SK102495A3 - Fibrinogen receptor antagonists and pharmaceutical agents containing them - Google Patents

Abstract

Compounds of the invention have formula (1) or (2), for example (3). The compounds have fibrinogen receptor antagonist activity.

Description

Fibrinogen receptor antagonists and pharmaceutical compositions containing them

Technical field

The invention relates to fibrinogen receptor antagonists and pharmaceutical compositions containing them. These agents inhibit the binding of fibrinogen and other proteins to platelets and inhibit platelet aggregation specifically at the site of binding to the fibrinogen IIb / IIIa receptor.

BACKGROUND OF THE INVENTION

Fibrinogen is a glycoprotein present in blood plasma that is involved in platelet aggregation and fibrin formation. Platelets are nucleus-like structures found in the blood of all mammals and participate in blood coagulation. The interaction of fibrinogen with the IIb / IIIa receptor site is a prerequisite for normal platelet function, as is generally known.

In the event that the vessel is damaged by injury or other means, the platelets adhere to the damaged subendothelial surface. The adhered platelets release biologically active substances and aggregate. Agglomeration is initiated by the binding of certain agents such as thrombin, epinephrine or ADP to specific platelet membrane receptors. Stimulation with these agents results in the secretion of hidden fibrinogen receptors on the platelet surface and binding of fibrinogen to the glycoprotein receptor complex IIb / IIIa.

Efforts have been made to use natural products as well as synthetic peptides to determine the mechanism of platelet adhesion and aggregation. For example, Rouslahti and Pierschbacher, Science 238: 491-497 (1987) describe adhesion proteins such as fibronectin, vitronectin, osteopontin, collagens, thrombospondin, fibrinogen and von Villebrand factor, which are present in the extracellular matrix and in the blood. These proteins contain the arginine-glycine-aspartic acid tripeptide, RGD, as a recognition site for glycoprotein IIb / IIIa. Tripeptides containing these substances are recognized by at least one member of the family of structurally related receptors, integrins, heterodimeric proteins with two membrane-related subunits. The authors report that the chain of tripeptides in individual proteins may be critical for recognition.

Cheresh, Proc. Natl. Acad. Sci., USA, 84, 6471-6475 (1987) describes an Arg-Gly-Asp group of adhesion receptor that is expressed by human endothelial cells and is structurally similar to platelet IIb / IIIa but is both antigenic and functional different. This receptor is directly involved in the association of endothelial cells with fibrinogen, von Villebrand factor and vitronectin.

In Pierschbacher and Rouslahti, J. of Biol. Chem., 262, 36, 17294-17298 (1987) suggests that the Arg-Gly-Asp chain could be a sufficient signal for receptor recognition and binding, so that the chain could be determinative. Various synthetic peptides have been made, and the authors conclude that the stereochemical structure of Arg-Gly-Asp, even in the case of enantiomeric substitution or addition to this chain, will substantially affect receptor-ligand interaction. The authors further demonstrate that following cyclization of the decapeptide by the formation of a disulfide bridge between the nonterminal residues of Pen and Cys, the efficacy of the peptide in inhibiting fibronectin binding is significantly reduced.

In Proc. Natl. Acad. Sci., USA, 81, 5985-5988 (1984), disclose tetrapeptide variants of the fibronectin recognition site that retain their efficacy. Peptides with a tetrapeptide recognition site are also described in U.S. Pat. Nos. 4,589,881 and 4,614,517. A number of large polypeptide fragments in the fibronectin binding cell region can favorably influence aggregation. By way of example, U.S. Pat. 4,517,686, 4,661,111 and 4,578,079.

Ruggeri et al., Proc. Natl. Acad. Sci., USA, 83, 5708-5712, 1986 discloses a variety of synthetic peptides up to sixteen amino acid residues in length, these peptides containing RGD and a valine residue bound to the aspartic acid residue in the RGD residue, which inhibit the binding of fibrinogen to platelets similar observations are reported in Koczewiak et al., biochem., 23, 1767-1774, 1984; Ginsberg et al., Biol. Chem., 260 (7), 3931-3936, 1985; and Haverstick et al., Blood, 66 (4), 946-952, 1985. 275,748 and 298,820.

A variety of low molecular weight polypeptides have been isolated from snake venoms. These factors appear to have a high affinity for the gpIIb / IIIa complex. For example, Huang et al., J. Biol. Chem., 262, 16157-16163, 1987, and Hzang et al., Biochemistry 28: 661-666 (1989) discloses the primary structure of the trigramin venom, a 72 amino acid polypeptide comprising the RGD subunit. Echistatin is another poison that has a high affinity for the gpIIb / IIIa complex. This polypeptide contains 49 amino acids, the RGD subunit, and a variety of disulfide bridges, as also reported in Gan et al., J. Biol. Chem., 263, 19827-19832 (1988) and Dennis et al., Proc. Natl. Acad. Sci., USA, 87, 2471-2475, 1989. However, these serpent poisons also have high affinity for other members of the receptor family, including vitronectin and fibronectin, and are therefore not selective for the gpIIb / IIIa complex.

It is known that the Arg-Gly-Asp tripeptide chain is present in some polypeptides that can favorably affect or inhibit the aggregation effect of fibronectin and vitronectin, but in some cases this chain has poor efficacy. It is currently unclear how other amino acids bound to this chain can affect the specificity of the binding. U.S. Pat. No. 5,023,233 (Merck & Co., Inc.) discloses cyclic hexapeptides that comprise the Arg-Gly-Asp chain are useful inhibitors of platelet aggregation. U.S. Pat. No. 5,037,808 discloses platelet aggregation inhibitors of the indolyl type that appear to antagonize the interaction between fibrinogen and / or extracellular matrix proteins and platelet gpIIb / IIIa receptor. U.S. Pat. No. 5,037,808 also discloses guanidine peptide mimetic compounds which retain the remainder of Asp and cause inhibition of platelet aggregation. International patent application WO9014103 describes the use of antibody-polypeptide conjugates in which the polypeptides comprise an Arg-Gly-Asp chain, RGD.

International patent application WO9111458 discloses the use of large cyclic peptides containing RGD, to which proline residues are bound to this group, which are inhibitors of platelet aggregation. International patent application WO9101331 discloses small cyclic platelet aggregation inhibitors, which are synthetic cyclic pentapeptides containing the Arg-Gly-Asp tripeptide and thioether linkages in the ring. U.S. Pat. No. 5,051,405 also discloses the use of peptides and pseudopeptides, such as N-amidinopiperidine-3-carboxyglycyl-Laspartyl-L-valine, for inhibiting platelet aggregation and blood clot formation in mammals. In European patent application no. H445796 discloses linear compounds which may include piperazinyl or piperidinyl derivatives. In European patent no. No. 437,367 discloses linear polypeptides that antagonize the fibrinogen receptor. U.S. Pat. No. 5,256,812 describes compounds of general formula

R ¹ -A- (V) _and -X- (CH ₂ ) _b - (Y) _c -BZ-COOR, wherein R 1 represents a guanidine or amidine group, and A and B are selected from specific monosubstituted aryl or heterocyclic groups.

Thus, a variety of compounds or peptide analogs are disclosed as agents that can inhibit platelet aggregation by inhibiting fibrinogen binding to these platelets.

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel fibrinogen receptor antagonists with significant binding efficiency useful for the above purposes. These substances should be suitable for the treatment of serious diseases and disorders, including various complications that lead to the formation of blood clots within the blood vessels and embolisms. These include, in particular, myocardial infarction, stroke and inflammation of the veins as diseases which still require new and effective substances capable of antagonizing the fibrinogen receptors.

SUMMARY OF THE INVENTION

The invention relates to fibrinogen receptor antagonists of the formula I

(1) for example a compound of formula 3

(3)

These compounds are effective as fibrinogen receptor antagonists.

In the compounds of formula 1

8

Q- (CH ₂ ) _n - (NC) _a - AB - C - (N) _b - (R) _c - C - R means

Q any of the groups

NH NH

II II

H ₂ N = C-; H ₂ N — C-NH-; R ⁷ HN-;

(1) or a 9-membered mono- or bicyclic ring system containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur and optionally substituted with R ⁸ ,

AB is a fused ring system with a common carbon and nitrogen atom in which

A represents a 5, 6 or 7-membered saturated or unsaturated ring containing 1, 2 or 3 heteroatoms selected from oxygen, sulfur or nitrogen; and

B represents a 5, 6 or 7-membered saturated or unsaturated ring containing 1, 2 or 3 heteroatoms from

Ί

R ¹

R ²

R ⁴ oxygen, sulfur or nitrogen, is hydrogen, alkyl of 1 to 4 carbon atoms, a group selected from -N (R ⁸⁾ 2, -N (R ⁸⁾ SO 2 R ^7, NR ⁸ CO ₂ R ^7,

NR ⁸ C (O) R ⁷ , NR ⁸ C (O) N (R ⁷ ) R ⁸ , N (R ⁸ ) SO ₂ N (R ⁷ ) R ⁸ ,

N (R ⁸ ) SO 2 N (R ⁸ ) C (O) OR ⁷ , C (O) N (R ⁷ ) 2 or form a cyclic group with R ** as defined below, means a hydrogen atom, a straight or branched alkyl (C 1 -C 4) alkyl, (C 1 -C 4) alkyl aryl or aryl means hydrogen, straight or branched (C 1 -C 4) alkyl, (C 1 -C 4) cycloalkyl or (C 1 -C 4) alkenyl, is CH, CH (CH _{2) n,} or, if R ³ is adjacent to the N (R ⁴⁾ group, and

C (CH _{2) n,}

K o

R ** is COOH, CH ₂ OH, C (O) N (R ⁷ ) ₂ , CO ₂ R 6, tetrazole, acylsulfonamide, P (OH) ₂

H or forms with the group

where y is an oxygen or sulfur atom,

R ⁷ represents a hydrogen atom, a straight or branched chain alkyl of 1 to 4 carbon atoms, an optionally substituted, straight or branched chain lower alkenyl, an alkyl aryl of 1 to 4 carbon atoms in the alkyl moiety, a substituted aryl or a 5- or 6-membered a heteroaryl having 1, 2 or 3 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the alkyl radical may be substituted by a hydroxy or alkoxy group having 1 to 4 carbon atoms and the substituted aryl may be substituted by 1, 2 or 3 substituents selected from a halogen atom, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms,

R @ 5 represents a hydrogen atom or a straight or branched chain alkyl of 1 to 4 carbon atoms, is hydrogen, alkyl of 1 to 4 carbon atoms or aryl,

n means the whole number 0 to 7 and means the whole number 0 or 1 b means the whole number 0 or 1 C means the whole number 0 or First

as well as pharmaceutically acceptable salts thereof.

In one embodiment of the invention, the compounds of the invention can be represented by the general formula 1

(D where

Q represents one of the groups

Η ₂ Ν

η ₂ ν

ΝΗ

Η (CH ₂ ) - - ^N y ΝΗ Η

I

R ⁸ (CH _{2) n} R ⁸ ny- ^ - (CH _{2) d '}

ABOUT

NH

H ₂ N or

n means the whole number 0 to 7 n ' means the whole number 0 to 3 and means the whole number 0 or 1 b means the whole number 0 or 1 C means the whole number 0 or 1 R ⁴ means hydrogen, direct or

carbon atoms, cycloalkyl of 1 to 4 carbon atoms or alkenyl of 1 to 4 carbon atoms, r5 is CH or -CH (CH2) _n ,

ABOUT

R is hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, alkylaryl of 1 to 4 carbon atoms in the alkyl moiety, or aryl; is H, C 1 -C 4 alkyl, N (R ⁸⁾ 2, -N (R ⁸⁾ SO 2 R ^7, NR ⁸ _CO2 R @ ^7, NR ⁸ C (O) R ^7,

NR ⁸ C (O) N (R ⁷⁾ R ^8, -N (R ⁸⁾ SO ₂ N (R ⁷⁾ R ^8, -N (R ⁸⁾ SO 2 N (R ⁸⁾ C (O) OR ^7, C (O) N (R ⁷⁾ 2, or forms with R a cyclic group,

R ⁶ denotes COOH, CH 2 OH, C (O) N (R ⁷ ) 2, CO ₂ R ⁹ , tetrazole, acylsulfonamide, P (OH) ₂

II o

or forms a cyclic group with the group

y where y is an oxygen or sulfur atom,

R represents a hydrogen atom, a straight or branched chain alkyl of 1 to 4 carbon atoms, an optionally substituted, straight or branched chain lower alkenyl, an alkylaryl of 1 to 4 carbon atoms in the alkyl moiety, a substituted aryl or a 5- or 6-membered alkyl group; ring-containing teroaryl containing 1, 2 or 3 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the alkyl group may be substituted by a hydroxy or alkoxy group having 1 to 4 carbon atoms and the aryl may be substituted by 1, 2 or 3 substituents from a halogen atom, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms,

Q

R represents a hydrogen atom or a straight or branched chain alkyl of 1 to 4 carbon atoms,

R1 is hydrogen, C1-C4 alkyl or aryl, and is an integer of 0 or 1,

A represents a 5, 6 or 7-membered saturated, partially saturated or unsaturated ring containing 1, 2 or 3 heteroatoms from the group O, S or N,

B represents a 5, 6 or 7-membered saturated, partially saturated or unsaturated ring containing 1, 2 or 3 heteroatoms from the group O, S or N, wherein A and B form a fused ring with a common carbon and nitrogen atom.

In the compounds of the invention, components with centers of symmetry can form racemates, racemic mixtures or individual enantiomers and / or diastereomers. All such isomeric forms are within the scope of the invention.

In the group of compounds of this embodiment, the compounds of the invention may be represented by the general formula 1

8

Q- (CH 2) _n - (NC) _a - AB - C - (N) b - (R) _c - C - R (1) where AB is selected from the groups

where

V is N or CR ^7a

D is CH ₂ , CH ₂ -CH ₂ , CH ₂ C (R ⁷ ) ₂ CH ₂ or

where

X is N or CR ³ , wherein

R ³ is CN, C (O) N (R ⁷ ) R ⁸ ,

O _r (CH ₂ ) _n .

or

λ

A subgroup of these compounds are compounds of Formula 1

Q- (CH ₂ ) _n - (NC) _a - AB C - (N) _b - (R ⁵ ) _c - C - R ⁸ (D where AB stands for

where

V is N or CH and

D is CH ₂ -CH ₂ or CH ₂ C (R ⁴ ) ₂ CH ₂ .

Another group of compounds of this embodiment are compounds of Formula 1

Q- (CH ₂ ) _n - (NC) _a - AB - C - (N) _b - (r 1 - C - R * (D where AB is selected from the group

where

V is N or CR ^7a

D is CH ₂ , CH ₂ -CH ₂ , CH ₂ C (R ⁷ ) ₂ CH ₂ or

where

X is N or CR ³ , wherein

R ³ is CN, C (O) N (R ⁷ ) R ⁸ ,

A subgroup of this group of Formula I compounds are all

R ² R ⁶

Q- (CH ₂ ) _n - (NC) _and - AB

C - (N) _b - (R ⁵ ) _c - C - R ⁸ (D where a is 1, a

AB is selected from the group

where

V is N or CR? and

D is CH ₂ , CH ₂ -CH ₂ , CH ₂ C (R ⁷ ) ₂ CH ₂ or

where

X is N or CR ³ , wherein

R ³ is CN, C (O) N (R ⁷ ) R ⁸ ,

Another subgroup of the general formula (1) of these compounds are compounds

ABOUT

II

Q- (CH ₂ ) n - (NC) a - AB - C - (N) _b - (r 1 - C - R ⁸ (D where a represents 0, and

AB is selected from the group

where y ³ is 0 or

Specific examples of the compounds of the invention may be the following pharmaceutically acceptable salts and salts thereof:

H HNSO0C4H9 g

s

HN

N 1

HN

HN

HN

ΗΝ

Ο

Ο

Ν

.Ν

Ν ‘Ν '

I

Η, CO ₂ H

Η

k_N- /

COOH

Η HNSO

\ /

CHΗΝ

Q Ph

Ο

NN

N

N

CO ₂ H

Ο

Η

and

CH <

Other examples of compounds of the invention are:

COOH

HN

ABOUT

/ Γ N> N- _n IH ' ¹ .co ₂ h

H HNSO ₂

HN

NCO ₂ H

CH

H //

Pharmaceutically acceptable salts are to be understood as meaning non-toxic salts of the compounds of the invention, which are generally obtainable by reaction of the free base with a suitable organic or inorganic acid. Examples of such salts may be acetate, benzenesulfonate, benzoate, bicarbonate, hydrogen sulphate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsinanylate, hydrobresorinate, hydroborosaminoinide, hydroborosaminoinide, hydroborosaminoinide, hydrobromorecin, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate, palmitate, pantothenate, phosphate, salicylate, stearate, subacetate, succinate, tannate, tartrate, toclat, tosylate, triethiodide or valerate.

By "pharmaceutically effective amount" is meant an amount of active ingredient or composition that elicits a biological response in a tissue, system or animal that is sought by a researcher or physician. The term anticoagulant sp includes heparin and warfarin. The term thrombolytic agent includes streptokinase and tissue plasminogen activator. Platelet aggregation agents include, but are not limited to, aspirin, ticLopidine, and dipyridamole.

The term alkyl means a straight chain or branched alkane, alkene or alkyne.

The term aryl means a 5 to 10-membered unsaturated mono or bicycl. circular system.

The term heteroaryl means aryl containing 1, 2, 3 or 4 heteroatoms.

The term heteroatom means N, O or S.

The term cyclic, unless otherwise defined, means a mono- or bicyclic saturated group with 5 to 10 ring members.

The term heterocyclic includes the term cyclic containing 1, 2, 3 or 4 heteroatoms.

In the compounds of the invention, the heteroaryl and heterocyclic groups contain at most 2 oxygen atoms or 2 sulfur atoms.

The term alkoxy includes an alkyl moiety as defined above.

The terms arylalkyl and alkylaryl 1 include an alkyl moiety as defined above and an aryl moiety as defined above.

The term halogen refers to fluorine, chlorine, iodine and bromine.

