, 1H), 3.95 (m, 2H), 7.70 (m, 3H),

7.8 (d, 1H), 8.05 (m, 2H), 8.10 (dd, 2H), 8.30 (d, 1H), 8.35 (s, 1H), 8.75 (d, 1H); bt, 2H), 9.0 (bd, 2H).

•, 'A ^1. ··

Example '81: - /. .. '.

2- [2- (2-naphthylsulfonyl) amino] -3 - {[3-phenyl-3 - ({4- (4-piperidyl) -2- [2- (4-methyl) -pyridine]] dihydrochloride dihydrochloride. _'t piperidyl) ethyljbutanoyl} amino) butanoyl] amino} propanoic acid (CRL43196).' · ,. - ¹ - ', · </. starting material: compound 35' * '/

Yield = 87%

MS (ES): m / z 706 (M + H) ^{+ 1} H-NMR ^I (4.00. MHz, DMSO-d ₆₎ δ 1.00 .1,40 (m, 4H), 1.65 (dd, 4H), 2.10 2.75 (bd, 4H), 3.00- (m, 1H), 3.10 3.75 (m, 1H), 3.98 (q, 1H), 7, 25. 7.80 '(m, 1H), 8.00 (t, 1H), 8.10. 8.45 (d, 1H), 8.48 (m, 1H), 8.75 (m, 4H), 1.25 (m, 6H); (m, 1H), 2.40 (m, 1H),. (bs, 4H), 3.25 (m, 1H), (m, 5H), 7.65 (m, 2H); (m, 3H), 8.30 (t, 1H), (bt, 2H); 9.05 (bt, 2H) Example 82 :.

2 - [(2-naphthylsulfonyl) amino] -3 - {[((3R) -1- {4- (4-piperidyl) -2- [2- (4'-piperidyl) ethyl] butanoyl}} dihydrochloride hexahydro-3-pyridyl) carbonyl] amino} propane (CRL43197)

^Γ · · · * * * * «« ««

Starting substance: Compound 36 ·

Yield = 93% ·

MS (ES): m / z 670 (M + H) ^{+ 1} H-NMR (400MHz, DMSO-d 6): δ 1.05 (m, 4H), 1.25 ~ 1.60 (m, 14H) 1.73 (bt, 4H); 2.00 (m, 1H); 2.45 (m, 1H); 2.75 (m, 1H);

6H), 3, 10 (m, 5H), 3.35 (m, IH) , 3.90 (m, 2H), 4.30 (dd, IH), 7.70 (m, 2H), 7.80 (m, IH) , 8.00 (m, 1H), 8.10 (m, 3H), 8.40 (m, 2H), 8.85 ~ 9, 25 (m, 3H)

Example 83:

2 - [(2-naphthylsulfonyl) amino] -3 - {[2-phenyl-2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) ethanoyl] amino acid dihydrochloride } Propane (CRL43210) -, ',

Starting material: Compound 91 '. ₄ 1

Yield = 94% ·

@ ¹ H-NMR (400 MH: z, DM SO -dg) : δ 0], 95 (m, - IH), !, 0 ^1.5 (m, 13H) , 1.60 (bd , 2H) t 1.7 O (bd, 2H) ), '2 / 35 ( m, 1H ) 2, 70 (m, 4H), 3, 15 (m, 5H), 3, 25 (m, 1Ή). 3.95 (m, IH), 5.50 (t, IH), 7.25 (m, 5H), 7, 65 (m, 2H) 7.80 (d, IH), 8.01 (d, IH), 8, 10 (m, IH), 8, 15 Dec (d, IH) 8.30 (q, IH), 8.40 (with, IH), 8.50 (t, 2H), 8, 75 (bs, 2H) 9.0 0 (bs , 2H) •

Example 84:

2 - [(2-naphthylsulfonyl) amino] -3 - {[2 ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) propanoyl] amino} propanoic acid dihydrochloride (CRL43214) .

Starting material: compound 92

Yield = -89% .....

1 H-NMR (400 MHz, DMSO-d ₆ ): δ 1.00 (d, 3H), 1.08 (m, 4H), 1.27 (m, 6H), 1.42 (m, 4H), 1.70 (bd, 4H), 2.12 (m, 1H),

2.73 (bd, 4H), 3.00 (m, 1H), 3.20 (bs, 4H), 3.48 (m, 1H), 3.89, (q, 1H), 4, 18 (t, 1H), 7.65 (m, 2H), 7.82 (d, 1H),

7.95 (d, 1H), 8.06 (d, 2H), 8.15 (q, 2H), 8.35 (d, 1H),

8.40 (s, 1H), 8.85 (m, 2H), 9.10 (bs, 2H).

