MXPA00011884A - Sulfonic acid or sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds - Google Patents

Abstract

The compounds of formula (I) herein exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula (I), compositions containing compounds of formula (I), and their use, for treating a patient suffering from, or subject to, a physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.

Description

FIELD OF THE INVENTION The compounds of the formula I have a useful pharmacological activity and are therefore incorporated in pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. . More specifically, they are factor Xa inhibitors. The present invention is directed towards compounds of the formula I, compositions containing compounds of the formula I, and their use for the treatment of a patient suffering from conditions that can be improved by the administration of a Factor Xa inhibitor or subjected to to conditions that can be improved by the administration of a Factor Xa inhibitor. Factor Xa is the penultimate enzyme in the coagulation cascade. Both free Xa factor and factor Xa assembled in the prothrombinase complex (factor Xa, factor Va, calcium and phospholipid) are inhibited by the compounds of formula I. Inhibition of factor Xa is obtained by direct formation of complexes between the inhibitor and the enzyme, and therefore is independent of the plasmatic antithrombin III co-factor. The effective inhibition of factor Xa is achieved by the administration of the compounds either by oral administration, continuous intravenous infusion, intravenous administration of bohole or through any other parenteral route in such a way that the desired effect of preventing the formation induced by thrombin Xa factor from prothrombin. An anticoagulant therapy is indicated for the treatment and prophylaxis of various thrombotic conditions of both veins and arteries. In the arteries, the abnormal formation of thrombi is primarily related to arteries of the coronary, cerebral and peripheral systems. Diseases associated with thrombotic occlusion of these vessels mainly include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke and intermittent claudication as well as coronary or peripheral artery bypass grafting (CABG). A chronic anticoagulant therapy may also be beneficial to prevent luminal narrowing (restenosis) of the vessel that occurs frequently after PCTA and CABG, and to maintain the vascular access opening in patients undergoing hemodialysis for a long time. As for the veins, the pathological formation of thrombi frequently occurs in the veins of the lower extremities after abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT also predisposes the patient to a higher risk of pulmonary thromboembolism. Disseminated intravasicular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections, and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors which results in the formation of clots that put life in danger in the vessels of certain organ systems. The indications mentioned above include some of the possible clinical situations but not all of them where an anticoagulant therapy is justified. Those skilled in the art will be aware of the circumstances that require either an acute anticoagulant therapy or a chronic prophylactic anticoagulant therapy. COMPENDIUM OF THE INVENTION This invention focuses on compounds of the formula I, below, as well as pharmaceutical use for the treatment of a patient suffering from a physiological disorder capable of being modulated by the inhibition of Factor Xa activity: contains at least one nitrogen atom, or a bicyclic heteroaryl group that includes a first ring close to Z and a ring distant relative to said first ring, said distant ring includes at least one nitrogen atom; Z is alkenyl, - (CH2) rC (0) NR "(CH) 3-, - (CH2) SR" NC (0) (CH) r-, - (CH2) rNR "(CH2) s- or - (CH2) SNR "(CH2) r-; Ri is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, R'0 (CH2) x-, R'02C (CH2) x-, R'C (O) (CH2) X-, Y1YNC (0) (CH2) x-, or Y ^ NÍO ^) * -; R 'and R "are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkenyl, optionally substituted heteroaralkenyl, optionally substituted aralkyl or optionally substituted heteroaralkyl; R2 is hydrogen, optionally substituted aralkyl, optionally substituted heteroaralkyl; optionally substituted aralkenyl, optionally substituted heteroaralkenyl, R3R4NC (0) (CH2) x-, R3S (0) p- or R3RNS (0) p-; R3 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl, or optionally substituted heteroaralkenyl, or Ri and R together with the -NS (0) p- portion or the -NS (0) portion p-NR- through is of which Ri and R- are attached form an optionally substituted heterocycle of 5 to 7 members; and R 4 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or R 3 and R 4 together with the nitrogen to which R 3 and R 4 are attached form a heterocyclyl from 4 to 7 members optionally substituted; Xi and Xia are independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or X and Xia together form oxo; X2 and X2a are H, or together form oxo; X3 is H, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or, optionally substituted heteroaralkyl, or X3 and one of Xi and Xia together form a cycloalkyl of 4 'to 7. • members; X 4 is H, optionally substituted alkyl, optionally substituted aralkyl, or hydroxyalkyl; Xs, Xsa and Xsb are independently selected from among H, R5R6N-, (hydroxy) HN-, (alkoxy1 HN-, or (amino) HN-, R7O-, R5R6NC0-, R5R6NS02-, R7C0-, halo cyano, nitiro and • 10 R8 (0) C (CH2) q-, and where is a bicyclic heteroaryl group, one of X5, Xsa and sb is a substituent that is alpha for a nitrogenp of and is selected from the group consisting of H, hydroxy and H; N-, (optionally substituted lower alkyl) HN (hydroxy) HN-, (alkoxy) HN-, or well (amino) HN- which replaces the Y e Y are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl or optionally substituted heteroaralkyl, or Y "and Y2 together with the N through which Y * and Y" are united form a 4 to 7 membered heterocyclyl; R5 and Rd are, independently, H or alkyl inrf | erior • optionally substituted, or one of R5 and Re is H and the other 5 of R5 and R6 is Ra (0) CCH2- or lower acyl; R7 is H, optionally substituted lower alkyl, lower acyl or R8 (0) CCH2-; R8 is H, optionally substituted lower alkyl, alkoxy or hydroxy; ^ 10 m is 0, 1, 2 or 3; p and r are, independently 1 or 2; q is 0 or 1, s is 0, 1 or 2; and x is 1, 2, 3, 4, or 5, or else a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof. DETAILED DESCRIPTION OF THE INVENTION As used above and throughout the description of the invention, the following terms, unless otherwise indicated, have the following meanings: Definitions "Patient" includes both humans and other mammals. "Alkyl" refers to an aliphatic hydrocarbon group which may be straight or branched chain having from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have from 1 to about 12 carbon atoms in the chain. The term "branched" means that one or more lower alkyl groups, for example methyl, ethyl or propyl, are attached to a linear alkyl chain. The term "lower alkyl" refers to an alkyl group having from about 1 to about 4 carbon atoms' in the chain which may be straight or branched. The alkyl group may be substituted by one or more "alkyl group substituents" which may be the same or different and include halo, cycloalkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl, aracyloxycarbonyl, heteroaralkyloxycarbonyl or either R9R10NCO-, where R9 and Ro are independently, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or R9 and Rio together with the N through which Ra and Rio are attached form a 4- to 7-membered heterocyclyl. Exemplary alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl benzyloxycarbonylmethyl, pyridylmethyloxycarbonylmethyl. "Alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched, having from about 2 to about 15 carbon atoms in the chain. The groups Preferred alkenyl have from about 2 to about 12 carbon atoms in the chain, more preferably from about 2 to about 4 carbon atoms in the chain. Branched indicates that one or several lower alkyl groups such as for example methyl, ethyl or propyl are attached to a linear alkenyl chain.

• "Lower alkenyl" refers to having about 2 to about 4 carbon atoms in the chain, which may be straight or branched. The alkenyl group may be substituted by one or more halo or cycloalkyl groups. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl. "Cycloalkyl" refers to a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms. Cycloalkyl rings Exemplary monocyclics include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group is optionally partially unsaturated or optionally substituted by one or more halo, methylene (H2C =), alkyl, fused aryl or heteroaryl merged. Exemplary multicyclic cycloalkyl rings include 1-decalin, adamant- (1- or 2-) yl and norbornyl. "Heterocyclyl" refers to a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms. Preferred rings include from about 5 to about 6 ring atoms where one of the ring atoms is oxygen, nitrogen or sulfur. The heterocyclyl is optionally partially unsaturated or optionally substituted by one or more alkyl, halo, aryl, heteroaryl, fused aryl or fused heteroaryl. Exemplary monocyclic heterocyclyl ring systems include pyrrolidyl, piperidyl, tetrahydrofuranyl, tetrahydrothienyl 'and tetrahydrothiopyranyl. The thio or nitrogen portion. { of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Exemplary multicyclic heterocyclic ring systems include 1, -diazabicyclo- [2, 2, 2] octane and 1,2-cyclohexanedicarboxylic acid anhydride. "Aryl" refers to a monocyclic or multicyclic, aromatic hydrocarbon ring system of 6 to 10 members. Exemplary aryl includes phenyl or naphthyl, which may be substituted with one or more ring system substituents which may be the same or different, wherein the "ring system substituents" are as defined herein.

The term "ring system substituent" refers to substituents attached to an aromatic or non-aromatic ring system, including hydrogen, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroyia, alkylsulfoyl, arylsulphonyl, heteroarylsulphonyl, alkylsulphyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused cycloalkyl, fused heterocyclyl, arylazo, heteroarylazo, R9R10N-, R9R10NCO- or R9R10NSO1-, where R9 and Rio 'are, independently, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aracyl, or optionally substituted heteroaralkyl, or R9 and Rio together with the N through which R? and R ?: are bonded form a 4- to 7-membered heterocyclyl. When a ring system is saturated or partially saturated, the "ring system substituents" further include methylene (CH2 =). oxo (0 =) or uncle (S =). Preferred ring system substituents include hydrogen, alkyl, hydroxy, acyl, aryl, aroyl, aryloxy, halo, nitro, alkoxy, cyano, alkoxycarbonyl, acylamino, alkylthio, R9R? 0N-, R9R? 0NCO- and R9R?: NS02-, where R9 and R1 are, independently, optionally substituted alkyl, aryl, aralkyl or heteroaralkyl. Preferably, the preferred phenyl group substituents are hydroxy, halogen, alkyl and amino. The term "heteroaryl" refers to an aromatic monocyclic or multicyclic hydrocarbon ring system of about 5 to about 10 members, wherein one or more of the carbon atoms in the ring system is / are another element (s) ( s) than carbon, for example, nitrogen, oxygen or sulfur. A nitrogen atom in the ring system may optionally be oxidized to the N-oxide. When the heteroaryl is a multicyclic hydrocarbon ring system, then one of said ring systems is optionally fully or partially saturated. The "heteroaryl" may also be substituted by one or more of the aforementioned "ring system substituents". Exemplary heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo [2, 1-b] thiazolyl, thiono [3,2-bipyridyl, thieno [2, 3-b] pyridyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl and 1,2,3,4-tet-rahydroisoquinolinyl. When the heteroaryl is a multicyclic hydrocarbon ring system, then it can! be linked to the rest of the molecule through any atom of the ring system capable of said binding. Preferred heteroaryl groups in the Ri substituent include benzothienyl, thienyl, thienopyridyl, isoquinolinyl and quinolinyl, all of which may be optionally substituted. Groups Preferred bicyclic heteroaryls include isoquinolinyl, quinolinyl, benzothienyl, isoquinolinyl, isoquinazolinyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, (1, 2- or 2, 3) benzodiazinyl and imidazopyridyl. Heteroaryl groups Preferred monocyclics include pyridyl. Preferred heteroaryl groups in the R3 substituent include benzothienyl, thieno [3,2- b] pyridyl, naphthyl, or thieno [2,3-b] pyridyl. "Aralkyl" refers to an aryl-alkyl group wherein aryl and alkyl are in accordance with that described above.

Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthalenemethyl. "Heteroaralkyl" refers to a heteroaryl-alkyl group wherein heteroaryl and alkyl are in accordance with previously described. Preferred heteroalkyl contain a lower alkyl portion. Exemplary heteroaralkyl groups include thienylalkyl, pyridylalkyl, imidazolylalkyl, pyrazinylalkyl, 5-benzimidazolylmethyl, indolylmethyl, pyrazolylmethyl, and thiazolylmethyl. "Aralkenyl" refers to an aryl-alkenyl group wherein the aryl and the alkenyl are in accordance with the previously described. Preferred aralkenyls contain a portion • 10 lower alkenyl. An exemplary aralkenyl group is 2-phenetenyl. "Heteroaralkenyl" refers to a heteroaryl-alkenyl- group wherein heteroaryl and alkenyl are in accordance with what has been previously described. The Preferred heteroaralkenyls contain a lower alkenyl moiety. Examples of heteroaralkenyl groups include thienylallyl, thienyl-2-ethenyl, pyridyl-2-ethenyl, imidazolyl- • 2-ethenyl and pyrazinyl-2-ethenyl, thienylpropenyl, pyridylpropenyl, i-idazolylpropenyl and pyrazinyl-propenyl.

"Hydroxyalkyl" refers to an HO-alkyl- group in which alkyl is in accordance with previously defined. Preferred hydroxyalkyls contain lower alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 1-hydroxyethyl. "Acyl" refers to a group H-CO- or alkyl-CO- wherein the alkyl group is in accordance with that previously described. Preferred acyls contain lower acyl. Exemplary acyl groups include formyl, acetyl, • Propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl. "Aroyl" refers to an aryl-CO- group wherein the aryl group is in accordance with that previously described. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl. "Alkoxy" refers to an alkyl-O- group wherein the alkyl group is in accordance with that previously described. Groups • 10 alkoxy examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy and t-butoxy. "Aryloxy" refers to an aryl-O- group wherein the aryl group is in accordance with that previously described. Exemplary aryloxy groups include phenoxy and naphthoxy. "Heteroaryloxy" refers to a heteroaryl-O- group in which the heteroaryl group is in accordance with that previously described. Exemplary heteroaryloxy groups include thienyloxy. "Aralkyloxy" means an aralkyl-O- group wherein the aralkyl groups are in accordance with previously described. Exemplary aralkyloxy groups include benzyloxy and 1- or 2-naphthylmethoxy. "Alkylthio" refers to an alkyl-S- group in which the alkyl group is in accordance with that previously described. Exemplary alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.

"Arylthio" refers to an aryl-S- group in which the aryl group is in accordance with that previously described. Exemplary arylthio groups include phenylthio and naphthylthio. "Aralkylthio" refers to an aralkyl-S- group on the basis of the aralkyl group in accordance with that previously described. An exemplary aralkylthio group is benzylthio. "R9R10N-" refers to a substituted or unsubstituted amino group, where R9 and Rio are in accordance with what previously described. Exemplary amino groups include amino • 10 (H2N-), methylamino, ethylmethylamino, dimethylamino, diethylamino, pyrrolidino and piperidino. "Alkoxycarbonyl" refers to an alkyl-0-CO- group where alkyl is as defined herein. Exemplary alkoxycarbonyl groups include (methoxy-, ethoxy- and t-butoxy) carbonyl. "Aryloxycarbonyl" refers to an aryl-0-CO- group, where aryl is as defined herein. Groups • Exemplary aryloxycarbonyl include phenoxycarbonyl and naphthoxycarbonyl. "Aralkoxycarbonyl" means an aralkyl-O-CO- group wherein aralkyl is as defined herein. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl. "R9R? ONCO-" refers to a substituted or unsubstituted carbamoyl group, where Rg and Rio are in accordance with previously described. Exemplary carbamoyl groups are carbamoyl (H2NCO-) and dimethylcarbamoyl (Me2NCO-). "RQRIONS02" refers to a substituted or unsubstituted sulphamoyl group, where R9 and Rio are in accordance with • previously described. Exemplary sulfamoyl groups are sulfamoyl (H2NS02-) and dimethylsulphamoyl (Me.NSO ._-). "Acylamino" is an acyl-NH- group where acyl is in accordance with that defined herein. "Aroylamino" is an aroyl-NH- group where aroyl is in accordance with what is defined herein. ? "Alkylsulfonyl" refers to an alkyl-S02- group where alkyl is as defined herein. Preferred groups are the groups in which the alkyl group is lower alkyl. "Arsenisulfonyl" refers to an aryl-S02- group wherein aryl is as defined herein. "Alkylenenyl" refers, for example, to a methylenyl, ethylenyl or propylenyl group. • "Halo" refers to fluorine, chlorine, bromine or iodine. Preferably fluoro, chloro or bromo, and more preferably refers to fluoro or chloro. PREFERRED MODALITIES A preferred embodiment of the present invention is a method for the treatment of a patient suffering from a physiological disorder that can be modulated by the inhibition of a Factor Xa activity by administration of a therapeutically effective amount of a compound of the formula I. A preferred compound aspect of the invention is the • compound of formula I where Rx is H, heteroaralkyl Optionally substituted, optionally substituted alkenyl, optionally substituted aralkyl or optionally substituted alkyl. Another aspect of preferred compound of the invention is the compound of formula I wherein R2 is RS (0) p-, and with greater • R3S preference (0) p- where p is 2. Another aspect of preferred compound of the present invention is the compound of formula I wherein R2 is hydrogen, optionally substituted aralkyl, optionally substituted heteroaralkyl, aralkenyl optionally Substituted, optionally substituted heteroaralkenyl, or R3R4NC (0) (CH2) x ~. Another aspect of preferred compound of the invention is the compound of formula I wherein R3 is • hydrogen, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thienyl, Optionally substituted benzothienyl, optionally substituted thienopyridyl, optionally substituted quinolinyl, or optionally substituted isoquinolinyl; more preferably R3 is optionally selected from substituted naphthyl, optionally substituted thienyl, Optionally substituted benzothienyl, and optionally substituted thienopyridyl. Another aspect of the preferred compound of the invention is the compound of the formula I wherein R2 is selected from the group consisting of 25 + KP ~ + cR, + c. fifteen OR "? ^ K> O h * c cl o o 15 Another aspect of preferred compound of the invention is the • composed of the formula I where R2 is selected within the ru or sue consists of Another aspect of preferred compound of the invention is the compound of formula I wherein R2 is • Ra is hydrogen, alkyl, hydroxy, alkoxy, Y ~ Y ~ N-, halogen, -C02R, -CYONY, - (CH2)? ORi, - (CH1) xNY "lY :, or -CN; Rt. and Rc are independently selected from hydrogen, • 10-hydroxy, alkoxy, Y: Y2N-, halogen, -CO; Rd, -C (0) NYxY2, (CH2) xOR, - (CE2) xliYlY2, -CN, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl , optionally substituted aryl, optionally substituted heteroaryl, optionally aralkyl Substituted, optionally substituted heteroaralkyl, optionally substituted aralkenyl or optionally substituted heteroaralkenyl, or Rc. and R0 together with the carbon atoms through which they are attached form a fused cycloalkyl of 5 to 7 members optionally Substituted, either an optionally substituted 5 to 7 membered fused heterocyclyl ring or an optionally substituted 6 membered fused aryl, or an optionally substituted 5 to 6 membered fused heteroaryl ring; R d is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl; Y1 and Y2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y1 and Y2 together with the N through which Y1 and Y2 are attached in a heterocyclyl of 4 to 7 members; Zi is S or -CH = CH-; and • 10 x is 1, 2, 3, 4 or 5. Another aspect of preferred compound of the invention is the compound of formula I wherein R3 is optionally substituted aralkenyl or optionally substituted heteroaralkenyl, more preferably Optionally substituted heteroaralkenyl. Another aspect of preferred compound of the invention is the compound of the formula I wherein when R3 is aralkenyl Optionally substituted or optionally substituted heteroaralkenyl, then the alkenyl portion of the same is of the formula Another aspect of preferred compound of the invention is the compound of formula I where when K-. is optionally substituted aralkenyl or heteroralkyl enyl ^ P optionally substituted, then the alkenyljo portion thereof is of the formula Where one of Qi and Q2 is hydrogen, lower alkyl (with greater Preferably methyl), or halo (more preferably fluorine or chlorine) and the other of Qi and Q2 is lower alkyl (more preferably methyl), or halo (with higher preferential fluorine or chlorine). Another aspect of preferred compound of the invention is the compound of formula I wherein when R3 is optionally substituted aralkenyl, then the aryl portion thereof is phenyl substituted with halo; more preferably, phenyl substituted by chlorine. Another aspect of preferred compound of the invention is the compound of the formula I wherein when R3 is optionally substituted heteroaralkenyl, then the heteroaryl portion thereof is thienyl substituted with halo, more preferably 2-chlorothien-5-yl. Another aspect of preferred compound of the invention is the compound of the formula I wherein Z is methylenyl.

Another aspect of preferred compound of the invention is the compound of formula I wherein is selected within the group consisting of Another aspect of preferred compound of the invention is the compound of formula I wherein is selected within the group consisting of Another aspect of preferred compound of the invention is the compound of formula I wherein Zi is -CH = CH-; and R and c together with the carbon atoms through which Rb and Rc are attached form an optionally substituted 5- or 6-membered heteroaryl, which preferably contains at least one heteroatom which is preferably N, or a ring of optionally substituted 6-membered aryl, and wherein said optional substituents are preferably selected from chloro, hydroxy and amino. Another preferred compound aspect of the invention is the compound of the formula I wherein Z_ is -CH = CH-; Pc is hydrogen; and Rc is a heteroaryl ring optionally • substituted, preferably a 5- or 6-membered heteroaryl ring, which more preferably contains at least one heteroatom which is preferably N or S, or an optionally substituted 6-membered aryl ring, and wherein said optional substituents they are preferably chlorine, hydroxy or amino. Another aspect of preferred compound of the invention is the compound of formula I wherein Zi is S (sulfur). • Another aspect of preferred compound of the invention is the compound of formula I where Z? it is S sulfur); and R¡_¡ and Rc together with the carbon atoms through which Rb and Rc are attached form an optionally substituted 5- or 6-membered heteroaryl ale, preferably containing at least one heteroatom which is preferably N, or a ring of 6-member aril optionally substituted, and where said optional substituents are preferably chloro, hydroxy or amino. Another aspect of preferred compound of the invention is the compound of the formula I wherein Z; it is S (sulfur); Rc is • hydrogen; and Rc is an optionally substituted heteroaryl ring, preferably a 5- or 6-membered heteroaryl ring, preferably containing at least one heteroatom which is preferably N or S, or an optionally substituted 6-membered aryl ring and wherein said optional substituents are preferably chloro, hydroxy or • 10 amino. Another aspect of preferred compound of the invention is the compound of formula I wherein Z is methylenyl, and m is 1. Another aspect of preferred compound of the invention is the compound of formula I wherein X2 and X2a are together oxo. Another aspect of preferred compound of the invention is the compound of formula I wherein each of Xi, Xia, X3 and X. is • Another aspect of preferred compound of the invention is the compound of formula I wherein it is an isoquinoline which is optionally preferred or * more preferably isoquinolinyl is attached to Z at its 7 position.