Oxy is an oxygen atom, oxo is an oxygen atom bound by a double bond. The term thio means a sulfur atom. According to the common nomenclature used throughout the application, the terminal part of the side chain is first described, and then other functional groups towards the site of attachment. For example, an alkyl of 1 to 5 carbon atoms substituted with an alkylcarbonylamino group of 1 to 6 carbon atoms in the alkyl moiety means

H O

Ci. ₅ alkyl NCC, galkyl schemes and the following examples are used

shortcuts the following meaning: BOC (Boc) I tert-butoxycarbonyl, Pd-C palladium on active DMF dimethylformam i d DMSO d. methylsulfox; d

as a catalyst

CBZ carbobenzyloxy ch ₂ or ₂ methylene chloride I WANT ₃ chloroform EtOH ethanol MeOH methanol EtOAc acetate HOAc acetic acid BOP benzotriazol-1-yloxytris (dimethylamino) - phosphoniumhexaflurophosphate EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide Oxone potassium peroxymonosulfate LDA lithium DMA N, N-dimethylaniline HOBT hydroxybenzotriazole. Use for medical purposes

The compounds of the invention can be used to inhibit the protein complex of integrin related to cell association. Thus, these agents may be administered to patients in cases where inhibition of platelet aggregation is desired.

Some of the compounds of the invention are rapidly removed from the bloodstream and are particularly useful for inhibiting platelet aggregation. These compounds are particularly useful in peripheral artery surgeries (arterial grafts, cervical endarterectomy) and in cardiovascular procedures in arterial manipulation and other organs, as well as in contact of platelets with artificial surfaces, where they are easily aggregated. Platelets can then form blood clots and embolisms. For this reason, it is advisable to administer these substances to surgical patients in such a way as to avoid such symptoms.

The compounds of the invention may be administered in oral form, for example, as tablets, capsules, optionally with a delayed release of the active ingredient, pills, powders, granules, elixirs, elixirs, suspensions, syrups and emulsions. However, they can also be administered intravenously in the form of injections or infusions, intraperitoneally, subcutaneously, under the tongue, in the nose or intramuscularly in conventional dosage forms. An effective but non-toxic amount of the selected substance is always used.

The compounds of the invention may be administered to patients in whom thrombosis is to be prevented by inhibiting fibrinogen binding to the platelet membrane glycoprotein complex IIb / IIIa as a receptor. Thus, these agents can be used in peripheral artery surgical procedures, as mentioned above, in cardiovascular procedures and the like.

In cardiovascular procedures, extracorporeal circulation is often used to oxygenate blood. The platelets adhere to the surface of the device for this extracorporeal circulation. This adhesion depends on the interaction between gpIIb / IITa in the platelet membrane and fibrinogen adsorbed on the surface of the circuit, as explained in detail in Gluszko et al., Amer. J. Physiol., 252 (H), 615-621 (1987). Platelets released from artificial surfaces have impaired function. The compounds of the invention may be used to prevent platelets from adhering to said surfaces.

The compounds according to the invention have further use in preventing the formation of blood clots, thromboses, thromboembolisms and re-occlusion after previously cured thrombosis, after angiopathy or after coronary vessel procedures such as bypass. The compounds may also be used to prevent myocardial infarction.

The doses of the compounds of the invention are selected depending on a variety of factors such as the age, weight, sex and general condition of the patient, the severity of the disease being treated, the route of administration, kidney and liver function, as well as the compound or salt thereof. The resulting dose will be determined by the doctor or veterinarian.

For oral administration, the daily dose will range from 0.01 to 100 mg / kg, preferably 0.05 to 100 mg / kg, and especially 0.1 to 20 mg / kg. For intravenous administration, a dose of 1 to 10 micrograms / kg per minute during the infusion is preferred. Preferably, the compounds of the invention are administered in divided doses of two, three, or four times daily. In addition, preferred compounds may be administered by the nasal mucosa or transdermally in the form of known patches. In transdermal use, however, it will be continuous rather than intermittent administration of the active ingredients.

The compounds of the invention may typically be administered in admixture with suitable pharmaceutical carriers, diluents or excipients, hereinafter collectively referred to as carriers, selected according to the mode of administration envisaged, e.g. in the case of oral administration, the active compounds may be formulated tablets, capsules, elixirs, syrups and the like, with appropriate excipients according to conventional pharmaceutical procedures.

For example, in the case of oral administration in the form of a tablet or capsule, the active ingredient may be admixed with a nontoxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, calcium hydrogen phosphate, calcium sulfate, mannitol, sorbitol and the like. for oral administration in liquid form, a liquid carrier such as ethanol, glycerol, water and the like can be used. In addition, binders, glidants, disintegrants and colorants can also be used, if desired or necessary. Suitable binders are, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn-based sweeteners, natural or synthetic gums such as acacia, gum tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. The glidant may be, for example, sodium oleate or stearate, magnesium stearate, benzoate, acetate or sodium chloride and the like. The disintegrant may be, for example, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

The compounds of the invention may also be administered by means of a liposome system, for example in the form of small or larger unilamellar or multilamellar spherical formations. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of the invention may be delivered to the site of use or desired effect by means of monoclonal antibodies, such as specific carriers to which the active compounds are bound. The compounds of the invention may also be coupled to soluble polymers as targetable carriers. These polymers can be, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidephenol-type copolymers or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds of the invention may be bound to biodegradable polymers to provide controlled release of the active ingredient, such as polylactic acid, polyglycolic acid, and copolymers of these acids, polyepsilocaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydrates or polycyanoacrylates, polycyanoacrylates investigated copolymers of hydrogels.

The compounds of the invention may also be co-administered with other suitable anticoagulants such as hepacin, aspirin, warfarin, dipyridamole and other compounds that inhibit blood clot formation, which may also be co-administered with thrombolytic agents such as plasminogen activators or streptokinase to achieve beneficial effects in the treatment of various pathological conditions in blood vessels.

The novel compounds of the present invention can be prepared by the procedures set forth in the following examples. The most preferred compounds of the invention are the compounds listed in the Examples section. However, any combination of these compounds or any combination of functional groups in the molecules of the compounds may be used. The following examples illustrate the preparation of the compounds of the invention. It will be understood, however, that any known variations commonly practiced in similar procedures may be made. All temperatures are in degrees Celsius.

The biological activity of the compounds of the invention in vitro will also be exemplified. One of the assays used to evaluate the fibrinogen receptor antagonist activity is based on the evaluation of the inhibition of platelets sti31 mulled by ADP. Agglomeration requires fibrinogen to bind fibrinogen platelets at the appropriate site of the receptor. Inhibitors of fibrinogen binding cause aggregation inhibition. In an ADP-stimulated platelet aggregation assay, human platelets are isolated from fresh blood, stored in dextrose and citrate solution after differential centrifugation, followed by gel filtration (Sepharose 2B) in pH 7.4-free Tyrodes buffer, free of divalent ions. and containing 2% bovine serum albumin.

Platelet aggregation is measured at 37 ° C in a clump meter (Chronolog). The reaction mixture contains 2 x 10 6 / ml human platelets after gel filtration, 100 micrograms / ml fibrinogen, 1 mM calcium ions and test substance. Agglomeration is started by adding 10 mM ADP 1 minute after mixing the other ingredients. The reaction is then allowed to proceed for at least 2 minutes. The degree of aggregation inhibition is then expressed as a percentage of the aggregation rate that can be observed in the absence of inhibitor. The IC 50 for a particular compound is the dose of that compound which causes 50% inhibition of aggregation compared to a control experiment in which no inhibitor is used.

The basic processes for making the compounds of the invention will be schematically described below.

DETAILED DESCRIPTION OF THE INVENTION

Scheme A

Preparation of sulfonamide intermediates

CONH ₂ NaOH

H ₂ O / dioxane h ₂ n4co ₂ h

H

A-1 nC ₄ H ₉ SO ₂ Cl. CONH * (C ₄ H ₉ ) SO ₂ NH from CO ₂ HH

Δι2

1. Br, NaOH

2. Boc ₂ 0, NaOH, _{NH Boc} THF / H ₂ O r (C ₄ H _{g) 2} SO ₂ H NH't'CO

A-3

L-asparagine-α-butanesulfonamide (N- (n-butylsulfonyl) -Lasparagine), compound A-2

A solution of 6.45 g, 48.9 mmol of L-asparagine and 2.0 g, 50.0 mmol of sodium hydroxide in 100 mL of 50% aqueous dioxane was cooled to 0 ° C in an ice bath. To the vigorously stirred mixture was added alternately 2.2 g (55.0 mmol) of sodium hydroxide in 50 ml of water and 7.0 ml (53.9 mmol) of butanesulfonyl chloride over 30 minutes. Then the reaction mixture is concentrated to a volume of 50 ml of L under reduced pressure, the aqueous residue is cooled, acidified. The reaction mixture was washed with concentrated hydrochloric acid and extracted with ethyl acetate (3.times.100 ml). The organic extracts were dried over sodium sulfate and evaporated to a volume of approximately 50 mL, 50 mL of anhydrous ether was added and the resulting white precipitate was collected by filtration in vacuo to give compound A-2, mp 154-155 ° C.

L-p-Boc-α-butanesulfonamido-p-aminoalanine (2- (S) - (n-butylsulfonylamino) -3- (N-Boc-aminopropionic acid), A-3

A solution of 6.04 g (151 mmol) of sodium hydroxide in 50 ml of water was cooled to 0 DEG C. and 1.40 ml (26.9 mmol) of bromine was added. The resulting solution was stirred at 0 ° C for 5 minutes. A cooled solution of Compound A-2 (5.23 g, 20.7 mmol) and sodium hydroxide (1.66 g, 41.4 mmol) in water (15 ml) was then added in one portion, and the mixture was stirred at 0 ° C for 5 minutes. Heat at 80 ° C for 15 minutes. The solution is then cooled to 25 ° C, acidified by the addition of 11 ml of 12 M hydrochloric acid and stirred until gas evolution ceases. The solution was then basified by the addition of 2 M sodium hydroxide, then 20 ml of THF and 9.0 g, 41.4 mmol of di-tert-butyl dicarbonate were added. The mixture was stirred overnight at 25 ° C, then THF was removed under reduced pressure and the alkaline aqueous phase was extracted with 2 x 50 mL ethyl acetate. The aqueous phase is then acidified with 10% potassium bisulfate and extracted with 3 x 100 ml ethyl acetate. The acidic extracts are combined, dried over sodium sulfate and evaporated to give product A-3 as a white solid, mp 111-112 ° C.

HCl (C ₄ H ₉ ) SO ₂ NH

H

NH Boe

CO ₂ H (C ₄ Hq) SO ₂ NH

h ₂ co ₂ h

A-4

(2- (S) - (n-Butylsulfonylamino) -3-aminopropionic acid (A-4)

A solution of 3.83 g, 11.8 mmol of Compound A-3 in 200 mL of ethyl acetate was cooled to 0 ° C and hydrogen chloride gas was bubbled through the solution for 5 minutes. The solution is then warmed to 25 ° C, stirred for a further 30 minutes and then evaporated under reduced pressure to 50% of its volume, then diluted with 100 ml of ether. The resulting white solid was filtered off under vacuum to give solid product A-4.

Ethyl 2- (S) - (n-butylsulfonylamino) -3-aminopropionate (A-5)

A solution of 1.0 g (3.8 mmol) of Compound A-4 in 50 mL of anhydrous ethanol was saturated with hydrogen chloride gas and then refluxed for 3 hours. Then the solvent was evaporated to give pure product A-5 as a white solid.

1 H-NMR (300 MHz, CD ₃ OD): δ 4.38 (m, 2H), 4.32 (m, 1H), 4.23 (m, 2H), 2.85 (m, 2H), 1.65-1.45 (m, 4H), 1.3 (t, 2H),

0.96 (t, 3 H).

NaOH

A-7

N-tosyl-L-asparagine (A-6)

L-asparagine (10.0 g, 75.7 mmol) was placed in a 500 mL round bottom flask equipped with a magnetic stirrer and addition funnel. 85 ml, 1.1 equivalents of 1 M sodium hydroxide are then added. P-Toluenesulfonyl chloride (15.88 g, 83.27 mmol) was dissolved in ethyl acetate (100 mL) and added to the reaction mixture with vigorous stirring. 85 ml, 1.1 equivalents of 1 M sodium hydroxide are placed in an addition funnel and then added dropwise with vigorous stirring over 2 hours. The reaction mixture was then stirred at room temperature for 2 hours. The organic and aqueous layers were separated and the aqueous layer was washed with ethyl acetate (2 x 50 mL). The aqueous layer was cooled to 0 ° C and then acidified with concentrated hydrochloric acid. A white crystalline solid is obtained, which, after recrystallization from hot water, yields compound A-6.

¹ H-NMR (300 MHz, DMSO-d 6): δ 7.91 (d, J = 8.79 Hz, 1H), 7.64 (d, J = 8.06 Hz, 2H), 7.32 ( s, d (overlapping), J = 8.06 Hz, 3H), 6.87 (br s, 1H), 4.03 (m, 1H), 3.32 (s, H ₂ 0), 2, 49 (m, 1H), 2.43 (d, d, J = 7.08, 15, 38 Hz, 1H), 2.35 (s, 3H), 2.21 (d, d, J = 6, 11, 15.38 Hz, 1H).

2 (S) -Tosylamino-3-aminopropionic acid (A-7)

A solution containing 22.0 g (550 mmol) of sodium hydroxide in 100 ml of water is cooled to 0 DEG C. and 5.03 ml (97.5 mmol) of bromine is added dropwise and then a solution of 21.5 g (75 ml) is added in one portion. 0 mmol of compound A-6 and 6.68 g, 161 mmol of sodium hydroxide in 50 mL of water, cooled to 0 ° C. The mixture was stirred for 20 minutes at 0 C and then heated for 30 minutes at 80 ^e C, then cooled. The cooled solution was adjusted to pH 7 with concentrated hydrochloric acid and the resulting white solid was filtered off to give product A-7.

1 H-NMR (300 MHz, DMSO-d ₆ ): δ 8.2-7.2 (br, 2H, (NH, COOH)), 7.70 (d, J = 8.18 Hz, 2H), 7.38 (J = 8.18 Hz, 2H), 3.7 - 3.0 (br, 2H, _(NH2, H ₂ 0)), 3.12 (q, J = 4.76 Hz, 1 H ), 2.99 (d, d,

J = 4.64, 11.96 Hz, 1H), 2.79 (d, d, J = 9.52, 11.96 Hz, 1H), 2.36 (s, 3H).

Acid tert. butyl-2 (S) - (toluenesulfonylamino) -3-amino-propionic (A-8)

5.0 g (19.4 mmol) of compound A-7 is suspended in 100 mL of dioxane in a 1 L pressure bottle. The vessel was cooled to -15 ° C and 100 mL of isobutylene was added. Concentrated sulfuric acid (5 ml) was added, the bottle was sealed and the mixture was stirred at room temperature for 36 hours. The bottle is then opened and the excess isobutylene is carefully discarded. The solution was diluted with 200 mL of ethyl acetate and washed with 200 mL of 1 N sodium hydroxide. The organic layer was dried over sodium sulfate, filtered and evaporated to afford product A-8 as a white crystalline solid.

^H-NMR (300 MHz, CDC1 _3): δ 7.68 (d, J = 8.18 Hz, 2H), 7.35 (d, J = 8.18 Hz, 2H), 3.85 (m H, 2.93-2.79 (m, 2H), 2.32 (s, 3H), 1.38 (s, 9H).

e

1-1

Scheme 1 0 ^{, Bu} ° ^2C in%, II CI3COCOCCI; 1 J N toluene nhnh ₂

Tert-Butyl 2-hydrazinopyridine-3-carboxylate (1-2)

A solution of 735 mg, 3.44 mmol of tert-butyl 6-chloronicotinate in 5 mL of ethanol was cooled to 0 ° C and a solution of 2.75 g, 86 mmol of anhydrous hydrazine in 5 mL of ethanol was added. The mixture is allowed to warm to 25 ° C, stirred for 20 hours and then heated to 60 ° C for 2 hours. The mixture was then dissolved in water and extracted with ethyl acetate. The organic portion was washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to give compound 1-2 as an oil which was used directly in the next step.

T. Butyl (2,3-dihydro-3-oxo-1,4-triazolo [4,3-a] pyridin-6-yl) carboxylate (1-3)

The obtained compound 1-2 was dissolved in 35 ml of toluene and the solution was slowly added to a solution of 1.15 g, 3.9 mmol of bis- (trichloromethyl) carbonate in 35 ml of toluene. The mixture was then refluxed for 1.2 hours, cooled, added to water and extracted with ethyl acetate. The organic portion was dried over sodium sulfate, evaporated, and purified by flash chromatography on silica gel to give compound 1-3.

¹ H-NMR (300 MHz, DMSO-d 6): δ 1.58 (s, 9H), 7.25 (d, 1H), 7.45 (d, 1H), 8.25 (s, 1H), 12.40 (s, 1 H).

1-5

ΗΝ

CH ₂ CH ₂ OH

2- (N-CBZ-piperidin-4-yl) ethyl iodide (1-4)

A mixture of 4- (2-hydroxyethyl) piperidine (Aldrich) (50 g, 38.7 mmol), saturated sodium bicarbonate (40 ml) and methylene chloride (150 ml) was mixed with benzyl chloroformate (6.05 ml, 42.5 mmol). The mixture was stirred at room temperature for 2.5 hours, then the organic layer was separated, washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give the protected alcohol. in the form of a colorless oil.

^T H-NMR (300 MHz, CDC1 _3): δ 7.26 (m, 5 H), 5.13 (s, 2H), 4.23 (d, 2H), 3.63 (t, 2H), 2 85 (t, 2H), 1.83 (d, 2H), 1.68 (m, 2H), 1.43 (m, 1H), 1.03 (m, 2H).

6.3 g (23.9 mmol) of this protected alcohol are mixed with 7.0 g (23.9 mmol) of triphenyl. phosphine, 6.06 g, 23.9 mmol of iodine, and 1.95 g, 28.7 mmol of imidazole in 100 ml of benzene, and the mixture is refluxed for 2.5 hours. The solution was cooled, filtered and the filtrate was evaporated. The residue is chromatographed on silica gel using 1: 1 ethyl acetate: hexane to give compound 1-4 as a white solid.