Example 85:

2 - ({[(7,7-Dimethyl-2-oxobicyclo [2.2.1] hept-1-yl [methyl] sulfonyl} amino) dihydrochloride) -3 - {[2 ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino [propane (CRL43215)

Starting material: compound 89

Yield = 90% -

¹ H-NMR (400MHz, DMSO-d 6): δ 0.80 (s, 3H) (with, 3H), 1.15 (m, 4H), 1.30 (m, 6H), 1.45 (m, 6H) 1.75 (bd, 4H), 1.90 (m, 2H), 2.05 (t, 1H), 2.15 (m, 1H), 2.35 (m, 2H), 2.75 (bq, 4H), 3.05 (d, 1H), 3.20 (bd, - 4H). 3.30 (m , IH), 3.35 (d, 1H), 3.50 (m, 1H), 3 ', 70 (dq, 2K) ', 4.00 . (m, -1 ») / 7.65 (d, 1H), 8.10 (m, 2H), 8.85%. (bs, 2H) 9.10 (bs , 2H).

Example 86: ' ₍

Acid dihydrochloride. (2R) -2 - [(2-naphthylsulfonyl) amino] -4 3 {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl [amino] acetyl] amino [propane (CRL42956)

(2R) -3 - ({2- ['(4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl [butanoyl] acid Amino] acetyl [amino] -2 - [(2-naphthylsulfonyl) amino] propane (compound 90) (8 g, 9.8 mmol) was dissolved in 30 mL ethyl acetate and then added at room temperature 150 mL. 3N ethyl acetate hydrochloric acid. Stirring was continued for 40 minutes and then ethyl acetate was added. Drying in vacuo gave a white powder. After addition of 500 ml of water, 5.92 g of a white solid was obtained by lyophilization.

Yield = 98% '·

[Α] _D + 9.5 (C = 0.15., H ₂ O) MS (ES): m / z 616 (Μ. + H) ⁺

¹ H-NMR (400 MHz, DMSO-) -d ₆ ): δ 1,1 (m, 4H), 1, 25 (m, 6H), 1, 45 (m, 4H), 1.7 (m, 4H) , 2.15 (m, IH), 2, 75 (bd, 4H) , 3.2 (bd, 5H), 3.4 (m, 1H) , 3, 55 (dq, 2H) , 3, 95 (q. IH) , 7, 7 (m, 2H), 7.8 (d, 1H), 8.0 (m, 3H), 8 , 15 (dd, [0100] 2H ) 8.35 (d, IH), 8.4 (s, 1H), 8.7 (bs, 2H) , 8.95 (bd, 2H)

Investigation of the platelet aggregation inhibitory activity of the compounds of formula I was performed in vitro, i.e. by direct contact of solutions of various concentrations of compounds with platelets freshly separated from a blood sample taken from standard animals from guinea pigs and healthy human subjects. who did not receive substances or drugs that could affect blood clotting. Anti-platelet aggregation activity (anti-aggregation activity) was also determined ex vivo / in vitro, i.e. after administration of the claimed compounds to guinea pigs to measure the intensity and duration of anti-aggregation activity induced by the proportion of test products absorbed and / or circulating in the blood.

AND

1, In vitro pharmacological studies

1.1. Guinea pig platelet tests

Blood was collected by intra-cardiac puncture of male Dunkin-Hartley guinea pigs. (about 330 g) in an amount of 4.5 ml per 0.5 ml of trisodium citrate (aqueous solution concentration: 1.55%) to completely prevent precipitation. Platelet-rich plasma (PRP) was obtained by centrifuging whole blood tubes for 15 minutes at 150 g.

- '89

4 »

The PRP samples were collected as a 'pool'. The platelets contained in the pool were counted using a Coulter ZM hematology automatic device: dilution was performed, if necessary, to achieve platelet plasma concentrations between 200,000 and

400 000 plates / mm ³ . Similarly, other samples from the pool were used to prepare platelet-poor plasma (PPP) by centrifugation at 1500 g for 15 minutes.