Another aspect of preferred compound of the invention is the compound of formula I wherein an optionally substituted quinolinyl; more preferably quinolinyl is attached to Z at its 7-position. Another aspect of preferred compound of the invention is the compound of formula I wherein • 10 an optionally substituted quinazolinyl1; more preferably, quinazolinyl is attached to Z in the position 7. Another aspect of preferred compound of the invention is the compound of formula I wherein • 2! 00 is an optionally substituted portion of the formula and W is S, O or NRu, where Ru is H, alkyl, aralkyl, heteroaralkyl, or R 8 (0) C (CH) -, and A 2 is independently CH or N; more preferably the portion • is joined to Z through the ring it contains, and with still greater preference, the portion is joined to Z through the ring it contains at position 2. Another aspect of preferred compound of the invention is the cost of Formula I wherein one of X5, Xsa and Xsb is H, hydroxy or amino, more preferably hydroxy or substituted amino in the ring next to a position adjacent to the position of the proximal ring on which Z joins. Another aspect of preferred compound of the invention is the compound of formula I wherein one of X5, Xsa and Xsb is a tee in the ring remote from the alpha position in a nitrogen, selected from H, H2N-, (optionally substituted lower alkyl) HN-, (hydroxy) HN-, and (amino) HN-. Preferred species according to the invention are selected from the group consisting of: methyl 3- [[1- (4-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] - methyl ester (5-chloro-lH-indol-2-ylmethyl) amino] propionic; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) - (3-ethylbutyl) amino] pyrrolidin-2-one; 5- 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [benzyl- (5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) thiazol-5-ylmethylamino] pyrrelidin-2-one; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2- ^ 10-ylmethyl) - (2H-pyrazol-3-ylmethyl)) amino] -pyrol ? din-2-one; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorobenzo [b] thiophen-2-ylmethyl) amino] pyrrolidin-2-one; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(β-chlorothieno [2, 3-b] pyridin-2-ylmethyl) amino] pyrrolidin-2-one; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(1 H -pyrrolo [2, 3-c] pyridin-2-ylmethyl) amino] pyrrolidin-2-one; 3-. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -ylamino] methyl} -lH-quinolin-2-one; 1- (7-aminothieno [3,2- b] pyridin-2-ylmethyl) -3- (R) - [(5-chloro-lH-20 indol-2-ylmethyl) amino] pyrrolidin-2-one; 2- (5-Chlorothiophen-2-yl) ethersulfonic acid [2-oxo-l- (lH-pyro [3, 2-c] pyridin-2-ylmethyl) pyrrolidin-3- (R) -yl] -amide; Isopropyl ester of acid. { [2- (5-chlorothiophen-2-yl) etensulfonyl] - [2-oxo-l- (lH-pyrrolo [3,2- c] pyridin-2-ylmethyl) pyrrolidin-3- (R) -yl] Not me} acetic; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one; [1- (4-aminoquin? lin-7-ylmethyl) -2-trifluoroacetate [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R, S) -yl] -amide] [1- (4-aminoquin? 5-chloro-lH-benzoimidazole-2-sulfonic acid-7-methoxynaphthalene-2-sulfonic acid-oxopyrrolidin-3- (R) -yl] amide; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid hydrochloride; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1- (1-hydroxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R; S) -yl] -amide; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R, S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] methylamide trifluoroacetate of 7-methoxynaphthalene-2-sulfonic acid; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amino benzo [b] thiophene-2-sulfonic acid trifluoroacetate; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -6-chloro-benzo [b] tipfen- • 2-sulfonic acid trifluoroacetate; 5-methoxynaphthalene-2-sulphonic acid [1- (1-amino-6-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide hydrochloride; [1- (6-methoxyiscquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (L-amino-6-methoxyisoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide acid 4- (2-chloro-β-nitrophenoxy) -benzenesulfonic acid trifluoroacetate; [1- (1, β-diaminoisoquinolin-7-ylmethyl) -2- 15-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (1,6-diaminoisoquinolin-7-yl-methyl) -2- • oxopyrrolidin-3- (S) -yl] -amide trifluoroacetate; [1- (2-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) yl] -amide of 7-methoxynaphthalene-2-sulphonic acid trifluoroacetate; [1- (2-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -6-chloro-benzo [b] thiofen-2-sulfonic acid trifluoroacetate; [1- (2-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -benzo [b] thiophene-2-sulphonic acid trifluoroacetate; • [1- (2-aminoquinolin-7-ylmethi) -2- 5-oxopyrrolidin-3- (S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (2-hydroxyquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid; [1- (2-aminoquinolin-5-ylmethyl) -2- • 10-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-sulfonic acid trifluoroacetate; [1- (2-aminoquinolin-5-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (2-hydroxyquinolin-5-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid; [1- (2-aminoquinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] amide • of 7-methoxynaphthalene-2-sulfonic acid; [1- (2-hydroxyquinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -20 'yl] -7-methoxynaphthalene-2-sulfonic acid; [1- (1H-Benzimidazol-5-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [2- (lH-benzimidazol-5-ylethyl) -2- I-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (4-aminoquinazolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (4-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [2- (6-aminothieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (7-aminothieno [2, 3-c] pyridin-3-ylmethyl) -2-oxopyrrolidin-3 (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (7-Hydroxy-thieno [2, 3-c] pyridin-3-yl-methyl) -2-oxo-pyrrolidin-3 (S) -yl] -7-methoxy-naphthalene-2-sulfonic acid trifluoroacetate; [1- (4-aminothieno [3,2- c] pyridin-3-ylmethyl) -2-oxopyrrolidin-3- (R, S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (4-hydroxythieno [3,2-c] pyridm-3-l-methyl) -2-oxopyrrolidin-3- (R, S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (4-aminothieno (3, 2-c) pyridin-3-yl-methyl) -2-oxopyrrolidin-3 (R, S) -yl] -benzo [b] thiophen-2-trifluoroacetate sulfonic; [1- (l-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S y) -yl] -amide of thieno [3,2- b] pyridine-2-sulfonic acid; [1- (L-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S y) - yl] -amido of thieno [2, 3-b] pyridine-2-sulfonic acid; 4-pyridin-3-yl-thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (Si) -yl] -amide; [2-Oxo-l- (lH-pyrrolo [3, 2-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide of 5 'chloro- [2, 2'] biothiophenyl- 5-sulfonic; [2-oxo-l- (lH-pyrrolo [3, 2-c] pyridin-2-ylmethyl) -pyrrolidin-3- (10) (S) -yl] -amide of 2- (5-chloro-thiophene-2) -yl) -etensulfonic; [1- (L-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amino-5'-chloro- [2, 2 '] bithiophenyl-5-sulfonic acid; 2- (5-Chloro-thiophen-2-yl) -etensulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 15-Chloro-benzo [b] thiophene-2-sulphonic acid [1- (4-amino-quinazolin-β-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -amide trifluoroacetate; • [1- (4-amino-thieno [2, 3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide of 6-chloro-20-benzo [trifluoroacetate] b] thiophene-2-sulphonic; [1- (4-Amino-thieno [3.2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amido-6-chlorobenzo [b] thiophene- trifluoroacetate 2-sulfonic; [1- (4-Amino-thieno [3,2-d] pyrimidin-7-yl-25-methyl) -2-oxo-pyrrolidin-3 (S) -yl] -amino-5-chloro-2-trifluoroacetate , 2 '] bitiofeni1-5-2 sulfonic; [3, 2-b] pyridine-2-sulfonic acid [1- (1, 6-diamino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; • [1- (l-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -5-yl] -amide of 2- (5-chloro-thiophen-2-yl) -etensulfonic acid; [1- (L-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amino-5'-chloro- [2, 2 '] -bromophenyl-5-sulfonic acid; [2-oxo-l- (lH-pyrrolo [3,2-c] pyridin-2-ylmethyl) -p-rrolidin-3 (S) -yl] -amide of 2- (5-chloro-thiophen-2 -amide) il) - • 10 ethersulfonic; 3- (R) -5-chlorothiophen-2-yl) -ettensulfonic acid [1- (4-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate; 2- (S) - [[1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] - (6-chlorobenzo [b] thiophene) methyl ester trifluoroacetate -2-sulfonyl) -amino] -acetic; [1- (4-amino-quinolin-7-ylmethyl) -2'-oxo- #-pyrrolidin-3-yl] -amide of 2- (S) -6-chloro-benzo [b] thiophene-2-trifluoroacetate -sulfonic; [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 2- (s) - (5-chloro-thiophen-2-yl) - trifluoroacetate Etensulfonic; [1- (4-amino-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl [- thieno [3,2- b] pyridin-2-sulphonic acid ditrifluoroacetate; N- (3-amino-pyridin-4-yl) -2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -acetamide; 2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -N-pyridin-4-yl-acetamide; 5 trifluoroacetate of. { 2-oxo-l- [2- (pyridin-4-yl-amino) ethyl] -pyrrolidin-3- (S) -yl} 6-chlorobenzo [b] thiophene-2-sulphonic acid amide; . { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} 5'-chloro- [2, 2 '] -bothiophenyl-5-sulfonic acid amide; [2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl trifluoroacetate} 6-chloro-thieno [2, 3-b] pyridin-2-sulphonic amide; ditrifluoroacetate. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} thieno [3, 2-b] pyridine-2-sulphonic acid amide; . { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} 2- (5-chloro-thiophen-2-yl) -etensulfonic acid amide; ditrifluoroacetate. { 1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} - (S) -5'- 20 Chloro- [2,2 '] -bitiofeni-5-sulphonic acid amide; ditrifluoroacetate. { 1- [2- (2-amino-3-chloro-pyridin-4-yla) -ethyl] -2-oxo-pyrrolidin-3-yl} - (S) -6-chloro-benzo [b] thiophene-2-sulfonic acid amide; ((6-chloro-benzo [b] thiophen-2-sulfonyl) -25. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-methyl ester; (- il.} - amino) -acetic; ((6-Chloro-benzo [b] thiophen-2-sulfonyl) -. {2-oxo-l- [2-pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl acid trifluoroacetate} -amino) -acetic; 5 alil-. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} - 6-chloro-benzo [b] thiophene-2-sulfonic acid amide; methyl-. { 2-Oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} - 6-chloro-benzo [b] thiophene-2-sulfonic acid amide; trifluoroacetate. { 1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} - (S) -2- (5-chloro-thiophen-2-yl) -etensulfonic acid amide; ditrifluoroacetate. { 1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} - (S) -thieno [3, 2-b] pyridine-2-sulfonic acid amide; Methyl ([2- (5-chloro-thiophen-2-yl) -ethersulfonyl] -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-methyl ester -yl.}. -amino) -acetic; ([2- (5-Chloro-thiophen-2-yl) -ethersulfonyl] -. {2-oxo-l [2- (pyridin-4-ylamino) -ethyl] -20-pyrrolidin-3-isopropyl ester il.}. -amino) -acetic; ([2- (5-chloro-thiophen-2-yl) -ethersulfonyl] -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl trifluoroacetate .}. -amino) -acetic; (2-methoxy-ethyl) trifluoroacetate -. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} 2- (5-Chloro-thiophen-2-yl) -etensulfonic acid amide; ([2- (5-Chloro-thiophen-2-yl) -etensulfonyl] -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin ethyl ester trifluoroacetate -3-yl.}. -amino) -5-acetic; 3- (5-chloro-thiophen-2-yl) -N- trifluoroacetate. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} acrylamide; 1- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (4-chlorophenyl) urea trifluoroacetate; N- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -2- (5-chlorot.iophen-2-yloxy) acetamide trifluoroacetate; 1- (4-aminoquinazolin-7-ylmethyl) -3r (S) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 15- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5-chlorothiophen-2-yl) urea trifluoroacetate and trifluoroacetate of [1- ( 5-Chlorothiophen-2-carboxylic acid 4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide; 20 acid methyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - [3- (5-chlorothiophen-2-yl) acryloyl] amino} acetic; 6-Chlorobenzo [b] thiophene-2-sulphonic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -amide trifluoroacetate; [1- (l-aminoisoquinolin-7-ylmethyl-2-oxopyrrolidin-3- (R) -yl] thieno [3, 2-b] pyridyl-2-sulfonic acid trifluoroacetate; • 1- (trifluoroacetate) 4-aminoquinolin-7-ylmethyl) -3- (S) - (5- (5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one; 1- (4-aminoquinazolin-7-trifluoroacetate) ilmethyl) -3- (S - [3- (5-chlorothiophen-2-yl) allylamino] pyrrolidin-2-one; N- [1- (4-aminoquinazolin-7-ylmethyl-2-oxopyrrolidin-3-trifluoroacetate] (S) -yl] -3- (5-chlorothiophen-2-yl) acrylamide; • 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-) trifluoroacetate benzimidazol-2-ylmethyl) amino] pyrrolidin-2-or.a; acid methyl ester trifluoroacetate {. [l- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] [2- (5-Chlorothiophen-2-yl) etensulfonyl] amino} -acetic acid methyl trifluoroacetate { [L- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- ( S) -yl] (5-cioro-l-indol-2-ylmethyl) amino] acetic; • trifluoroacetate of acid methyl ester. { [1- (aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] [3-, 5- 20-chlorothiophen-2-yl) allyl] amino} acetic; acid methyl ester trifluoroacetate. { l- [l- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5-chlorothiophen-2-yl) ureido} acetic; N- [1- (4-aminoquinazolin-7-ylmethi) -2- 25 oxopyrrolidin-3- (R) -yl] -3- (5-chlorothiophen-2-yl) acrylamide trifluoroacetate; 1- (4-aminoquinazolin-7-ylmethyl) -3 (R) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- [1- (4-aminoquinazolin-7-ylmethyl) -2- • oxopyrrolidin-3- (R) -yl] -3- (5-chlorothiophen-2-yl) urea trifluoroacetate and -Chlorothiophen-2-carboxylic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -amide trifluoroacetate; acid methyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] (5-chloro-> 10H-indol-2-ylmethyl) amino] acetic; 1- (4-aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 5-chloro-benzo [b] thiophene-2-sulphonic acid trifluoroacetate; [1- (4-Amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide of 2- (5-chloro-thiophen-2) acid -il) - • ethersulfonic; trifluoroacetate of 7-methoxy-naphthalene-2-sulfonic acid; [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 2- (5-chloro-thiophen-2-yl) -ettensulfonic acid trifluoroacetate; [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [b] thiophene-2-sulphonic acid trifluoroacetate; (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5-chloro-5-benzo [5-trifluoroacetate] b] thiophene-2-sulphonic; (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of thieno acid [3, 2-b] ] pyridine-2-sulfonic acid; (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6- (10-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 6-chlorobenzoic acid (trifluoroacetate) [b] thiophene-2-sulphonic; (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5'-chloro- acid. { 2,2 '] bromo-phenyl-5-sulfonic acid; 15 (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 2- (5-chloro- thiophen-2-yl) -etensulfonic; • [(S) -1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5-chloro-benzoic acid [b] thiophene-2-sulphonic; [(S) -1- (-armino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5-chlorobenzoic acid [b] thiophen-2-sulphonic; [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5'-chloro- [-] - [- S] - trifluoroacetate [ 2,2 '] biothiophenyl-5-sulfonic; [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-phemethyl) -2-oxo-pyrrolidin-3-yl] -amide of thieno [3,2] - b] pyridine-2-sulphonic; 5 [(S) -1- (4-Amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrroline-3-yl] -amino-6-aminobenzo [trifluoroacetate] trifluoroacetate b] thiophene-2-sulphonic; [1- (4-Amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S-) -yl] -amide of 5'-chloro- • acid trifluoroacetate 10 [2.2 '] bromo-phenyl-5-sulphonic; [1- (4-Amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of thieno [3,2-b] -trifluoroacetate ] pyridine-2-sulfonic acid; and [(S) -1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 6-chloro-benzo [b] ] thiophen-2-sulphonic. More preferred species according to the invention are • selected from the group consisting of 3- [[1- (4-aminoquinolin-7-ylmethyl) -2-20-oxopyrrolidin-3- (R) -yl] - (5-chloro-1H-indole) methyl ester -2-ylmethyl) amino] propionic; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-ylmethyl) - (3-ethylbutyl) amino] pyrrolidin-2-one; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [benzyl- (5-chloro-lH-25 indol-2-ylmethyl) mino] pyrrolidin-2-one; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) thiazol-5-ylmethylamino] pyrrolidin-2-one; IJJ 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) - (2 H -pyrazol-3-ylmethyl) amino] pyrrolidin-2-one; 5- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chloro-benzo [b] thiophen-2-ylmethyl) amino] pyrrolidin-2-one; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorothieno [2, 3-b] pyridin-2-ylmethyl) amino] pyridin-2-one; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(lH-pyrrolo [2, 3- • 10 c] pyridin-2-ylmethyl) amino] pyrrolidin-2-one; 3-. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -ylamino] methyl} -lH-quinolin-2-one; 1- (7-aminothieno [3,2- b] pyridin-2-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one; [2- (5-chlorothiophen-2-yl) -ettensulfonic acid [2-oxo-l- (lH-pyrrolo [3,2-c] pyridin-2-ylmethyl) pyrrolidin-3- (R) -yl] -amide]; Isopropyl ester of acid. { [2- (5-chlorothiophen-2-yl) etensulfonyl] - [2-oxo-l- (lH-pyrrolo [3,2- c] pyridin-2-ylmethyl) pyrrolidin-3- (R) -yl] Not me} acetic; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-yl ethyl) amino] pyrrolidin-2-one; 5-Chloro-1H-benzoimidazole-2-sulfonic acid [1- (4-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (R) -yl] -amide; [1- (l-aminoisoquinolin-7-ylmethyl) -2- 25-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -7-methoxynaphthalene-2-sulphonic acid trifluoroacetate; 5-methoxynaphthalene-2-sulfonic acid [1- (1-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] methylamide trifluoroacetate; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -benzo [b] thiophene-2-sulphonic acid trifluoroacetate; [1- (l-ammoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -6-chloro-benzo [b] thiophene-2-sulfonic acid trifluoroacetate; [1- (1,6-diaminoisoquinolin-7-ylmethyl) -2-15-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulphonic acid trifluoroacetate; 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (1,6-diaminoisoquinolin-7-yl-methyl) -2- • oxopyrrolidin-3- (S) -yl] -amide trifluoroacetate; [1- (2-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (2-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -6-chloro-benzo [b] thiophene-2-sulphonic acid trifluoroacetate; trifluoroacetate of benzo [b] thiophene-2-sulfonic acid [1- (2-aminoquinolin-7-ylmethyl) -1-oxo-pyrrolidin-3- (S) -yl] -amide; [1- (4-aminothieno [3,2- c] pyridin-2-ylmethyl) -2-OXO-3-y1] trifluoroacetate] 7-methoxynaphthalene-2-sulfonic acid amide; [1- (4-aminothieno [3,2- c] pyridin-2-ylmethyl) -2-OXO-3-Y1] benzo [b] thiophene-2-sulfonic acid trifluoroacetate; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide 5-pyridin-4-yl-thiophene-2-sulfonic acid trifluoroacetate; trifluoroacetate of [5-pyridin-3-yl-thiophene-2-sulfonic acid [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidm-3- (S) -yl] -amide; [1- (4-aminoquinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide-benzothiophene-2-sulfonic acid trifluoroacetate; [2-Oxo-l- (IH-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [b] thiophen-2 acid -sulfonic; [2-Oxo-l- (lH-pyrrolo [3, 2-b] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid; [2-Oxo-l- (lH-pyrrolo [3, 2-b] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide of 6-chlorobenzo [b] thiophene -2-sulphonic; [2-Oxo-l- (lH-pyrrolo [2, 3-c] pyridin-2-yl ethyl) -pyrrolidin-3 (S) -yl] -amide of 6-chloro- • benzo [b] ] thiophene-2-sulfonic acid; 5 [2-oxo-l- (lH-pyrrolo [2, 3-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of thieno [3,2-b] pyridine-2-sulfonic acid; [1- (l-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of thieno [3,2- b] pyridine-2-sulfonic acid; ™ 10 [2-oxo-l- (lH-pyrrolo [3,2- c] pyridin-2-ylmethyl) -pyrrolidm-3- (S) -yl] -amide of 5'-chloro- [2, 2] '] bromo-phenyl-5-sulfonic acid; [1- (4-Amino-thieno [2, 3-d] pyrimidin-6-yl-ethyl) -2-oxo-pyrrolidin-3 (S) -yl] -6-chlorobenzo [6] thiophen-2-sulphonic; [1- (4-Amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -6-chlorobenzo [trifluoroacetate] trifluoroacetate ] thiophene-2-sulfonic acid; • [1- (4-Amino-thieno [3,2-d] pyrimidin-7-yl-ethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amido-5-chloro-20-trifluoroacetate [ 2,2 '] bromo-phenyl-5-2-sulfonic acid; [3, 2-b] pyridine-2-sulfonic acid [1- (1, 6-diamino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 2- (5-Chlorothiophen-2-yl) -etensulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 5'-chloro- [2, 2 '] -bromophenyl-5-sulfonic acid; [2-Oxo-l- (lH-pyrrolo [3, 2-c] pyridin-2-ylmethyl) -pyrrolidin-3 - (S) -yl] -amide of 2- (5-chloro-thiophen-2) acid -yl) -etensulfonic; 5 - (R) -5-chlorothiophen-2-yl) -ethersulfonic acid [1- (4-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate; 2- (S) - [[1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] - (6-chloro- • 10-benzo [b]] methyl ester trifluoroacetate thiophen-2-sulfonyl) -amino] -acetic; 2- (S) -6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate; [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 2- (s) - (5-chloro-thiophen-2-yl) - trifluoroacetate Etensulfonic; [3- (4-amino-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide of thieno [3,2- b] pyridin-2-sulfonic acid ditrifluoroacetate; N- (3-amino-pyridin-4-yl) -2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -acetamide; 2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -N-pyridin-4-yl-acetamide; trifluoroacetate. { 2-oxo-l- [2- (pyridin-4-yl-amino) ethyl] -25-pyrrolidin-3- (S) -yl} 6-chlorobenzo [b] thiophene-2-sulphonic acid amide; [2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} 5'-chloro [2, 2 '] bitio-phenyl-5-sulfonic acid amide; • trifluoroacetate of. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -5-pyrrolidin-3-yl} 6-chloro-thieno [2, 3-b] pyridin-2-sulfonic acid amide; [2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl ditrifluoroacetate} thieno [3, 2-b] iridin-2-sulfonic acid amide; • 10 [2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} 2- (5-chloro-thiophen-2-yl) -etensulfonic acid amide; ditrifluoroacetate. { 1- [2- (2-amino-3-chloro-pyridin-4-yla) -ethyl] -2-oxo-pyrrolidin-3-yl} - (S) -5'-chloro- [2,2 '] -bitiofeni-1-5-sulphonic acid amide; 15 ditrifluoroacetate. { 1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} - (S) -6-chloro-benzo [b] thiophene-2-sulfonic acid amide; ((6-chloro-benzo [b] thiophen-2-sulfonyl) - (2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3 (-yl.) methyl ester - 20 amino) -acetic acid ((6-chloro-benzo [b] thiophen-2-sulfonyl) -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] trifluoroacetate] 3-pyrrolidin-3 (-yl) -amino) -acetic acid; allyl- {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3 (-il.}. ~ 6-chloro-benzo [b] thiophene-2-sulfonic acid amide; methyl-. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3 (- yl) -amide of 6-chloro-benzo [b] thiophene-2-sulfonic acid, trifluoroacetate of { 1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl}. -amide (S) -2- 5 (5-Chloro-thiophen-2-yl) -etensulfonic; (1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl ditrifluoroacetate .} - (S) -thieno [3,2- b] pyridine-2-sulfonic acid amide ([2- (5-chloro-thiophen-2-yl) - • 10 etensulfonyl] - methyl ester - {.2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid isopropyl ester ([2- (5-chloro- thiophen-2-yl) -ethersulfonyl] -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic acid; ([2- (5-Chloro-thiophen-2-yl) -ethersulfonyl] -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic; (2-methoxy-ethyl) - [2-oxo-l- [2- pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} 2- (5-chloro-20-thiophen-2-yl) -etensulfonic acid amide; ([2- (5-chloro-thiophen-2-yl) -etensulfonyl] - [2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-ethyl ester trifluoroacetate il.}. -amino) -acetic; 3- (5-chloro-thiophen-2-yl) -N- trifluoroacetate. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} acrylamide; 1- [1- (4-aminoquinazolin-7ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (4-chlorophenyl) urea trifluoroacetate; N- [1- (4-aminoquinazolin-7-ylmethyl) -2- • oxopyrrolidin-3- (S) -yl] -2- (5-chlorothiophen-2-yloxy) acetamide trifluoroacetate; 5 - (4-aminoquinazolm-7-ylmethyl) -3- (S) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5-chlorothiophen-2-yl) urea trifluoroacetate and [1- (4-trifluoroacetate)] 5-chloro-thiophene-2-carboxylic acid -aminoquinazolin-7-ylmethyl) -2- 10 oxopyrrolidin-3- (S) -yl] -amide; acid methyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - [3- (5-chlorothiophen-2-yl) acryloyl] amino} acetic; 15-Chloro-benzo [b] thiophene-2-sulphonic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -amide trifluoroacetate; trifluoroacetate of [3, 2-b] pyridine-2-sulphonic acid [1- (1-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -amide; 1- (4-aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [3- (-chlorothiophen-2-yl) allylamino] pyrrolidin-2-one rifluoroacetate; N- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5-chlorothiophen-2-yl) acrylamide trifluoroacetate; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; • acid methyl ester trifluoroacetate. { [I- (4-5-aminoquinin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] [2- (5-chlorothiophen-2-yl) -etensulfonyl] -amino} acetic; acid methyl ester trifluoroacetate. { [1- (4-aminoquinin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] (5-chloro-l-indol-2-ylmethyl) amino] acetic acid; • [[1- (aminoquinin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] [3- (5-chlorothiophen-2-yl) allyl] amino acid methyl trifluoroacetate} acetic; acid methyl ester trifluoroacetate. { l- [l- (4-aminoquinin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5- 15-chlorothiophen-2-yl) ureido} acetic; N- [1- (4-aminoquinin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -3- (5-chlorothiophen-2-yl) acrylamide trifluoroacetate; 1- (4-aminoquinin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 20- [1- (4-aminoquinin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -3- (5-chlorothiophen-2-yl) urea trifluoroacetate and trifluoroacetate of [1- ( 5-chloro-thiophen-2-carboxylic acid 4-aminoquinin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -amide; 25 methyl acid ester trifluoroacetate. { [L- (4-aminoquinin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] (5-clbro-H-indol-2-ylmethyl) amino] acetic; 1- (4-aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-1 H -benzimid-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 5-Chloro-benzo [b] thiophene-2-sulphonic acid [1- (4-amino-quinin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; [1- (4-Amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 2- (5-chloro-thiophene) 2-yl) - • 10 -sulphonic; trifluoroacetate of 7-methoxy-naphthalene-2-sulfonic acid; [1- (4-amino-quinin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 2- (5-chloro-thiophen-2-yl) - trifluoroacetate Etensulfonic; [1- (4-amino-quinin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [b] thiophene-2-sulphonic acid trifluoroacetate; 20 (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5-chlorobenzo [b] thiophen-2-sulphonic; (S) - [1- (4-Amino-thieno [3,2- d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of thieno acid [3,2- 25] b] pyridine-2-sulfonic acid; (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 6-chloro-benzoic acid [b] thiophene-2-sulphonic; (S) - [1- (4-amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate of. 5'-α-loro- [2, 2 '] bitiophene-5-sulphonic acid; (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 2- (5-chloro- thiophen-2-yl) -etensulfonic; [(S) -1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5-chloro-benzo [b] -amide ] thiophene-2-sulfonic acid; [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5-chloro-benzo [b] -amide ] thiophene-2-sulfonic acid; [(S) -1- (4-Amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5'-chloro- [2-trifluoroacetate] , 2 '] bitiofeni1-5-sulphonic; [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of thieno [3, 2-b] trifluoroacetate ] pyridine-2-sulfonic acid; [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 6-chloro-benzo [b] ] thiophene-2-sulfonic acid; [1- (4-Amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide of 5'-chloro- [2, 3-d] pyrimidin-7-ylmethyl] -2- , 2 '] bitiofeni1-5-sulphonic; trifluoroacetate of [1- (4-amino-thieno [3,2-d] pyrimid! in-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of thieno acid, [3, 2-b] pyridine-2-sulfonic acid; and [(S) -1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 6-chloro-benzo [b] thiophen-2-sulfonic acid. Even more preferred species according to the invention are selected from the group consisting of d-: [1- (6-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide acid trifluoroacetate; -methoxyaphthalene-2-sulfonic; 1- (4-aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; [2-oxo-l- (lH-pyrrolo [3, 2-c] pyridin-2-ylmethyl) -pyrrolidin-3- (s) -yl] -amide of 2- (5-chloro-thiophen-2 -amide) il) -etensulfonic; [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 2- (5-chloro-thiophen-2-yl) -etensulfonic acid trifluoroacetate; (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 2- (5-chloro- thiophen-2-yl) -etensulfonic; trifluoroacetate of [3, 2-b] pyridine-2-sulfonic acid [1- (1-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -amide; tri luroacetate of. { 2-oxo-l- [2- (pyridin-4-ylamino) ethyl] -pyrrolidin-3- (S) -yl} 6-chlorobenzo [b] thiophen-2-sulphonic acid amide; 5 (6-Chloro-benzo [b] thiophen-2-sulfonyl) -. {2-oxo-l- [2- (pyroindin-4-ylamino) -ethyl] -pyrrole-1-methyl ester 3- (-yl.}. ~. Amino) -acetic; [2-oxo-l- (IH-pyrrolo [2, 3-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -ditri luoroacetate il] -amide of thieno [3,2- • 10 b] pyridine-2-sulfonic acid; [1- (l-amino-isoquinolin-7-ylmethyl) -2t-oxo-pyrrolidin-3- (S) trifluoroacetate ) -yl] -thieno [3, 2-b] pyridine-2-sulfonic acid amide; [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) trifluoroacetate ) -yl] -2- (S) -5- (5-Chloro-thiophen-2-yl) -etensulfonic acid amide and [1- (1,6-diamino-isoquinolin-7-yl-) -methyl bistrifluoroacetate ) -2-Oxo-pyrrolidin-3- (S) -yl] -amide of 6-chlorobenzo [b] thiophene-2-sulfonic acid This invention also encompasses all combinations of preferred aspects of the invention mentioned herein A compound of formula I can be prepared by the application or adaptation of All known methods, we refer to methods used to date or described in the literature. A preparation mode according to the present invention for the preparation of a compound of the formula I wherein Arj, R_, R, X: -, X, Xs, XSÜ, -, Z and m are in accordance with that defined above, X-, and X_3 are H and X and X: - ,, • together, they form oxo, can be prepared by coupling a compound of the formula II where X < , X and m are in accordance with what is defined above, X: 15 and Xia are H, X: and X, together form oxo, and P; is a carbamate (alkyl, aralkyl or aryl) with the compound of formula III • Where Ar is a bicyclic heteroaryl, Xs, X =. Xs and Z are in accordance with what is defined above, and one of Xs, X -,., Is H, chlorine, bromine or aryloxy in the position alf, a to the nitrogen of the distant ring of Ari, and L is a labile group 5 as for example chlorine, bromine, iodine, or optionally alkylsulfonyloxy or lower arylsulfonyloxy, to provide a compound of the formula IV X5a (IV). fifteen A compound of formula IV is converted into a compound of • Formula I through the methods described here. A compound of the formula III can be prepared by the reaction of a compound of the formula V, Where X is H, RsRcN-, R70-, R = R < sNCC-, RsR, SO-, R7CO-, halo, nitro or Re (0) C (CHJ a-, and where an amino or hydroxy fl group thereof is suitably protected by an amino or hydroxy protecting group, n is from 0 to 2, and Ar is a monocyclic ring of aryl or heteroaryl, with an appropriate malonic acid in a polar solvent such as for example pyridine or ethanol and a base such as, for example, piperidine or refluxing pyridine to provide a compound of the formula SAW • 10 fifteen where R: _. is H, X;: fixed on the carboxymethyl portion, ideno in accordance with what is described above. Alternatively, a compound of the formula V can be reacted with a suitable Wittig reagent in an inert solvent such that THF provides a compound of formula VI where R2 is lower alkyl, X ^ ~ fixed on the carboxymethylidene portion or is lower alkyl, the ester is hydrolyzed in the corresponding carboxylic acid, where Ri: is H, through a • Strong appropriate acid or alkaline base. The < Corresponding acid is converted into the chloride of! acid Using standard methods, such as for example thionyl chloride, or is converted into the mixed anhydride in a polar solvent or for example acetone or THF to form an activated acyl compound. The activated acyl compound is then treated with a solution of NaN3 in water at a temperature from about -10 ° C to about 25 ° C to provide the corresponding acyl azide. The acyl azide compound is then heated slowly? in an inert solvent such as benzene or toluene at a temperature of about 60 ° C to about 110 ° C and then concentrated under vacuum and heated in an inert solvent with a higher boiling point such as 1,2-dichlorobenzene or phenylether at a temperature from about 180 ° C to about 240 ° C with a catalyst such as iodine or tributylamine for • obtain a compound of formula VII, Where X5: is H, R5R6N-, RO-, RsReNCO-, RsReNSO; -, R-CO-, halo, cyano, nitro or eR8 (O) C (CH2) q-, and where an amino group or hydroxy thereof are suitably protected by an amino or hydroxy protecting group, n is 0, either 2, and Ar2 is a monocyclic aryl or heteroaryl ring.