1 H-NMR (300 MHz, CDCl ₃ ): δ 7.26 (m, 5H), 5.14 (s, 2H), 4.23 (d, 2H), 3.86 (m, 4H), 1, 85 (d, 2H); 1.68 (m, 2H); 1.45 (m, 2H);

1 H), 1.03 (m, 2H).

3- [2,3-Dihydro-3-oxo- [2- (N-CBZ-piperidin-4-yl) -ethyl] -1,2,4-triazolo [4,3-a] pyridine-6- yl] carboxylic acid (1-5)

Compound 1-3 (350 mg, 1.6 mmol) was dissolved in acetonitrile (20 mL), potassium carbonate powder (630 mg) was added and the solution was heated at 60 ° C for 20 h. The mixture was cooled to 25 ° C, poured into water and extracted with ethyl acetate. The organic portion was dried over sodium sulfate, evaporated, and flash chromatographed on silica gel using 35% ethyl acetate in hexane to give the desired ester as a yellow oil.

This crude tert-butyl ester is converted to the acid by treatment with a mixture of 15 mL of methylene chloride and 15 mL of trifluoroacetic acid at 0 C C, then heated at 25 C. C for 1.2 h. Then the mixture is evaporated to dryness in vacuo, the residue is mixed with water and extracted with ethyl acetate. The organic portion was dried over sodium sulfate, concentrated, and the product was crystallized from ethyl acetate-

dad and of ether in a ratio of 25: 1, thus get the resulting product 1-5 ako light yellow powder. ¹ H-NMR (300MHz, DMSO-d6): δ 1.05 (m, 2H) 1.45 (m, 1 H), 1.75 (m , 4H), 2 79 (m, 2H), 3.95 (q. 4H) 5.05 (s, 2H) 7.30 (m, 6H), 7.50 (d, 1 H), 8.25 (s, 1H).

CBZ (CH ₂ ) ₂

/

CBZ

3 - [[[2,3-Dihydro-3-oxo- [2- (N-CBZ-piperidin-4-yl) ethyl] -1,2,4-triazolo [4,3-a] pyridine- 6-yl] carboxylamino] propionic acid (1-6)

A solution of 75 mg, 0.18 mmol of compound 1-5 in 1 mL of dimethylformamide was mixed with 40 mg, 0.26 mmol of hydroxybenzotriazole, and then 87 μΐ, 0.5 mmol of diisopropylethylamine, 40 mg, 0.25 mmol of ethyl- 1-aminopropionate hydrochloride and 50 mg, 0.26 mmol of EDC. The resulting mixture was stirred at 25 ° C for 15 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic portion was washed with water and saturated brine, dried over sodium sulfate and evaporated to give the desired ester.

This crude ester was dissolved in 5 mL of THF and 5 mL of water and 0.37 mL of a 1 M aqueous lithium hydroxide solution was added. The mixture was stirred at 25 ° C for 3 hours, then dissolved in water and extracted with ethyl acetate. The organic portion was washed with water and saturated brine, dried over sodium sulfate and evaporated to give the title product 1-6, mp 201-203 ° C with decomposition.

Me ₃ Sil, CH ₃ CN

1-7

3 - [[[2,3-Dihydro-3-oxo-2- [2- (piperidin-4-yl) ethyl] 1,2,4-triazolo [4,3-a] pyridin-6-yl] acid ] carboxyl] amino] propionic (1-7)

A solution of Compound 1-6 (64 mg, 0.129 mmol) in acetonitrile (15 mL) was treated with iodotrimethylsilane (107.0 mg, 0.533 mmol) at 0 ° C and stirred for half an hour. The reaction is quenched by pouring the mixture into water and extracted with diethyl ether, and the extract is chromatographed on silica using a 10: 1: 1 mixture of ethanol, ammonia and water to give a white foam. After crystallization from ethanol, the resulting product 1-7 is obtained as a white solid, m.p. 267-269 ° C.

CBZN) - (CH ₂ ) ₂ -N

N

COOH

CICO ₂ i-Bu, Et ₃ N CH ₂ Cl ₂ / \ X0 ₂ H ^H 2 ^N χ NHSO ₂ C ₄ H ₉ H ²

./-ARE YOU

NH4-NH4N-NHSO ₂ C ₄ H ₉ n

A-4

Me Sil _q as ₂ h ^{CH? CN}

HN

p H r NHSO ₂ C4 H ₉ H

2- (S) - [6- (Butylsulfonyl) amino] -3 - [[[2,3-dihydro-2-oxo-2- [2- (N-CBZ-piperidin-4-yl) ethyl] -1], 2,4-triazolo [4,3-a] pyridin-6-yl] carboxyl] amino] propionic acid (1-8)

Compound 1-5 is bound to compound A-4 in the manner described for compound 1-6 to give product 1-8.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 8.26 (t, 1H), 8.50 (s, 1H),

7.63 (d, 1H), 7.54 (d, 1H), 7.4-7.31 (m, 6H), 5.01 (s,

2H), 4.10 (m, 1H), 3.96 (m, 4H), 3.60 (m, 1H), 3.46 (m,

1H), 2.95 (t, 2H), 2.73 (brm, 2H), 1.71 (m, 2H), 1.53 (m, 2H)

2H), 1.46 (m, 1H), 1.01 (m, 2H), 0.83 (t, 3H).

2- (S) - [(N-Butylsulfonyl) amino] -3 - [[[2,3-dihydro-3-oxo-2 - [(piperidin-4-yl) ethyl] -1,2,4-triazole] [ 4,3-a] pyridin-6-yl] carboxyl] amino] propionic acid (1-9)

Compound 1-8 is treated with trimethylsilyl iodide in methyl cyanide as described for compound 1-7 to afford the desired product 1-9.

¹ H-NMR (300 MHz, D ₂ O): δ 8.10 (s, 1H), 7.43 (d, 1H), 7.15 (d, 1H), 4.00 (m, 4H), 3.60 (d, 2H), 3.31 (m, 2H), 3.23 (d, 2H), 3.93 (m, 2H), 3.81 (t, 2H), 1.93 (d 2H, 1.80 (m, 2H), 1.6-1.23 (m, 7H), 0.85 (t, 3H).

Scheme 2

NBS, BPO CCI ₄

CH ₃ O ₂ C _x 2;

br

2-3

Methyl 6-methylpyridine-3-carboxylate (2-2)

A solution of 5 g, 36.5 mmol of 6-methylnicotinic acid (2-1) in 100 ml of anhydrous methanol is placed in a 250 ml three-necked flask equipped with an addition funnel, a perpendicular reflux condenser and a drying tube containing calcium chloride. The reaction solution was cooled to -15 ° C and an ice-acetone bath and sulfonyl chloride (5 mL, 69.1 mmol) was added dropwise. The solution was then refluxed for 3 hours, then cooled and the solvent was evaporated under reduced pressure. The resulting white solid was treated with 60 mL of saturated sodium bicarbonate solution and extracted with 3 x 50 mL of methylene chloride. The extracts were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting oil crystallizes on standing to give the resulting product 2-2 as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 9.05 (d, J = 1.4 Hz, 1H), 8.08 (dd, J = 1.4 and 6.8 Hz), 7.19 (d, J = 6.8 Hz, 1H), 3.98 (s, 3H), 2.63 (s, 3H).

Methyl 6-bromomethylpyridine-3-carboxylate (2-3)

10.6 g, 71.5 mmol of 2-2 are mixed with 12.73 g,

71.5 mmol NBS, 100 mg benzoyl peroxide and 200 ml carbon tetrachloride and the mixture was refluxed for 18 hours under an inert atmosphere. Then the reaction solution was cooled, filtered and evaporated to an orange oil which was flash chromatographed on silica gel using 20% ethyl acetate in hexane to give the desired pyridyl bromide 2-3. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 9.05 (d, J = 1.4 Hz, 1H), 8.08 (dd, J = 1.4 and 6.8 Hz), 7.19 (d, J = 6.8 Hz, 1 H), 5.38 (s, 2 H), 3.98 (s, 3 H).

BOC

CO ₂ CH ₃ triphosgene DMA, toluene

CO ₂ CH ₃

Methyl 6- [2- (N-Boc-piperidin-4-yl) ethylamino] methylpyridine-3-carboxylate (2-5)

A mixture of 1.0 g, 4.34 mmol of 2-3, 2.16 g, 10.0 mmol of 2-4 and 0.66 g, 4.4 mmol of potassium carbonate in 100 mL of anhydrous methyl cyanide was placed in a flask with 250 ml, and the mixture was refluxed for 3 hours, then cooled and filtered. The filtrate was evaporated under reduced pressure and the residue was chromatographed on silica gel using 10% methanol in ethyl acetate as eluent to give 2-5 as a yellow residue.

¹ H-NMR (CDCl ₃ ): δ 9.18 (d, J = 1.4Hz, 1H), 8.15 (dd, J =

1.4 and 6.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.08 (br.d, J = 12 Hz, 2H), 3.98 (s, 2H), 3.95 (s, 3H), 2.75 (overlapping m, 6H), 1.78 (d, J = 12.0 Hz, 2H), 1.5 (overlapping with m, 4H), 1.4 (s, 9H). 0.98 (m, 2H).

- 45 Methyl-1- (chlorocarbonyl) -2,3-dihydro-3-oxo-2 - [[2- (N-Bocpiperidin-4-yl) ethyl] imidazole [1,5-a] pyridin-6-yl ] carboxylate (2-6)

Compound 2-5 (480 mg, 1.27 mmol) was dissolved in toluene (50 mL), N, N-dimethylaniline (645 mL, 4.08 mmol) was added and the solution was cooled to 0 ° C. A solution of 1.13 g, 3.18 mmol of triphosgene in 15 mL of toluene is then added dropwise over 30 minutes. The resulting solution was heated at 100 ° C for 1.5 h, washed twice with 1 M hydrochloric acid, water, and brine (50 mL each), dried over sodium sulfate and evaporated to give 515 mg of a yellow crystalline solid. 2-6.

1 H-NMR (CDCl ₃ ): δ 8.82 (d, J = 1.4Hz, 1H), 8.25 (d, J = 6.8Hz, 1H), 7.91 (d, J = 6.8 Hz, 1H), 4.08 (br.d, J = 12 Hz, 2H), 3.98 (s, 2H), 3.95 (s, 3H), 2.75 (overlapping m, 6H), 1.78 (d, J = 12.0 Hz, 2H), 1.5 (overlapping m, 3H),

1.4 (s, 9H). 0.98 (m, 2H).

side

CO ₂ CH ₃

Et _? NH-HCl

CH ₂ Cl ₂ , NaHCO ₃

2-6

CO ₂ CH ₃

2-7

Methyl l - [(N, N-diethylamino) carbonyl] -2,3-dihydro-3-oxo-2 - [[2- (N-Boc-piperidin-4-yl) ethyl] imidazo [l, 5-a pyridin-6-yl] carboxylate (2-7)

0.3 g (0.64 mmol) of 2-6 was dissolved in 100 mL of methylene chloride and 105 mg (0.97 mmol) of diethylamine hydrochloride was added along with 50 mL of saturated sodium bicarbonate solution. The biphasic mixture was stirred for one hour, then the organic layer was separated and washed with 50 ml of 10% citric acid and then with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated to give the product 2-7.

¹ H-NMR (CDCl ₃ ): δ 8.45 (d, J = 1.4Hz, 1H), 7.15 (dd, J =

1.4 and 6.8 Hz, 1H), 6.78 (d, J = 6.8 Hz, 1H), 4.08 (m, 4H), 3.95 (s, 3H), 3.51 ( m, 4H), 2.75 (m, 3H), 1.78 (d, J = 12.0 Hz, 2H), 1.5 (overlapping m, 4H), 1.4 (s, 9H), 1.1 (t, 6H), 0.98 (m, 2H).

T. butyl-1 - [[(N, N-diethylamino) carbonyl] -2,3-dihydro-3-oxo-2 - [[2- (N-Boc-piperidin-4-yl) ethyl] imidazole [1] [5-a] pyrimidin-6-yl] carbonyl] aminopropionate (2-8)

Compound 2-7 (315 mg, 0.64 mmol) was dissolved in methanol (10 mL) containing water (15 mL) and 1 M sodium hydroxide (0.725 mL) was added and the mixture was stirred at room temperature for 3.5 h. The organic solvent was evaporated under reduced pressure, the aqueous residue acidified with citric acid and extracted with methylene chloride. The organic extracts were washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give the desired acid.

¹ H-NMR (CDCl ₃ ): δ 8.32 (d, J = 1.4 Hz) 1H), 7.10 (dd, J = 1.4 and 6.8 Hz, 1H), 6.78 (d, J = 6.8Hz, 1H), 4.08 (m, 4H) 3.51 (m, 4H); 2.75 (m, 3H); 1.78 (d, J) = 12.0 Hz, 2H), 1.5 (overlaps with m, 4H), 1.4 (s, 9H), 1.1 (t, , 6H), 0.98 (m, 2H).

ΗΝ

105 mg, 0.215 mmol of this acid was dissolved in 10 mL of methylene chloride, 48 mL, 0.47 mmol of Et2 N was added and the solution was cooled to -10 ° C. Isobutyl chloroformate (30 ml, 2.36 mmol) was added and the mixture was stirred at -10 ° C for 30 min. A solution of 58.7 mg, 323 mmol of β-alanine-tert-butyl ester hydrochloride and 32 ml, 0.323 mmol of Et ₃ N in 10 ml of methylene chloride was then added and the solution was allowed to warm to room temperature. Then the solution was washed with 10% citric acid, water and saturated sodium chloride solution (10 ml each) and dried over sodium sulfate, evaporated and the residue chromatographed to give the product 2-8.

1 H-NMR (CDCl ₃ ): δ 8.16 (s, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.63 (t, J = 5.6 Hz, 1H), 4.08 (m, 4H), 3.51 (m, 6H), 2.75 (m, 2H), 2.45 (m, 2H) 1.78 (d, J = 12.0 Hz, 2H), 1.5 (overlapping m, 6H), 1.4 (s, 9H), 1.37 (s, 9H), 1.1 (t, 6H), 0.98 (m, 2H).

1 - [[(N, N-Diethylamino) carbonyl] -2,3-dihydro-3-oxo-2 - [[2- (piperidin-4-yl) ethyl] imidazole [1,5-a] pyridin-6- acid yl] carbonyl] propionic (2-9)

Compound 2-8 (100 mg, 0.16 mmol) was dissolved in ethyl acetate (20 mL) and anhydrous hydrogen chloride was bubbled through the solution at 0 ° C for 5 min, then stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure, the residue was triturated with ethyl acetate and filtered to give the title product 2-9.

¹ H-NMR (DMSO-d 6): δ 8.90 (br.s, 1H), 8.60 (br.s, (s, 1H), 7.6 (t, 3H), 7.1 (d (1H),

4H), 3.51 (m, 6H), 2.75 (m, 2H),

J = 12.0 Hz, 2H), 1.5 (overlaps

0.98 (m, 2 H).

8.60 (br •with, 1H), 8.3 89 (D, 1H), 4.08 (M, 45 (M, 2H), 1.78 (D, m. 6H), 1.1 (T, 6H),

₂ , Ph ₃ P

HN ^/ -A-CH ₂ CH, OH BOCN ₂ -CH ₂ CH ₂ OH -7- / NaOH ^m- dioxane imidazole benzene

2-11

BOC

CH ₂ CH ₂ NH ₂

CH ₂ CH ₂ I 1. NaN ₃ , DMSO g ₀ Q _N 2. Ph ₃ P, THF

2i12

2- (N-Boc-piperidin-4-yl) ethanol (2-11)

130 g, 1.0 moles of 4-piperidine-2-ethanol (2-10, Aidrich) are dissolved in 700 ml of dioxane, cooled to 0 ° C and 336 ml, 1.0 moles of 3 M sodium hydroxide are added and 221.8 g, 1.0 moles of di-tert-butyl dicarbonate. Remove the ice bath and stir the reaction overnight. The reaction mixture was then concentrated, diluted with water and extracted with ether. The ether layers were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give the final product 2-11.

Rf = 0.37 in 1: 1 ethyl acetate: hexanes using ninhydrin as a dye.

¹ H-NMR (CDCl ₃ ): δ 4.07 (bs, 2H), 3.7 (bs, 2H), 2.7 (t, J =

12.5 Hz, 2H), 1.8-1.6 (m, 6H), 1.51 (s, 9H), 1.1 (ddd, J = 4.3, 12.5 and 12.0 Hz) , 2H).

2- (N-Boc-piperidin-4-yl) ethyl iodide (2-12)

10.42 g, 0.048 mol of compound 2-11 is dissolved in 400 ml of benzene, then 4.66 g, 0.068 mol of imidazole, 15.24 g, 0.05 mol of triphenylphosphine and 0.048 mol of iodine are added at room temperature. After 6 hours, the reaction mixture was filtered and the filtrate was evaporated to give a dark residue. This residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexanes to afford 2-12 as a yellow oil.

2- (N-Boc-piperidin-4-yl) -ethylamine (2-4)

To 27.9 g, 0.082 mol of compound 2-12 dissolved in 40 mL of DMSO was added 5.01 g, 0.086 moles of sodium azide at room temperature, and the resulting solution was heated at 65 ° C for 2 hours. The cooled reaction mixture was diluted with 250 mL of ethyl acetate, extracted with 2 x 100 mL of water and 2 x 50 mL of saturated sodium chloride solution, then dried over magnesium sulfate. Removal of the solvent gave the desired azide as a pale yellow oil, Rf = 0.5 using silica gel and 70% acetone in hexane.

To 19.3 g, 0.076 moles of this azide in a mixture of 400 mL of THF and 195 mL of water was added 80.0 g (0.305 mol) of triphenylphosphine simultaneously at room temperature. The mixture was stirred at room temperature for 3 hours and then the organic solvent was evaporated in vacuo. The residue was acidified to pH 2 using a 10% potassium hydrogen sulfate solution and then extracted with 4 x 100 mL of ethyl acetate. The organic extracts are extracted with 2 x 100 ml of 10% potassium bisulfate, the aqueous phases are combined and the pH is adjusted to 10 by addition of 2 M sodium hydroxide. The solution was then extracted with 4 x 200 mL methylene chloride. The extracts were combined, dried (MgSO 4) and the solvent was evaporated to give the product 2-4 as an oil.