Kinetic studies of platelet aggregation were performed by adding a collagen solution (1 µg / ml) to the PRP volume using a Chronolog-Corporation (490-D1 or 560 VS) aggregometer using optical detection of thrombus occurrence.

The 50% inhibitory concentration (IC.50) was determined. performed by adding a given volume of solvent to the samples from the PRP (reference control) pools and increasing the concentration of the compounds to: 1.5 χ '10' ⁸ M, 7 χ 10 ^-8 M, 1.5 x 10 ' ⁷ M, 3 χ 10 ^{7 7} M, 7 χ ΙΟ ⁷ M, 1.5 x 10 ₍₍ ⁶ M and 7 χ 10 ⁵ M. Aggregation inhibition measurements were performed * after 3 minutes of contact at 37 ° C with agitation.

.1.2. Studies on human platelets

A group of ten healthy human subjects of the same age were sampled by venous puncture. in an elbow well and collected in a glass tube containing an aqueous 0.129 M sodium citrate solution (1 volume citrate solution per 9 volumes of blood). Each tube was then centrifuged first at 20 ° C and 100 g for 15 minutes to obtain platelet-rich plasma. (plasma-rich plasma - PRP); after removal of this PRP, the tube was centrifuged again at 2000 g for 15 minutes, this time to obtain platelet-poor plasma (PPP).

• * • ·· • • • · • '·  · · •. ·, · • • ' • · • ·· · • 9 • · • · • · · • · • · · ·· • > <· ·

Platelets were counted for each PRP sample identified using a Coulter ZM counter. Each sample was used to measure changes in the inhibition of aggregation of blood platelets initiated by addition of a solution of Chromo-par Reagent collagen glucose from Coultronics (used at a concentration of 5 pg (ml) as a function of adding increasing concentrations of each compound in a range covering the interval 10 ⁸ Μ - » 10 ' ⁵ M (examples of concentrations: χ ΙΟ ^-8 M, χ 10' ⁷ M, 3 χ 10 ' ⁷ M, 10' ⁷ M, 8 χ ΙΟ ' ⁶ Μ, β χ ΙΟ ^-6 M,' 4 χ ΙΌ ⁶ M, 2 χ ^{6 6} Μ, 10 ^{6 6} M, 5 χ ΙΟ ^{5 5} Μ, 10 ^{5 5} M) Prior to this, an aqueous 10 ^{3 3} M solution was prepared for each compound. solvents (reference value) on the platelet aggregation was carried out by 'each series of measurements and was done after' 3 minutes of contact at 37 ° C with stirring. · 'h' ·,. u _'.?. ..

From the measured percent inhibition. blood aggregation.

,. _with -s-platelets for each concentration of each compound the concentration of 50% inhibition (IC 50) was calculated.

2. Ex vivo / vitro pharmacology studies in guinea pigs

Evaluation of antiplatelet activity of compounds on platelets was performed by the same guinea pigs as above (Dunkin-Harteley breed) Administration of each product at doses ranging from 150 mg / kg to 10 mg / kg of each vehicle / 5 ml / kg (gastric rout - gr): 1, 2, 4, 6, 8 or 12 hours before blood collection from a fixed guinea pig. The distribution of treated animals was random. . '

Blood was collected and then processed under the same conditions as described above for in vitro studies.

The results of inhibition of platelet aggregation for each concentration tested allow for calculation

-. 92 ·· • · ·

·· • · «> y * · • · · ··· ι · · · · _• Λ.

• · «· ·· IC ₅₀ of each test product and the kinetics of the inhibitory effect and its duration.

The results are summarized in the following table:

Examples Compound CRL IC ₅₀ (M) in vitro g.r. 4 inhibition in guinea pigs .ex vivo Guinea pig Human a = iso mg / kg a = io mg / kg lh 2h lh 2h 6 42548 1.4x10'®. 2.7x10® -9 -4 7  42549 - IO ' ⁵ . -39 '0 - - 8 42590 3.5X10 * ⁵ 1.6X10 * ® -10 -31 - 29 42591 1.3x10 * ⁵ IC * ⁵ -35 -23 16. 42592 3.5x10 * ® 8.5X10 ' ⁷ -54 . -47 -5 5 7 '42630 ’ 2.0x10’® '2.8x10 * ⁷ -63 -66 .-15 9 42639 5.0x10'® -53 -5 - -, - 10 42660 ' 1.3X10 ' ⁵ 9.2X10 * ⁷ -14 -18 , - ♦ - 17 42 678 .7.4x10'® 6.0x10'® -19 - 12 42722 9.8x10 * ⁷ 1.5x10 * ® \ -74 -68 26 42724 4.4X10 ' ⁷ 5.3x10 * ⁷ '-77 -68 ' -41 ' -20. . 25 ' 42731 2.9x10 ⁵ - -33 -48 27 Mar: '42796 1.9x10'® 4.4x10 * ® - - - - 23 42811 ' 1.5x10’® 1.1x107® -73 -75 -18- - . 73 0 42913. 1.2x10 ' ⁷ 1.4x1 O * ⁷ -72 -67 - 31 42914 4.4x10 * ® 5.8X10 * ⁷ - .. -81 -81 32 42 9 69 'l .2x10' ⁵ -8 -8 33 42985 7. 1x10 * ⁷ 4.9x1 O * ⁷ -, -14 -5 34 42986 5 ,. Ox10 ⁷ 8.9X10 * ⁷ - - -19 -8 . 35 42999 1.8x10 * ® 1.3x10 * ® C- - , -5. o · 36 43000 4.1x10’® 7.2x10 * ® - - -63 -69 78 43 021 '. 4.6x10 * ® .. IO * ⁷ . , - - -65 -7-3 37 43031 1.4X10 * ⁷ 1..3-10 * ⁷ - - • -9 -16 '39 . 43033 7 .2.5x10 ' ⁷ - - - -32 -10-

- '· 92

9 ♦ 99 9 9 • • 9 9 9 9 9 * 9 9999 9 9 9 9 9 9 9 9

9 »9, 99

r —.......... , 15 43042 4.3x10’® 1.5X10 ⁷ -84 -26 40 43043 4.0X1Ó ⁷ - - - -32 -10 41 43055 8.6x10® - - - 13 1 46 43056 1.2x10’® - - - -15 -4 42 43057 , 4. 2x10 ' ⁷ - - -14 -26 44 43058 5. 1x10 ⁷ - - -22 -35 . 45 ' 43059 5. Ox10 ⁷ - - - -36 -51 46 43060 3. 8x10 ' ⁷ - - - -18 -31 47 43061 1.9x10 ⁶ - - - -4. -17 48 43068 4. 2x10 ⁷ - - - -61 -15 49 43069 4,9xl0 ⁸ 5.6xl0 ⁸ - - -69 -68 50 43070 3.3x10® ^; - - - -22 -39 51 43078 1.1X10 ⁵ - - '4 -21 '52 43079 3. 5x10 ' ⁸ 9.3X10 ⁸ -58. -30. 53 • 43080. 3.7x10 ' ⁸ 7.3X10 ⁸ - - -73 '-9 54 43120 l. * 3x10® - - - -.40 -15 55 43121 3.5x10® - - -21 -17 56 43122 2.3x10 ' ⁷ - - -61, -50 57 43123 8.3X10 ⁷ - - L  -, -38. --24- 58 43124 5.9x10 ' ⁷ _ · - r-  -36. - -21 59 43125 6.6x10 ⁸ 1.5X10 ⁷ - - -66. -34 '. 60 43131 6.6x1'O ' ⁷ - - -53 -32 61 43132 1.4x10 ⁶ - - -21 -9 62 43133. 9.5x10 ' ⁸ - - - -69 -33 63 43134 5.3xl0 ⁸ 10® - -69 -50 64 43142 3. 7x10 ' ⁷ - - -65 -5 '65 43143 2. Ox10 ⁷ - - -65 -12 66 43144 5x10 ⁷ - - - -18 0 68 43147 1.8X10 ' ⁷ - - -72 -71 69 43158 1.9X10® - - '- '-69 -3 70 43159 4. Ox10 ⁷ - - - -32 -34 71 43160 6.3X10 ⁸ 1.9X10 ' ⁷ - ” - -72 -70 ^: 72 43161 3.4x10 ' ⁷ - - - -60 -67

ί »

- 93

The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a salt thereof with pharmaceutically acceptable acids.

More particularly, the present invention provides compounds for inhibiting platelet aggregation comprising an effective amount of these compounds.

It is also an object of the present invention

a method for inhibiting the binding of fibrinogen to platelets in a mammal comprising administering an effective amount of one. of these compounds to that mammal,. a method of treating thrombus in a patient comprising administering to said patient an effective amount of one of these compounds,.