Alternatively, the acyl azide compound can be added directly to an inert high-boiling solvent such as phenyl ether at a temperature (k about 190 ° C to about 240 ° C with a catalyst such as iodine or tributylamine to obtain the compound of the formula VII: A compound of the formula VIII, fifteen prepared in accordance with the description in Syn., 739 (1975) • which is incorporated herein by reference, wherein X5 is H, R5R6N-, R-O-, RsRcNCO-, RsRjNSO: -, R7CO-, halo, cyano, nitro or R8 (O) C (CH;) -, and where an amino or hydroxy group thereof is suitably protected by an amino or hydroxy protecting group, n is 0, 1, or 2, and Ar2 is a monocyclic aryl ring or heteroaryl, of the formula VII above, or ethe compounds wherein the amino or hydroxy portions are When properly protected by an amino or hydroxy protecting group, it can be chlorinated using standard methods such as P0C13 or P0C13 / PC15 to obtain the following • corresponding chlorinated intermediates such as compounds of the formula (IX) and (X), wherein X_-, n and Ar: are as defined above.

In addition, a compound of the formula IX and of the formula X wherein Xsc is a protected amino moiety where the protection is • achieves a labile acid group such as acyl or dibenzylidene can be deprotected using methods Standards such as a strong acid in an alcohol solvent such as for example ethanol or a polar solvent such as for example ethyl acetate to provide the free amine which can then be chlorinated as indicated above. Alternatively, the free amine can be released by the The action of P0C13, but in any of the cases the free amine can be protected with an ad-protective group such as, for example, dibenzylidene. A compound of formula XI, such as compounds of formulas IX and X, where Ari, Xs, X5a and Xsb are in accordance with what is defined above, and one of X5, Xsa, Xsb is chlorine at the alpha position for the nitrogen of the Ari distant ring when ARX is bicyclic, and the methyl portion is fixed on the proximal ring of Arx, it can be treated with NaBr or an arylhydroxy compound as for example Phenol and potassium hydroxide to provide a compound of the formula XI wherein the chlorine in the alpha position of the nitrogen of the distal ring of Ari is replaced by bromine or aryloxy in this position. The methyl portion of the compound of the formula XI, where Ari, X5 X5a and Xs are in accordance with what is defined above, provided that when X., Xia and X-; c is hydroxy or amino which bears a hydrogen, then the hydroxy and the amino are protected by hydroxy protecting groups and or appropriate amino, can be halogenated using standard conditions such as N-halosuccinimide and benzoyl peroxide in an inert solvent such as for example carbon tetrachloride to provide the corresponding halomethyl compound of formula III where L is bromine, chlorine or iodine, and one of X., X; 3 and X_- is chloro, bromo or aryloxy in the alpha position for the nitrogen of the distal ring of Ar- .. Alternatively, a compound of formula III where A is CH, W is NH and Z is methylenyl, L is halo, one of X5, X5. and Xs is in the ring of 5 members of x) and is a substituent in accordance with the definition r T "up or one where the amino or hydroxy portions are adequately protected, another of X = _, X = .5 and X_- is found in 6 members of is a substituent, in accordance with that defined above or one where the amino or hydroxy portions are suitably protected, and the other of Xs, Xsa and X ... is hydrogen, chlorine, bromine or aryloxy and is alpha substituted for ene in the 6 member ring it can be prepared by the reaction of a compound of the formula XI I, formula XI I I or formula 15 XH Ia (Xllla) 20 (prepared according to that described in J. Het Chem., 29, 359 (1992); Bull. Soc. Chim. Beleg. 301 (1970); and J. Med. Chem .3_3, 2087 (1990), the contents of which are incorporated herein by reference) wherein W is NH and X6 is H, with P0C13 or 25 POCI3 / PCI5 in accordance with that described above to obtain the corresponding chloro compound. A compound of formula XII or formula XIII wherein W is NH and X- is H can be deprotected using standard methods such • as with benzenesulfonyl chloride using a strong base 5 such as for example sodium hydroxide in a halogenated solvent such as for example dichloromethane in the presence of a phase transfer catalyst such as for example tetrabutylammonium chloride to provide a compound of formula XII or Formula XIII where W is N-SO: Ph and X is H. • 10 treated with a strong base such as for example sodium hydride, lithium hexamethyldisilazide or lithium diisopropylamine in an inert organic solvent such as tetrahydrofuran or dimethylformamide at a temperature of about -78 ° C to about 25 ° C, followed by by The addition of ethyl chloroformate to provide a compound of the formula XII or of the formula XIII wherein W is N-S02Ph and X7 is -C02 lower alkyl, which in turn may be • converted to a compound of formula XII or formula XII where W is N-S02Ph and X7 is -CH; 0H using agents standard hydride reductants such as lithium aluminum hydride in an appropriate organic solvent such as for example diethylether at a temperature of about -10 ° C to about 25 ° C. Then, a compound of formula XII or formula of W is N-S02Ph and X is -CH2OH may be Halogenated using standard conditions such as PBr3 in an organic solvent such as diethyl ether to provide a compound of formula III as defined above. • Alternatively, a compound of formula III can be prepared by the condensation of an appropriate beta-aryl or beta-heteroaryl amino acid of formulas XIV or XV, NH, CO, H? 7f WtC .O. H .. (XIV) or x? D W NH2 (XV) Where W and X- are as defined herein, with Gold reagent under basic conditions using sodium hydride or another equally strong base followed by an acid preparation. The resulting compound is then processed in accordance with that described above for Provide a compound of the formula III. A compound of the formula II in accordance with that defined above is treated with a strong base such as for example sodium hydride, lithium hexamethyldisilylazide or lithium diisopropylamine in an inert organic solvent such as Example tetrahydrofuran or dimethylformamide at a temperature from about -78 ° C to about 25 ° C followed by the addition of a compound of formula III above where one of X =, X__ v X_t is found alpha substituted • in a nitrogen of the ring distant from is hydrogen, chlorine, bromine or aryloxy, and L is a good leaving group with for example chlorine, bromine, or iodine to provide a compound of formula IV above. • 10 Alternatively, a compound of formula IV where fifteen A is CH, W is NH and Z is methylenyl, L is halo, one of X5, X = and X. is in the ring of 5 members of is a substituent in accordance with that defined above or one where the amino or hydroxy portions are suitably protected, another one of Xs, Xsa and XÍO is found in the 6-membered ring of is a substituent in accordance with that defined above or one where the amino or hydroxy portions are suitably protected, and the other of Xs, sa and sb is hydrogen, chlorine, bromine or aryloxy and is alpha substituted on the ring nitrogen. 6 members of • 10 Ar! , can be prepared by the alkylation of an alkyl or aralkyl ester of (2-oxopyrrolidin-3- (S) -yl) -carbamic acid with propargyl bromide in the presence of a base as for example sodium hydride. The resulting alkyne is heated (100-120 ° C) with a halopyridine optionally substituted with hydroxy, alkoxycarbonylamino, or sulfhydryl, • a catalyst such as Pd (PPh3); C1;, copper iodide and triethylamine in a suitable solvent such as for example acetonitrile in a sealed container or in DMF, for 2-20 hours. When the pyridine is substituted with a hydroxyl portion, furopyridines are isolated directly if the pyridine is substituted with an alkoxycarbonylamino moiety, further treatment with DBU a about 60 ° C in DMF provides pyrrolopyridines. Subsequent deprotection provides the desired 2- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -furopyridines or alkyl esters of pyrrolcpyridine-l-carboxylic acid. These • compounds are sulfonylated in the normal way (using arenesulfonyl chlorides and case as for example triethylamine) and in the case of furepyridines, it is purified. (HPLC) to obtain [2-oxo-l- (furopyridinyl-metii; pyrrolidin-3- (S) -yl] -amides of arensulonic acid generally as the salts of TFA In the case of pyrroiepyridines, a further step of 10 deprotection (such as acid for BOC protecting groups) provides corresponding [2-oxo-l- (pyrrolopyridinyl-methyl) -pyrrolidin-3- (S) -yl] -amides of arenesulfonic acid. The P portion of the compound of the formula IV is then removed by the appropriate deprotection procedures known for the carbations such as strong acid, strong base, or catalytic hydrogenation to provide a compound of the formula XVI, where Ar :, X_ , Xca, Z and m are in accordance cor. io defined above.

(XVI).

The amine of the compound of the formula XVI released by the removal of P_ is then coupled to a compound of the formulas XVIII or XVIII • R_S (0)? HaIo or R: .R4NS (0)? Kalo; 5 (xviii) (xvi :: where R_, R4, and p are in accordance with the definition defined above, and Halo is a halogen atom such as chlorine, for example, using a base such as trialkylamine in inert solvent, for example dichloromethane, tetrahydrofuran, ether or acetonitrile at a temperature from about 0 ° C to about 100 ° C in the presence or absence of an activating agent such as dimethylaminopyridine (DMAP) to provide a compound of the formula XIX where Ar :, R., R3, R, X., X -.a, X;, X;., X., X., Xs, Xia, X = .r, Z and are in accordance with the definition above . Compounds represented by formula XIX where one of Xs, 25 X5a and Xs is alpha substituted on a nitrogen of the ring distant from is bromine or chlorine can be converted into the corresponding aryloxide by reaction with an arylhydroxy compound such as for example phenol, a strong alkaline base as by potassium hydroxide at a temperature of 70 ° C to about 120 ° C. The aryloxide intermediate (Y = ArO-) is then treated with an ammonium salt as per Example of ammonium acetate at a temperature of about 90 ° C to 180 ° C to provide a compound of formula I wherein Ari, R :, R3, R, Xi, Xia, X ?, X2a, Xa, X4, X? , Xsa, Xsb, Z and m are in accordance with the above defined, and where one of X5, X5a and X5 is alpha substituted on a nitrogen of the distant ring of Alternatively, a compound of formula XIX wherein one of X3, Xsa and Xsb is alpha substituted on a ring nitrogen distant from is bromine or chlorine can be treated with an arylhydroxy such as for example phenol, and an ammonium salt, such as for example ammonium acetate at a temperature of about 90 ° C to 180 ° C to provide copresents represented by the formula I where Ar_, R_, R_, R, X :, Xu, • X :, X_, X3, X4, X =, Xsa, Xbc, Z and m are in accordance with the definition above, and where one of X-, X-_ and X - * is alpha substituted on a ring nitrosene distant from Alternatively, a compound of the formula I can be prepared starting from a compound of the formula XX. where X3, X4, P and m are in accordance with io defined above and P_ is alkyl, aralkyl or arylc, by amination Reductive using one (heteroaryl) alquin.ina of the formula XXI NH2 I 2 X5a (XXI) wherein Arx, Xs, Xsa, Xst and Z are in accordance with that defined above, in an alcohol solvent such as methanol and an imine reducing reagent such as sodium cyanoborohydride or sodium triacetoxyborohydride a temperature from about 0 ° C to about 100 ° C to provide the cyclic structure represented by formula IV which is then converted to a compound of formula I in accordance with that described above. • A compound of the formula XXI used in the reductive amination described above can be prepared by treating a compound of the formula III wherein one of X5, X5a, Xsb is H or aryloxy in the alpha position of the nitrogen of the ring distant from Arx , and L is a labile group as per For example chlorine, bromine, iodine or the like, with sodium azide followed by reduction using standard reduction methods such as triphenylphosphine in solvents as per • water / tetrahydrofuran example or catalytic reduction. A compound of the formula I wherein Ri is other than H can Prepare by starting with a compound of the formula I wherein Ri is H by dissolution in an inert organic solvent such as for example tetrahydrofuran, dioxane, or dimethylformamide at a temperature from about 0 ° C to about 100 ° C. The resulting solution will be A base such as for example sodium hydride or potassium carbonate and a compound of formula XXII. XXII where Ri is in accordance with that defined above, except that Ri is not H, and Halo is a halogen such as bromine or chlorine. A compound of the formula I which includes a heteroaryl group containing one or more nitrogen ring atoms, preferably imine (= N-), can be converted into the compound • corresponding where one or more nitrogen ring atoms of the heteroaryl portion is / are oxidized in an N-oxide, preferably by reaction with a peracid, for example, peracetic acid in acetic acid or acid m- chloroperoxybenzoic acid in an inert solvent such as, for example, Dichloromethane, at a temperature from about room temperature to reflux, preferably at an elevated temperature. • The compounds of the present invention are useful in the form of the free base or acid or in the form of a salt pharmaceutically acceptable. All forms are within the scope of the present invention. When a compound of the present invention is replaced by a basic portion, acid addition salts are formed and are simply a more convenient way of use; and in the In practice, the use of the salt form inherently corresponds to the use of the free base form. The acids that can be used to prepare the acid addition salts preferably include the acids they produce, when • Pharmaceutically acceptable salts are combined with the free base, that is, salts whose anions are not toxic to the patient in the pharmaceutical doses of the salts, so that the beneficial inhibitory effects on the factor Xa activity inherent in the Free base are not vitiated by collateral effects attributable to anions.