= 0.3 using silica gel and 10% methanol in chloroform / ammonia.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 4.05 (broad d, 2H), 2.72 (t, J = 7.2 Hz, 2H), 2.62 (m, 2H), 1, 64 (d, J = 12.2 Hz, 2H), 1.43 (s, 9H), 1.42-1.32 (m, 5H), 1.09 (m, 2H).

Scheme 3

H

1 HCl, CH ₃ OH (3-1 a)

2. K ₂ CO ₃ , CH ₃ CN Br ₂ CH ₂ CH ₂ Br

br

3-1

3-2

Dimethyl 1- (2-bromomethyl) pyrazole-3,5-diacarboxylate (3-2)

A solution of 75 g (431 mmol) of pyrazole-3,5-dicarboxylic acid in 1 L of anhydrous methanol is treated by passing anhydrous hydrogen chloride gas. The hydrogen chloride was passed through for 30 minutes, then the solution was allowed to cool to room temperature and allowed to stand for 16 hours. The solution was then refluxed for 3 hours, then cooled and the solvent was evaporated under reduced pressure. The resulting white solid was treated with 600 mL of saturated sodium bicarbonate solution and extracted with 3 x 500 mL of methylene chloride. The extracts were combined, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The resulting white solid was recrystallized from methanol with anhydrous ether to give the resulting dimethylpyrazole-3,5-dicarboxylate (3-1a). ¹ H-NMR (CDCl ₃ ): δ 7.38 (s, 1H), 3.98 (s, 3H), 3.93 (s, 3H).

To a solution of 5.0 g (27.2 mmol) of this ester in 150 mL of anhydrous acetonitrile was added 5.2 g (40.0 mmol) of potassium carbonate and 25.0 mL (291 mmol) of 1,2-dibromomethane. The resulting mixture was refluxed under argon. After 25 minutes, the resulting suspension was cooled, filtered, and the filtrate was evaporated to dryness under reduced pressure, then stored under high vacuum for 12 hours. The resulting white solid was recrystallized from hexane to give the resulting product 3-2 as a white solid.

¹ H-NMR (CDCl ₃ ): δ 7.38 (s, 1H), 5.03 (t, J = 8.2 Hz, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.75 (t, J = 8.5 Hz, 2H).

br

side

CH ₂ CH ₂ NH ₂

2-4

3-2

DIEA, Cl CH ₃ CN

Methyl- [4,5,6-tetrahydro-4-oxo-5- [2- (N-Boe-piperidin-4-yl) ethyl] pyrazolo [1,5-a] pyrazin-2 -yl] carboxylate (3-3)

A solution of 14.0 g, 48.0 mmol of compound 3-2, 25 mL, 144 mmol of diisopropylethylamine, 12.0 g, 52.6 mmol of Boc-4-ami52 noethylpiperidine and 2.39 g, 0.3 mmol of potassium iodide in 250 ml of methyl cyanide was refluxed under nitrogen for 4.5 hours, then the mixture was filtered and evaporated under reduced pressure. The resulting yellow residue is chromatographed on silica gel using ethyl acetate to give the resulting product 3-3 as an off-white crystalline solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.15 (s, 1H), 4.29 (t, J = 7.0 Hz, 2H), 3.93 (br.d, J = 12, 0 Hz, 2H), 3.76 (s, 3H), 3.61 (t, J = 5.3 Hz, 2H), 3.42 (t, J = 7.3 Hz, 2H), 2.65 (t, J = 7.6Hz, 2H), 1.55 (d, J = 12.5Hz, 2H), 1.38 (m, 2H), 1.33-1.25 (m, 1H) 1.27 (s, 9H); 1.01 (m, 2H).

A solution of 14.05 mg, 0.335 mmol of lithium hydroxide in 10 mL of water was added to a solution of 90.81 mg, 0.223 mmol of the compound.

3-3 in 10 ml of methanol, the mixture is heated at 60 ° C for 2.5 hours, then cooled and the methanol is evaporated under reduced pressure. The remaining aqueous phase was acidified with a 10% aqueous citric acid solution and then extracted with 2 x 50 ml methylene chloride. The organic extracts were combined, dried over sodium sulfate and evaporated to give the title acid as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.43 (s, 1H), 4.48 (t, J = 7.0

Hz, 2H), 4.01 (br.d, J: = 12.0 Hz, 2H) 3.77 (t, J = 5.3) Hz, 2H), 3.51 (t, J = 7.3 Hz, 2H), 2.71 (t, J = 8.3Hz, 2H), 1.72 (d, J = 12.5 Hz, 2H), 1.53 (m, 2H), 1.42-1.37 (M, 1H), 1.35 (s, 9H), 1.10 (m, 2H).

BocN- \

OH

1. LiOH, CH ₃ OH, H ₂ O

2. CICO ₂ -i-Bu, NMM.THF / CH 2 CO ₂ H ₂ n 1 X

H NHSO ₂ C ₄ H ₉

BocN- \

NHSO ₂ C ₄ H ₉

M

2 (S) - [(n-Butylsulfonyl) amino-3- [4,5,6,7-tetrahydro-4-oxo-5- [2- (N-Boc-piperidin-4-yl) ethyl] pyrazole acid [1,5-a] pyrazin-2-yl] carbonyl] aminopropionic acid (3-4)

1.75 ml, 13.35 mmol of isobutyl chloroformate is added to a solution containing 4.98 g, 12.72 mmol of this acid and 1.53 ml, 14.00 mmol of N-methylmorpholine in 100 ml of THF, the solution is cooled to The mixture was stirred under an atmosphere of anhydrous nitrogen for 1 hour, after which time HPLC analysis of the sampled sample showed that the reaction was over 90% complete. The N-methylmorpholine hydrochloride is filtered off and the filtrate is poured into a solution of 4.30 g, 16.54 mmol of compound A-4, 4.27 mL, 33.10 mmol of diisopropylethylamine, 60 mL of THF and 20 mL of water. THF was evaporated under reduced pressure, the aqueous portion was acidified with saturated sodium bisulfate and extracted with ethyl acetate (3 x 200 mL). The extracts were combined, dried over sodium sulfate, filtered and evaporated to a red oil, from which product 3-4 crystallized as a white solid.

1 H-NMR (DMSO-d ₆ ): δ 8.31 (t, J = 6Hz, 1H), 7.62 (d, J =

8.5 Hz, 1H), 7.01 (s, 1H), 4.43 (t, J = 6.6 Hz, 2H), 4.11 (m, 1H), 3.92 (d, J = 12 Hz, 2H), 3.80 (t, J = 6.6 Hz, 2H), 3.51 (t, J = 7.3 Hz, 2H), 3.65 (m, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 1.70 (d, J = 11 Hz, 2H), 1.53 (m, 2H) ), 1.60 - 1.49 (overlapping m, 5H), 1.40 (s,

9Η), 1.28 (q, J = 7.1Hz, 2H), 1.05 (m, 2H), 0.79 (t, J =

7.1 Hz, 3H).

2 (S) - [(n-Butylsulfonyl) amino-3 [4,5,6,7-tetrahydro-4-oxo-5- [2- (piperidin-4-yl) ethyl] pyrazole [1,5] acid monohydrochloride -a] pyrazin-2-yl] carbonyl] aminopropionic acid (3-5)

HN

N

I

H

CO ₂ H NSO ₂ C ₄ H

A solution of Compound 3-4 (278 mg, 0.437 mmol) in ethyl acetate (30 mL) was cooled to 0 ° C and hydrogen chloride gas was bubbled through for 3 minutes. The reaction mixture was then allowed to warm to room temperature, stirred for 30 minutes and then evaporated to dryness on a rotary evaporator. The residual white solid was recrystallized from 90:10 ethanol / water, filtered and dried under vacuum with phosphorus pentoxide to give the title product 3-5 as a white solid.

1 H-NMR (DMSO-d ₆ ): δ 8.95 (br.s, 1H), 8.33 (t, J = 5.7 Hz, 1H), 7.64 (d, J = 9 Hz, 1H), 7.02 (s, 1H), 4.35 (t, J = 5.1Hz, 2H), 4.10 (m, 1H), 3.81 (t, J = 5.2Hz, 2H), 3.6-3.4 (m, 4H), 3.21 (d, J = 10.5 Hz, 2H), 2.95 (t, J = 7.8 Hz, 2H), 2, 81 (br.m, 2H), 1.96 (d, J = 11Hz, 2H), 1.62-1.2 (overlapping m, 9H), 0.80 (t, J = 7.3Hz) , 2H).

Scheme 4

CO ₂ H

NHCBZ

CH ₃ OH

HCl hci-h ₂ n ^x 2

H

CO ₂ CH ₃

NHCBZ

4-1

4-1 a

Methyl 2 (S) -N-benzyloxycarbonylamino-3-aminopropionate hydrochloride (4-la)

Conventionally supplied 2 (S) -N-benzyloxycarbonylamino-3-aminopropionic acid (Fluka) is refluxed in methanolic hydrochloric acid for 2.5 hours, then the mixture is evaporated and the residue is crystallized from methanol / ether to give a solid. material.

¹ H-NMR (300 MHz, DMSO-d 6): 5.15 (s, 2H), 4.56 (m, 1H), 2H).

final product 4-la as white δ 7.63 (m, 5H), 5.93 (d, 1H),

3.95 - 3.83 (m, 2H), 3.73 (s,

side

CO ₂ H x - x., CO ₂ CH ₃ ⁿ NHCBZ

4-1a

4-3

Methyl-2 (S) - [(CBZ) amino] -3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2 (N-Boc-piperidin-4-yl) ethyl]] pyrazolo [1,5-a] pyrazin-2-yl] carbonyl] amino] propionate (4-2)

A solution of 5.6 g, 14.0 mmol of compound 3-3, 4.5 g, 15.5 mmol of N _and J methyl ester _and -Cbz-L-2,3-diaminopropionic acid hydrochloride, 2.37 g, 15.5 mmol HOBT and 4.1 mL, 29.5 mmol Et 2 N in 65 mL anhydrous DMF were stirred at room temperature under nitrogen for 48 hours. The DMF is then evaporated under reduced pressure and the residue is dissolved in 700 ml of ethyl acetate and washed successively with 100 ml of saturated sodium bicarbonate solution, water, 10% citric acid, water again and saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The resulting clear glassy mass was chromatographed on silica gel using 3% methanol in methylene chloride to afford pure 4-2 as a white solid.

¹ H-NMR (CDCl ₃ ): δ 7.43 (m, 5H), 7.35 (s, 1H), 7.18 (t, J =

6.5 Hz, 1H), 5.98 (d, J = 6.8 Hz, 1H), 5.09 (s, 2H), 4.59 (m, 1H), 4.38 (m, 2H) 4.10 (br.d, J = 12Hz, 2H), 3.8 (s,

3H), 3.73 (t, J = 5.3 Hz, 2H), 2.71 (t, J = 8.3 Hz, 2H),

1.72 (d, J = 12.5 Hz, 2H), 1.53 (m, 2H), 1.42-1.37 (m,

1H), 1.35 (s, 9H), 1.10 (m, 2H).

Methyl L-2 (S) -amino-3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2- (N-Bocp.perperidin-4-yl) ethyl] pyrazole] [1,5-a] pyrazin-2-yl] carbonyl] amino] propionate (4-3)

To a solution of 4-2 (6.3 g, 10.26 mmol) in methanol (700 mL) was added 10% palladium on charcoal (650 mg) and the resulting mixture was stirred at 50 psi hydrogen for 48 hours. The catalyst was filtered off through Celite and the filtrate was evaporated to a colorless glass which was triturated with diethyl ether and filtered to give 4-3 as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.43 (m, 5H), 7.35 (s, 1H), 7.18 (t, J = 6.5 Hz, 1H), 5.98 (d, J = 6.8 Hz, 1 H), 5.09 (s, 2 H),

4.59 (m, s, 3H), 1.72 (d, 1.35 (s,

1H), 4.38 (m, 2H), 4.10 (br.d, J = 12 Hz, 2H), 3.81 3.73 (t, J = 5.3 Hz, 2H), 2.71 (t, J = 8.3 Hz, 2H), J = 12.5 Hz, 2H), 1.53 (m, 2H), 1.42-1.37 (m, 1H) 9H), 1.10 (m, 2H).

Methyl 2 (S) - (acetylamino) -3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2 (N-Boe-Piperidin-4-yl) ethyl] pyrazolo [1 5-a] pyrazin-2-yl] carbonyl] amino] propionate (4-4) ml, 0.76 mmol of acetic anhydride is added to a solution of 350 mg, 0.69 mmol of compound 4-3, cooled to 0 ° C, in 10 mL of THF. The resulting solution is allowed to warm to room temperature, stirred at this temperature for 18 hours, then evaporated and the residue is dissolved in 50 ml of ethyl acetate and washed successively with 25 ml of sodium bicarbonate solution each time, water, 10% potassium hydrogen sulphate, water and saturated. sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated to a colorless residue which was chromatographed on silica gel using 3% methanol in methylene chloride to afford 4-4 as a white solid.

¹ H-NMR (CDCl ₃ ): δ 7.29 (m, 1H), 7.24 (t, J = 6.4 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H) 4.79 (m, 1H), 4.38 (m, 2H), 4.10 (br.d, J = 12Hz, 2H), 3.81 (s, 3H), 3.80 (m, 2H), 3.73 (t, J = 5.3Hz, 2H), 2.71 (t, J = 8.3Hz, 2H), 2.01 (s, 3H),

1.72 (d, J = 12.5 Hz, 2H), 1.57 (m, 2H), 1.42-1.37 (m,

1H), 1.37 (s, 9H), 1.09 (m, 2H).

2 (S) - (Acetylamino) -3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2- (piperidin-4-yl) ethyl] pyrazolo [1,5-a] pyrazine] -2-yl] carbonyl] amino] propionic acid (4-5)

A solution of 203 mg, 0.38 mmol, 4-4, 0.76 mL, 0.76 mmol 1 M lithium hydroxide, 5 mL water, 5 mL methanol, and 5 mL THF was stirred overnight at room temperature. The organic solvent is evaporated under reduced pressure, the residue is diluted with 25 ml of water, acidified with 10% potassium bisulfate and extracted with ethyl acetate. The ethyl acetate extract was washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give the desired acid.

¹ H-NMR (CDCl ₃ ): δ 7.93 (br, 1H), 7.81 (br, 1H), 7.29 (s, 1H), 4.79 (m, 1H), 4.34 (m (2H), 4.10 (br.d, J = 12Hz, 2H), 3.80 (br.m, 2H), 3.73 (br.t, 2H), 2.71 (t, J = 8.3 Hz, 2H), 2.11 (s, 3H), 1.72 (d, J = 12.5 Hz, 2H), 1.57 (m, 2H), 1.42

- 1.37 (m, 1H), 1.37 (s, 9H), 1.12 (m, 2H).

This acid (169 mg, 32.8 mmol) was dissolved in ethyl acetate (50 mL), cooled to 0 ° C and anhydrous hydrogen chloride was bubbled through the solution for 30 min. Then the solvent was evaporated in vacuo, the residue was triturated with anhydrous ether, the solution was filtered and dried with phosphorus pentoxide to give the product 4-5 as a white solid, mp 150-156 ° C.

4-3

HCl h ₂ n 2

H NHCBZ

4-1

BocN (CH ₂ ) ₂ - _{N at 2} h

1. H ₂ . Pd / C

- H N

2. HCl / EtOAc

N

NHCBZ

2 (S) - [(Cbz-amino)] - 3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2- (N-Cbz-piperidin-4-yl) ethyl] pyrazole] [1,5-a] pyrazin-2-yl] carbonyl] amino] propionic (4-6)

Compound 4-3 is reacted with N _α 4 f _and -CbzL-2,3-diaminopropionic acid (4-1, Fluka) as described for compound 3-4 to give compound 4-6, a double protected addition product .

2 (S) -Amino-3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2 (piperidin-4-yl) ethyl] pyrazolo [1,5-a] pyrazin-2-yl] carbonyl] amino] propionic (4-7)

Compound 4-6 is treated with hydrogen in the presence of palladium on charcoal to give the desired acid with a melting point of 157 ° C, then the boe is removed by treatment with a mixture of hydrochloric acid and ethyl acetate to give pure 4- 7, m.p. 195-198 ° C.

NH 1 H 2 NH _X / CH ₂ CH ₃ NH X

H NHSO ₂ C ₄ H ₉

CO ₂ CH ₃ CISO ₂ C ₄ H ₉

NMM, THF

Methyl 2 (S) - [(n-Butylsulfonylamino)] - 3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2- (N-Cbz-piperidin-4-yl) ethyl] pyrazolo [1,5-a] pyrazin-2-yl] carbonyl] amino] propionate (4-8)

A solution of Compound 4-3 (0.30 g, 0.61 mmol), n-butylsulfonyl chloride (0.91 mmol) and N-methylmorpholine (50 mL) in THF (50 mL) was stirred at room temperature for 12 h. Then the solvent was evaporated under reduced pressure and the resulting oil was dissolved in 50 ml of methylene chloride, the solution was washed with 50 ml of 10% potassium bisulfite, dried over sodium sulfate, filtered and evaporated. The resulting residue is chromatographed on silica gel to give the glassy product 4-8.

¹ H-NMR (CDCl ₃ ): δ 8.31 (t, J = 6Hz, 1H), 7.62 (d, J = 8.5Hz, 1H), 7.01 (s, 1H), 4 43 (t, J = 6.6Hz, 2H), 4.11 (m, 1H), 3.92 (d, J = 12Hz, 2H), 3.83 (s, 3H), 3.80 (t, J =

6.6 Hz, 2H), 3.51 (t, J = 7.3 Hz, 2H), 3.65 (m, 2H), 3.51 (t, J = 6.8, 2H), 2, 96 (t, J = 7.2Hz, 2H), 1.70 (d, J = 11Hz, 2H), 1.53 (m, 2H), 1.60-1.49 (overlap in, 5H) 1.40 (s, 9H), 1.28 (q, J = 7.1Hz, 2H), 1.05 (m, 2H), 0.79 (t, J = 7.1Hz, 3H) ).