·. a method of preventing a thromotic risk in a patient comprising administering an effective amount of one of: a ^. from these ·.·.; compounds to this patient. ¹ _ 'i, * _s 1

In particular, the compounds of formula (I) may be used in the following areas: (i) Acute prevention of arterial thrombotic risk during cardiac surgery (coronary bypass) (or interventional) cardiology (transluminal percutaneous angioplasty, endarctectomy, stenting).

- in these situations, the compounds are added to prevent arterial thrombotic risk; oral administration of acetylsalicylic acid begins before the intervention (150-500 mg / orally) and then continues as follows; intravenous infusion of unfractionated heparin starting during intervention and thereafter exceeding 48 to 96. .

. hours. Administration of the compound of formula I may then be performed either orally (0.5 to 1.5 mg / kg) at the same time as aspirin, or by intravenous infusion (0.25 to 1 mg / kg / 24 hours) in combination or without combination with bolus. Mon 48

• • • • • • • · '· · • • • * • · • • . · • • · • ♦ • •. · · • • · · · • • · · • · · '· • • « • • · ·

hours, if the treatment is performed intravenously, it will be exchanged for oral administration (0.25 to 10 mg / kg in two doses at 12 hour intervals) to facilitate hospital care and then outpatient treatment.

ii) Secondary prophylaxis of arterial thrombotic risk in patients prone to unstable angina or myocardial infarction: in these situations, the high bioavailability of the claimed compounds, ie the ability to rapidly reach circulating concentrations that are effective due to the ability to inhibit fibrinogen binding to platelets orally during the period in which patients exhibit this risk of arterial thrombosis. In these situations, the compounds may preferably be administered in the range of 1 to 3 oral doses per. day, due to their high bioavailability and their long duration of action can. dosages may be selected in the range of 0.5 to 10 mg / kg. Pharmaceutical compositions which include one • ^'1 4 ^{4 -1} of active basic ingredients' described in the present application include active látkubuď in base form or in pharmaceutically acceptable salt form or alternatively in the form of a prodrug comprising an ester functional group, said functional group is removed in vivo after oral administration. These pharmaceutical compositions include carriers and excipients known to those skilled in the art. The latter component is selected from the pharmaceutical compositions disclosed in Pharmacopoeia. Examples which may be mentioned for the preparation of pharmaceutical forms for oral administration are: starch, magnesium stearate, talc, gelatin, agar, pectin, lactose, polyethylene glycols, etc. The pharmaceutical forms that may be used will be selected from the following, swallowable and non-swallowable tablets, gel capsules, lozenges, granules, powders. According to the characteristics of the pathological condition being treated and the morphology of each • ·

- -95.-, *

The patient's daily oral dose will be between 0.02 and 50 mg / kg / day administered in 1 to 3 doses uniformly distributed to maintain an effective level of binding to platelet GpIIb / IIIa receptors.

By means of an intravenous route of administration, the pharmaceutical forms for the acute phase of treatment are designed to allow individual dosing based on the inhibition of platelet aggregation, which is most effective for the immediate development of the operation. In this context, the lyophilisate and the pre-prepared solution for infusion allow the dosage to be individually modified over the dose range of 0.01 mg / kg / day to 20-mg / kg / day.

JOINT ADVOCATE OFFICE

ALL GREEN

CALCIUM GREEN BUCKET AND PARTNERS

120 00 Prague 2, Hálkova 2 Czech Republic

Claims (13)