• Even though pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product such as, for example, when salt is formed only for purposes of purification, and identification, or when employed as an intermediate in the preparation of a pharmaceutically acceptable salt by • ion exchange procedures. Salts, pharmaceutically acceptable within the scope of Present invention are the salts derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, acid Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts include the following: hydrohalides, • example, hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-B-hydroxynaphthoates, gentisatcs, mesylates, isothionates and di-p-toluoyltartrates, methanesulfonate, ethanesulfonate, benzenesulfonate, p- • 10-toluenesulfonate, cyclohexyl-sulfamate and quinate, respectively. In accordance with a further feature of the invention, acid addition salts of the compounds of this invention are prepared by the reaction of the base Free with the appropriate acid by application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are • prepared either by dissolving the free base in an aqueous solution or an aqueous-alcoholic solution or else Suitable solvents containing the appropriate acid and isolating the salt by evaporation of the solution or by reaction of the free base and the acid in an organic solvent, in this case the salt is separated directly or can be obtained by concentration of the solution.

The compounds of this invention may be regenerated from the acid addition salts by the application or adaptation of known methods. For example, compounds of • origin of the invention can be regenerated from its acid addition salts by treatment with an alkaline substance such as, for example, aqueous sodium bicarbonate solution or aqueous ammonia solution. When a complement of the invention is replaced by an acid portion, base addition salts can be formed and are simply a more convenient way of use; and in practice, the use of the salt form inherently corresponds to the use of the free acid form. The bases that can be used to prepare the base addition salts, preferably include the salts they produce, in combination with the free acid, pharmaceutically acceptable salts, that is to say, salts whose cations are not toxic to the animal organism in the pharmaceutical doses of the salts in such a way that the beneficial inhibitory effects on the activity of Factor Xa inherent to the free acid do not are vitiated by collateral effects attributable to the cations. Pharmaceutically acceptable salts, which include for example alkali metal and ferrous alkali metal salts, within the scope of the present invention are salts derived from the following bases: sodium hydride, Sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N '- • dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonium hydroxide, and the like. Metal salts of compounds of the present invention can be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the selected metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent used may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as For example, methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as, for example, ethyl acetate. Such reactions are usually carried out at room temperature but can be carried out, if desired, with heating. Amine salts of the compounds of the present invention can be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as > ------- i____i acetonitrile, or else ketones such as acetones. Amino acid salts can be prepared in a similar manner. The base addition salts of the compounds of the present invention can be regenerated from the salts by the application or adaptation of known methods. For example, compounds of origin of the invention can be regenerated from their base addition salts by treatment with an acid, for example, hydrochloric acid. The salt forms according to the present invention also include compounds having a quaternized nitrogen. The quaternized salts are formed by methods such as by alkylation of a hybridized spJ or sp2 nitrogen in the compounds. As will be apparent to those skilled in the art, some of the compounds of this invention do not form stable salts. However, acid addition salts are more likely to be formed by the compounds of this invention having a heteroaryl group containing nitrogen and / or possessing an amino group as the substituent. Preferred acid addition salts of the compounds of the invention are salts wherein there is no acidic leaving group. In addition to being useful per se as active compounds, the salts of compounds of the present invention are useful for the purification purposes of the compounds, for example, by exploiting differences in solubility between the salts and the compounds of origin, products collaterals, and / or initial materials by techniques well known to those skilled in the art. Compounds of the present invention may contain asymmetric centers. These asymmetric centers can present, independently, either the (R) or (S) configuration. It will also be apparent to those skilled in the art that certain compounds of formula I may exhibit geometric isomerism. Geometric isomers include • 10 cis and trans forms of the compounds of the invention having an alkenyl moiety. The present invention comprises the individual geometric isomers and the stereoisomers and mixtures thereof. Such isomers can be separated from their mixtures by the application or adaptation of well-known methods, for example, chromatographic techniques and rectalization techniques, or are prepared separately to • starting from the appropriate isomers of their intermediate products, for example, by application or adaptation of methods described here. The starting materials and intermediates are prepared by the application or adaptation of known methods, for example, methods described in the Reference Examples or their apparent chemical equivalents. The present invention is further exemplified, without limitation, by the following examples illustrating the preparation of the compounds according to the invention. In the nuclear magnetic resonance (NMR) spectra the • Chemical shifts are expressed in ppm relative to tetramethylsilane. The abbreviations have the following meanings: s = singlet; d = doublet; t = triplet; m = multiplet; dd = doublet of doublets, ddd = doublet of doublets of doublets, dt = doublet of triplets, b = width, bs = singlet wide, q = quartet, AB = pattern of AB. • 10 EXAMPLE 1 [1- (1-aminoisoquinolin-7-? L-methyl) -2-oxopyrrolidin-3 (R, S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid A. trifluoroacetate A. Chloride of 3-p-tolyl-acryloyl 15 Thionyl chloride (9.44 mL, 129.5 mmol) is added dropwise to a solution of 3-p-tolyl-acrylic acid (20 g, 123.3 mmol) in benzene (50 mL) at a temperature of 0 ° C. Allowed • that the resulting solution is heated to room temperature and then heated to reflux for 2 hours. The mixture is Concentrate to dryness in the rotovap to give the crude product (22.3 g, 123.3 mmol) which is taken in the next step. XH NMR (CDC13, 300 MHz) d 7.80 (d, ÍH), 7.50 (d, 2H), 7.26 (d, 2H), 6.58 (d, ÍH), 2.40 (s, 3H). 25 B. 3-p-Tolyl-acryloyl azide 3-p-Tolyl-acryloyl chloride (22.3 g, 123.3 mmol) in dioxane (50 L) was slowly added to an ice-cooled solution of sodium azide (16 g). , 246.6 mmol) in water / dioxane • (50 mL, 1/1, volume / volume) in order to maintain the temperature between 5 and 10 ° C. The mixture was stirred for 1.5 hours and then poured into 300 g of ice. The resulting white solid was filtered and washed with additional water. The solid (20.72 g, 110.7 mmol) was dried in P20s under vacuum overnight and employed in the next step without • 10 additional purification. XH NMR (CDC13, 300 MHz) 6 7.73 (d, ÍH), 7.45 (d, 2H), 7.21 (d, 2H), 6.38 (d, ÍH), 2.38 (s, 3H). MS, [M] "= 187 C. 1- (2-isocyanato-vinyl) -4-methyl-benzene 3-p-Tolyl-acryloyl azide (20.72 g, 110.7 mmol) is heated in benzene (100 g. mL) slowly at a temperature of 75 ° C for 3.5 hours and then concentrated to give a brown oil (approximately 20 g).

• This material was taken in the next step without further purification. 20 X H NMR (CDCl 3, 300 MHz) d 7.18 (d, 2 H), 7.12 (d, 2 H), 6.53 (d, ÍH), 6.40 (d, ÍH), 2.32 (s, 3H). The MS, [M] '= 159. D. 7-Methyl-2H-isoquinolin-1-one Iodine (0.63 g, 2.51 mmol) is added to a solution of 1- (2-isocyanato-vinyl) -4-methyl-benzene (approximately 20 g. , 125. 6 mmol) in o-dichlorobenzene (125 mL), then heated to reflux (180 ° C) overnight. The mixture is cooled to room temperature and then concentrated to dryness. The residue is purified by column chromatography eluting • with 40% EtOAc / hexanes. The product (6.23 g, 39.1 mmol) is obtained as a tan solid. lH NMR (CDC13, 300 MHz) d 12.25 (bs, ÍH), 8.21 (s, ÍH), 7.42 (bs, 2H), 7.14 (d, ÍH), 6.50 (d, ÍH), 2.46 (s, 3Hj.The MS, [M] ~ = 159. E. l-chloro-7-methyl-so-quinoline ^ 10 7-Methyl-2H-isoquinolin-1-one (2.1 g, 13.2 mmol) in phosphorus oxychloride is refluxed for 13 hours. (30 mL). The mixture is cooled to room temperature, then concentrated to a smaller volume. The residue is diluted with ice water and the pH is adjusted to approximately 15 8 by the slow addition of 10 N NaOH. The aqueous solution is extracted with methylene chloride (4 x 20 mL) and the combined organic layers are washed with brine, dried in MgSO, filtered and concentrated. The resulting dark oil is purified by column chromatography eluting with 25% EtOAc / hexanes to give the product (1.6 g, 9 mmol) as a light yellow solid. XH NMR (CDCl 3, 300 MHz) d 8.18 (d, HH), 8.05 (d, HH), 7.71 (d, HH), 7.55 (m, 2H), 7.55 (s, 3H). MS, [M] + = 177, 179, Cl pattern. 25 F. 7-Bromomethyl-1-chloro-isoquinoline N-bromosuccinimide (1.10 g, 6.19 mmol) and benzoyl peroxide (0.39 g, 1.13 mmol) are added. ) to a solution of 1-chloro-7-methylisoquinoline (1 g, 5.63 mmol) in carbon tetrachloride (70 mL). The resulting mixture is heated to reflux for 5 hours and then cooled to room temperature and diluted with methylene chloride. The organic layer is washed with IN NaOH and brine, then dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 10% EtOAc / hexanes to 25% W 10 EtOAc / hexanes to give the product (1.4 g, 5.46 mmol) as a white solid. XH NMR (CDC13, 300 MHz) d 8.31 (s, ÍH), 8.28 (d, ÍH), 7.86 (d, 1H), 7.77 (dd, ÍH), 7.58 (d, ÍH), 4.69 (s, 2H) . The MS, [M] + = 255, 257, Cl pattern, Br. 15 G. tert-butyl acid ester (2-oxopyrrolidin-3- (S) -yl) -carbamic acid (S) -Boc-diaminobutyric acid ( 25 g, 115 mmol), • triethylamine (35 g, 344 mmol), and hydroxybenzotriazole (19.3 g, 143 mmol) in THF (300 mL). L- (3- 20 dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (27.4 g, 143 mmol) is added to the solution. The solution is heated to a temperature of 60 ° C for 15 minutes. A white precipitate is formed and the solution is maintained at a temperature of 60 ° C for 4 hours. After this time, the solution is filtered and the collected liquid is concentrated. The crude product is purified by column chromatography in a gradient of 1% MeOH / CHCl2 at 3% MeOH / CH; Cl_ to give the title compound (19.6 g, 98 mmol) as a white solid.

• XH NMR (CDC13, 300 MHz) d 6.17 (bs, ÍH), 5.08 (bs, ÍH), 4.12 5 (m, ÍH), 3.33 (m, 2H), 2.65 (m, ÍH), 2.00 (m, ÍH), 1.42 (s, 9H). H. [1- (1-Chloro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester. Sodium hydride (0.24 g, 6.05 mmol, dispersion in • 10% mineral oil) to a solution of [2-oxopyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester (1.18 g, 5.89 mmol) in THF / DMF (62 L, 9/1 , volume / volume) at a temperature of 0 ° C. The mixture is stirred for 2 minutes, then it is added dropwise through a cannula solution of 7-bromomethyl-1-chloro-isoquinoline (1.4 g, 5.46 mmol) in THF (10 mL). The resulting yellow solution is stirred for 1 hour at a temperature of 0 ° C, then at room temperature for 3 hours. The reaction mixture is quenched with a saturated solution of Ammonium chloride, then diluted with EtOAc. The organic layer is washed with water and brine, then dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 50% EtOAc / hexanes at 70% EtOAc / hexanes to provide the product (1.67 g, 4.44 mmol) as a white foamy solid. : H NMR (CDC13 300 MHz) d 8.25 (d, ÍH), 8.12 (s, ÍH), 7.83 (d, ÍH), 7.68 (dd, ÍH), 7.58 (d, ÍH), 5.55 (bs, ÍH) , 4.71 (AB, 2H), 4.30 (m, ÍH), 3.26 (m, 2H), 2.60 (m, ÍH), 1.98 (, ÍH), 1.46 (s, 9H). The MS, [M] ~ = 376, 378, Cl pattern. I. 3- (S) -amino-1- (l-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-one hydrochloride To a solution of tert-butyl acid ester [l- (l-chloro-isoquinolin -7-ylmethyl) -2-oxopyrrolidin-3 (S) -yl] -carbamic acid (2.1 g, 5.6 mmol) in EtOAc (170 mL) at a temperature of 0 ° C, HCl gas is bubbled for 5 minutes. The solution is stirred at a temperature of 0 ° C for 15 minutes, and then the ice bath is removed and the solution is allowed to warm to room temperature. After 4 hours at room temperature, the solution is concentrated and the remaining solid is washed with ether to give the title compound (1.74 g, 5.6 mmol) as a pale yellow solid. XH NMR (DMSO-de, 300 MHz) 5 8.64 (d, 3H), 8.31 (d, ÍH), 8.18 (s, ÍH), 8.10 (d, ÍH), 7.90 (d, ÍH), 7.80 (d, ÍH), 4.71 (AB, 2H), 4.10 (m, ÍH), 3.30 (, 2H), 2.41 (m, ÍH), 1.98 (m, ÍH). FAB MS, [M + H] + = 276. J. 7-Methoxynaphthalene-2-sulfonyl chloride To a solution of 7-hydroxynaphthalene-2-sulfonic acid, sodium salt (15 g, 60.9 mmol) in H20 / ethanol (150 mL, 2: 1) is added solid NaOH ( 2.68 g, 67 mmol) at room temperature. The mixture is stirred until the formation of a 4k homogeneous solution and then dimethyl sulfate is added (6.34 mL, 67 mmol). A precipitate forms slowly and the The mixture is stirred for a period of 16 hours. The crude mixture is concentrated in vacuo and the residue is stirred in absolute EtOH (100 mL) as a paste for 2 hours. The precipitate is filtered and dried. The solid is heated to reflux in 95% EtOH (100 mL) for 2 hours, allowed to cool • at room temperature, filter and dry to provide 12.6 g of crude 7-methoxynaphthalene-2-sulfonic acid, sodium salt. A mixture of the sodium salt of sulfonic acid (12.6 g, 48.6 mmol) in phosphorus oxychloride (20 mL) and phosphorus pentachloride (13.2 g, 63.2 mmol) is slowly heated to a temperature of 60 ° C until the formation of a homogeneous solution and then heated to a temperature of 120 ° C for 4 hours. The resulting mixture is cooled in a bath • ice and slowly add a mixture of ice / ice water, with stirring. The mixture is diluted with water and extracted with CHC13 (2 x 100 mL). The combined organic layers are washed successively with water, saturated NaHCO 3 solution and saturated NaCl. The organic phase is dried over anhydrous MgSO 4, filtered and concentrated to provide 10 g of a crude oil. The raw product is purified by column chromatography in a gradient of 5% EtOAc / hexanes to 30% EtOAc / hexanes to give the title compound (3.8 g, 4.8 mmol) as a white crystalline solid. • P NMR (CDC13, 300 MHz) d 8.49 (d, ÍH), 7.96 (d, ÍH), 7.85 (d, 5 2H), 7.39 (dd, ÍH), 7.29 (d, ÍH), 3.99 (s, 3H). The MS, [MT = 256. K. [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -7-methoxy-naphthalene-2-sulphonic acid 3- (S) -hydrochloride is suspended amino-1- (1-chloro- • 10-isoquinolin-7-ylmethyl) -pyrrolidin-2-one (1.74 g, 5.6 mmol) in CH 3 CN (120 mL). To this solution is added triethylamine (2.35 mL, 16.9 mmol) followed by 7-methoxynaphthalene-2-sulfonyl chloride (1.52 g, 5.93 mmol). The mixture is stirred overnight, then concentrated to dryness. The product Crude is purified by column chromatography eluting with a gradient of 2% MeOH / CH2Cl2 at 5% MeOH / CH2Cl2 to give the title compound (2.7 g, 5.4 mmol) as a light yellow solid. : H NMR (CDCl 3, 300 MHz) d 8.35 (d, 1H), 8.27 (d, ÍH), 8.08 (s, ÍH), 7.91 (d, ÍH), 7.80 (d, ÍH), 7.78 (s, ÍH), 7.74 (dd, ÍH), 7. 56 (s, ÍH), 7.51 (d, ÍH), 7.30 (dd, ÍH), 7.24 (d, ÍH), 5.42 (d, ÍH), 4.63 (AB, 2H), 3.95 (s, 3H), 3.78 (m, ÍH), 3.25 (m, 2H), 2.60 (m, 1H), 2.08 (m, ÍH). FAB MS, [M + H] + = 496, 498, Cl pattern. 25 L_. [1- (1-phenoxy-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R, S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid. Phenol (6.81 g, 72.4 mmol) is added. and potassium hydroxide ert (0.41 g, 7.31 mmol) to [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-acid Sulfonic acid (1.8 g, 3.6 mmol) and heated to a temperature of 90 ° C until obtaining a homogeneous mixture. The mixture is stirred overnight at a temperature of 90 ° C, and then cooled to room temperature and diluted with methylene chloride (100 mL) and water. The aqueous layer is neutralized to a pH 7 using IN HCl, and then the two layers are separated and the aqueous layer is extracted with additional methylene chloride. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 30% EtOAc / hexanes to 60% EtOAc / hexanes to give the product (1.66 g, 3-irnol) as a white solid. "H NMR (CDCL3, 300 MHz) d 8.40 (s, ÍH), 8.20 (s, ÍH), 7.94 (d, HH), 7.82 (d, HH), 7.74 (d, HH), 7.70 (d, HH), 7.51 (dd, 1H), 7.40 (m, 2H), 7.15 - 7.30 (, 7H), 5.80 (bs) , ÍH), 4.60 (AB, 2H), 3.98 (s, 3H), 3.82 (m, ÍH), 3.20 (m, 2H), 2.52 (m, 1H), 2.04 (m, ÍH). FAB, [M + H] + = 554. [1- (l-aminoisoquinolin-7-ylmethyl) -2- 25 oxopyrrolidin-3- (R, S) -yl] -amide of trifluoroacetate -methoxyaphthalene-2-sulphonic. In a round bottom flask equipped with a water condenser, it is heated to a temperature of 160 ° C [1-phenoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 5-methoxynaphthalene-2-sulfonic acid (0.318 g, 0.574 mmol) and ammonium acetate (5 g, 65 mmol) at a temperature of 160 ° C. After about 6 hours, the homogeneous mixture is cooled to room temperature and the mixture is purified by RP-HPLC eluted with a gradient of 10% CH3CN / H20 (0.1% • 10 TFA) to 100% CH3CN. The appropriate fractions are lyophilized to provide the racemic compound of the title (0.157 g, 0. 266 mmol) as a white solid. l NMR (DMSO-d6, 300 MHz) d 8.95 (bs, 2H), 8.39 (s, 1H), 8.23 - 8.29 (m, 2H), 8.02 (d, ÍH), 7.95 (d, ÍH), 7.93 (d, ÍH), 15 7.77 (d, ÍH), 7.74 (dd, ÍH), 7.65 (d, ÍH) 7.58 (d, ÍH), 7.35 (dd, ÍH), 7.24 (d, ÍH), 4.56 (AB, 2H), 4.20 (m, ÍH), 3.89 (s, 3H), 3.15 (m, 2H), 2.05 (m, 1H), 1.60 (m, ÍH). FAB MS, [M + H] + = 477. EXAMPLE 2 Hydrochloride of [1- (l-aminoisoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid. In a round-bottomed flask equipped with a cold finger condenser, phenol (0.569 g, 6 mmol) and [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) were melted. -yl] -amido-7-ethoxynaphthalene-2-sulfonic acid (0.2 g, 0.4 mmol) at a temperature of 70 ° C. The mixture is stirred for 5 minutes and then ammonium acetate (0.462 g, 6%) is added. • mmol) and heated to a temperature of 115 ° C for 2 5 hours. After that time, additional ammonium acetate (0.462 g, 6 mmol) is added. After 2 hours, the reaction mixture is cooled to room temperature and then partitioned between EtOAc and 0.5 N NaOH. The organic layer is separated and washed with water and brine, and then dried in water. • 10 Na2SO4, filtered and concentrated. The resulting residue is partially purified by RP-HPLC eluting with a gradient of 10% CH3CN / H20 (0.1% TFA) to 100% CH3CN. The appropriate fractions are concentrated in vacuo. The solid that is precipitated out of the solution is then filtered, dried and purified again by er chromatography. column eluting with 5% MeOH / CH2CL :. This product is then triturated with cold MeOH and the collected solid is suspended in MeOH and cooled to • 0 ° C. HCl (g) is bubbled through the paste for a few minutes during which time the entire solid is dissolved in the solution. The solvent is removed in vacuo and the title product 80.11 g, (0.214 mmol) is washed with ether and dried. XH NMR (DMSO-de, 300 MHz) d 13.30 (bs, ÍH), 9.18 (bs, 2H), 8. 32 (s, ÍH), 8.25 (d, ÍH), 7.99 (d, ÍH), 7.85 - 7.91 (m, 25 2H), 7.60 - 7.80 (m, 3H), 7.50 (s, ÍH,, 7.25 (dd , ÍH), 7.18 (d, ÍH), 4.51 (AB, 2H), 4.23 (m, ÍH), 3.85 (s, 3H), 3.12 (m, 2H), 1.95 (m, ÍH), 1.65 (m, ÍH). FAB MS, [M + H] '= 477. Melting point 187-192 ° C. • The enantiomeric purity is 88% in accordance with that determined by analytical Chiralpak AD reverse phase HPLC. EXAMPLE 3 [1- (L-Aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulphonic acid trifluoroacetate. • The title compound is prepared by resolution of the racemic compound described in Example 1, part M using a HPLC column Chiralpak AD (55% EtOH / Heptane (0.1% TFA)). XH NMR (DMSO-de, 300 MHz) d 8.95 (bs, 2H), 8.39 (dIH), 8.30 15 (s, ÍH), 8.23 (d, ÍH), 8.04 (d, ÍH), 7.95 (d, ÍH), 7.93 (d, ÍH), 7.77 (d, ÍH), 7.74 (dd, ÍH), 7.65 (d, ÍH), 7.58 (d, ÍH), 7. 35 (dd, ÍH), 7.24 (d, ÍH), 4.56 (AB, 2H), 4.20 (m, ÍH), • 3.89 (s, 3H), 3.15 (m, 2H), 2.05 (m, ÍH), 1.60 (, ÍH). FAB MS, [M + H = 477. 20 The enantiomeric purity is 96.3% ee in accordance with that determined by analytical Chiralpak AD reverse phase HPLC. [a] D + 3.16 ° (MeOH). EXAMPLE 4 [1- (L-Aminoisoquinolin-7-ylmethyl) -2- 25-oxopyrrolidin-3- (R) -yl] -amide of 7-methoxynaphthalene-2-sulphonic acid trifluoroacetate. The title compound is prepared by resolution of the racemic compound described in Example 1, part M • using a Chiralpak AD HPLC column (55% EtOH / Heptane 5 (.1% TFA)). : H NMR (DMSO-d5, 300 MHz) d 8.95 (bs, 2H), 8.39 (dIH), 8.30 (s, ÍH), 8.23 (d, ÍH), 8.04 (d, ÍH), 7.95 (d, ÍH), 7.93 (d, ÍH), 7.77 (d, ÍH), 7.74 (dd, ÍH), 7.65 (d, ÍH ^, 7.58 (d, ÍH), 7.35 (dd, ÍH), 7.24 (d, ÍH) ), 4.56 (AB, 2H), 4.20 (m, ÍH), • 10 3.89 (s, 3H), 3.15 (m, 2H), 2.05 (m, ÍH), 1.60 (m, ÍH). FAB MS, [M + H] + = 477. The enantiomeric purity is 90.7% ee in accordance with that determined by analytical Chiralpak AD reverse phase HPLC. [a] D-3.89 ° (MeOH). EXAMPLE 5 [1- (1-hydroxyisoquinolin-7-yl-methyl) -2-oxopyrrolidin-3 (R, S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid. [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid (0.07g, 0.14) mmol), prepared in accordance with that described in Example 1, part K, is treated with dioxane (1 mL) and 10% aqueous NaOH (3 mL) and heated at reflux for 48 hours. The reaction is cooled, acidd with 1 N HCl and extracted with CH2C12. The organic layer is separated, dried and concentrated. He The residue is purd by column chromatography eluting with 2.5% MeOH / CH; CL. The product fractions are collected, concentrated and precipitated with dilute HCl / ether to give the title compound (0.041 g, 0.086 • mmol). 5: H NMR (CDCl 3, 300 MHz) d 8.41 (s, ÍH), 8.25 (d, ÍH), 7.9.3 (d, ÍH), 7.85 (d, ÍH), 7.76 (d, ÍH), 7.58 ( AB, ÍH), 7.39 (s, ÍH), 7.24 (dd, ÍH), 7.17 (d, 1H), 6.66 (bs, 1H), 4.55 (AB, 2H), 4.20 (, ÍH), 3.92 (s, 3H), 3.19 (m, 2H), 2.20 (m, ÍH), 1.59 (m, ÍH), 1.70 (m, ÍH). FAB, [M + H] + = 478. • 10 Elemental analysis calculated with 1.6 mcl H, 0 C = 58.42%, H = 4.71%, N = 8.18%; found C = 59.30%, H = 5.04%, N = 7.96%. EXAMPLE 6 [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R, S) -yl] -methylamide of 7- 15-methoxy-naphthalene-2-sulfonic acid trifluoroacetate. A. [1- (1-amino-iso-quinolin-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -methylamide of 7-methoxynaphthalene-2-sulfonic acid. ^ p To a solution of 7-methoxynaphthalene-2-sulphonic acid [1- (1-chloro-iso-quin.-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -amide ( 0.151g, 0.304 mmol) in aceto (20 mL) is added potassium carbonate (0.084 g, 0608 mmol) followed by methyl iodide (0.12 mL, 1.93 mmol). The resulting mixture is heated to reflux overnight, then cooled to room temperature and diluted with methylene chloride. The The solution is washed with a saturated solution of NaHCOs, water and brine. The organic layer is dried over MgSO4, filtered and concentrated. The residue is purd by column chromatography eluting with 5% MeOH / CH: Cl; to provide the • product (0.093 mg, 0.18 mmol) in the form of an oil. 5 lE NMR (CDCL ^, 300 MHz) d 8.41 (s, ÍH), 8.04 (s, ÍH), 8.23- 8.26 (m, 2H), 8.07 (s, ÍH), 7.90 (d, ÍH), 7.90 ( d, ÍH), 7.77 (s, ÍH), 7.75 (s, ÍH), 7.58 (dd, ÍH), 7.28 (m, ÍH), 4.63 (AB, 2H), 3.92 (s, 3H), 3.24 (m , 2H), 2.82 (s, 3H), 2.32 (m, ÍH), 2.05 (m, ÍH). B. [1- (1-phenoxy-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R, S) -yl] -methylamide of 7-methoxynaphthalene-2-sulfonic acid. The title compound is prepared according to Example 1, part L using [1- (l-phenoxy-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -methylamide of acid 7. - 15-methoxy-naphthalene-2-sulphonic acid instead of [1- (1-chloro-isoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxy-naphthalene-2-sulfonic acid . XH NMR (CDCL3, 300 MHz) d 8.45 (s, ÍH), 8.20 (s, ÍH), 7.90 (d, ÍH), 7.81 (d, ÍH), 7.74 (d, ÍH), 7.70 (d, ÍH) , 7.54 (dd, ÍH), 7.38 - 7.45 (, 3H), 7.14 - 7.30 (, 6H), 5.00 (m, ÍH), 4.62 (AB, 2H), 3.88 (s, 3H), 3.25 (m, 2H), 2.81 (s, 3H) ), 2.30 (m, ÍH), 2.01 (m, ÍH). C. [1- (l-Amino-isoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (R, S) -yl] -methylamide of 7-ι-trifluoroacetate methoxynaphthalene-2-sulfonic acid.