Scheme 5 ch ₃ o ₂ c

NCO ₂ CH ₃

CO ₂ CH ₃

3-1 a

NaN ₃ , DMSO

-25 °, 5 hr

CO ₂ CH ₃

1. _H2, Pd / C. EtOH

2. C ₆ H ₆ , reflux

NaOH, CH ₃ OH, H ₂ O

5-5

side

side

Scheme 5 - continued

OH

NH

HOBT, Et ₃ N, CH ₂ Cl ₂ ^ COpCoHc h ₂ n x ²²⁵

H NHSO ₂ C ₄ H _g

A-5 _/ ^ \ ^ - CO ₂ C ₂ H ₅ H _'NHSO2 C ₄ H ₉

1. NaOH, CH ₃ OH, H ₂ O

2. HCl, EtOAc

Dimethyl 1- (3-bromopropyl) pyrazole-3,5-dicarboxylate (5-1)

The compound is obtained as a white crystalline solid using 1,3-dibromopropane in the procedure described above for the preparation of compound 3-2.

¹ H-NMR (CDCl ₃ ): δ 7.38 (s, 1H), 4.95 (t, J = 8.2 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.75 (t, J = 8.5 Hz, 2H), 2.51 (m, 2H).

Dimethyl 1- (3-azidopropyl) pyrazole-3,5-dicarboxylate (5-2)

A solution of Compound 5-1 (1.0 g, 3.45 mmol) in DMSO (10 mL) was treated with NaN ₃ (0.883 g, 13.8 mmol ₎ and stirred at 25 ° C for 5 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic extracts were combined, washed with 2 x 100 mL water and 1 x 100 mL saturated sodium chloride solution, dried over sodium sulfate and evaporated to give compound 5-2 as a colorless oil.

Methyl 5,6,7,8-tetrahydro-4-oxo-4H-pyrazolo [1,5-a] [1,4] diazepin-2-yl-carboxylate (5-3)

A solution of compound 5-2 (851 mg, 3.25 mmol) in absolute ethanol (100 mL) was treated with 10% palladium on charcoal (100 mg) and shaken in a Parr hydrogenator at 50 psi for 5 hours. The catalyst was filtered through celite and the filtrate was evaporated to give 800 mg of a colorless oil. NMR analysis shows that this material is a mixture of 1- (3-aminopropyl) dimethylpyrazole-3,5-dicarboxylate and cyclic diazapineone. The mixture is dissolved in 50 ml of benzene and the solution is refluxed for 15 hours, then evaporated. The resulting off-white solid was recrystallized from methylene chloride-hexane to give 5-3 as a white solid.

Melting point: 220-221 ° C.

¹ H-NMR (CDCl ₃ ): δ 7.36 (s, 1H), 6.42 (br.t, 1H), 4.58 (t,

J = 8.0 Hz, 2H), 3.95 (s, 3H), 3.39 (dt, J = 7.2 Hz, 2H),

2.31 (m, 2 H).

Methyl-5,6,7,8-tetrahydro-4-oxo-5- [2- (N-Boc-piperidin-4-yl) ethyl] -4H-pyrazolo [1,5-a] [1,4] Diazepin-2-yl-carboxylate (5-5)

To a solution of Compound 5-3 (175 mg, 0.83 mmol) in DMF (50 mL) was added 60% sodium hydride (36 mg, 0.91 mmol), the mixture was stirred under nitrogen at 15 ° C for 30 min. A solution of 283 mg is added dropwise over 20 minutes,

0.83 mmol of 2- (N-Boc-piperidin-4-yl) ethyl iodide in 25 mL of DMF. The resulting solution was stirred at -15 ° C for 30 minutes, then allowed to warm to room temperature and stirred overnight. Then

The DMF was evaporated under reduced pressure and the residue was redissolved in ethyl acetate, filtered and chromatographed on silica gel using ethyl acetate as eluent to give pure glassy product 5-5.

¹ H-NMR (CDCl ₃ ): δ 7.24 (s, 1H), 4.50 (t, J = 7.0 Hz, 2H), 3.93 (br.d, J = 12 Hz, 2H) 3.94 (s, 3H), 3.61 (t, J = 5.3 Hz, 2H), 3.42 (t, J = 7.3 Hz, 2H), 2.7 (br.t, J = 6.3 Hz, 2H), 2.3 (m, 2H), 1.55 (d, J = 12.5 Hz, 2H), 1.38 (m, 2H), 1.33-1, 25 (m, 1H); 1.27 (s, 9H); 1.01 (m, 2H).

5,6,7,8-Tetrahydro-4-oxo-5- [2- (N-Boc-piperidin-4-yl) ethyl] -4H-pyrazolo [1,5-a] [1,4] diazepin-2 -yl-carboxylic acid (5-6)

A solution of 166 mg (0.395 mmol) of 5-5 in 10 mL of methanol was treated with 0.435 mL, 0.43 mmol of 1 M sodium hydroxide. The resulting solution was stirred at room temperature for 18 hours and then the methanol was evaporated under reduced pressure. The remaining aqueous phase was acidified with a 10% aqueous citric acid solution and extracted with 2 x 50 ml methylene chloride. The organic extracts were combined, dried over sodium sulfate, and evaporated to give 5-6 as a white solid.

^X H-NMR (CDC1 _3): δ 7.29 (s, 1H), 4.52 (t, J = 7.0 Hz, 2H), 4.12 (br d, J = 12 Hz, 2H) 3.94 (s, 3H), 3.61 (t, J = 5.3)

Hz, 2Η), 3.42 (t, J = 7.3 Hz, 2H), 2.7 (br.t, J = 6.3 Hz,

2H), 2.3 (m, 2H), 1.55 (d, J = 12.5 Hz, 2H), 1.38 (m, 2H),

1.33-1.25 (m, 1H), 1.27 (s, 9H), 1.01 (m, 1H).

Ethyl-2 (S) - [(n-butylsulfonyl) amino] -3 - [[[5,6,7,8-tetrahydro-4-oxo-5- [2- (N-Boe-Piperidin-4-y1) ethyl -4H-pyrazolo [1,5-a] [1,4] diazepin-2-yl] carbonyl] amino] propionate (5-7)

To a solution of 147 mg (0.36 mmol) of 5-6 in 5 mL of methylene chloride was added 115 mg (0.40 mmol) of ethyl 2 (S) -n-butanesulfonamido-3-aminopropionate (A-5), 49 mg, 0 36 mmol of HOBT and 0.10 mL, 0.724 mmol of Et2N in 50 mL of methylene chloride and the solution was stirred under nitrogen at room temperature for 18 h. The reaction solution is washed successively with 20 ml of saturated sodium bicarbonate, water, 10% citric acid, again with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The resulting clear glassy product was chromatographed on silica gel using 5% methanol in ethyl acetate to give pure product 5-7. ¹ H-NMR (CDCl ₃ ): δ 7.32 (s, 1H), 7.24 (t, J = 6.8 Hz, 1H),

5.54 (t, J = 7.2Hz, 1H), 4.43 (t, J = 7.8Hz, 2H), 4.32 (m, 1H), 4.28 (q, J = 7) 1 Hz, 2H), 4.10 (br.d, J = 12 Hz, 2H), 3.85 (m, 2H), 3.61 (t, J = 5.3 Hz, 2H), 3, 42 (t, J = 7.3 Hz, 2H), 3.03 (t, J = 7.1 Hz, 2H), 2.7 (br.t, J = 6.3 Hz, 2H), 2, 3 (m, 2H), 1.65-1.45 (overlapping m, 7H), 1.38 (m, 2H), 1.33-1.25 (m, 1H), 1.37 (s, 9H), 1.30 (t, J = 7.4Hz,

3H), 1.01 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H).

2 (S) - [(n-Butylsulfonyl) amino] -3 - [[[5,6,7,8-tetrahydro-4-oxo-5- [2- (piperidin-4-yl) ethyl] -4H-pyrazole] [1,5-a] [1,4] diazepin-2-yl] carbonyl] amino] propionic acid (5-8)

To a solution of compound 5-7 (100 mg, 0.156 mmol) in methanol (10 mL) was added 1 M sodium hydroxide (160 mL, 0.16 mmol) and water (10 mL). The solution was stirred at room temperature for 3.5 hours, then the methanol was evaporated under reduced pressure, the aqueous phase was acidified with 10% citric acid and extracted with 2 x 50 ml methylene chloride to give the resulting acid.

¹ H-NMR (CDCl ₃ ): δ 17.24 (t, J = 6.8 Hz, 1H), 7.28 (s, 1H),

6.0 (d, J = 7.2Hz, 1H), 4.43 (t, J = 7.8Hz, 2H), 4.32 (m, 1H), 4.10 (br.d, J = 12 Hz, 2H), 3.85 (m, 2H), 3.61 (t, J = 5.3 Hz, 2H), 3.42 (t, J = 7.3 Hz, 2H), 3, O 3 (t, J = 7.1

Hz, 2H), 2.7 (br.t, J = 6.3 Hz, 2H), 2.3 (m, 2H), 1.65

1.45 (overlapping m, 7H), 1.38 (m, 2H), 1.33-1.25 (m,

1H), 1.37 (s, 9H), 1.01 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H).

mg of this acid in 15 ml of ethyl acetate was cooled to 0 ° C and hydrogen chloride gas was bubbled through for 3 minutes. The reaction mixture was warmed to room temperature, stirred for 30 minutes and then evaporated on a rotary evaporator. The white solid obtained is triturated with ether, spread in vacuo with phosphorus pentoxide as a white solid.

¹ H-NMR (DMSO-d ₆ ): δ 8.95 (br.s, 1H), 7.64 (d, J = 9 Hz, 1H), 7

Hz, 2H), 4.10 (m, 1H), 3.81 (t, (m, 4H)), 3.21 (d, J = 10.5 Hz,

2H), 2.81 (br.m, 2H), 1.96 (d, (overlapping m, 9H), 0.80 (t, J solution was filtered and dried to give compound 5-8)

1H), 8.33 (t, J = 5.7Hz, (s, 1H), 4.35 (t, J = 5.1)

J = 5.2 Hz, 2H), 3.6-3.4 2H), 2.95 (t, J = 7.8 Hz,

J = 11 Hz, 2H), 1.62-1.2 = 7.3 Hz, 2H).

Scheme 6

1. Acetone, H ₂ O

2. H ₂ , Pd / C EtOH

6-1 A. cis

6-1 B. trans

Scheme 6 - continued

TFA

CH ₂ CI _{2 3} , ₂

CO ₂ tBu

Ethyl 3-oxo-2- [2- (N-Boc-piperidin-4-yl) ethyl] octahydroimidazo [1,5-a] pyridin-6-yl] carboxylate (51A, 6-1B)

Dissolve 514 mg, 1.1 mmol of 2-6 in 25 mL of acetone, add 10 mL of water and heat at 60 ° C for 3.5 hours. The acetone was evaporated under reduced pressure and the resulting yellow precipitate was filtered off. This crude material was dissolved in 100 ml of toluene and refluxed for 3 hours. Thereafter, toluene was evaporated to a yellow solid.

500 mg, 1.11 mmol of this solid are dissolved in 100 ml of ethanol, 75 mg (10% palladium on charcoal) are added and the mixture is shaken on a Parr hydrogenator at 50 psi for 13 hours. The resulting colorless oil was chromatographed on silica gel using a mixture of 70% ethyl acetate and 30% hexane to give 268 mg of the reducing product cis-6-ΙΑ and 132 mg of the product trans-6-ΙΒ.

Isomer 6-1A 1 H-NMR (CDCl ₃ ): δ 4.15 (m, 1H), 4.06 (m, 2H), 3.68 (s, 3H), 3.41 (m, 2H), 3 22 (m, 1H); 2.90 (m, 1H); 2.80 (m, 2H); 2.68

(m, 2H) , 2.43 (m, 1 H), 2.16 (m, 1 H), 1.81 (M, 1H), 1.69 (M, 2H), 1 60 (m, 1H), 1.45 (with, 9H), 1.43 (M, 3H), 1.39 (M, 1H) 1.11 (m , 2H). isomer 6-1B ^X H-NMR (cdci ₃ ) : δ 4.34 (M, 1H), 4.06 (M, 2H), 3.68 (with, 3H), 3.40 (m , 3H), 3.36 (m, 1H), 3.30 (m, 1H), 3.11 (M, 1H), 2.8 (m, 1 H) , 2.84 (m, 1 H), 2.84 (m, 1 H), 2.67 (M, 2H), 2.63 (M, • 1H), 2 30 (m, 1H), 1.69 (M, 2H), 1.67 (M. 2H), 1.60 (M, 1H) 1.45 (s , 9H), 1.41 (m, 1H), 1.09 (m, 2H).

Tert-butyl (±) cis - [[[3-oxo-2- [2- (N-Boc-piperidin-4-yl) ethyl] octahydroimidazo [1,5-a] pyridin-6-yl] karbony1 amino] propionate (6-2)

Compound 6-1A is hydrolyzed by treatment with 1 M sodium hydroxide in methanol / water as described for compound 1-6 to give the desired acid. This acid is coupled to t-butyl β-alanine ester as described for compound 2-8 to give product 6-2.

¹ H-NMR (CDCl ₃ ): δ 6.32 (t, 1H), 4.06 (m, 2H), 3.98 (m, 1H), 3.56 (m, 5H), 3.21 ( m, 2H), 2.91 (m, 1H), 2.92 (m, 1H), 2.80 (m, 2H), 2.40 (t, 2H), 2.23 (m, 1H), 2.09 (m, 1H), 1.81 (m, 3H), 1.69 (m, 2H), 1.60 (m, 1H), 1.45 (s, 18H), 1.43 (m .

3H), 1.11 (m, 2H).

(±) - cis - [[[3-Oxo-2- [2- (piperidin-4-yl) ethyl] L] octahydroimidazo [1,5-a] pyridin-6-yl] carboxylic acid bony 1] amino] propionic (6-3)

The 65.3 anhydrous was 0.200 stirred and mg, 0.13 mmol of compound 6-2 was dissolved in 10 mL of methylene chloride and the solution was cooled to 0 ° C. Add ml of trifluoroacetic acid, then evaporate under reduced pressure under 1 hour pressure to give 6-3.

¹ H-NMR (CD ₃ OD): δ 4.06 (m, 2H), 3.91 (m, 1H), 3.56 (m, 5H), 3.21 (m, 2H), 2.91 (m, 1H), 2.92 (m, 1H), 2.80 (m, 2H), 2.40 (t, 2H), 2.23 (m, 1H), 2.09 (m, 1H) 1.81 (m, 3H), 1.68 (m 2H), 1.60 (m, 1H), 1.28 (m, 3H), 0.91 (m, 2H).

side

CO ₂ CH nh ₂

ClSQ ₂ NHCO ₂ CH ₂ Ph CH ₂ Cl ₂ , Et ₃ N

CO ₂ CH ₃

NHSO ₂ NHCO ₂ CH ₂ Ph

1. LiOH.THF

2. HCl, EtOAc

W

7-2

CO ₂ H

NHSO ₂ NHCO ₂ CH ₂ Ph

Methyl 2 (S) - [(N-CBZ-Aminosulfonyl) amino] -3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2- (N-Boc-piperidin-4 -y1) ethyl] pyrazolo [1,5-a] pyrazin-2-yl] carbonyl] amino] propionate (7-1)

To a solution of 45.1 μΐ, 0.508 mmol of chlorosulfonyl isocyanate in methylene chloride cooled to 0 ° C was added 53 mL, 0.500 mmol of benzyl alcohol. The reaction mixture was allowed to stand for 90 minutes at 0 ° C and then a solution of 250 mg, 0.508 mmol of 4-3 in methylene chloride containing 142 mL, 1.0 mmol of triethylamine was added. The reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. The pH of the reaction mixture was adjusted to 3.0 with aqueous sodium bisulfite solution and the product was extracted with 3 x 10 mL of methylene chloride. The organic extracts were combined and chromatographed on silica eluting with 95% methylene chloride and 5% methanol to afford 7-1.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.40 (s, 9H), 2.65 (t, 2H), 3.65 (s, 3H), 5.10 (s, 2H), 6 65 (d, 1H); 7.2-7.5 (m, 6H); 8.90 (s, 1H).

2 (S) - [(N-CBZ-Aminosulfonyl) amino] -3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2- (N-Boc-piperidin-4-yl)]] ethyl] pyrazolo [1,5-a] pyrazin-2-yl] carbonyl] amino] propionic acid (7-2)

To a solution of 100 mg of compound 7.1 in 5 mL of THF was added 0.6 mL of 1 M lithium hydroxide and the mixture was stirred at room temperature for 18 hours. The reaction was then quenched by the addition of aqueous sodium bisulfite solution, pH 3.0, and the product was extracted with ethyl acetate (2.times.15 ml). Evaporation of the extracts gave the desired acid.

¹ H-NMR: 1.4 (s, 9H), 2.6 (br.t, 2H), 7-1-7.2 (br.m, 5H), 7.3 (s, 1H).

This acid was dissolved in ethyl acetate, cooled to -5 ° C, and hydrogen chloride gas was bubbled through the solution. The reaction mixture was evaporated and flash chromatographed. using ethyl acetate to give product 7-2 with a melting point greater than 200 ° C with decomposition.

Η 5.92, N 14.20% Η 6.09, N 13.80%.

Analysis: calculated C 44.86, found C 44.50,

2 (S) - (Aminosulfonyl) amino-3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2- (piperidin-4-yl) ethyl] pyrazolo [1,5-a]] pyrazin-2-yl] carbonyl] amino] propionic acid (7-3)

A solution of 70 mg of compound 7-2 in 20 ml of methanol is treated with 35 mg of 10% palladium on charcoal and the mixture is hydrogenated under 1 atm of hydrogen for 18 hours overnight. The mixture was filtered and evaporated to give 46 mg of an oil which was dissolved in ethyl acetate, cooled to 0 ° C and hydrogen chloride gas was bubbled through the mixture for 30 minutes. Evaporation of the reaction mixture afforded 7-3 as a white solid, mp &gt; 200 ° C, FAB, MS, M + 1 = 458.