PATENT CLAIMS ¹ -C-NH- (CH ₂ ) m -R 5 Wherein m = 1 to 4 and R ₅ is selected from phenyl, methoxyphenyl, indole, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuryl, - 101. a. R ₂ is hydrogen, ii) or R 1 is hydrogen and R ₂ is selected from the groups of formula: -NH-CO-Rg, wherein Rg is selected from C1-C4 alkoxy, C3-C7 cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups, and groups of the formula: -NH-SO 2 -R 7, wherein R 7 is selected from: -C 1 -C 5 alkyl groups optionally substituted with one or more groups selected from halogens, hydroxyl groups and trifluoromethyl groups; mono- or bicyclic C ₃ -C ₁₂ cycloalkyl groups; of mono-, bi- or tricyclic C 8 -C ₁₄ aryl groups. .. heteroaryl groups chosen from pyridyl, thienyl., chinolylpvé, benzodioxanyl, benzodioxolyl, and. isoxazylové ¹ groups; 1-phenyl (C1-C4) alkyl and naphthyl (C1-C4) alkyl groups; - and groups in which -aryl and heteroaryl groups which are optionally substituted with one or more groups selected independently from halogen, C 1 -C ₄ alkyl, trifluoromethyl, C 1 -C ₄ ; 102 alkylthio, C1-C4 alkyloxy, C1-C4 alkylsulfonyl, nitro, di ((C1-C4) alkyl) amino, and -COOR, -CH ₂ COOR or O-CH ₂ -COOR, wherein R is C 1 -C 4 alkyl group, iii) R ₃ is selected from hydrogen, C 1 -C 4 alkyl and phenyl (C 1 -C 4) alkyl; iv) and Z 1 and Z ₂ are hydrogen or an amine protecting group, and addition salts thereof with pharmaceutically acceptable acids. 1. Compounds of formula: In which:. . (i) either R 1 is selected from -C 1 -C 4 alkyl, C 3 -C 12 mono or bicyclic cycloalkyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ . alkynyl groups, these groups being optionally substituted with groups selected from halogens and hydroxyl groups; mono-, bi- or tricyclic C8-Cu aryl groups,. heteroaryl groups selected from pyridyl, thienyl, furyl, quinolyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups; -phenyl (C1-C4) alkyl and naphthyl (C1-C4) alkyl groups optionally substituted on the aryl ring, -aryl and heteroaryl groups which are optionally substituted with one or more groups selected independently from halogen, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 C ₉ -C ₄ alkylthio, C 1 -C ₄ alkylsulfonyl, C 1 -C 4 alkyloxy, nitro and -COOR, -CH 2 COOR or -O-CH 2 -COOR, wherein R is C 1 -C 4 alkyl, -groups of formula -C -NR ₄ R _'4 wherein R ₄ and R' ₄ are selected from 0 _0χ-8 alkyl and mono- or polycyclic C3 -C12 cycloalkyl groups, which groups are optionally substituted by groups selected from halogens and hydroxyl groups, R _'4 can also be hydrogen, or alternatively _R4 and _R'4 together form a tetramethylene or pentamethylene group, these last two groups being optionally themselves substituted, particularly C ₆ -C ₁₄ aryl or (C ₆ -C _4), aryl (C1-C4 ) an alkyl radical; - group formula ... -C-NH- (CH _{2) m} -R ₅ ^0th where m = I to 4, and R ₅ is selected from phenyl, methoxyphenyl, indole, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuryl groups, and _R2 is hydrogen ii) or R _x is hydrogen and R ₂ is selected from groups of formula: -NH-CO-R ₆ wherein R ₆ is selected from C 1 -C 4 alkoxy, C 3 -C 7 cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups, and groups of the formula: -NH-SO ₂ -R ₇ · · · · · · · · ·, · · · · · · · · · · · · · · · · · · · · · · · · · · · 4 Where R ₇ is selected from: ' -C 1 -C 5 alkyl groups optionally substituted with one or more groups selected from halogens, hydroxyl groups and trifluoromethyl groups; -C2-C5 alkenyl groups; mono- or bicyclic C3-C12 cycloalkyl groups; mono-, bi- or tricyclic Ο ₆ -Οχ ₄ aryl groups; heteroaryl groups selected from pyridyl, furyl, thienyl, quinolyl, benzodiaxanyl, benzodioxolyl, isoxazolyl, benzodioxinyl, benzothienyl, thiazolyl, pyrazolyl, benzofuryl and benzothiazolyl groups; - · -phenyl (C 1 -C 4) alkyl and naphthyl (C 1 -C 4 alkyl groups); - and formula groups: ((%)) Wherein n = 1, 2 or 3 and B is selected from -CH 2 -, O or S and -NH 2. -aryl- and heteroaryl groups which are optionally substituted with one or more groups selected independently from halogens, C 1 -C ₄ alkyl, C 3 -C 7 cycloalkyl, trifluoromethyl, C 1 -C 4 alkylthio groups, C 1 -C ₄ alkyloxy groups, C 1 -C ₄ alkylsulfonyl, nitro, di _((Ci-C4) alkyl) amino and groups --COOR, --CH2 nebo_ _{w -0-CH2} -C0pR where. R is C 1 -C ₄ alkyl, phenyl and naphthyl, and heteroaryl groups selected from thienyl, furyl and pyridyl; iii) R ₃ is selected from hydrogen, C 1 -C ₄ alkyl, and phenyl (C 1 -C 4); ₄ ) alkyl groups; . iv) A is selected from the group -ΝΗ-CHR 10-, -NH-CHR ₁₀ -CH ₂ - and ρ = 1 or 2; -R 10 is selected from hydrogen and C 1 -C ₄ alkyl and C ₆ -C ₁₄ aryl, v) and Z 1 and Z ₂ are hydrogen or an amine protecting group, and addition salts thereof with pharmaceutically acceptable acids. * V 2 - [(1,3-benzodioxol-5-ylsulfonyl) amino] -3 - ([2 - ((4- (4-piperidyl) -2- [2- (4104-4 piperidyl) ethyl] butanoyl} amino) acetyl) 2 - [(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- (2- (4-piperidyl)]) ethyl] butanoyl} amino) acetyl] amino} propanoic acid 2 - [(1-benzothiophen-2-ylsulfonyl) amino] -3 - {(2 - ((4 (4-piperidyl)) -2- (2- ( 4-piperidyl) ethyl] butanoyl} amino) acetyl] amino (propanoic acid; 2 - {[(2,5-dimethyl-3-furyl) sulfonyl] amino (-3 - {[2 ({4- (4-piperidyl) - 2- (2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino (propane; 2 - {[(4-fluoro-1-naphthyl) sulfonyl] amino} -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl]. butanoyl} amino) acetyl amino - propanoic acid 2 - {[(4-chloro-1-naphthyl) sulfonyl] amino) - 3 - {[2 - ((4 (4-piperidyl)) -2- [2- (4- ')] Piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanoic acid 2 - [(1-benzofuran-2-ylsulfonyl) amino] -3 - {[2 - ((4- (4-piperidyl)) -2- [2- (4- (piperidyl) ethyl] butanoyl (amino) acetyl] amino (propanoic acid; 2 - ((2,3-dihydro-1H-inden-5-ylsulfonyl) amino) 3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino) propanoic acid 2 - [(5-phenyl-2-thienyl)] sulfonyl] amino} -3 - {[2 - ((4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino (propanoic acid) 2 - [(5,6, 7,8-tetrahydro-2-naphthalenylsulfonyl) amino] 3 - {[2 - ((4- (4-piperidyl) -2- (2- (4-piperidyl) ethyl) butanoyl (amino) acetyl) amino) propanoic acid; (2-naphthylsulfonyl) amino] -3 - ([3 - ((4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) propanoyl] amino) (2R) -2 - [(2-naphthylsulfonyl) amino] -3 - ([2 - ((4- (4piperidyl) ethyl) butanoyl} amino) acetyl] amino} propane and • kk · · 105 their addition salts with pharmaceutically acceptable acids. 2 - ({[5- (dimethylamino) -1-naphthyl) sulfonyl} amino) -3 - {[2 - ((4 (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] aminopropanoate; 2 - {[(5,7-dimethoxy-2-naphthyl) sulfonyl] amino) -3 - {[2-7 ']. ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propane; 2 - [- (3-pyridylsulfonyl) amino] 3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanoic acid; 2 - [(2-thienylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino (propanoic acid; 2S) -2 - ([(6-methoxy-2-naphthyl) sulfonyl] amino} -3 {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl] amino) acetyl] amino} propanoic acid; 2 - [(mesitylsulfonyl) amino] -3 - {[2 - ({4- (4 _Λ. piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino propane; F · 2 - '{[(4-methylphenyl) sulfonyl] amino} -3- {[2- ({4 -' (4 * ^r piperidyl) -2- [2- (4 ·. (piperidyl) ethyl] butanoyl} amino) acetyl] amino (propanoic acid) 2 - {{((3-trifluoromethyl) phenyl] sulfonyl) amino} -3- {{2 - ({4- (4-piperidyl) -2- [2- (4-. piperidyl) ethyl] butanoyl} amino) acetyl] aminopropane; -; 2- {[(3-nitrophenyl) sulfonyl] amino} -3- {[2 - (. {4.