The title compound is prepared according to Example 1, part M using [1- (1-phenoxy-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R, S) -yl] -amide of 7- • methoxynaphthalene-2-sulfonic acid instead of [1- (1-phenoxy-5-isoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (R, S) -yl] -amide of 7- methoxynaphthalene-2-sulfonic acid. XH NMR (CDCl-d6, 300 MHz) d 9.00 (bs, 2H), 8.40 (s, ÍH), 8.26 (s, ÍH), 8.04 (d, ÍH, 7.90-7.95 (m, 2H), 7.79 (d , ÍH), 7.71 (dd, 1H), 7.65 (d, ÍH), 7.56 (d, ÍH), 7.32 (d, ÍH), 7.21 (d, ÍH), 4.95 (m, ÍH), 4.54 (AB, 2H), 3.86 (s, 3H), 3.20 (m, 2H), 2.65 (s, 3H), 2.00 (m, ÍH), 1.75 (, ÍH). FAB, [M + H] + = 491. Elemental analysis calculated with 1.5 mol of H, 0 C = 53.25%, H = 4.79%, N = 8.87%; found C = 53.43%, H = 4.50%, N = 8.58%. EXAMPLE 7 [1- (l-amino-isoquinclin-7-yl-methyl) -2- trifluoroacetate. oxopyrrolidin-3- (S) -yl] -methylamide of 7-methoxynaphthalene-2-sulfonic acid. The title compound is prepared by resolution of the The racemic compound described in Example 6, part C using a Chiralpak AD HPLC column (55% EtOH / Heptane (0.1% TFA)). XH NMR (DMSO-de, 300 MHz) d 13.5 (bs, 1H), 9.20 (bs, 2H), 8.40 (dIH), 8.26 (s, ÍH), 8.04 (d, ÍH), 7.90 - 8.00 (m , 2H), 7.79 (d, 1H), 7.71 (dd, ÍH), 7.65 (d, ÍH), 7.58 (d, ÍH), 7.34 (d, ÍH), 7.23 (d, ÍH), 4.98 (m, ÍH), 4.54 (AB, 2H), 3.86 (s, | 3H), 3.20 (, 2H), 2.68 (s, 3H), 2.05 (m, ÍH), 1.80 8m, ÍH). FAB MS, [M + H] t = 491. • The enantiomeric purity is 92.6% ee in accordance with that determined by analytical Chiralpak AD reverse phase HPLC. EXAMPLE 8 Trifluoroacetate of benzo [b] thiophene-2-sulfonic acid [1- (1-amino-isoquinolin-7-yl-methyl] -2-oxopyrrolidin-3- (S) -yl] -amide. • 10 A. Benzo [b] thiophene-2-sulfonic chloride. To a solution of tianaphthalene (11.8 g, 88.1 mmol), in THF (400 mL) at a temperature of -78 ° C n-BuLi is added (55 L of a 1.6 M solution in hexanes, 88.1 mmol). After 15 minutes, the solution is added by cannula to a solution pre-cooled (-78 ° C) of S02 (200 g) in THF (100 L). After the addition, the solution is allowed to warm to room temperature. After 0.5 hours the solution is concentrated. The residue is suspended in hexanes (400 mL) and cooled to 0 ° C. To the solution is added S02C12 (12.5 g, 92.5 mmol). After stirring for 15 minutes, the solution is concentrated. The residue is dissolved in EtOAc. The organic solution is washed with saturated NH4C1 (aqueous), H2O and saturated NaCl (aqueous). The organic layer is dried over MgSO4, filtered and concentrated. The crude product is dissolved in CH2C12 and filtered through a plug of silica gel. The organic solution is then concentrated. The resulting solid is triturated with hexane to give the title compound (12.1 g, 38 mmol). • XH NMR (CDCL3, 300 MHz) d 8.16 (s, ÍH), 7.97 (m, 2H), 7.57 (m, 5 2H). B. [1- (L-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of benzo [b] thiophen-2-sulfonic acid. The title compound is prepared according to that described in example 1, part K, using benzo chloride [b] thiophene-2-sulfonyl in place of 7-methoxynaphthalene-2-sulfonyl chloride. : H NMR (CDCL3, 300 MHz) d 8.29 (d, ÍH), 8.12 (s, 1H), 7.93 (s, ÍH), 7.84 - 7.92 (m, 2H), 7.82 (d, ÍH), 7.54 - 7.62 (m, 2H), 7.46 - 7.52 (m, 2H), 5.50 (d, ÍH), 4.66 (AB, 2H), 3.95 (, HH), 3.25 (m, 2H), 2.65 (m, HH), 2.15 (, HH). FAB, [M + H] + = 472, 474, standard Cl. C. [1- (L-amino-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] - trifluoroacetate benzo [b] thiophene-2-sulfonic acid amide. The title compound was prepared according to that described in example 2, using [1- (1-chloro-isoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -amide of benzo [b] thiophene-2-sulfonic acid as starting material. No extractive treatment was carried out. The raw product is purified by RP-HPLC eluting with a gradient of 10% CH3CN / H20 (0.1% TFA) at 100% CH;, CN. The appropriate fractions are lyophilized to provide the title compound as a white solid. • P NMR (DMSO-de, 300 MHz) d 9.00 (bs, 2H), 8.65 (d, ÍH), 8.30 5 (s, ÍH), 8.07 - 8.15 (m, 3H), 8.05 (d, ÍH), 7.94 (d, ÍH), 7.80 (d, ÍH), 7.68 (d, ÍH), 7.45 - 7.58 (m, 2H), 7.22 (d, ÍH), 4.55 (AB, 2H), 4.31 (m, ÍH) , 3.25 (, 2H), 2.20 (, ÍH), 1.73 (m, ÍH). FAB MS, [M + H. ~ = 453. EXAMPLE 9 • 10 [1- (l-amino-isoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -amide trifluoroacetate 6-chloro-benzo [b] thiophene-2-sulfonic acid. A. l-chloro-3- (2, 2-dimethoxy-ethyl-sulfonyl) -benzene. To a solution of 3-chlorothiophenol (2.4 g, 16.6 mmol) in THF (200 mL) at a temperature of 0 ° C is added bromoacetaldehyddimethylacetal 82.8 g, 16.6 mmol). To the solution is added sodium hydride (0.70 g, 17.4 mmol, dispersion in 60% mineral oil). The reaction is stirred for 16 hours, then quenched by addition of 1 NH 4 Cl saturated (aqueous). The solution is diluted with EtOAc. The organic layer is washed with saturated NaCl (aqueous). The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with hexane. The title compound (3.7 g, 15.9 mmol) is obtained in the form of an oil.

; H NMR (CDCL3, 300 MHz) d 7.32 (m, HH), 7.25 (m, HH), 7.12 (m, HH), 4.47 (m, HH), 3.07 (s, 3H), 3.07 (s, 3H ), 3.02 (s, 3H). B. 4-chloro-benzo [b] -thiophene and 6-cyoro-ber.zo [b] -thiophene. • A solution containing polyphosphoric acid (8 g) and 5 chlorobenzene (50 mL) is heated to reflux. A solution containing l-chloro-3 (2-2, dimethoxy-ethyl-sulfonyl) -benzene (2.7 g, 11.6 mmol) in chlorobenzene (5 mL) is added dropwise to the refluxing polyphosphoric acid solution. After 6 hours, the solution is cooled to room temperature. The The solution is diluted with CH2C12 and washed with water and saturated NaCl (aqueous). The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with hexanes to give the title compounds (2.4 g, 9 mmol) in form of a 1: 1 isomeric mixture. H NMR (CDCl3, 300 MHz) d 7.88 (m, 1H), 7.75 (m, 2H), 7.42 (m, 2H). MS, [M] + = 168, 170, Cl Cl pattern. 6-chloro-benzo [b] thiophen-2-s-l-phonyl chloride. The title compound is prepared according to the procedure described in Example 8, part A, substituting the mixture of 4-chloro-benzo [b] thiophene and 6-chlorobenzo [b] thiophene for tianaphthalene. The crude product is purified by column chromatography eluting with hexanes to give the title compounds as well as 4-25-chlorobenzo [b] thiophene-2-sulfonyl chloride as white solids. 6-Cioro-benzo [b] thiophene-2-sulfonium chloride. P NMR (CDCL3, 300 MHz) d 8.11 (s, ÍH), 7.88 (m, 2H), 7.50 (m, ÍH). • 4-Chloro-benzo [b] thiophene-2-sulfonyl chloride. 5: H NMR (CDCl, 300 MHz) d 8.32 (m, HH), 7.81 (, HH), 7.53 (m, 2H). D. [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl-6-chloro-benzo-b] thiophen-2-sulfonic acid amide. The title compound is prepared as in example 1, • Part K, using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride instead of 7-methoxynaphthalene-2-sulfonyl chloride. XH NMR (CDCL3, 300 MHz) d 8.29 (d, ÍH), 8.12 (s, ÍH), 7.91 (s, ÍH), 7.87 (m, ÍH), 7.83 (d, ÍH), 7.80 (d, ÍH) , 7.60 (d, ÍH), 7.58 (dd, ÍH), 7.42 (dd, ÍH), 5.50 (d, ÍH), 4.65 (AB, 2H), 15 3.95 (m, ÍH), 3.25 (, 2H), 2.65 (m, ÍH), 2.15 (m, ÍH). FAB, [M + H] + = 506, 508, Cl pattern. E. [1- (l-amino-isoquinolin-7-yl-metii) -2- • oxopyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [b] thiophen-2-acid. sulphonic The title compound was prepared according to that described in example 2, using [1- (1-chloro-isoqulnolin-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 6-chlorobenzo [b] thiophene-2-sulfonic acid as starting material. No extractive treatment was carried out. The raw product is purified by RP-HPLC eluting with a gradient of 10% CH3CN / H20 (0.1% TFA) to 100% CH3CN. The appropriate fractions are lyophilized to provide the title compound as a solid. • -H NMR (DMSO-de, 300 MHz) d 9.00 (bs, 2H), 8.71 (d, ÍH), 8.29 5 (bs, ÍH), 8.05 (s, ÍH), 8.01 (d, ÍH), 7.94 (d, ÍH), 7.80 (d, ÍH), 7.65 (d, ÍH), 7.55 (dd, ÍH), 7.21 (d, ÍH), 4.58 (AB, 2H), 4.30 (m, ÍH), 3.20 ( , 2H), 2.20 (m, ÍH), 1.75 (, ÍH). FAB MS, [M + H] + = 487, 489, Cl pattern. EXAMPLE 10 • 10 [1- (L-amino-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulphonic acid hydrochloride. A. 6-methoxy-7-methyl-2H-isoquinolin-l-one 3- (3-methoxy-4-methylphenyl) propenoic acid is suspended (5.33 g, 27.7 mmol) (prepared according to the procedure described in J. Med. Chem. 1991, 34, 1662-1668) in benzene (30 L) and treated dropwise with thionyl chloride (2.22 mL, 30.5 mmol) at a temperature of 0 ° C. The reaction is heated to reflux and maintained for 1 hour. The parts The volatiles are removed in vacuo and the resulting solid is dissolved in dioxane and dropwise added a mixture of sodium azide (3.6 g, 55.4 mmol) in water / dioxane (30 mL, 1: 5) at a temperature of 0 °. C. After stirring for 1 hour, the solution is poured into ice water, the precipitate is collected and washed with water. The solid is dried under vacuum in P205 (24 hours), dissolved in benzene (30 Ml) and heated to reflux slowly over a period of about 4 hours. The benzene is removed to provide 2- (3-me oxy-4-methyl-phenyl) vinyl isocyanate in the form of a brown oil. The oil is absorbed in o-dichlorobenzene, treated with iodine and heated to reflux for 3.5 hours. The particles are removed and the residue is mixed with 2.5% MeOH / CH2Cl3 (10 mL), and then allowed to stand overnight at room temperature. The resulting solid is collected, washed with hexane and ether, and dried to provide the title compound (2.67 g, 14.1 mmol). l NMR (CDCL3, 300 MHz) d 11.80 (bs, ÍH), 8.18 (s, ÍH), 7.16 (d, ÍH), 6.86 (s, ÍH), 6.51 (d, ÍH), 3.94 (s, 3H) , 2.35 (s, 3H), 2.35 (s, 3H). The MS, [M] + = 189. B. 7-Bromomethoxy-1-chloro-6-methoxy-isoquinoline 6-methoxy-7-methyl-2H-isoquinolin-1-one (2.6 g, 13.7 mmol) is converted to 6-methoxy-7-methyl-2-chloroisoquinoline (2.45 g, 11.8) by the method described in Example 1, part E. A part of this material (1.20 g, 5.8 mmol) is converted to 7-bromomethyl-l-chloro-6-methoxy-isoquinoline (0.8 g, 2.8 mmol) by the method described in Example 1, part F. XH NMR (CDCL3, 300 MHz) d 8.30 (s, ÍH), 8.22 (d, ÍH), 7.49 (d, ÍH), 7.10 (s, ÍH) , 4.70 (s, 2H), 4.06 (s, 3H). The MS, [M] + = 285, 287, Cl pattern. C. [1- (1-Chloro-6-methoxyisoquinolin-7-yl-methyl) -2-oxopyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester. Sodium hydride (0.057 g, 1.4 mmol, dispersion is suspended • in 60% mineral oil) in anhydrous THF (5 mL) and treated with a solution of tert-butyl acid (2-oxopyrrolidin-3- (S) -yl) -carbamic acid ester (0.223 g, 1.1 mmol ) and 7- bromomethyl-l-chloro-6-methoxy-isoquinoline (0.32 g, 1.1 mmol) in THF / DMF (10 mL, 6: 1) at a temperature of 0 ° C. The reaction mixture is heated to room temperature, hectic • 10 for 3 hours, paid for by the addition of NHi-Cl and diluted with EtOAc. The layers are separated. The organic layer is washed with saturated NaCl, dried over Na 2 SO 4, filtered and concentrated to give a white solid. The solid is collected, washed with a small amount of EtOAc and plentiful amounts of Et20 to provide the title compound (0.18 g, 0.47 mmol). L 'U NMR (CDCL3, 300 MHz) d 8.22 (d, ÍH), 8.06 (s, ÍH), 7.51 (d, ÍH), 7.11 (s, ÍH), 5.20 (bs, ÍH), 4.68 (AB, 2H), 4.23 (m, ÍH), 3.98 (s, 3H), 3.21 (m, 2H), 2.65 (m, ÍH), 1.90 (s, 9H).

FAB MS, [M + H] + = 387. D. [1- (1-chloro-6-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid. [1- (1-Chloro-6-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester (0.15 g, 0.37 mmol) is converted to [1- (1-Chloro-6-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid (0.08 g, 0.15 mmol) by the method described in Example 1, Parts I and K. lE NMR (CDCL3 / CD3OD, 300 MHz) d 8.40 (s, ÍH), 8.14 (d, ÍH), 7.99 (s, ÍH), 7.95 (d, ÍH) ), 7.83 (d, ÍH), 7.78 (d, ÍH), 7.55 (d, ÍH), 7.28 (s, ÍH), 7.13 (s, ÍH), 4.62 (s, 2H), 4.0 (s, 3H) , 3.97 (s, 3H), 3.89 (dd, ÍH), 3.2 - 3.4 (m, 2H), 2.52 (, ÍH), 2.07 (m, ÍH). FAB, [M + H] + = 526. E. [1- (L-amino-6-methoxyisoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide hydrochloride. 7-methoxynaphthalene-2-sulfonic acid. [1- (L-Chloro-6-methoxyisoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid (0.080 g, 0.15 g. mmol) and phenol (0.430 g, 4.6 mmol) with stirring at a temperature of 70 ° C for 5 minutes. Ammonium acetate (0.354 g, 4.6 mmol) is added and the reaction mixture is heated to a temperature of 115 ° C for about 5 hours. Additional ammonium acetate (0.177 g, 2.3 mmol) is added and the reaction is heated for an additional 3 hours. The reaction is cooled and partitioned between 0.5 N NaOH and CH2C12. The organic layer is dried in Na 2 SO 4 and concentrated. The residue is purified by column chromatography eluting with 5% MeOH / CH2Cl2. The product fractions are collected and concentrated in a small volume, and then the residue is acidified with HCl / IN ether to give a beige solid (0.046 g, 0.095 mmol). XH NMR (CD3OD, 300 MHz) d 8.38 (s, ÍH), 8.05 (d, ÍH), 7.88 (d, ÍH), 7.80 (d, ÍH), 7.44 (d, ÍH), 7.32 (d, ÍH) , 7.30 (s, ÍH), 7.23 (dd, ÍH), 7.07 (d, ÍH), 4.53 (AB, 2H), 4.23 (t, ÍH), 3.98 (s, 3H), 3.89 (s, 3H), 3.30 (m, 2H), 2.22 (m, ÍH), 1.89 (, ÍH). FAB, [M + H] + = 478. Elemental analysis calculated with 1.4 mol of H20 C = 54.96%, H = 5.29%, N = 9.86%; found C = 54.81%, H = 5.12%, N = 9.71%. EXAMPLE 11 [1- (6-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R, S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid trifluoroacetate. A suspension of [1- (1-chloro-6-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid in methanol / CH2Cl2 ( 35 mL, 6: 1) is treated with THF (5 Ml), AcOH (5 mL) and 10% Pd on carbon (0.04 g). The suspension is stirred under a hydrogen atmosphere for 7 hours. The suspension is filtered, then the filtrate is concentrated and the residue purified by RP-HPLC eluting with a gradient of 10% CH3CN / H20 (0.1% TFA) to 100% CH3CN. The appropriate fractions are lyophilized to give the title compound as a white solid (0.325 G, 0.66 mmol).