Scheme 8

co ₂ c ₂ h ₅

NaH.THF

BrCH ₂ CH ₂ Br

ABOUT

side

CH ₂ CH ₂ NH ₂ £ 4

KI, DIEA

BOC-N _{(CH2) 2-N}

co ₂ ch ₃

1. LiOH, CH ₃ OH, H ₂ O

2. EDC, HOBT.TEA

8-3

HChH ₂ N

CO ₂ tBu

Scheme 8 - continued

Diethyl 1- (2-bromomethyl) pyrrole-2,4-dicarboxylate (8-2)

A solution of 5.50 g, 29.4 mmol of diethylpyrrole-2,4-dicarboxylate in 200 mL of tetrahydrofuran was cooled in an ice bath and a suspension of 6.5 g, 68.6 mmol of 60% sodium hydride in 50 mL of tetrahydrofuran was added. . The reaction vessel was allowed to warm to room temperature. The mixture is stirred at this temperature for one hour, then 25.2 ml, 294 mmol of 1,2-dibromoethane are added and the mixture is boiled for 24 hours. under reflux. 50 ml of water are then added and the mixture is evaporated on a rotary evaporator to remove tetrahydrofuran. To the residue was added 100 mL of saturated sodium bicarbonate solution, and the resulting solution was extracted with 4 x 50 mL of methylene chloride. The organic extracts were combined and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was rotary evaporated to a yellow solid which was recrystallized from hexane / ethyl acetate 80:20 to give product 8-2 as a yellow solid.

¹ H-NMR (DMSO-d 6): δ 7.83 (d, 1H), 7.15 (d, 1H), 4.69 (t, 2H), 4.25 (m, 4H), 3.78 (t, 2H), 3.31 (water), 1.29-1.22 (m, 6H).

Ethyl [4,5,6,7-tetrahydro-4-oxo-5- [2- (N-Boc-piperidin-4-yl) ethyl] pyrrolo [l, 5-a] pyrazin-2-yl] carboxylate (8-3)

3.30 g, 10.4 mmol, 1.0 equivalent of alkyl bromide 8-2, 3.52 g, 15.5 mmol, 1.5 equivalents of compound 2-4, 5.18 g, 31.2 mmol of potassium iodide, 5.42 ml, 31.2 mmol, 3.0 equivalents of diisopropylamine and 50 ml of acetonitrile are combined and the resulting suspension is refluxed for 24 hours, then evaporated on a rotary evaporator to remove acetonitrile. Saturated aqueous sodium bicarbonate solution (100 ml) was added and the mixture was extracted with ethyl acetate (5 x 50 ml). The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated to a brown oil. This crude product was subjected to column chromatography using silica. The column was eluted with methylene chloride and then methylene chloride containing 1% methanol to give pure product 8-3 as a white solid.

¹ H-NMR (CDCl ₃ ): δ 7.32 (d, 1H), 7.29 (d, 1H), 4.28 (q, 2H),

4.19-4.00 (m, 4H), 3.7-3.6 (t, 2H), 3.6-3.5 (t, 2H), 2.68 (t, 2H), 1, 8-1.7 (br.m, 2H, water), 1.6-1.4 (s, m, 11H), 1.33 (t, 3H), 1.2-1.1 (m, 2H) ).

T. butyl [4,5,6,7-tetrahydro-4-oxo-5- [2- (N-Boc-piperidin-4-yl) ethyl] pyrrolo [1,5-a] pyrazin-2-yl] aminopropionate (8 -4)

620 mg, 1.54 mmol of compound 8-3, 160 mg, 4.00 mmol,

2.6 equivalents of lithium hydroxide monohydrate, 15 ml of water and 10 ml of methanol are mixed in a 50 ml round bottom flask equipped with a stirrer. The solution was stirred at room temperature for 4 hours and then heated at 90 ° C for 1 hour. The methanol residues were evaporated on a rotary evaporator and the aqueous residue was acidified with 10% potassium sulfate and then extracted with 4 x 50 mL ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated to give the desired acid as a white solid.

¹ H-NMR (DMSO-d ₆ ): δ 7.51 (d, 2H), 6.84 (d, 1H), 4.19 (m, 2H), 3.90 (br.d, 2H), 3.63 (m, 2H), 3.43 (m, 2H), 3.4-3.2 (water), 2.6-2.8 (br., 2H), 1.66 (d, 2H) 1.43 (m, 2H).

1.36 (s, 9H), 1.1-0.9 (m, 2H).

150 mg, 554 mmol of this acid, 117 mg, 0.609 mmol of EDC, 82.2 mg, 0.609 mmol of 1-hydroxybenzotriazole, 0.300 mL,

1.11 mmol, 4.0 equivalents of triethylamine, 111 mg, 0.609 mmol of β-alanine tert-butyl ester and 10 mL of methylene chloride were mixed in a 100 mL round bottom flask equipped with a magnetic stirrer. The resulting solution was stirred overnight at room temperature. The solvent was removed on a rotary evaporator and the residue was chromatographed on a silica column. The eluent was methylene chloride, methylene chloride with 2% methanol and then 4% methanol. The product fractions were combined to give 8-4 as a white solid.

¹ H-NMR (CDCl ₃ ): δ 7.32 (d, 1H), 7.04 (d, 1H), 6.58 (m, 1H), 4.2-4.0 (m, 4H), 3.7-3.5 (m, 6H), 2.68 (t, 2H), 2.51 (t, 2H), 1.70 (m, 3G, water), 1.53 (m, 2H) 1.45 (s, 9H), 1.21, 1.0 (m, 2H).

4,5,6,7-tetrahydro-4-oxo-5- [2- (piperidin-4-yl) ethyl] [1,5-a] pyrazin-2-yl] aminopropionic acid (8-5)

Compound 8-4 (180 mg, 0.347 mmol) and ethyl acetate (10 mL) were combined in a 50 mL round bottom flask. The suspension is cooled in a water bath. The suspension is bubbled through

1.5 minutes hydrogen chloride gas. The reaction flask was allowed to warm to room temperature and the solvent was removed by filtration in vacuo to give product 8-5 as a white solid, mp 248-249 ° C.

¹ H-NMR (DMSO-d 6): δ 9.0-8.5 (br, 2H), 8.05 (m, 1H), 7.42

(d, 1 H), 7.05 (d, 1 H), 4.15 (m, 2H), 3.62 (m, 2H) 3.5 - 3.3 (m, 4H, water), 3.25 - 3.15 (Clay, br, 2H) , 2,85 - 2.7 (br, 2H). 2.5 -2.4 (m, 4H), 1.81 (D, 2H), 1 , 6-1.4 (M, 3H), 1.4 - 1,2 (m, 2H).

Scheme 9

BOCNH

H

CO2C2H5 ^NH2 ciso ₂ nhc ₄ h ₉

BOCNH

H

CO2C2H5 NHSO ₂ NHC ₄ H ₉

9-1 py, CH ₂ Cl ₂

9-2

HCl

ElOAc ^ CO ₂ C ₂ Hc ^H 2 ^N 4 X _N HSO ₂ NHC ₄ H ₉

EDC, HOBT DMF, £ 3

side

NH? \ 4

H

CO2C2H5 NHSO ₂ H ₄ NHC

1. NaOMe, MeOH

2. HCl, EtOAc

HN

H '

CO ₂ H nhso ₂ nhc ₄ h ₉

Ethyl 2 (S) -amino-3- (N-Boc-amino) propionate (9-1) g, 96.2 mmol of commercially available 2 (S) -3-diaminopropionic acid (Fluka) is dissolved in 200 ml of absolute ethanol, the solution is saturated with anhydrous hydrogen chloride and boiled

2.5 hours under reflux. The solvent was evaporated and the residue was recrystallized from ethanol / diethyl ether to give ethyl ester dihydrochloride as a hygroscopic white solid.

This material was suspended in 200 ml of methylene chloride cooled to -50 ° C. Triethylamine (7.0 ml, 51 mmol) was then added and the mixture was stirred for 5 minutes. A solution of di-tert-butyl dicarbonate (5.30 g, 24.3 mmol) in methylene chloride (100 mL) was added dropwise over 30 min and the mixture was stirred at -50 ° C for 1.5 h, then warmed to room temperature. . The solution was washed with water (2 x 100 mL), dried over sodium sulfate and evaporated. The resulting residue is chromatographed on silica gel using methylene chloride and methanol 80:20 to give the pure product 9-1.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 6.03 (br. T, 1H), 4.35 (m, 1H), 3.85 (m, 2H), 3.23 (m, 2H) 1.21 (t, 3H).

Ethyl 2 (S) -n-butylaminosulfonylamino-3- (N-Boc-amino) propionate (9-2)

A solution of product 9-1 (500 mg, 2.15 mmol) in methylene chloride (10 mL) was treated with pyridine (261 mL, 3.23 mmol) and n-butylsulfamoyl chloride (406 mg, 2.37 mmol). The solution was stirred at room temperature for 3 hours, then the gel was eluted with 30% acetone to give product 9-2 as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.43 (d, 1H), 4.98 (t, 1H), 4.40 (br. S, 1H), 4.10 (q, 2H) , 4.05 (m, 1H), 3.56 (m, 2H), 3.08 (m, 2H), 1.8-1.2 (overlapping multiplets, 16H), 0.90 (t, 3H) ).

Pouring on a silicone net for77

Ethyl 2 (S) - (n-butylaminosulfonylamino) -3-aminopropionate (9-3)

A solution of 612 mg, 1.65 mmol, of product 9-2 in 50 mL of ethyl acetate was cooled to -5 ° C and bubbled with anhydrous hydrogen chloride for 30 minutes. The mixture was evaporated and the product isolated to give 9-3 as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 5.82 (d, 1H), 4.56 (br. S, 1H),

4.20 (q, 2H), 4.02 (m, 1H), 3.45 (m, 2H), 3.01 (m, 2H), 1.9-1.36 (m, 7H), 0 93 (t, 3H).

Ethyl-2 (S) - [(N-butylaminosulfonylamino)] - 3 - [[4,5,6,7-tetrahydro-4-oxo-5- [2- (piperidin-4-yl) ethyl] pyrazolo [1 5-a] pyrazin-2-yl] carbonyl] aminopropionate (9-4)

Compounds 9-3 and 3-3 bind to EDC and HOBT in DMF as in Compound 1-6 to give 9-4.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.29 (s, 1H), 7.19 (t, 1H), 5.43

(D. 1H), 4.41 (T, 2H), 4.26 (Q, 2H), 4.20 (M, 1H), 4.08 (D, 2H); 3.86 (M, 2H); 3.76 (m, 2H); 3.60 (t, 2H), 3.08 (t, 2H), 1.78 (D, 2H), 1.6 - 1.08 (m, 8H) , 1.43 (s, 9H) 0.92 (t *

3H).

2 (S) - [(n-Butylaminosulfonylamino)] - 3 - [[4,5,6,7-tetrahydro-4-oxo-5- [2- (piperidin-4-yl) ethyl] pyrazolo [1,5- a] pyrazin-2-yl] carbonyl] aminopropionic (9-5)

Hydrolysis of product 9-4 with NaOMe, isolation of the crude acid followed by treatment with HCl in ethyl acetate as for compound 5-7 affords 9-5 as a white solid, mp 155-160 ° C.

Scheme 10

CH ₃ O ₂ C

HCl

H ₂ N 2 ^{O 2} ° ^Bt

CH ₂ Br K ₂ CO ₃ , CH ₃ CN

NH 'triphosgene

COotBu,. ^'2 toluene, DMA

1. NH ₄ OH, CH ₂ Cl ₂ > 0

2. MeO ₂ C-SO 4 NEt ₃

CH ₂ Cl ₂

3. 1N NaOH

1. EDC, HOBT, Et ₃ N BOCN

2. TFA

CH ₂ CH ₂ NH

2-4 .CO ₂ H

N- [2- (5-carbomethoxy) pyridylmethyl] -β-alanine tert-butyl ester (10-1)

A mixture of 871 mg, 3.79 mmol of 2-3, 2.7 g, 15 mmol of β-alanine tert-butyl ester hydrochloride and 4.5 g, 30 mmol of potassium carbonate in 100 mL of anhydrous methyl cyanide was placed in a 250 mL flask. and refluxed for 3 hours, then cooled and filtered. The filtrate was evaporated under reduced pressure and chromatographed on silica gel using ethyl acetate as a glass.

¹ H-NMR (CDCl ₃ ): δ 9.18 (d, J = 1.4 and 6.8 Hz, 1H), 7.39 (d, J = 3.95 (s, 3H), 3.04 (t, 2H), 2.60

in z CIM is obtained Product 10-1 1.4 Hz, 1H) 8.1 (dd, J = .alpha.) 6.8 Hz, 1H) 4.08 (s, 2H). (T, 2H), 1.4 [s, 9H].

Tert-Butyl 2- (2-carboxyethyl) -1-chlorocarbonyl-3-oxo-2,3-dihydroimidazo [1,5-a] pyridine-6-carboxylate (10-2)

The product 10-1 (800 mg, 2.71 mmol) was dissolved in toluene (50 mL). The solution was then cooled to 0 ° C, N, N-dimethylaniline (2.0 mL, 16.7 mmol) was added, and then a solution of triphosgene (1.7 g, 5.7 mmol) in toluene (15 mL) was added dropwise over 30 min. . Then the solution was warmed to 25 ° C, stirred for 3 hours, then washed with 2 x 50 mL 1 M HCl, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to give the product 10-2 as a yellow crystalline solid. solid.

¹ H-NMR (CDCl ₃ ): δ 8.83 (d, J = 1.4Hz, 1H), 8.25 (d, J = 6.8Hz, 1H), 7.82 (dd, J = 1.4 and 6.8 Hz, 1H), 4.43 (t, J = 7.2 Hz, 2H), 3.98 (s, 3H), 2.75 (t, J = 7.2 Hz, 2H), 1.4 (s, 9H).

Tert-Butyl 2- (2-carboxyethyl) -1-cyano-3-oxo-2,3-dihydroimidazo [1,5-a] pyridine-6-carboxylate (10-3)

Compound 10-2 (250 mg, 0.65 mmol) was dissolved in methylene chloride (100 mL), ammonium hydroxide (10 mL) was added and the biphasic mixture was stirred for one hour, then the organic layer was separated and washed with 10 mL 10% citric acid and 50 mL. saturated sodium chloride solution, dried over sodium sulfate and evaporated.

150 mg, 0.42 mmol of the residue are dissolved in 100 ml of methylene chloride, then 1.48 mmol of Burgess reagent, an methoxycarbonylsulfamoyltriethylammonium hydroxide inner salt, are added in three portions over 2 hours. The resulting solution was stirred at room temperature for 1 hour, then evaporated and the residue chromatographed on silica gel using hexane / ethyl acetate 1: 1 to afford the nitrile in quantitative yield. This material is saponified using 1 M lithium hydroxide to give the desired carboxylic acid 10-3.

¹ H-NMR (CDCl ₃ ): δ 8.75 (s, 1H), 7.43 (d, 1H), 7.18 (d, 1H),

4.21 (t, 2H), 2.85 (t, 3H), 1.4 (s, 9H).

3- [1-Cyano-3-oxo-6- (2- (piperidin-4-yl) ethylcarbamoyl) -2,3-dihydroimidazo [1,5-a] pyridin-2-yl] propionic acid (10 -4)

170 mg, 0.51 mmol of 10-3 was dissolved in 10 mL of methylene chloride, 71 mL, 0.51 mmol of Et ₃ N was added along with 69.3 mg, 0.51 mmol of HOBT, 98.6 mg, 0, 52 mmol of EDC and 117.2 mg, 0.51 mmol of compound 2-4. The mixture was stirred under nitrogen for 18 hours, then washed with 10 ml of 10% citric acid, water and saturated sodium chloride solution each time, then dried over sodium sulfate, evaporated and chromatographed to give 215 mg (0.43 mmol) of product as a yellow solid. solid. This material was deprotected by treatment with trifluoroacetic acid in methylene chloride to give the trifluoroacetate of product 10-4 as a yellow solid, mp 173 ° C.

¹ H-NMR (300MHz, DMSO-d): δ 1, 75 (s, 1 H, 7.43 (t, 1 H), 7.31 (d, 1 H) , 7.15 (d, 1H), 4.23 (T, 2H), 3.41 (T, 2H), 3.23 (D, 2H), 2 82 (m, 2H) . 1.85 (d, 2H) 1.53 (m, 2H), 1.41 (m, 1H),

1.32 (m, 2 H).

Scheme 11

Br 2 x CO ₂ tBu

HCl-H ₂ N

K ₂ CO _{3 l} ch ₃ cn

1. LiOH, H ₂ O, CH ₃ OH

ch ₃ o ₂ c - γ η NN

CO ₂ tBu

2.BocN

EDC, HOBT

CH ₂ CH ₂ NH ₂

2-4

HOL / EtOAc

CO ₂ H

Methyl- [4,5,6,7-tetrahydro-4-oxo-5- [3-tert. butylpropionyl)] pyrazolo [1,5-a] pyrazin-2-yl] carboxylate (11-1)

1.4 g, 4.8 mmol of 3-2, 0.90 g, 5 mmol of β-alanine tert-butyl ester hydrochloride and 0.78 g, 5.28 mmol of potassium carbonate in 150 mL of methyl cyanide are boiled for 4.5 hours under nitrogen, then the mixture is cooled, filtered and evaporated under reduced pressure. The resulting yellow residue was chromatographed on silica gel using 2% methanol in methylene chloride as eluent to give the resulting diester 11-1 as a colorless glass.

¹ H-NMR (CDCl ₃ ): δ 7.31 (s, 1H), 4.48 (t, 2H), 3.93 (s, 3H), 3.61 (ΐ, 2H), 2.71 ( δ, 2H), 2.35 (t, 2H), 1.23 (s, 9H).