-. (4-piperidyl) -2- [2- ^(4? piperidyl) ethyl] butanoyl Jamin) -acetate ethyl] aminopropane; 2 - {[[3,5-dimethyl-4-isoxazolyl) sulfonyl] amino} -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) -4- (4-piperidyl)]]] -; piperidyl) ethyl] butanoyl] amino) acetyl] amino] propane; 2 - [(phenylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] propanoic acid; (2S) -2 - [(2-naphthylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2 '[2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino] propanoic acid; 2 - [([1,1'-biphenyl] -4-ylsulfonyl) amino] -3 - {[2 - ({4 (4-piperidyl) -2- [2- (4-piperidyl) ethyl]] butanoyl} amino) - ,,. acetyl] amino] propane; ,. 2 - [(1-naphthylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino (propanoic acid); Compounds according to claim 1 - in which: i * i) either R 1 is selected from C -C ₄ alkyl, C ₃ -C _i2 .or mono bicyclic. cycloalkyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl groups, which groups are optionally substituted by groups selected from halogen and hydroxyl; - 100 mono-, bi- or tricyclic C ₆ -C ₁₄ aryl groups; -heteroaryl groups selected from pyridyl, thienyl, furyl, quinolyl, benzodiaxanyl, benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups; -phenyl (C 1 -C ₄ ) alkyl and naphthyl (C 1 -C 4) alkyl groups optionally substituted on the aryl ring, -aryl and heteroaryl groups which are optionally substituted with one or more groups selected independently from halogen, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkyloxy, nitro and -COOR groups, CH 2 COOR or -O-CH 2 -COOR, wherein R is a C 1 -C 4 alkyl group, -group formula: ——C — NR ₄ R ' ₄ In which R ₄ and R ' ₄ are selected from C 1 -C 8 alkyl and mono- or polycyclic C 3 -C 12 cycloalkyl groups, wherein these groups are optionally substituted with groups selected from halogens and hydroxyl groups, R' ₄ may also be hydrogen, or alternatively R 4 ₄ and R ' ₄ together form a tetramethylene or pentamethylene group, the latter two groups being optionally substituted, in particular by a C ₆ -C ₁₄ aryl or (C ₆ -C ₁₄ ) aryl (C ₁ -C ₄ ) alkyl radical; - groups of formula: 3. Compounds according to claim 1, in which R ₃ - H, and R ₂ is a group -NH-SO2 vzorce--R7 · '· * /' / ¹ as well. * Compounds according to claim 3, in which R 2 _? is selected from naphthyl, substituted naphthyl, phenylthienyl and biphenyl groups. · · ' Compounds according to claim 1 which are: ethyl (2S) -2 - [(2-naphthylsulfonyl) amino] -3 - {[2 - ({4- (4-piperidyl) -2- [2- (4-piperidyl)] ethyl] butanoyl} amino) acetyl amino] propanoate; 3- (1,3-benzodioxol-5-yl) -3 - {- [2- ({4- (4-piperidyl) 2- [2- (4- ')]. piperidyl) ethyl] butanoyl} amino) acetyl] amino} propane; A process for preparing compounds of formula (I) and ( _x ) by reacting an acid of formula Rg (III) or a ₂₎ reacting an acid of the formula · • 'R -N O - 106 * -. (IV) · in which R _{8 and} R ₈ are protecting groups, with an amine of formula • (V) to form compounds of formula (1b): Rs (lb) (b) where appropriate, by converting a group R ₂ into another group R ₂ , c) and, optionally, removing the protecting groups. A pharmaceutical composition comprising, as an active compound, a compound according to claim 1. Use of the compounds according to claim 1 for the manufacture of an antithrombotic pharmaceutical product. t k - 107 • ·· ·· · · • · · • ‘· · · • - • · • · · • · · · · · ·· l · • • ·· ' • · · · · • • · A method of inhibiting platelet binding of fibrinogen in a mammal comprising administering to said mammal an effective amount of a compound of claim 1. A method of inhibiting platelet aggregation in a patient comprising administering to said patient an effective amount of a compound of claim 1. A method of treating thrombosis in a patient comprising administering to the patient an effective amount of the compounds of claim 1. A method of preventing a thrombotic risk in a patient, comprising administering to said patient an effective amount of a compound of claim 1. 13. A compound of the formula: * · ⁸ J / K \ (II) in which R ₈ and R ₉ are protecting groups and A has the meaning uvedený'U -nároku first 14; Compounds of formula