: H NMR (CD3OD, 300 MHz) d 9.37 (s, ÍH), 8.40 (d, ÍH), 8.38 (d, ÍH), 8.23 (d, ÍH), 8.15 (s, ÍH), 7.93 (d, ÍH) ), 7.85 (d, ÍH), 7.77 (dd, ÍH), 7.66 (s, ÍH), 7.35 (s, ÍH), 7.27 (dd, ÍH), • 4.66 (AB, 2H), 4.28 (t, ÍH), 4.12 (s, 3H), 3.92 (s, 3H), 3.40 5 (m, 2H), 2.35 (m, ÍH), 1.92 (m, ÍH) . FAB, [M + H] t = 492. Elemental analysis calculated with 1.2 mol of H20 C = 53.66%, H = 4.57%, N = 6.70%; found C = 53.62%, H = 4.38%, N = 6.67%. EXAMPLE 12 [1- (L-Amino-6-methoxyisoquinolin-7-yl- • 10-methyl) -2-oxopyrrolidin-3- (R, S) -yl] -amide trifluoroacetate 4- (2-chloro-6-) nitrophenoxy) benzenesulfonic acid. [1- (L-Chloro-6-methoxyisoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester (0.845 g, 2 mmol) in ester is converted to ester tert-butyl [1- (L-amino-6-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid (0.08 g, 0.15 mmol ) (carbohydrate (0.314 g, 0.081 mmol) by the method described in Example 10, part E. A portion of this material (0.285 g, 0.7 mmol) is deprotected from In accordance with that described in example 1, part I, to provide [1- (l-apyne-6-methoxyisoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] -Rammine dihydrochloride (0.28 g, 0.78 mmol) and coupled with 4- (2-chloro-6-nitrophenoxy) benzenesulfonyl chloride (0.35 g, 1 mmol) in accordance with that described in Example 1, part K. The material obtained by subjecting it to extractive treatment and column chromatography is further purified by RP HPLC to give the title compound 80.04 g, O.067 • mmol). 5 P NMR (CD3OD, 300 MHz) d 8.14 (s, ÍH), 8.07 (d, ÍH), 7.92 - 7.98 (m, 3H), 7.53 - 7.60 (, 2H), 7.40 (s, ÍH), 7.18 ( d, ÍH), 7.05 (d, 2H), 4.63 (AB, 2H), 4.18 (t, ÍH), 4.06 (s, 3H), 3.36 (m, 2H), 2.32 (m, ÍH), 1.87 (m , ÍH). FAB, [M + H] * = 598, 600, Cl pattern. Elemental analysis calculated with 1.5 mol of H20 C = 47.13%, H = 3.82%, N = 9.48%; found C = 47.07%, H = 3.66%, N = 9.24%. EXAMPLE 13 [1- (1,6-Diamino-isoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (R, S) -yl] -amide of 7-methoxynaphthalene-2-sulphonic acid trifluoroacetate. A. 3- (3-Acetamido-4-methylphenyl) propenoic acid To a solution of 3-acetamido-4-methylbenzaldehyde (14 g, 79 mmol) in pyridine (210 mL) is added piperidine (3.9 mL, 39.4 mmol) and Malonic acid (15.26 g, 146.6 mmol). The mixture is heated at a temperature of 100 ° C for 4 hours, and then stirred at room temperature overnight. The solution is concentrated in vacuum and then diluted with water. Cold 1N HCl is added to the paste until the pH reaches approximately 4. the solid product (16.178g, 73.8 mmol) is collected and washed extensively with water. The title compound (16188 g, 73.8 mmol) is then dried in P205 in vacuo overnight to give a white solid. P NMR (DMSO-de, 300 MHz) d 12.30 (bs, ÍH), 9.30 (bs, ÍH), • 7.65 (s, ÍH), 7.51 (d, ÍH), 7.42 (d, ÍH), 7.25 (d, ÍH), 6.42 5 (d, 1H), 2.25 (s, 3H), 2.09 (s, 3H) . The MS, [M + H] * = 220. B. 3- (3-Acetylamino-4-methyl-phenyl) -acyloyl azide To the paste of 3- (3-acetamido-4-methylphenyl) propenoic acid (20.11 g, 91.7 mol ^ in acetone (450 mL) a a temperature of 0 ° C is added triethylamine (12.8 mL, 91.8 mmol) followed by Dropwise addition of ethyl chloroformate (11.8 mL, 123 mmol) in a period of 10 minutes. The resulting yellow paste is stirred using a mechanical stirrer for 1.5 hours, then slowly added a solution of sodium azide (8.94 g, 138 mmol) in water (25 mL) to keep the temperature below 5 ° C. The thick mixture is stirred at a temperature of 0 ° C for 1 hour and then the ice cloth is removed and the reaction mixture is allowed to warm to room temperature. The suspension is poured into water (800 mL) and then filtered. The solid The remainder is washed extensively with water and dried under vacuum in P2O5 overnight to give the product as a pale yellow solid (21.40 g, 87.6 mmol). XH NMR (CDCl3, 300 MHz) d 8.10 (s, ÍH), 6.51 (d, ÍH), 7.22 (m, 2H), 6.95 (bs, ÍH), 6.38 (d, ÍH), 2.29 (s, 3H) , 2.21 (s, 3H).

The MS, [M + H] + = 244.

C. N- (7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl) -acetamide To a solution of diphenylether (250 L) and tributylamine (11.9 mL, 49.9 mmol) at a temperature of 220 -240 ° C is added a • 3- (3-acetylamino-4-methyl-phenyl) -acyloyl azide paste (12.2 g, 49.9 mmol) in diphenylether. After 2 hours the yellow solution is cooled to room temperature, drained in hexane (800 mL). A brown solid precipitates and the title product (3.56 g, 16.5 mmol) is obtained as a light yellow solid • 10 by recrystallization from DMF / MeOH. XH NMR (DMSO-de, 300 MHz) d 11.00 (bs, 1H), 9.35 (s, ÍH), 7.98 (s, ÍH), 7.89 (s, ÍH), 7.05 (m, ÍH), 6.45 (d, ÍH), 2.32 (s, 3H), 2.12 (s, 3H). The MS, [M + H] x = 216. D. 6-amino-7-methyl-2H-isoquinolin-l-one 15 Heat to reflux in EtOH (0.84 mL) N- (7-methyl-1-oxo-l, 2-dihydro-isoquinolin-6-yl) ) -acetamide (0.366 g, 1.69 mmol) and concentrated HCl (0.5 mL). After 6 hours, the concentration • mix until dry, and after dilution with water and becomes basic using NaOH IN until reaching a pH of approximately 10. The aqueous solution is extracted with methylene chloride (4 x 50 L) and the organic layers are combined and washed with brine, dried over MgSO, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 3% MeOH / CH 2 Cl 2 at 5% MeOH / CH 2 Cl 2 to give the title product (0.200 g, 1.15 mmol) as a white solid. XH NMR (CDCl3, 300 MHz) d 8.90 (bs, HH), 8.06 (s, 1H),, 6.90 (m, 1H), 6.65 (s, HH), 6.28 (d, HH), 4.05. { bs, 2H), 2.20 (s, • 3H). The MS, [M + H] t = 174. E. l-Chloro-7-methyl-isoquinolin-6-ylamine The title compound is prepared according to that described in example 1, part E using 6-amine-7-methyl-2H-isoquinolin-1-one. as initial material. The crude product is purified by column chromatography eluting cpn a • 10 gradient of 5% MeOH / CH2Cl2 at 10% MeOH / CH2Cl2 to provide the title compound as a yellow solid. P NMR (CDC13, 300 MHz) d.8.05 (d, HH), 8.00 (s, ÍH), 7.30 (d, HH), 6.90 (s, ÍH), 4.25 (bs, 2H), 2.4C (s, 3H). EJI MS [M] + = 192.194, Cl pattern. F. Benzhydrylidene- (1-chloro-7-methyl-isoquinolin-6-yl) -amine To a solution of 1-chloro-7-methyl-isoquinolin-6-ylamine (O.lg, 0.52 mmol) in MeOH (5%). mL) at a temperature of 0 ° C is introduced by bubbling HCl gas for one minute and then the solvent is removed in vacuum. The remaining white solid is diluted with 1,2-dichloroethane and benzophenoneimine (0.14 mL, 0.89 mmol) is added. The resulting suspension is heated to reflux for 48 hours, then cooled to room temperature and concentrated to dryness.

The crude material is diluted with CH2C12 and washed with a saturated solution of NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography using 10% EtOAc / hexanes as eluent to give the title compound (0.159 g, 0.45 mmol) in the form of yellow oil. : H NMR (CDC13, 300 MHz) delta 8.05 (d, 2H), 7.80 (, '2H), 7.45-7.55 (, 4H), 7.20-7.30 (m, 3H), 7.10 (, 2H), 6.75 (s) , ÍH), 2.50 (s, 3H). FAB MS, [M + H] t = 357, 359, Cl. G. Pattern. Benzhydrylidene- (7-bromomethyl-l-chloro-isoquinolin-6-yl) -amine The title compound is prepared in accordance with that described in Example 1, part F, using benzhydrylidene- (1-chloro-7-methyl- isoquinolin-6-yl) -amine as starting material. The title compound is obtained in the form of an oil. XH NMR (CDC13, 300MHz) delta.8.33 (s, ÍH), 8.06 (d, ÍH), 7.84 (, 2H), 7.41 (m, 4H), 7.32 (, 4H), 7.20 (d, 1H), 6.66 (s, ÍH), 4.79 (s, 2H). FAB MS, [M + H] + = 435, 437, Cl, pattern of! Br. H. tertbutyl acid ester. { 1- [6- (Benzhydrylidene-amino) -l-chloro-isoquinolin-7-ylmethyl] -2-oxopyrrolidin-3- (S) -yl} I carbamic The title compound is prepared according to that described in Example 1, part H, using benzhydrylidene- (7-bromomethyl-1-chloro-isoquinolin-6-yl) -amine in place of 7- bromomethyl-1. -chloroisoquinoline. The crude product is purified by column chromatography eluting with gradient of 10% EtOAc / hexanes to 30% EtOAc / hexane to # provide the compound in the form of a 5 fluffy yellow solid. : H NMR (CDC13, 300MHz) delta 8.09 (d, ÍH), 8.01 (s, ÍH), 7.80 (m, 2H), 7.20-7.45. (m, 9H), 6.70 (s, ÍH), 5.30 (d, ÍH), 4.65 (AB, 2H), 4.21 (m, ÍH), 3.32 m, 2H), 2.70 (, ÍH), 1.95 (m, ÍH), 1.46 (s, 9H). FAB MS, [M + H]] '= 555, 557, standard Cl. 10 I_. ['l- (6-amino-l-chloro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid tert-butyl acid ester. { 1- [6- (Benzhydrylidene-amino) -1- chloro-isoquinolin-7-ylmethyl] -2-oxopyrrolidin-3- (S) -yl} The carbamate is deprotected according to that described in Example 1, part I to provide 3- (S) -amino-1- (6-amino-1-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-hydrochloride. -one and is coupled with 7-methoxynaphthalene-2-sulfonyl chloride according to that described in example 1, Part K. The material obtained after the extractive workup is purified by chromatography on cplumna eluting with a gradient of 30% EtOAc / hexane at 60% EtOAc / hexanes to give the product. XH NMR (CDCI3, 300MHz) delta 8.34 (s, ÍH), 8.02 (d, ÍH), 7.93 (s, ÍH), 7.87 (d, ÍH), 7.79 (d, ÍH), 7.72 (dd, ÍH), 7.29 (d, ÍH), 7.26 (d, ÍH), 7.25 (s, ÍH), 6.77 (s, ÍH), 5.61 (bs, ÍH), 4.93 (bs, 2H), 4.49 (AB, 2H), 3.92 (s, 3H), 3.85 (m, ÍH), 3.20 (, 2H), 2.52 (, ÍH), 2.05 (, ÍH). Spraying EM • ions, [M + H] "= 511, 513, Cl. Standard 5. [1- (1,6-Diamino-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl trifluoroacetate ]] -amido-7-methoxynaphthalene-2-sulfonic acid amide The title compound is prepared according to example 2 using [1- (6-amino-1-chloro-isoquinolin-7- (10-ylmethyl) -2-oxopyrrolidine] -3- (S) -yl] -amide, 7-methoxynaphthalene-2-sulfonic acid as starting material No extractive treatment is carried out The crude product is purified by RP-HPLC eluting with a gradient of 10% CH3CN / H2O (0.1% TFA) to 100% CH2CN The appropriate fractions are lyophilized to provide the title compound as a white solid. XH NMR (DMSO-de, 300MHz) delta.12.15 (bs, ÍH), 8.34-8.38 (d, 2H), 8.24 (d, ÍH), 7.95 (d, ÍH), 7.90-7.93 (d, 2H), 7.618 (dd, ÍH), 7.53 (d, ÍH), 7.38 (d, ÍH), 7.30 (dd, ÍH), 6.83 (d, ÍH), 6.78 (s, ÍH), 6.49 (bs, 2H), 4.26 (AB, 2H), 4.20 (m, ÍH), 3.90 (s, 3H), 3.06 (m, 2H), 2.00 (m, ÍH), 1.60 (, ÍH1). FAB MS, [M + H] ~ = 492. EXAMPLE 14 [1- (1,6-Diamino-isoquinolin-7-yl-methyl) trifluoroacetate] 2-oxo-pyrrolidin-3- (S) -yl] -amide of 6-c-chloro-benzo [b] thiophene-2-sulfonic acid A. [1- (6-amino-l-chloro-isoquinolin-7- 6-chloro-benzo [b] thiophene-2-sulphonic acid ester-tert-butyl acid ester (2-oxo-pyrrolidin-3- (S) -yl] -amide. { 1- [6- (Benzhydrylidene-amino) -1-chloro-isoquinolin-7-ylmethyl] -2-oxopyrrolidin-3- (S) -yl} -carbamic is deprotected in accordance with that described in Example 1, part I to provide 3- (S) -amino-1- (6-amino-1-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-hydrochloride. and is coupled with 6-chloro-benzo [b] thiophene-2-sulfonyl chloride according to that described in Example 1, part K. The material obtained by being subjected to extractive treatment is purified by column chromatography eluting with a gradient from 20% EtOAc / hexane to 60% EtOAc / hexanes to provide the product. P NMR (CDC13, 300MHz) delta 8.05 (d, ÍH), 8.02 (s, ÍH), 7.89 (s, ÍH), 7.86 (d, ÍH), 7.81 (d, ÍH), 7.44 (dd, ÍH), 6.82 (s, ÍH), 5.40 (d, ÍH), 4.90 (bs, 2H), 5.42 (AB, 2H), 3.95 (m, 1H), 3.30 (m, 2H), 2.65 (m, ÍH), 2.05 (my h) . Ion spray MS, [M + H] * = 521, 523, Cl pattern. B_. [1- (1,6-Diamino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl-6-chloro-benzo [b] thiophene-2-sulphonic acid trifluoroacetate The title is prepared according to that described in example 2 using [1- (6-amino-l-chloro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 6- chloro-benzo [b] thiophene-2-sulfonic acid as starting material. No extractive treatment is carried out. The crude product is purified by RP-HPLC eluting with a • gradient of 10% CH3CN / H20 (0.1% TFA) to 100% CH3CN / H20. The appropriate 5 fractions are lyophilized to provide the title compound as a tan solid. : H NMR (DMS0-ds, 300 MHz) delta 12.05 (bs, ÍH), 8.70 (d, ÍH), 8.35 (bs, 2H), 8.00-8.05 (m, 2H), 7.94 (s, ÍH), 7.51 (d "ÍH), 7.38 (m, ÍH), 6.71-6.80 (m, 2H), 6.51 (bs, 2H), 4.30 (m, l 3H), • 10 3.20 (m, 2H), 2.15 (m, ÍH), 1.71 (m, ÍH). Ion Spray MS, [M + H] * = 502, 504, Cl standard. EXAMPLE 15 [1- (2-Aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3"(S) -yl Trifluoroacetate ] -amide of 7-methoxα-naphthal, en-2-sulphonic acid A. 7-methyl-lH-quinolin-2-one and 5-methyl-lH-quinolin-2-one The title compounds were prepared from of m- • toluidine and cinnamoyl chloride in accordance with the procedure described in Synt? esis 1975, 739. The residue The obtained crude solid is triturated in Et20 / hexanes and filtered to provide a mixture of product isomers in a ratio of 1.5: 1 between 7-methyl-1H-quinolin-2-one to 5-methyl-1H-quinolin-2. ona in the form of a beige solid. Several attempts of purification through crystallization fractional in methanol offered only a mixture enriched by 2: 1 as exemplified in the subsequent step. P NMR (DMS06, 300MHz) delta 7.85 (d, ÍH), 7.53 (d, ÍH), 7.09 (s, ÍH), 7.01 (d, ÍH), 6.42 (d, ÍH), 2.38 (s, 3H) for • minor isomer (7-methyl); and G.8.03 (d, ÍH), 7.38 (dd, ÍH), 5 7.17 (s, ÍH), 7.01 (d, ÍH), 6.51 (d, ÍH), 2.50 (s, 3H) for minor isomer (5 -methyl). B. 2-Chloro-7-methyl-quinoline and 2-chloro-5-methyl-quinoline The title compounds were prepared according to that described in Example 1, part E using a 2: 1 mixture of • 10 7-methyl-lH-quinolin-2-one and 5-methyl-lH-quinolin-2-one in place of 7-methyl-2H-isoquinolin-1-one. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc / CH2Cl2 at 10% EtOAc / CH2Cl2: to provide a 2: 1 mixture between 2-chloro-7-meth1-quinolma and 2-chloro-methyl-quinoline in the form of a beige solid. ^ NMR (CDC13, 300 MHZ) delta.8.02 (d, ÍH), 7.78 (s, ÍH), 7.68 (d, ÍH), 7.30 (d, ÍH), 2.56 (s, 3H) for major isomer (7- ethyl); and D 8.25 (d, 2H), 7.86 (d, HH), 7.60 (dd, ÍH), 7.39 (m, 2H), 2.65 (s.3H) for minor isomer (5-methyl) ?. C. C. 7-Bromomethyl-2-chloroquoline and 5-bromomethyl-2-chloro-quinoline The title compounds are prepared according to that described in Example 1, part F using a 2: 1 mixture of 2- chloro-7-methyl-quinoline and 2-chloro-5-methyl-quinoline in place of l-chloro-7-methyl-isoquinoline. The resulting crude polymer mixture is easily purified by trituration in EtOAc / hexanes to give the 7- bromomethyl-2-chloro-quinoline as a colored solid. • beige (7.4g, 38%). 5"H NMR (CDC13, 300MHz) delta 8.10 (d, ÍH), 8.00 (s, ÍH), 7.82 (d, ÍH), 7.60 (d, ÍH), 4.67 (s, 2H), a 2: 1 mixture enriched with 5-bromomethyl-2-chloro-quinoline and 7-bromomethyl-2-chloro-quinoline is isolated in the form of a beige-colored solid (6.8 g) of the concentrated filtrate by • 10 fractional recrystallization from Et020 / hexanes / EtOAc. : H NMR (CDCl 3, 300 MHz) delta 8.43 (d, ÍH), 8.09 (dd, ÍH), 8.03 (m, ÍH), 7.68 (m, ÍH), 7.50 (d, ÍH), 4.88 (s, 2H ) for major isomer (5-bromomethyl). D. [1- (2-Chloro-quinolin-7- 15 -imethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester The title compound is prepared from ester tert-butyl. - butyl acid (2-oxo-pyrrolidin-3- (S) -yl) -carba • according to that described in example 1, part H using 7-bromomethyl-2-chloro-quinoline instead of 7- 20 bromomethyl-1-chloro-isoquinoline. The crude product is triturated in 20% EtOAc / hexanes and filtered to provide the title compound as a beige solid. P NMR (CDCI3, 300MHz) delta 8.10 (d, 1H), 7.83 (s, ÍH), 7.80 (d, ÍH), 7.46 (d, ÍH), 7.40 (d, ÍH), 5.17 (bs, 1H) , 4.68 (AB, 2H), 4.25 (m, ÍH), 3.26 (m, 2H), 2.64 (m, ÍH), 1.88 (m, ÍH), 1.46 (s, 9H). E. 7- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -2-chloro-quinoline hydrochloride • The title compound is prepared in accordance with described in Example 1, Part I employing [1- (2-chloro-quinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester as the starting material. The title compound is obtained in the form of a white solid. • 10: H NMR (CDC13, 300 MHz) delta.8.75 (d, ÍH), 8.06 (s, ÍH), 7.86 (d, ÍH), 7.58 (d, ÍH), 4.69 (AB, 2H), 4.15 ( , 2H), 3.35 (m, 2H), 2.43 (m, ÍH), 2.04 (, ÍH). F. 1- (2-Cioro-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid amide The title compound is prepared in CH2C12 instead of CH3CN In accordance with that described in example 1, part K employing 7- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -1-chloro-isoquinoline hydrochloride in place of hydrochloride of 7- ( 3- (S) -amino-2-oxopyrrolidin-1-methyl) -1-chloro-isoquinoline and 7-Methoxynaphthalene-2-sulfonyl chloride according to that prepared in Example 1, part J. The crude product is triturated in 20% EtOAc / hexanes and filtered to provide the title compound as a white solid. XH NMR (CDCl 3, 300 MHz) delta.8.38 (s, ÍH), 8.08 (d, 1H), 7.92 (d, ÍH), 7.81 (d, ÍH), 7.76 (m, 3H), 7.38 (d, ÍH), 7.36 (d, IH), 7.30 (dd, ÍH), 7.25 (m, ÍH), 5.44 (s, ÍH), 4.61 (s, 2H), 3.96 (s, 3H), 3.78 (m, ÍH), 3.23 (m, 2H), 2.60 (m, ÍH), 2.10 (m, ÍH). FAB MS, [M + H] ~ = 496, 498, Cl pattern. Elemental analysis calculated C = 60.54%, H = 4.47%, N = 8.47%, Cl = 7'.15%, found C = 60.44%, H = 4.18%, N = 8.45, Cl = 7.19%. G. [1- (2-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfone acid co-converts [1- (2-chloro 7-methoxy-naphthalene-2-sulfonic acid in the title compound when heated to 125 ° C in accordance with that described in Example 2. The crude product is partially purified by RP-HPLC eluting in a gradient of 10% CH3CN / H2O (0.1% TFA) to 60% CH3CN / H20 (0.1% TFA) and the appropriate fractions of product are concentrated in vacuo., are filtered and triturated with MeOH according to the previously described to offer the title compound in the form of a white solid. : H NMR (DMS0-d6, 300 MHz) delta 8.62 (bs, 2H), 8.38 (s, ÍH), 8.31 (d, ÍH), 8.25 (d, ÍH), 8.03 (d, ÍH), 7.94 (d , ÍH), 7.86 (d, ÍH), 7.72 (d, ÍH), 7.55 (s, ÍH), 7.43 (s, 1H), 7.32 (dd, ÍH), 7.27 (d, ÍH), 7.01 (d, ÍH), 4.50 (AB 2H), 4.11 (m, ÍH), 3.88 (s, 3H), 3.09 (m, 2H), 2.00 (m, ÍH), 1.58 (, ÍH). Ion spray MS of [M + H] "= 477. Calculated elemental analysis C = 54.93%, H = 4.27%, N = 9.49%, found C = 54.69%, H = 4.24%, N = 9.30%. Enantiomeric purity is 81.9% in accordance with that determined by analytical Chiralpak RP-HPLC • EXAMPLE 16 5 [1- (2-aminoquinolin-7-iimeti'l) -2-oxopyrrolidin-3- (S) - trifluoroacetate - il] -amido of 6-c-iorobenzo [b] thiophene-2-sulfonic acid A. [1- (2-chloro-quinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) ryl] - 6-chloro-benzo [b] thiophene-2-sulfonic acid amide • 10 The title compound is prepared in CH; C1; instead of CH3CN from 7- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -2-chloro-quinoline hydrochloride in accordance with that described in Example 1, part K, using 6-Chlorobenzo [b] thiophene-2-sulfonyl in accordance with that prepared in Example 9, part A, B and C in place of 7- methoxynaphthalene-2-sulfonyl chloride. The crude product structured from EtOAc / hexanes to provide the title compound as a beige solid. : H NMR (DMSO-d6, 300 MHz) delta 8.77 (d, ÍH), 8.42 (d, ÍH), 8.27 (s, ÍH), 8.07 (s, ÍH), 8.04 (d, ÍH), 8.02 (d, ÍH), 7.75 (s, ÍH), 7.58 (d, ÍH), 7.52 (dd, ÍH), 7.48 (d, 1H), 4.55 (AB, 2H), 4.28 (m, ÍH), 3.18 (m, 2H), 2.18 (m, 1H), 7.71 (m, ÍH). Ion spray MS, [M + H] t = 506, 508, Cl. Standard B. [1- (2-aminoquinolin-7-ylmethyl) -2- 25 oxopyrrolidin-3- (S) -yl trifluoroacetate ] 6-chlorobenzo [b] thiophene-2-sulfonic acid amide [1- (2-Chloro-quinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo acid ib. iofen-2-sulfonic • in the title compound when heated to a temperature of 120 ° C in accordance with that described in example 2. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH 3 CN / H; -1% TFA) to 80% CH3CN / H0 (0.1% TFA), and the appropriate product fractions are lyophilized to provide the title compound in shape of a tan solid. X NMR (DMSO-de, 500 MHz) delta 8.73 (d, 1H), 8.34 (d ,, ÍH), 8.29 (s, ÍH), 8.07 (s, ÍH), 8.03 (d, ÍH), 7.89 (d , ÍH), 7.54 (dd, ÍH), 7.52 (d, ÍH), 7.47 (d, ÍH), 7.31 (d, 1H), 7.04 (d, ÍH), 6.94 (d, ÍH), 6.42 (d, ÍH), 4.53 (AB, 2H), 4.22 (m, ÍH), 3.18 (, 2H), 2.18 (m, ÍH), 1.72 (m, 1H, FAB MS, [M + H] ~ = 487. EXAMPLE 17 [1- (2-aminoquinolin-7-ylmethyl) -2 trifluoroacetate - benzo [b] thiophene-2-sulphonic acid oxopyrrolidin-3- (S) -yl] -amide A. [1- (2-chloro-quinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S ) -yl] -benzo [b] thiophene-2-sulfonic acid amide The title compound is prepared in CHCi3 instead of CH3CN from 7- (3- (S) -amino-oxopyrrolidin-1-hydrochloride. ilmethyl) -2-chloro-quinoline according to that described in example 1, part K employing benzo [b] thiophene-2-sulfonyl chloride in accordance with that prepared in example 8, part A instead of sodium chloride. -methoxy-naphthalene-2-sulfonyl The crude product is triturated from CH 2 Cl 1 to give the title compound as a beige solid, LH NMR (CDC 13, 300 MHz) delta 8.08 (d, 1H), 7.95. (d, ÍH), 7.88 (m, 2H), 7.99 (d, ÍH), 7.76 (s, ÍH), 7.49 (m, 2H), 7.39 (m, 2H), 5.62 (s, ÍH), 4.64 (s, 2H), 3.95 (m, 1K), 3.27 (, 2H), • 10 2.65 (m, ÍH), 2.16 (m, ÍH). B. [1- (2-aminoquinolin-7-ylmethi) -2-oxopyrrolidin-3- (S) -yl] -amino benzo [b] thiofen-2-sulfonic acid trifluoroacetate [1- (2-chloro)] -quinolin-7-ylmethi) -2-oxo-pyrrolidin-3- (S) -yl] -amide of benzo [b] thiophene-2-sulfonic acid in the title compound when heated to a temperature of 130 ° C. conformance with that described in example 2. The crude product is purified by RP-HP1C eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) to 60% CH3CN / H; 0 (0-1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a tan solid. XH NMR (DMSO-d6 '500 MHz) delta 8.68 (d, ÍH), 8.35 (d, ÍH), 8.09 (dd, ÍH), 8.06 (s, ÍH), 8.02 (dd, ÍH), 7.90 (d, 1 HOUR) , 7.52 (, 2H), 7.45 (s, ÍH), 7.32 (d, ÍH), 7.04 (d, 1H), 4.53 (AB, 2H), 4.22 (m, ÍH), 3.17 (m, 2H), 2.18 (m, ÍH), 1.72 (, ÍH). MS ion spray, [M + H] "= 453 EXAMPLES 18 AND 19 • [1- (2-aminoquinolin-7-ylmethyl) -2- 5-oxopyrrolidin-3- (S) -yl] -methylamide trifluoroacetate of 7-methoxynaphthalene-2-sulfonic acid and methyl- [2-oxo-l- (2-oxo-l, 2-dihydro-quinolin-7-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of acid, 7- methoxynaphthalene-2-sulfonic A. [1- (2-Chloro-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - • 10-methoxy-7-methoxy-naphthalene-2- sulfonic acid [1- (2-chloro-quinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid (0.4 g, 0.81 mmol), prepared in accordance with example 15, part F, DMF (20 mL) is dissolved and cooled to a temperature of 0 °.