3- [4,5,6,7-Tetrahydro-4-oxo-2- (2-piperidin-4-yl) ethylcarbamoyl) pyrazolo [1,5-a] pyrazin-5-yl] propionic acid (11-2) )

A solution containing 145 mg, 3.41 mmol of lithium hydroxide in 10 mL of water was added to a solution of 1.0 g, 3.1 mmol of ester * 11-1 in 10 mL of methanol, and the mixture was heated at 60 ° C for 2.5 h. The mixture is then cooled and the solvent is evaporated off under reduced pressure.

The remaining material was acidified with 10% citric acid and extracted with 2 x 100 ml methylene chloride. The organic extracts were combined, washed with water, dried and evaporated to give the desired acid as a colorless glass.

¹ H-NMR (CDCl ₃ ): δ 7.21 (s, 1H), 4.48 (t, 2H), 3.63 (t, 2H), 2.71 (t, 2H), 2.32 (t, 2H) t, 2H), 1.23 (s, 9H).

500 mg, 1.62 mmol of this acid is dissolved in 10 mL of methylene chloride and 220 mg, 1.62 mmol of HOBT are added along with 309 mg, 1.62 mmol of EDC and 356 mg, 1.63 mmol of compound 2-4. The mixture was stirred under nitrogen for 16 hours and then washed with 10 ml of 10% citric acid, water and saturated sodium chloride solution each time, then dried over sodium sulfate, evaporated and chromatographed to give a colorless foam. This material was deprotected using a solution of hydrochloric acid in ethyl acetate to give the hydrochloride of compound 11-2 as a white solid, mp 192-194 ° C.

¹ H-NMR (300 MHz, DMSO-d 6): δ 9.0 (br. S, 1H), 8.35 (m, 1H), 6.99 (s, 1H), 4.38 (t, J) = 6.0 Hz, 2H), 3.83 (t, J = 5.5 Hz, 2H), 3.64 (t, J = 7.1 Hz, 2H), 3.30-3.1 (m 4H), 2.85 1.65 (q, 2H), 2.54 (t, J = 7.1Hz, 2H), 1.85-1.75 (s, br., 2H), 1, 60-1.20 (overlapping m, 5H).

CH ₃ O ₂ C,

N ‘N

br '

Scheme 12 _{CO2 CH3} gX _{N-CH 2} CH _{2 NH;}

Í2zl

K ₂ CO ₃ , CH ₃ CN

N -> - (CH ₂ ) ₂ -N

ABOUT

N / E - CO ₂ CH ₃

12-2

1. LiOH, H ₂ O, CH 3 OH

CH,

NH

CO ₂ tBu ^H NHSO:

ABOUT

CH,

TFA, CH ₂ Cl ₂

ABOUT

CO ₂ H

N NHSO ₂ - (Q)

CH,

12-4

2- (4-Pyridyl) ethylamine (12-1)

A solution of ammonium chloride in 200 ml of water is placed in a 1 liter bottle. Then 4-vinylpyridine (56.4 ml, 0.52 mol) and methanol (150 ml) were added and the mixture was heated at 60 ° C for 18 hours. The reaction mixture was then cooled to 0 ° C in an ice bath and then basified by the addition of 30% sodium hydroxide. The alkaline solution was extracted with methylene chloride (5 x 100 ml) and the combined extracts were dried and evaporated. Distillation of the residue in vacuo gave 12-1 as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.53 (d, J = 6.1 Hz, 2H), 7.25 (d, J = 6.1 Hz, 2H), 3.02 (t 2 H, 2.77 (t, 2H), 1.4 (br. S, 2H).

Methyl [4,5,6,7-tetrahydro-4-oxo-5- [2- (pyridin-4-yl) ethyl] pyrazolo [1,5-a] pyrazin-2-yl] carboxylate (12-2) )

A solution of 1.4 g, 4.8 mmol of 3-2, 0.645 g, 5.28 mmol of 4- (2-aminoethylpyridine) and 0.78 g, 5.28 mmol of potassium carbonate in 150 mL of methyl cyanide was boiled under nitrogen under reflux for a total of 4.5 hours, then the mixture is cooled, filtered and evaporated under reduced pressure. The resulting yellow residue was redissolved in DMF (50 mL) and sodium hydride (200 mg of a 60% dispersion in oil) was added and the resulting mixture was heated at 90 ° C for 3 h, then evaporated under reduced pressure and chromatographed on silica gel. using 20% methanol in methylene chloride to give a total of 0.91 g, 3.0 mmol of ester 12-2 as a light yellow glassy solid in 68% yield.

¹ H-NMR (CDCl ₃ ): δ 8.32 (d, 2H), 7.52 (d, 2H), 7.34 (s, 1H), 4.48 (t, 2H), 3.91 ( s, 3H), 3.61 (t, 2H), 2.71 (t, 2H), 2.35 (t, 2H).

T-butyl 2 (S) - [(p-toluenesulfonyl) amino] -3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2- (4-pyridyl) ethyl] pyrazolo [1 5-a] pyrazin-2-yl] carboxylate (12-3)

A solution of 130 mg, 3.05 mmol of lithium hydroxide in 10 mL of water was added to a solution of 910 mg, 3.0 mmol of 12-2 in 10 mL of methanol, heated at 60 ° C for 2.5 h. is evaporated under reduced pressure. The residue is purified by Dowex-50V ion exchange resin to give the desired acid as an off-white solid, mp 187 ° C.

300 mg, 0.78 mmol of this acid are suspended in 50 mL of anhydrous DMF, 293 mg, 81 mmol of A-8, 150 mg, 0.78 mmol of EDC, 105 mg, 0.78 mmol of HOBT and 87 mL are added. 0.78 mmol of N-methylmorpholine and the resulting clear solution was stirred at 25 ° C for 19 h. The solution is then diluted with 100 ml of ethyl acetate, washed successively with 25 ml of sodium bicarbonate, water and saturated sodium chloride solution each time, dried over sodium sulfate and evaporated to give the final product 12-3.

¹ H-NMR (300 MHz, DMSO-d 6): δ 8.63 (d, 2H), 7.80 (d, 2H), 7.58 (d, 2H), 7.29 (t, 1H), 6.93 (s, 1H), 5.95 (d, 2H), 4.40 (t, 2H), 4.08 (m, 1H), 3.86-3.74 (m, 4H), 3 35-3.20 (m, 2H), 3.10 (t, 2H), 1.30 (s, 9H).

2 (S) - [(p-toluenesulfonyl) amino] -3 - [[[4,5,6,7-tetrahydro-4-oxo-5- [2- (4-pyridyl) ethyl] pyrazole] trifluoroacetate [1, 5-a] pyrazin-2-yl] carboxylic acid (12-4)

Compound 12-3 is deprotected with trifluoroacetic acid in methylene chloride and then purified by reverse phase chromatography to give trifluoroacetate 12-4, m.p. 182-185 ° C.

¹ H-NMR (300 MHz, DMSO-d 6): δ 8.72 (br. D, 2H), 8.19 (t, 1H),

8.00 (d, 1H), 7.81 (d, 2H), 7.58 (d, 2H), 7.19 (d, 2H), 6.85 (s, 1H), 4.40 (t 2H, 4.01 (m, 1H), 3.83-3.76 (m, 4H),

3.48 (m, 1 H), 3.26 (m, 1 H), 3.10 (t, 2 H).

Scheme 13

1. uoh, h ₂ o / thf ² Ή ₂ Ν ^ χ ^θ2ΐΒυ

H NHSO ₂ —dJVcHa

A-8

TFA

CH ₂ Cl ₂

Scheme 13 - continued

1. SH ₂ , Pyridine / Et ₃ N

2. CH ₃ I, acetone

3. NH ₄ Cl, CH ₃ OH

Methyl 5,6,7,8-tetrahydro-4-oxo-5- [3- (cyanophenyl) methyl-4H-pyrazolo [1,5-a] [1,4] diazepin-2-yl] carboxylate (13-1) )

A solution of 3.02 g, 14.5 mmol of compound 5-3 in 60 mL of anhydrous DMF was cooled to 0 ° C and 636 mg, 15.98 mmol of sodium hydride was added as a 60% dispersion in oil. The resulting mixture was stirred at 0 ° C for 1.5 hours and then a solution of 3.11 g, 15.89 mmol of 3-cyanobenzyl bromide in 50 mL of DMF was added dropwise. The resulting mixture was stirred at 25 ° C for 18 hours, then diluted with 200 mL of ethyl acetate and washed with 3x100 mL of water and 100 mL of saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from methylene chloride / methanol to give 13-1 as a white solid.

¹ H-NMR (CDCl ₃ ): δ 7.85 (s, 1H), 7.78 (d, J = 8Hz, 1H), 7.59 (d, J = 8Hz, 1H), 7.46 (m, 1H); 7.30 (s, 1H); 4.80 (s, 1H);

4.43 (t, J = 8Hz, 2H), 3.89 (s, 3H), 3.38 (t, J = 8Hz,

2H), 2.09 (m, 2H).

T-butyl 2 (S) - [(p-toluenesulfonyl) amino] -3 - [[[5,6,7,8-tetrahydro-4-oxo-5 - [(3-cyanophenyl) methyl] -4H-pyrazolo [ 1,5-a] [1,4] diazepin-2-yl] carbonyl] amino] propanoate (13-2)

A solution of 1.5 g, 4.04 mmol of ester 13-1 in 100 mL of THF was mixed with 5.1 mL, 5.1 mmol of 1 M lithium hydroxide and 100 mL of water, and the mixture was stirred at 25 ° C for 1.5 h. C. THF was evaporated under reduced pressure and the aqueous residue acidified with 1M hydrochloric acid. The resulting precipitate was filtered off in vacuo to give the desired product as a white solid. ¹ H-NMR (CDCl ₃ ): δ 7.95 (s, 1H), 7.73 (d, 1H), 7.53 (d, 1H),

7.43 (m, 1 H), 7.30 (s, 1 H), 4.85 (s, 2 H), 4.43 (t, 2 H), 3.31 (t, 2 H), 2.08 (m, 2 H) ).

1.0 g (3.23 mmol) of the above acid was mixed with 1.24 g (3.54 mmol) of Compound A-9, 400 mg, 3.54 HOBT, 641 mg, 3.54 mmol of EDC in 100 mL of methylene chloride. 403 micrograms, 3.83 mmol of Ν-methyimoriloline are added and the resulting solution is stirred at room temperature for 16 hours, then washed successively with 100 ml of saturated sodium bicarbonate, 10% potassium bisulfite and saturated sodium chloride, and then dried over sodium sulfate. filtered and evaporated. The residue is chromatographed on silica gel with ethyl acetate to give 13-2 as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.73 (d, J = 6.8 Hz, 2H), 7.68

(with, 1H), 7.65 (D, 1H), 7.51 (m, 1H), 7.37 (d, J = = 6, 8 Hz, 2H), 7.20 (D, 1H) , 7.18 (t, 1H), 5.63 (d, J = 6.5) Hz, 1H), 4.80 (with, 2H), 4. 77 (m, 1H) 4.45 (t, 2H); 3.85 (M, 1H), 3.08 (M, 1H), 3 40 (t, 2 H) 2.43 (s, 3H), 2.19 (M, 2H), 1.65 (with, 9H).

2 (S) - [(p-toluenesulfonyl) amino] -3 - [[[5,6,7,8-tetrahydro-4-oxo-5 - [(3-cyanophenyl) methyl] -4H-pyrazolo [1,5- a] [1,4] diazepin-2-yl] carbonyl] amino] propanoate (13-3)

A solution of 13-2 in 15 mL of methylene chloride was treated with 5 mL of TFA. The resulting solution was stirred at 0 ° C for 2.5 hours and then evaporated to give 13-3 as a colorless solid.

^X H-NMR (300 MHz, CDC1 _3): δ 7.73 (d, J = 6.8 Hz, 2H), 7.65 (s, 1H), 7.65 (d, 1H), 7.50 (m, 1H), 7.31 (d, J = 6.8Hz, 2H), 7.3 (d, 1H), 7.28 (t, 1H), 6.15 (d, J = 6, 5 Hz, 1H)

4.80 (s, 2H), 4.63 (m, 1H), 4.43 (t, 2H), 3.82 (m, 1H),

3.65 (m, 1H); 3.48 (m, 2H); 2.43 (s, 3H); 2.19 (m, 2H).

2 (S) - [(p-Toluenesulfonyl) amino] -3 - [[[5,6,7,8-tetrahydro-4-oxo-5 - [(3-amidinophenyl) methyl] -4H-pyrazole] [1] 5-a] [1,4] diazepin-2-yl] carbonyl] amino] propionic acid (13-4)

Compound 13-3 (400 mg, 0.73 mmol) was dissolved in 10 mL of pyridine / Et ₃ N 4: 1. The solution was saturated with hydrogen sulfide and stirred until the nitrile was no longer detectable by HPLC (2.5 hours). Excess hydrogen sulfide is removed by passing a stream of nitrogen through the solution. Increase90 ϊ

The white solution was then evaporated and the residue was triturated with 1M hydrochloric acid and filtered to give a yellow solid. This material was dissolved in 15 mL of acetone, 250 µL of methyl iodide was added and the mixture was heated to 50 ° C until the thioamide was no longer detectable by HPLC (2 hours). The solvent and excess methyl iodide were evaporated and the residue was redissolved in methanol containing 144 mg, 1.14 mmol of ammonium carbonate. The solution is heated at 50 ° C for 12.5 hours, then evaporated and the product 13-4 is isolated by preparative reverse phase chromatography.

¹ H-NMR (300 MHz, DMSO-d6): δ 9.38 (with, 2H), 9.17 (with. 2H) 8.19 (t , 1H) 8.16 (d, 2H). 7.78 (with, 1H), 7.75 (M, 2H) 7.63 (m , 1H) 7.60 (d, 2H). 7.21 (D, 2H), 6.93 (with, 1H) 4.81 (s , 2H) 4.40 (t, 2H). 3.93 (M, 1H), 3.40 (M, 2H) 3.35 (m, 2H), 2.23 (s, 3H); 2.13 (m, 2H)

Scheme 14

2. 10% PdonC, H ₂

ch ₃

Scheme 14 - continued

CHc

14-3

H ¹ H - S-CHg-HI x

DMF, Et ₃ N 2. TFA, CH ₂ Cl ₂

Scheme 14 - continued

14-5

Methyl 5,6,7,8-tetrahydro-4-oxo-5- (3-chloropropyl) -4H-pyrazolo [1,5-a] [1,4] diazepin-2-yl] carboxylate (14-1) )

Compound 5-3 (2.0 g, 95 mmol) is alkylated by treatment

1.5 ml, 10.5 mmol of 1-chloro-3-bromopropane as described for compound 13-1 to give 14-1 as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.28 (s, 1H), 4.58 (t, 2H), 3.93 (s, 3H), 2.78 (t, 2H), 2 68 (t, 2H); 2.46 (t, 2H); 3.27 (m, 2H); 2.18 (m, 2H).

5,6,7,8-tetrahydro-4-oxo-5- (3-azidopropyl) -4H-pyrazolo [1,5-a] [1,4] diazepin-2-yl] carboxylic acid (14-2)

A solution of 909 mg, 3.2 mmol of the above chloride and 620 mg, 9.5 mmol of NaH ₃ in 15 mL of DMF was stirred at room temperature for 36 hours. The solution was then diluted with 50 mL of ethyl acetate, washed with 3 x 50 mL of water, dried over sodium sulfate, filtered and evaporated to give the azide as a white solid. Hydrolysis of this material afforded 14-2 as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 7.00 (s, 1H), 4.41 (t, 2H), 3.52 (t, 2H), 3.41 (t, 2H) 3.26 (t, 2H); 2.20 (m, 2H);

1.80 (m, 2 H).

T-butyl 2 (S) - [(p-toluenesulfonyl) amino] -3 - [[[5,6,7,8-tetrahydro-4-oxo-5- (3-aminopropyl) -4-pyrazolo [1,5- -a] [1,4] diazepin-2-yl] carbonyl] amino] propionate (14-3)

Acid 14-2 is bound to compound A-9 in the manner described above for compound 13-2 to give the desired product as a white solid. This material was dissolved in ethanol and hydrogenated using 10% palladium on charcoal under a hydrogen atmosphere to afford 14-3 as a white solid.

^{Χ Η-ΝΜΚ} (300 MHz, _DMSO-d6): δ 8.18 (t, 1H), 7.68 (d, 2H), 7.23 (d, 2H), 6.98 (s, 1H) 4.4 (m, 3H), 3.93 (t, 2H), 3.48-3.2 (m, 6H), 2.78 (t, 2H), 2.43 (s, 3H), 2.69 (m, 2H).

1.86 (m, 2H); 1.08 (s, 9H).

2 (S) - (p-Toluenesulfonylamino) -3 - [[[5,6,7,8-tetrahydro-4-oxo-5- (3-guanidinopropyl) -4H-pyrazolo [1,5-a]] [ 1,4] diazepin-2-yl] carbonyl] amino] propionic (14-4)

A solution of 60 mg, 0.1 mmol of 14-3 in 5 mL of DMF is mixed with 90 microliters, 0.5 mL of DIPEA and 30 mg, 0.5 mmol of 3,5-dimethylpyrazole-1-carboxamidine and heated for 12 hours. to 80 ° C. The solution was evaporated and the residue was purified by chromatography on neutral alumina using a 80: 20: 1 mixture of methylene chloride, methanol and ammonia to give the desired product as a white solid. This material was deprotected by TFA and then purified by preparative reverse phase chromatography to afford 14-4 as a white solid.

¹ H-NMR (300 MHz, D ₂ O): δ 8.2 (t, 1H), 7.58 (s, 2H), 7.18 (d, 2H), 4.38 (t, 2H), 3.51 (m, 5H); 3.45 (t, 2H); 3.2 (m, 1H);

3.18 (m, 2H), 2.10 (s, 3H), 2.08 (m, 2H), 1.8 (m, 2H).

2 (S) - (p-Toluenesulfonylamino) -3 - [[[5,6,7,8-tetrahydro-4-oxo-5- [3- [N- (imidazolin-2-yl) amino] propyl] acid] -4H-pyrazolo [1,5-a] [1,4] diazepin-2-yl] carboxy] amino] propionic acid (14-5)

A solution of compound 14-3 is reacted with 2-methylthio-2-imidazoline hydroiodide as described for compound 14-4. The crude material was deprotected with TFA and the product 14-5 was isolated by preparative reverse phase chromatography.

¹ H-NMR (300 MHz, DMSO-dg): δ 8.20 (t, 1H), 8.10 (D, 2H) 7.60 (d, 2H) 7.21 (d, 3H), 6.86 (s, 1H), 4.46 (T, 2H) 4.01 (m, 2H). 3.8-3.5 (overlapping m, 8H), 2.23 (with, 3H)

2.10 (t, 2H), 1.80 (t, 2H).

Scheme 15

1. Isobutyl chloroformate NMM.THF

5zS

H ₂ N

CO ₂ H ^:> nhso ₂

2. Et ₃ N, THF, DIEA

A-7

15-1

HCl

CH ₂ Cl ₂

Scheme 15 - continued

ΗΝ

2 (S) - [(p-Toluenesulfonyl) amino] -3 - [[[5,6,7,8-tetrahydro-4-oxo-5- [2- (N-Boc-piperidin-4-yl)]] ethyl] -4H-pyrazolo [1,5-a] [1,4] diazepin-2-yl] carbonyl] amino] propionic acid (15-1)

A solution of compound 5-6 (5.0 g, 12.3 mmol) in THF (150 mL) was cooled to 0-10 ° C and N-methylmorpholine (2.11 mL, 19.2 mmol) was added via syringe. The mixture was stirred for 20 minutes and then 2.38 ml, 18.2 isobutyl chloroformate was added dropwise, and the resulting solution was stirred for half an hour to give the desired mixed anhydride.

7.00 g, 27.1 mmol of compound A-7, 125 mL of THF and 4.71 mL, 27.1 mmol of diisopropylethylamine were mixed in a 500 mL round bottom flask equipped with a magnetic stirrer. Water is then added until a clear solution is obtained. The resulting solution was cooled in an ice bath. A mixed anhydride suspension is added in one portion with vigorous stirring. After 20 minutes, the reaction mixture was evaporated to remove THF, the remaining aqueous material was acidified with 10% potassium bisulfite, and the resulting precipitate was filtered to give a white solid.

This material was chromatographed by flash chromatography using 230-400 mesh silica in a 10 x 20 cm column (EM Science). The column is eluted with a 98: 2: 0.2, 95: 5: 0.5, 90: 10: 1 mixture of methylene chloride, methanol and ammonium hydroxide and finally 85:15:

1.5 to give pure product 15-1 as a white solid. ¹ H-NMR (300 MHz, DMSO-d 6): δ 8.23 (q, J = 3.49 Hz, 1H), 7.64 (d, J = 8.20 Hz, 2H), 7.32 ( d, J = 8.20 Hz), 7.2-7.0 (br., 1H), 6.86 (s, 1H), 4.36 (t, J = 6.70 Hz, 2H), 3 89 (d, br, J

- = 12.21 Hz , 2H), 3.59 (π, 1H) 3.47 (t, J = 7.08 Hz, 2H), s J s 3,5 - 3.1 (m, br, 5H, Water), 2.8 - 2.6 (br, 2H); 2.33 (with, 3 J 3H), 2, 17 (t, J = = 6.74 Hz, 2H) 1.66 (d, br, J = 11.97 Hz, 2H), 1 55 - 1,45 (m, b r, 3H), 1.37 (s, 9H); 1.1 - 0,9 (M,

br, 2H).

2 (S) - [(p-Toluenesulfonyl) amino] -3 - [[[5,6,7,8-tetrahydro-4-oxo-5- [2- (piperidin-4-yl) ethyl] -4H] -pyrazolo [1,5-a] [1,4] diazepin-2-yl] carbonyl] amino] propionic acid (15-2)

7.42 g, 11.48 mmol of compound 15-1 was charged to a 1 liter flask with a magnetic stirrer. Methylene chloride is added and the mixture is cooled to 0-5 ° C. Hydrogen chloride gas was bubbled through the slurry with stirring. A solution formed and then a second precipitate. After bubbling for an additional 5 minutes, the vessel was allowed to warm to room temperature. After 30 minutes, the contents were concentrated and evaporated to give the resulting hydrochloride of compound 15-2 with a purity greater than 99% by HPLC analysis as a white solid.

This hydrochloride was chromatographed on Dowex 50X8-200 ion exchange resin (110 g, 4.1 milliequivalents / g). The resin was washed with 100 ml of water, methanol, water, 6 M hydrochloric acid and water each time. The eluent has a pH of 7. The hydrochloride of compound 15-2 is dissolved in 30 ml of water, applied to the column and the column washed with water, the pH of the eluent becoming very acidic. As soon as the pH returns to 7, the column is eluted with a 50:25:25 mixture of ammonium hydroxide, acetonitrile and water, using 1.5 L of the mixture. The fractions with the UV-active material were combined and evaporated in vacuo. The resulting white foam was dried under vacuum for 8 hours to give product 15-2.

¹ H-NMR (DMSO-d 6): δ 9.0-8.5 (br, 1H), 8.19-8.16 (m, 1H),

7.67 (d, J = 8.18 Hz, 2H), 7.32 (d, J = 8.18 Hz, 2H), 6.89 (s, 1H), 4.38 (t, J = 6) 84 Hz, 2H), 3.75-3.65 (m, br, 1H),

3.46 (t, br, 2H), 3.5-3.1 (m, br, 8H, water), 2.77 (t, br,

J = 11.36 Hz, 2H), 2.35 (s, 3H), 2.17 (t, J = 6.47 Hz, 2H),

1.80 (d, br, J = 12.7 Hz, 2H), 1.53-1.42 (m, br, 3H), 1.33-1.24 (m, br, 2H).

Using the above procedures, especially Schemes 3 and 4, the compounds of Table 1 can be prepared.

Table 1

m.p. ° C salt / 160 160-165 amphoteric ion

115-120 TFA

110-120 TFA

ABOUT

195-198 amphoteric ion

180-188 HCl

150-156 HCl

195-200 amphoteric ion

121-124 TFA

Table 1 continued

R

m.p. 'C sol

210-212 TFA

85-95 TFA

175-180 TFA

115-120 HCl

78-80 TFA

HCl

200 (dec.) HCl: 10 (dec.) HCl

Other compounds obtainable by the methods set forth in the Examples section are set forth in the following tables.

Table 2

WHAT

R A B heating

H | L _of C ₂ H _e

ABOUT

IL

C, H ‘N

2 ^m 5 HH 145-152 .ch ₃ “hh H 168-170 ch ₃

H, CH ₃ h 164-167 n;

.h

H H H 110-135

-CN H H 180-188

100

Table 2 continued

R A B t.topenia C2H5, ^2Hs H NHSO ₂ C ₄ H ₉ 156-160 t H _C ^CH3 H nhso ₂ c ₄ h ₉ 134-140 0 [1 cn ₃ ch ₃ H nhso ₂ c ₄ h ₉ 110-125

ABOUT

ABOUT H NHSO ₂ C ₄ H ₉ 130-135 H nhso ₂ c ₄ h ₉ 128-135 0 | I in* / ⁼ \ C ₂ H ₅ H ^CH 3 185-190

101

Table 3

NH- (CH ₂ ) _m -CH ₂ CO ₂ H

1

1

2

1

° C

110-115

115-120

121-123

135-141

140-145

102

Table 4

stoichiometry am idu jqH ⁺ p with respect to Hg chemical shift (ppm)

H C sharp 6:35 H trans 7:38 NHSO2C4H9 C sharp 6.31 NHSO ₂ C ₄ H ₉ trans 7.29

H 6 represents a hydrogen atom at the 6-position of the bicyclic structure

103

Table 5

R C _N ^ X ° ^{C 2 H H} NHR I R

H

H

CH,

SO ₂ C ₄ H ₉

melting ’C

110-116

186

164-171

164-170

135-140

not determined

173-174

185-189

178-179

104 n

.

CO ₂ H

ri r ₂ t.topenia H H 248-249 / = \ H NHSO _{2 -} 6 Ä CH ₃ 175-180 ch ₃ H 118-122 ch ₃ NHSOg - <^ ~ ^ _-CH3 155-160 ph H 137-139 ph N HSO ₂ —— CH ₃ 185-188 H / = \ nhso ₂ -Z a — ch ₃ 192-194 H 176-178 NHCO ₂ - Ph H NHSO ₂ C ₃ H ₇ 168-170 H nhso ₂ c ₂ h ₅ 173-174

- 105

Claims (16)

CLAIMS 1. Fibrinogen receptor antagonists of the general formula 1 Q- (CH ₂ ) _n - (NC) _a - AB - C - (N) _b - (R ⁵ ) _c - C - R ⁸ (D where any of the groups NH II H ₂ N — C - NH II; H ₂ N —C-NHR ⁷ HN — or A 4 to 9 membered mono- or bicyclic ring system containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur and optionally substituted with R ⁸ ; AB is a fused ring system with a common carbon and nitrogen atom in which A represents a 5, 6 or 7-membered saturated or unsaturated ring containing 1, 2 or 3 heteroatoms selected from oxygen, sulfur or nitrogen; and B represents a 5, 6 or 7-membered saturated or unsaturated ring containing 1, 2 or 3 heteroatoms selected from oxygen, sulfur or nitrogen, R is H, C 1 -C 4 alkyl, N (R ⁸⁾ 2, -N (R ⁸⁾ SO 2 R ^7, NR ⁸ CO ₂ R ^7, NR ⁸ C (O) N (R ⁷ ) R ⁸ , N (R ⁸ ) SO ₂ N (R ⁷ ) R ⁸ , some NR ⁸ C (O) R ⁷ , N (R ⁸ ) SO 2 N (R ⁸ ) C (O) OR ⁷ , C (O) N (R ⁷ ) 2 or forms with 106 is a cyclic group as defined below, ABOUT R is hydrogen, straight or branched (C 1 -C 4) alkyl, (C 1 -C 4) alkyl aryl or aryl, R ⁴ is hydrogen, straight or branched (C 1 -C 4) alkyl, (C 1 -C 4) cycloalkyl or C 1 -C 4 alkenyl, R 5 is CH, -CH (CH 2) _n , or when: R 2 is adjacent to both N (R ⁴ ) and -C (CH 2) _n , II o R 6 is COOH, CH ₂ 0H, C (O) N (R ⁷⁾ 2 »C0 ₂ R, tetrazole, an acylsulfonamide group, P (OH) ₂ II o or forms a cyclic group with R * wherein y represents an oxygen or sulfur atom, R 'represents a hydrogen atom, a straight or branched chain alkyl of 1 to 4 carbon atoms, an optionally substituted, straight or branched chain lower alkenyl, an alkyl aryl of 1 to 4 carbon atoms in the alkyl moiety, a substituted aryl or a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from nitrogen, sulfur or oxygen, wherein the alkyl radical may be substituted by a hydroxy or alkoxy group having 1 to 4 carbon atoms and the substituted aryl may be substituted by 1, 2 or 3 substituents selected from a halogen atom, a hydroxy group or an alkyl or alkoxy group having from 1 to 4 carbon atoms, ABOUT R represents a hydrogen atom or a straight or branched chain alkyl of 1 to 4 carbon atoms, 107 R9 is aryl, hydrogen, alkyl s (C 1 -C 4); n means Integer 0 to 7 and means integer 0 or 1 b means integer 0 or 1 C means integer 0 or 1 than and salts these compounds, acceptable from a pharmaceutical perspective. Compounds antagonizing claim 1 of the general formula 1 of the fibrinogen receptors according to 5 8 Q- (CH ₂ ) _n - (NC) _a - AB - C - (N) b - (R) _c - C - R (D where Q represents one of the groups 108 is an integer of 0 to 7, n 'is an integer of 0 to 3, and is an integer of 0 or 1, b is an integer of 0 or 1, c is an integer of 0 or 1, is hydrogen, straight or branched alkyl; (C 1 -C 4), (C 1 -C 4) cycloalkyl or (C 1 -C 4) alkenyl, R 5 is CH or -CH (CH 2) _n / ABOUT R is hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, alkyl aryl of 1 to 4 carbon atoms in the alkyl moiety or aryl, · R ¹ is H, C 1 -C 4 alkyl, N (R ⁸⁾ 2, -N (R ⁸⁾ SO 2 R ^7, NR ⁸ _CO2 R @ ^7, NR ⁸ C (O) R ^7, NR ⁸ C (O) N (R ⁷⁾ R ^8, -N (R ⁸⁾ SO ₂ N (R ⁷⁾ R ^8, -N (R ⁸⁾ SO 2 N (R ⁸⁾ C (O) OR ^7, C (O) N (R ⁷ ) 2 or forms a cyclic test with R 1, r 6 is COOH, CH ₂ OH, C (O) N (R ⁷ ) ₂ , CO ₂ R 4, tetrazole, acylsulfonamide, P (OH) ) _2, or forms with R ^{1 is a} cyclic group N-R where y represents an oxygen or sulfur atom, R represents a hydrogen atom, a straight or branched chain alkyl of 1 to 4 carbon atoms, an optionally substituted, straight or branched chain lower alkenyl, an alkylaryl of 1 to 4 carbon atoms in the alkyl moiety, a substituted aryl or a 5- or 6-membered heteroaryl in a ring containing 1, 2 or 3 heteroatoms from nitrogen, sulfur or oxygen, wherein the alkyl group may be substituted by a hydroxy or alkoxy group having 1 to 4 carbon atoms and the aryl may be substituted by 1, 2 or 3 substituents from a halogen atom, a hydroxy group or an alkyl or alkoxy group having from 1 to 4 carbon atoms, Q R represents a hydrogen atom or a straight or branched chain alkyl of 1 to 4 carbon atoms, R @ 1 represents hydrogen, C1 -C4 alkyl or aryl, A represents a 5, 6 or 7-membered saturated, partially saturated or unsaturated ring containing 1, 2 or 3 heteroatoms from the group O, S or N, B represents a 5, 6 or 7-membered saturated, partially saturated or unsaturated ring containing 1, 2 or 3 heteroatoms from the group O, S or N, wherein A and B form a fused ring with a common carbon and nitrogen atom. 110 Compounds antagonizing claim 2 of the general formula 1 of the fibrinogen receptors according to ^{11 11 1} 5 8 Q - (CH2) _n - <NC) _a - AB - C - (N) b - (R) _c - C - R (D) II o where AB is selected from o / -K v = where IN D is N or CR 1 and is CH ₂ , CH ₂ -CH ₂ , CH ₂ C (R ⁷ ) ₂ CH ₂ or is an integer from 0 to 3 N 111 where X is N or CR ³ , wherein R ³ is CN, C (O) N (R ⁷ ) R ⁸ , wherein n 'is 0 to 3, X 112 The fibrinogen receptor antagonists of formula 1 according to claim 3, wherein: Q- (CH ₂ ) _n - (NC) _a - AB - C - (N) _b - (R ⁵ ) _c - C - R ⁸ (1) where AB stands for where V is N or CH and D is CH ₂ -CH ₂ or CH ₂ C (R ⁴ ) ₂ CH ₂ . Compounds antagonizing fibrinogen receptors according to claim 2 of the general formula 1 Q- <£ H _{2) n} - (NC) _and - AB - C - (N) _b - ^(R?) _C - C - R (1) wherein AB is selected from the group 113 where V is N or CR ^7a D is CH ₂ , CH ₂ -CH ₂ , CH ₂ C (R ⁷ ) ₂ CH ₂ or h ₂ c ch ₂ (CH ₂ ) _n - (CH ₂ ) _n n 'means an integer from 0 to 3 where X is N or CR ³ , wherein R ³ is CN, C (O) N (R ⁷ ) R ⁸ , 114 Ο ο Ο y 3 wherein y 3 is O or H ₂ . n 'is 0 to 3. The fibrinogen receptor antagonist of the general formula 1 according to claim 5, wherein a represents an integer of 1, AB is selected from the group where V is N or CR ^7a D is CH ₂ , CH ₂ -CH ₂ , CH ₂ C (R ⁷ ) ₂ CH ₂ or 7H ₂ C CHo (CH ₂ ) _n - (CH ₂ ) _n a 115 N < where X is N or CR ^-3 , wherein CN, C (O) N (R ⁷ ) R ⁸ , O, or Compounds antagonizing the fibrinogen receptors of the general formula I according to claim 5, in which a represents 0, AB is selected from the group ABOUT 116 wherein y ³ is O or H 2. The compounds antagonizing claim 2 of the group of fibrinogen receptors according to the invention HN HN COOH 117 .COOH H HNSO ₂ - / ^CH COOH COOH H HSO ₂ -NHC ₄ H ₉ .COOH kT-rT _ / ⁼ \ H HNSO ₂ - * \\ CH ₃ ^H HNSO co ₂ c ₂ h _£ ² ~ Λ // CH, HN ABOUT N O 'N'N ^ ΐ h' co ₂ h H HNSO ₂ - < _K , - CH, HN ABOUT N ABOUT N-n 7 H '* ’ CO ₂ H H HSO ₂ C ₄ H ₉ 118 ^H HNSO ₂ —An-CH ₃ 119 ΗΝ Ο n Ο-ν '. 120 - 121 122 The fibrinogen receptor antagonists according to claim 8, selected from the group consisting of: 123 CH ₃ The fibrinogen receptor antagonists of claim 2 for use in inhibiting fibrinogen on platelets, inhibiting platelet aggregation, treating thrombus or embolus formation, or preventing thrombus or embolus formation in mammals. 11. A pharmaceutical composition for inhibiting the binding of fibrinogen to platelets in a mammal which comprises as its active ingredient the fibrinogen receptor antagonists of claim 1 and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition for inhibiting platelet aggregation in a mammal comprising, as its active ingredient, fibrinogen receptor antagonists according to claim 1 and a pharmaceutically acceptable carrier. * A pharmaceutical composition for the prevention of thrombus or embolus formation in mammals, characterized by Obsahuje comprising as its active ingredient the fibrinogen receptor antagonists of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment of thrombus or embolus formation in a mammal, characterized in that it comprises as its active ingredient the fibrinogen receptor antagonists according to claim 1 together with a pharmaceutically acceptable carrier. 124 A compound according to claim 1 of the formula and pharmaceutically acceptable salts thereof. A compound according to claim 15 of the formula