C. To the solution is added methyl iodide (0.28 g, 2.01 mmol) and sodium hydride (34 mg, 0.85 mmol, 60% mineral oil dispersion). The ice water bath is removed and the mixture is stirred at room temperature for 3 hours. The resulting solution is emptied into a separating funnel and diluted with EtOAc (100 mL). The organic layer is washed with IN HCl, H20, and saturated NaCl. The organic phase is then dried over MgSO4, filtered and concentrated. The crude residue is purified by column chromatography eluting in 10% EtOAc / CH2Cl2 to give the title compound (0.36g, 0.71 mmol) as a solid.

: H NMR (CDCl 3, 300 MHz) delta 8.44 (s, ÍH), 8.09 (d, 1H),, 7.92 (d, ÍH), 7.82 (dd, 1H), 7.78 (m, 3H), 7.42 (dd, ÍH), 7.4 (d, ÍH), 7.28 (dd, ÍH), 7.26 (s, ÍH), 5.00 (m, 1H), 4.62 (AB, • 2H), 3.94 (s, 3H), 3.23 (m, 2H), 2.84 (s, 3H), 2.33 (m, ¡ÍH), 2.03 (m, ÍH). B. [1- (2-aminoquinolin-7-ylmethyl) -2-oxopyrrc) lidin-3- (S) -yl] -methylamide of 7-methoxine-phthalene-2-sulphonic acid and methylene glycol - [2-oxo-1- (2-oxo-1-, 2- dihydro-quinolin-7-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of • 10 7-methoxynaphthalene-2-sulphonic acid It becomes [1- (2-chloro-quinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -methylamide of 7-methoxynaphthalene-2-acid sulfonic acid in the title compounds when heated to a temperature of 125 ° C in accordance with that described in Example 2. The crude mixture of products is purified by RP-HPLC eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) to 80% CH3CN / H2O (0.1% TFA) and the appropriate fractions of • product are lyophilized to provide [1- (2-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -ii] -20-metholamide of 7-methoxynaphthalene-2-sulfonic acid trifluoroacetate as a white solid . XH NMR (DMSO-de, 300 MHz) delta 8.42 (s, ÍH), 8.33 ÍH), 8.04 (d, ÍH), 7.96 (d, ÍH), 7.87 (d, ÍH), 7.70 (dd, ÍH) 7.58 (s, ÍH), 7.42 (s, ÍH), 7.35 (dd, ÍH), 7.31 (d, ÍH), 7.62 (d, ÍH), 4.93 (m, ÍH), 4.51 (AB, 2H), 3.89 (s, 3H), 3.18 (mi, 2H), 2.70 (s, 3H), 2.02 (s, 3H), 1.78 (m, ÍH). Ion spray MS, [M + H] '= 491. Elemental analysis calculated with 1.8 mol of H; 0 calcified C = 52.79%, H = 4.84%, N = 8.80%, found C = 52.80%, H = 4¡.35%, 5 N = 8.55%. Methyl 7- [2-oxo-l, 2-dihydro-quinolin-7-ylmethyl] -pyrrolidin-3- (S) -yl] -amide of 7-methoxy-naphthalene-2-sulfonic acid is also isolated from the mixture of the reaction as a by-product. • 10 XH NMR (DMSO-de, 300 MHz) delta 8.42 (s, ÍH), 8.04 (d, ÍH), 7. 97 (d, ÍH), 7.85 (d, ÍH), 7.70 (d, ÍH), 7.60 (d, ÍH), 7.58 (s, ÍH), 7.35 (dd, ÍH), 7.04 (s, ÍH), 6.98 (d, ÍH), 6.45 (d, ÍH), 4.90 (m, ÍH), 4.40 (AB, 2H), 3.89 (s, 3H), 3.15 (m, 2H), 2 . 71 (s, 3H), 2. 01 (m, ÍH), 1. 76 (m, ÍH). 15 Ion rostrate EM, [M + HT = 492. EXAMPLE 20 [1- (2-aminoquinolin-5-ylmethyl) -2- • oxopyrrolidin-3- (S) -yl-amide of 7-methoxynaphthalene-2-sulphonic acid trifluoroacetate. 20 A. [1- (2-Chloro-quinoin-5-ylmethyl) -2-oxopyrrolidin-3- (S) -ii] -carbamic acid tert-butyl ester The title compound is prepared from tertiary ester. butyl acid (2-oxopyrrolidin-3- (S) -yl] -carbamic acid in accordance with that described in example 1, part H using a 2: 1 mixture of 5-bromomethyl-2-chloro-quinoline and 7-bromomethyl-2-chloro-quinoline, in accordance with that prepared in example 15, part C, instead of 7- bromomethyl-1- chloro-isoquinolma. The mixture of orudo product • purified by column chromatography eluting cpn 1% 5 MeOH in 25% EtOAc / CH 2 Cl; to provide as the main product the title compound in the form of a beige solid. : H NMR (CDC13, 300MHz) delta 8.53 (d, ÍH), 7.98 (d, ÍH), 7.69 (dd, ÍH), 7.50 (d, ÍH), 7.41 (d, ÍH), 5.59 (d, ÍH) , 4.89 (AB, • 10 2H), 4.22 (m, ÍH), 3.19 (, ÍH), 3.12 (m, ÍH), 2.51 (m, ÍH), 1.86 (m, ÍH), 1.45 (s, 9H). B. 5- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -2-chloro-quinoline hydrochloride The title compound is prepared in accordance with that described in Example 1, part I using ester [1- (2-Chloro-quinolin-5-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] tert-butyl acid. carbamic as initial material. He • The title compound is obtained in the form of a white solid. X NMR (DMSO-de, 300 MHz) delta 8.63 (d, ÍH), 8.59 (bs, 3H), 20 7.94 (d, ÍH), 7.81 (m, ÍH), 7.65 (m, 2H), 4.89 (s) , 2H) 4.08 (m, HH), 3.24 (m, 2H), 2.34 (n, HH), 1.94 (m, HH). C. [1- (2-chloro-quinolin-5-ylmethyl) -2-oxo-pyrrolidin-3- (S1) -yl] -7-methoxy-naphthalene-2-sulfonic acid The title compound is prepared in CH2C12 instead of CH3CN 25 in accordance with that described in example 1, part K employing 5- (3- (S) -amino-2-oxopyrrolidin-1-yl ethyl) -2-chloro-quinoline hydrochloride in place of hydrochloride of 7 - (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -1-chloro-isoquinoline and • 7-methoxynaphthalene-2-sulfonyl chloride in accordance with prepared in Example 1, part J. The crude product is purified by column chromatography eluting in 25% EtOAc / CHCl2 to give the title compound as a light yellow solid. : H NMR (CDC13, 300 MHz) delta 8.36 (d, 1H), 8.33 (s, ÍH), 7.98 • 10 (d, ÍH), 7.91 (d, ÍH), 7.82 (d, ÍH), 7.73 (d, ÍH), 7.6¡6 (, ÍH), 7.42 (d, ÍH), 7.35 (d, ÍH) , 7.30 (dd, ÍH), 7.25, (dd, 1H), 5.40 (s, ÍH), 4.82 (AB, 2H), 3.94 (s, 3H), 3.71 (m, ¡ÍH), 3.12 (m, ÍH) ), 3.02 (m, ÍH), 2.50 (m, ÍH), 1.98 (m, ÍH), The MS, [M] "= 495, 497, Cl pattern. Calculated elemental analysis C = 60.54%, H = 4.47%, N = 8.47%, Cl = 7.15%, found C = 59.79%, H = 4.70%, N = 7.88%, Cl = 7.21%. D. [1- (2-aminoquinolin-5-ylmethyl) -2- • oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalen-2-suifonic acid trifluoroacetate. [1- (2-Chloro-quinolin-5-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] of 7-methoxy-naphthalene-2-sulfonic acid is converted to the title compound when heated to a temperature of 125 ° C in accordance with that described in the example ¡2. The crude product is partially purified by RP-HPLC eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) to 80% CH-.CN/H~0 '(0.1% TFA) and the appropriate fractions of the product are concentrated in vacuo, filtered, crushed with MeOH and then purified by column chromatography eluting with • a gradient of 1% MeOH / CH2Cl2 at 3% MeOH / CH2Cl2 for provide the title compound in a pale yellow solid. : H NMR (DMS0-d6, 300 MHz) delta 8.48 (d, ÍH), 8.37 (s,? 1H), 8.23 (d, ÍH), 8.03 (d, ÍH), 7.93 (d, ÍH), 7.72 ( , ÍH), 7.69 (d, ÍH), 7.60 (d, ÍH), 7.55 (s, ÍH), 7.33 (, 2H), 7.07 (d, 10 ÍH), 4.71 (AB, 2H), 4.11 (, ÍH) ), 3.88 (s, 3H), 3.00 (m, 2H), 1.94 (m, ÍH), 1.48 (m, ÍH). FAB MS, [M + H] "= 477. Elemental analysis with 2.5 mol of H20 calculated C = 50.98%, H = 4.14%, N = 8.38%, found C = 50.96%, H = 4.14%, N = 8.38% The enantiomeric purity is 84.5% ee in accordance with the determined by analytical Chiralpak AS RP-HPLC. EXAMPLES 21 AND 22 Trifluoroacetate of [1- (2-aminoquinolin-5-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -methylamide of 7-methoxynaphthalene-2-sulfonic acid and methyl- [2-oxo- l- (2-oxo-l, 2-dihydro-quinoin-5-ylmethyl) -pyrrolidin-3- (S) -yl-7-methoxynaphthalene-2-sulfonic acid amide A. [1- (2-chloro -quinolin-5-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -methyl ida of 7-methoxynaphthalene-2-sulfonic acid The title compound is prepared as in examples 18 and 19, part A employing [1- (2-chloro-quinolin-5-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid as the starting material. The crude product is purified by column chromatography eluting with 50% • EtOAc / hexanes to provide the title compound in the form of a white solid. : H NMR (CDC13, 300 MHz) delta 8.42 (s, ÍH), 8.38 (s, ÍH), 7.97 (d, ÍH), 7.91 (d, ÍH), 7.78 (, 2H), 7.66 (dd, ÍH) , 7.43 (d, ÍH), 7.25 (m, 2H), 4.92 (m, ÍH), 4.80 (AB, 2H), 3.92 (s, 3H), 3.08 (m, 2H), 2.74 (s, 2H), 2.22 (m, ÍH), 1.80 (m, ÍH). ^ 10 B. [1- (2-aminoquinolin-5-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -methylamide of 7-methoxynaphthalene-2-sulfonic acid and methyl- [2-trifluoroacetate] oxo-l- (2-oxo-l, 2-dihydro-quinolin-5-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 7-methoxy-naphthalene-2-sulfonic acid. [3-Methoxy-naphthalene-2-sulfonic acid [1- (2-chloro-quinolin-5-ylmethyl) -2-oxo-pyroindin-3- (S) -yl] -methyl-amide in the title compounds when heated to a temperature of 120 ° C in accordance with that described in example 2. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) to 80% CH3CN / H2O (0.1% TFA), and the appropriate product fractions are lyophilized to provide [l- (2-aminoquinoline-5-) trifluoroacetate. 6-oxo-pyrrolidin-3- (S) -yl] -methylamide of 7-methoxynaphthalene-2-sulfonic acid in the form of a solid white.

: H NMR (DMSO-de, 300 MHz) delta 8.46 (d, 1H), 8.39 (s, IH), 8.03 (d, ÍH), 7.96 (d, ÍH), 7.70 (m, 2H), 7.60 ( d, 1H), 7.58 (s, ÍH), 7.36 (dd, ÍH), 7.34 (d, ÍH), 7.06 (d, ÍH), 4.90 (m, • •••, 4.71 (AB, 2H), 3.89 (s, 3H), 3.11 (m, ÍH), 3.00 (m, ÍH), 5 2.63 (s, 3H), 1.95 (m, ÍH), 1.68 (, 1 HOUR) . FAB MS, [M + H] * = 491. Methyl- [2-oxo-l- (2-oxo-l, 2-dihydro-quinolin-5-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 7-rmethoxynaphthalene-2-sulfonic acid is isolated also of the reaction mixture as a by-product. • 10 XH NMR (DMSO-de, 300 MHz) delta 8.39 (d, ÍH), 7.89 (d, ÍH), 7.94 (d, ÍH), 7.68 (d, ÍH), 7.57 (s, ÍH), 7.42 (m, ÍH), 7.34 (dd, ÍH), 7.25 (d, ÍH), 7.05 (d, ÍH), 6.46 (d, ÍH), 4.88 (m, ÍH), 4.60 (AB, 2H), 3.89 ( m, ÍH), 2.97 (m, 1H), 2.63 (s 3H), 1.96 (, ÍH), 1.65 (m, ÍH). FAB MS, [M + H] "= 492. EXAMPLES 23 AND 24 [1- (2-Aminoquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene- 2-suphonic and [2-oxo-l- (2-oxo-1,2-dihydro-quinolin-6-ylnaethyl) -pyrrolidin-3- (S) -yl-a-ida of 7-methoxynaphthalene-2-acid sulphonic 20 A.6-Methyl-lH-quinolin-2-one The title compound is prepared from p-toluidine and cinnamoyl chloride according to the procedure described in Synthesis 1975, 739. The crude product obtained is ground in Et2 / hexanes and filtered to provide the composed of the title in the form of a beige solid which is used in the subsequent step. lE NMR (DMSO-de, 300 MHz) delta 11.60 (bs, ÍH), 7.82 (d, ÍH), 7. 41 (s, ÍH), 7.30 (d, ÍH), 7.18 (d, ÍH), 6.45 (d, ÍH), 2.30 • (s, 3H). B. B. 2-Chloro-6-methyl-quinoline The title compound is prepared according to that described in Example 1, part E using 6-methyl-1H-quinolin-2-one instead of 7-methyl-2H. -isoquinolin-l-one. The crude product was precipitated during the neutralization of the treatment and the solid is filtered and dried. The crude product is recrystallized from MeOH to give the title compound as a beige solid. P NMR (CDC13, 300 MHz) delta 8.02 (d, ÍH), 7.92 (d, ÍH), 7.60 (s, ÍH), 7.58 (d, ÍH), 7.33 (d, ÍH), 2.53 (s, 3H) . C. 6-Bromomethyl-2-chloro-quinoline The title compound is prepared according to that described in Example 1, part F using 2-chloro-6-methyl-quinoline in place of l-chloro-7-methyl -isoquinoline. The obtained crude residue is recrystallized from 50% EtOAc / hexanes to provide 7.4 g (38%) of 6-bromomethyl-2-chloro-quinoline linkage as a beige solid. XH NMR (CDCl 3, 300 MHz) delta 8.08 (d, ÍH), 8.02 (d, 1H), 7.83 (d, ÍH), 7.77 (dd, ÍH), 7.40 (d, 1H), 4.65 (s, 2H) . MS, [M] + = 256, 258, Cl. 25 D standard. [1- (2-Chloro-quinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) - tert-butyl ester il] -carbamic The title compound is prepared from the (2-oxopyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester of • conformance with that described in Example 1, part H 5 using 6-bromomethyl-2-chloro-quinoline in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is purified by column chromatography eluting with a gradient of 2% MeOH / CH2Cl2 to 4% MeOH / CHCl. To afford the title compound as a beige solid. • 10 X NMR (CDC13, 300 MHz) 5 8.08 (d, ÍH), 8.00 (d, ÍH), 7.69 (s, ÍH), 7.61 (dd, ÍH), 7.40 (d, ÍH), 5.23 (bs, ÍH), 4.67 (AB, 2H), 4.25 (m, ÍH), 3.26 (m, 2H), 2.63 (m, IH), 1.90 (, ÍH), 1.46 (s 9H). E. 6- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -5-chloro-quinoline hydrochloride The title compound is prepared according to that described in example 1, part I using ester butyl [1- (2-chloro-quinclin-6-yl-methyl) -2-oxopyrrolidin-3- (S) -yl) -carbamic acid tert- as starting material. He The title compound is obtained in the form of a white solid. XH NMR (DMSO-de, 300 MHz) d 8.74 (bs, ÍH), 8.48 (d, ÍH), 8.00 (s, ÍH), 7.95 (d, ÍH), 7.71 (d, ÍH), 7.60 (d, ÍH), 4.64 (AB, 2H), 4.11 (m, ÍH), 3.35 (m, 2H), 2.42 (m, 1H), 2.09 (m, ÍH).

F. [1- (2-chloro-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl) -amide of 7-methoxynaphthalene-2-sulfonic acid The title compound is prepared in CHC12 instead of ¡CH3CN in accordance with that described in example 1, part K • employing 6- (3- (S) -amino-2-oxopyrrolidin-1-yl-methyl) -2-chloro-quinoline hydrochloride as starting material and 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is triturated in CH2C1 and filtered to provide the title compound as a white solid. : H NMR (CDCL3, 300 MHz) d 8.36 (s, ÍH), 8.03 (d, ÍH), 7.37 (d, 10 ÍH), 7.91 (d, ÍH), 7.80 (d, ÍH), 7.75 (dd, ÍH), 7.60 (s, 1 ÍH), 7. 51 (dd, ÍH), 7.37 (d, ÍH), 7.29 (dd, ÍH), 7.25 (dd, ÍH), . 43 (s, ÍH), 4.58 (AB, 2H), 3.94 (s, 3H), 3.76 (m, ÍH), 3.22 (m, 2H), 2.59 (m, ÍH), 2.09 (, ÍH). FAB, [M + H] + = 496, 498, Cl pattern. Elemental analysis calculated C = 60.54%, H = 4.47%, N = 8.47%; found C = 60.43%, H = 8.37%, N = 7.06%. G. [1- (2-aminoquinolin-6-yl-methyl) -2-oxopyrrolidin-3- (S) -yl) -amide of 7-methoxynaphthalene-2-sulfonic acid and [2-oxo-l- (2 - oxo-1, 2-dihydro-quinolin-6-yl-methyl-pyrrolidin-3- (S) -ilj, 7-methoxy-naphthalene-2-sulfonic acid amide [1- (2-chloro-quinolin -6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl) -methylamide of 7-methoxynaphthalene-2-sulfonic acid in the title compounds when subjected to heating at a temperature of 130 ° C in accordance with with what is described in example 2. The raw mix of products is purified by RP-HPLC eluting with a gradient of 10% CH-; CN / H20 (0.1% TFA) to 60% CH3CN / H20 (0.1% TFA), and the appropriate product fractions are concentrated in vacuo and then further purified. by column chromatography eluting with 5% MeOH / CH2CL2 to give [1- (2- (5-aminoquinolin-6-ylmethyl) -2-oxopyrrolidm-3- (S) -yl) -amide of 7-rmethoxynaphthalene-2 acid -sulfonic in the form of a tan solid. : H NMR (DMSO-d, 300 MHz) d 8.38 (s, ÍH), 3.23 (d, ÍH) 8.03 (d, ÍH), 7.55 (s, ÍH), 7.41 (s, ÍH), 7.38 (d, ÍH), 7.32 (dd, • 10 HH), 7.25 (d, HH), 6.73 (d, HH), 6.43 (bs, 2H), 4.37 (AB, 2H), 4.10 (m, HH), 3.88 (s, 3H), 3.04 (m , 2H), 1.96 (m, ÍH), 1.51 (m, ÍH). FAB, [M + H] + = 477. Elemental analysis calculated with 0.6 mol of calculated H20. C = 61.58%, H = 5.22%, N = 11.49%; found C = 61.59%, H = 5.08%, N = 11.14%. The purity * 15 enantiomeric is 87.0% ee in accordance with that determined by analytical RP-HPLC Chiralpak AD. It is also isolated [2-oxo-l- (2-oxo-l- (2-oxo-l, 2-d? Hydro-? Quinolin-6-yl-methyl) -pyrrolidin-3- (S) -il) 7- methoxynaphthalene-2-sulfonic acid amide from the mixture of the reaction in the form of a minor by-product. XH NMR (DMSO-d6, 300 MHz) d 11.70 (bs, HH), 8.37 (s ÍH), 8.21 (d, HH), 8.01 (d, HH), 7.93 (d, HH), 7.82 (d, HH) ), 7.69 (d, ÍH), 7.56 (s, ÍH), 7.45 (s, ÍH), 7.32 (, 2H), 7.25 (m, ÍH), 6.47 (d, 1H), 4.35 (s, 2H), 4.12 (m, ÍH), 3.89 (m, 2H), 3.06 (m, 2H), 1. 97 (m, 1H), 1. 53 (m, 1H). FAB MS, [M + H] + = 478.

EXAMPLE 25 [1- (1H-Benzoimidazol-5-yl-met? L) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulphonic acid. - [1- (4-Nitrobenzyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid butyl ester The title compound is prepared from tert-butyl acid ester (2-oxopyrrolidin-3) - (S) -il) -carbamic in accordance with that described in example 1, part H • 10 using 4-nitrobenzyl bromide in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc / CH 2 Cl 2 at 25% EtOAc / CH 2 Cl 2 to give the title compound as a yellow solid. 15 P NMR (DMSO-d,, 300 MHz) d 8.20 (d, 2H), 7.43 (d, 2H) 5.18 (bs, 1H), 4.58 (AB, 2H), 4.22 (m, ÍH), 3.26 (, 2H), 2.65 (m, ÍH), 1.93 (m, 1H), 1.46 (s, 9H). • B. 3- (S) -a? T? Ino-1- (4-nitrobenzyl) -pyrrolidin-2-one hydrochloride. The title compound is prepared according to Example 1, part I, using tert. Ester. - [1- (4-Nitrobenzyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid butyl ester as starting material. The title compound is obtained in the form of a white solid. 25? E NMR (DMSO-ds, 300 MHz) d 8.65 (bs, 3H), 8.22 (d, 2H) ', 7.57 (d, 2H), 4.59 (AB, 2H), 4.22 (m, ÍH), 4.10 (m, ÍH), 3.32 (m, 2H), 2.40 (m, ÍH), 2.03 (, ÍH). C. 2,2, 2-trifluoro-N- [1-4-nitrobenzyl] -2-oxopyrrolidin-3- (S) - • il] -acetamide. The title compound is prepared in CHC1.; instead of i CH3CN according to the example, 1, part K using 3- (S) -amino-1- (4-nitrobenzyl) -pyrrolidin-2-one as the starting material and trifluoroacetic anhydride in place of 7-methoxynaphthalene-2-sulfonyl. The product • 10 crude is concentrated in vacuum and used in the state obtained in the subsequent step. P NMR (CDC13, 300 MHz) d 8.24 (d, 2H), 7.43 (d, 2H), 7.25 (bs, ÍH), 4.60 (AB, 2H), 4.44 (m, ÍH), 3.35 (m, 2H) , 2.80 (m, ÍH), 2.01 (, ÍH). 15 D. N- [1- (4-acetylamino-3-nitrobenzyl) -2-oxopyrrolidin-3- (S) -yl] -2,2, 2-trifluoroacetamide To a solution of 2, 2, 2-trifluoro- N- [1- (4-acetylamino-3-nitrobenzyl) -2-oxopyrrolidin-3- (S) -yl] -acetamide (0.75 g, 2.27 mmol) in AcOH (12 L) is added acetic anhydride (mL) and a catalytic amount of 10% palladium in activated carbon. The heterogeneous mixture is hydrogenated at room temperature in a Parr apparatus under a pressure of 49.217, kg / m2 (70 psi). After 4.5 hours, the reaction mixture is filtered through a pad of Celite, washed with CH, C12 and then MeOH. The crude product in concentrate-in vacuum to provide 1.2 g of crude N- [1- (4-acetylamino-3-benzyl) -2-oxopyrrolidin-3- (S) -yl] -2,2-trifluoroacetamide 'in the form of a residue (wet with HOAc). A solution of crude N- [l- • (4-acetylamino-3-benzyl) -2-oxopyrrolidin-3- (S) -yl] -2,2, 2, 5- tfluoroacetamide (1.2 g, wet with AcOH) in AcOH (12 mL) it is cooled to 0 ° C and acetic anhydride (1 mL) is added. The resulting mixture is treated with a catalytic amount of? A? 02, followed by dropwise addition of fuming H? 0 (3.8 mL). The reaction mixture is stirred at a temperature of • 10 0 ° C for 1.5 hours, then at room temperature for 1.5 hours. Upon re-cooling to a temperature of 0 ° C, a mixture of ice / ice water is slowly added with stirring. The mixture is further diluted with water and extracted with EtOAc (3 x 50 mL). The organic layers combined are washed twice with water. The organic phase is dried in anhydrous MgSO, filtered and concentrated. The crude product is purified by column chromatography • eluting with a gradient of 25% EtOAc / CH2Cl2 at 50% EtOAc / CH2Cl2 to give the title compound (0.65 g, 1.67 mmol) as a beige solid. : H? MR (CDC13, 300 MHz) d 10.27 (s, ÍH), 8.77 (d, ÍH), 8.08 (s, ÍH), 7.54 (m, ÍH), 7.40 (bs, ÍH), 4.51 (AB, 2H), 4.46 (m, ÍH), 3.34 (m, 2H), 2.78 (m, ÍH), 2.31 ( s, 3H), 1.98 (m, ÍH) for the main component of a rotamer mixture. 25 E. 3- (S) -amino-1- (4-amino-3-nitrobenzyl) -pyrrolidin-2-one To a solution of N- [1- (4-acetylamino-3-benzyl) -2-oxopyrrolidin -3- (S) -yl] -2,2,2-trifluoroacetamide (0.65 g, 1.67 mmol) in EtOH (4 mL) is added a solution of 1 N NaCjH (6 mL). The yellow mixture is heated to a temperature of 50 ° C for 3 hours and the result is a brown solution. The reaction mixture is allowed to cool and then concentrated in vacuo. The crude residue is diluted with water and 1 N NaOH (10 mL) and the aqueous phase is extracted with CHC13 (4 x 50 mL.) The combined organic layers are dried over anhydrous Na2SO, filtered and concentrated to provide the title compound (0.22). g, 0.88 mmol) in the form of a yellow solid which is used in this state in the subsequent step XH NMR (CDC13, 300 MHz) d 7.98 (s, ÍH), 7.30 (dd, ÍH), 6.79 (d , ÍH), 6.12 (bs, 2H), 4.36 (AB, 2H), 3.67 (m, ÍH), 3.19 (, 2H), 2.43 (m, ÍH), 1.71 (m, ÍH), F. [1- (4-amino-3-nitrobenzyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid The compound of is prepared in CH2C12 instead of CH3CN according to example 1 , part K using 3- (S) -amino-1 (4-amino-3-nitrobenzyl) -pyrrolidin-2-one in place of 7- (3- (S) -amino-2-oxopyrrolidin-1-hydrochloride il-methyl) -1-chloro-isoquinoline and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in Example 1, part J. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc / CH2Cl2 at 50% EtOAc / CH2Cl2 to give the title compound as a pale yellow solid. •: H NMR (CDC13, 300 MHz) d 8.37 (s, ÍH), 7.94 (s, ÍH), 7.92 (d, 5 ÍH), 7.82 (d, ÍH), 7.75 (dd, ÍH), 7.30 (dd) 1H), 7.25 (dd, ÍH), 7.19 (dd ÍH), 6.77 (d, ÍH), 6.12 (bs, 1H), 5.38 (bs, ÍH), 4.30 (AB, 2H), 3.94 (s, 3H) , 3.73 (m, ÍH), 3.18 (m; 2H), 2.58 (m, ÍH), 2.05 (, 1H). G. [1- (1H-Benzoimidazol-5-ylmethyl) -2- 10-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulphonic acid trifluoroacetate To a solution of [1- (4-amino-3-nitrobenzyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid (0.38g, 0.82 mmol) in 88% 88% HC02H (15 L ) one adds catalytic amount of 10% palladium on activated carbon. The heterogeneous mixture a is hydrogenated at room temperature in a Parr apparatus under a pressure of 49.217 kg / m2 (70 psi) of H; for 1 hour. The reaction mixture is filtered through a pad of Celite, washed with EtOAc and MeOH and the The filtrate is concentrated in vacuo. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) to 80% CH3CN / H20 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound ( 0.17g, 0.30 mmol) in form of a white solid.

? E NMR (DMSO-de, 300 MHz) d 9.38 (bs, ÍH), 8.38 (s, ÍH), 8.25 (d, ÍH) 8.03 (d, ÍH), 7.95 (d, ÍH), 7.78 (d, ÍH), 7.72 (dd, ÍH), 7.66 (bs, ÍH), 7.56 (s, ÍH), 7.35 (d, 2H), 7.32 (dd, • 1H), 4.48, (AB, 2H), 4.09 (m, ÍH), 3.88 (s, 3H), 3.06 (m, 2H), 5 1.96 (m, ÍH), 1.53 (m, ÍH). FAB MS, [M + H] "= 451. Elemental analysis calculated with 1.2 mol of calculated H20, C = 51.19%, H = 4.37%, N = 9.55%, found C = 51.19%, H = 3.95%, N = 9.36% EXAMPLE 26 [2- (lH-Benzoimidazol-5-ylmethyl) -2- • 10-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid A. Boc trifluoroacetate -L-Asp (H) -OBn Boc-L-Asp-OBn (15 g, 46.4 mmol) is dissolved in THF (50, mL) and cooled to a temperature of -10 ° C. The solution is treated with N-methylmorpholine (4.9 g, 48.7 mmol) and stirred for 5 minutes. To the solution is added dropwise isobutyl chloroformate (6.3 g, 46.4 mmol). After finishing the • addition, the mixture is stirred for 1 minute and then filtered through a pad of Celite. The filtering is cooled to -10 ° C. To the solution is added sodium borohydride (2.63 g, 70 mmol) which is pre-dissolved in water (50 L). The resulting solution is stirred for 2 minutes. The solution is drained in a separatory funnel and diluted with EtOAc (800 mL). The organic layer is washed with water and NaCl saturated. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The residue is added to a solution of oxalyl chloride (30 mL, 60 mmol, 2M solution in CH; C, 12) and methyl sulfoxide (7.25 g, 92.8 mmol) in CH2C12 (250 mL) at • a temperature of -78 ° C. The mixture is stirred at a temperature of -78 ° C for 40 minutes, and then triethylamine (14 g, 140 mmol) is added. The reaction mixture is stirred at -78 ° C for 1 hour and then stirred at room temperature for 30 minutes. The solution is emptied into a solution of citric acid / water 20% • 10 (200 mL). The resulting mixture is poured into a separatory funnel and the layers are separated. The organic layer is washed with water and saturated NaCl. The organic phase is dried over MgSO4, filtered and concentrated. The crude residue is purified by column chromatography eluting with a gradient from 10% EtOAc / hexanes to 30% EtOAc / hexanes to give the title compound (12.0 g, 39 mmol) as an oil. XH MR (CDC13, 300 MHz) d 9.68 (s, ÍH), 7.32 (m, 4H), 5.42 (bs, ÍH), 5.16 (s, 2H), 4.62 (m, 2H), 3.05 (ddd, 2H) , 1.40 (s, 9H). B. Tert-butyl acid ester. { 1- [2- (4-nitrophenyl) -ethyl] -2-oxopyrrolidin-3- (S) -yl} -carbamic To a solution of Boc-L-Asp-OBn (3.3 g, 10.7 mmol) dissolved in methanol (50 mL) are added molecular sieves of 4Á, -Nitrofenethylamine hydrochloride (4.35 g, 21.5 mmbl) and triethylamine (2.25 g, 22.2 mmol). The solution is stirred at room temperature for 45 minutes and then and the mixture is treated with sodium cyanoborohydride (0.72 g, 11.5 mmol).

• The reaction mixture is stirred at room temperature for 16 hours. After that time, NaOH IN (10 mL) is added followed by water (25 mL). The resulting mixture is stirred for 30 minutes and then concentrated in vacuo to a smaller volume. The solution is diluted with EtOAc (250 mL), filtered through a pad of Celite, and washed with • 10 water and EtOAc. The solution is emptied into a separating funnel and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic layers are washed cor. HCl IN, H20, a saturated solution of NaHCO3 and saturated NaCl. The organic phase is dried over MgSO4, filtered and concentrated. He The crude residue is purified by column chromatography eluting with a gradient of 50% EtOAc / CH2Cl2 to give the title compound (1.46 g, 4.18 mmoi; • form of a pale yellow solid. lE NMR (CDC13, 300 MHz) d 8.17 (d, 2H), 7.39 (d, 2H), 5.12 (bs, ÍH), 4.09 (m, ÍH), 3.63 (m, 2H), 3.25 (m, 2H), 2.99 (t, 2H), 2.62 (m, ÍH), 1.83 (m, ÍH), 1.44 (s, 9H). C. 3- (S) -amino-1- [2- (4-nitrophenyl) -ethyl-pyrrolidin-2-one hydrochloride The title compound is prepared in accordance with described in Example 1, part I, using tert-butyl acid ester. { 1- [2- (4-nitrophenyl) -ethyl] -2-oxopyrrolidin-3- (S) -yl} -carbámico as initial material. The title compound is obtained in the form of a beige solid. •: H NMR (CDC13 / CD30D, 300 MHz) d 8.77 (bs, ÍH), 8.72 (bs, ÍH), 5 8.16 (d, 2H), 7.45 (d, 2H), 4.15 (m, ÍH), 3.59 (t, 2H), 3.38 (m, 2H), 2.98 (t, 2H), 2.58 (m, ÍH), 2.37 (m, ÍH). D. 2,2,2-trifluoro-N-. { 1- [2- (4-Nitrophenyl) -ethyl] -2-oxopyrrolidin-3- (S) -yl} -acetamide The title compound is prepared in CH2C12 instead of CH3CN # 10 according to example 1, part K using 3- (S) -amino-1 [2- (4-nitrophenyl-ethyl] -pyrrolidin-2-one hydrochloride as starting material and trifluoroacetic anhydride instead of 7- Methoxynaphthalene-2-sulfonyl The crude product is concentrated in vacuum and used in this state in the subsequent step. : H NMR (CDC13, 300 MHz) d 8.17 (d, 2H), 8.15 (bs, HH), 7.39 (d, 2H), 4.40 (m, HH), 3.70 (m, HH), 3.55 (m, 1H ), 3.34 (m, • 2H), 2.99 (t, 2H), 2.68 (m, ÍH), 1.96 (m, ÍH). AND_. N-. { 1- [2- (4-acetylamino-3-nitrophenyl) -ethyl] -2-20-oxopyrrolidin-3- (S) -yl] -2,2,2-trifluoroacetamide The title compound is prepared in accordance with that described in Example 25, part DD, using 2,2,2-trifluoro-N-. { 1- [2- (4-nitrophenyl) -ethyl] -2-oxopyrrolidin-3- (S) -yl] -acetamide as starting material. The intermediate product Crude is concentrated in vacuo to provide N- [l- [2- (4-acetylamino-3-nitrophenyl) -ethyl] -2-oxopyrrolidin-3- (S) -yl] -2,2,2-trifluoroacetamide in the form of a residue (wet with HOAc) that is also used directly in the nitration step. The heating of the reaction mixture of nitric acid at room temperature is allowed and it is stirred for 18 hours. The crude product is purified by column chromatography eluting with a gradient of 25% EtOAc / CH2Cl2 at 50% EtOAc / CH2Cl to give the title compound as a solid. XH NMR (CDC13, 300 MHz) d 10.24 (s, ÍH), 8.70 (d, ÍH), 7.98 (bs, ÍH), 7.40 (d, ÍH), 7.26 (bs, ÍH), 4.43 (m, ÍH), 3.58 (m, 2H), 3.38 (m, 2H), 2.94 (m, 2H), 2.66 ( m, HH), 2.06 (s, 3H), 1.98 (m, HH) for the main component of a rotamers mixture. F. 3- (S) -amino-1- [2- (4-amino-3-nitrophenyl) -ethyl] -pyrrolidin-2-one The title compound is prepared according to that described in example 25, part F, using N-. { l -? [2- (4-acetylamino-3-nitrophenyl) -ethyl} -2-oxopyrrolidin-3- (S) -yl] -2,2,2-trifluoroacetamide as starting material. The reaction mixture is stirred at room temperature for 18 hours. After a similar treatment, the organic phase is concentrated in vacuo to provide the title compound as a yellow solid which is used in this state in the subsequent step.

: H NMR (CDCl 3, 300 MHz) d 7.90 (s, ÍH), 7.25 (d, ÍH), 6.8¡0 (d, ÍH), 6.24 (bs, ÍH), 3.48 (m, 3H), 3.26 (m, 2H), 2.77 (t, '2H), 2. 40 (m, ÍH), 2.25 (bs, 3H), 1.69 (m, ÍH). • G. { 1- [2- (4-amino-3-nitrophenyl) -ethyl] -2-oxopyrrolidin-3! - (S) -5-yl} 7-methoxynaphthalene-2-sulfonic acid amide The title compound is prepared in CH 2 Cl; instead of, CH3CN according to example 1, part K using 3- (S) -amino-1- [2- (4-amino-3-nitrophenyl) -ethyl] -pyrrolidin-2-one, instead of 7- (3- (S) -oxopyrrolidin-1-yl-methyl) - • 10-chloro-isoquinoline hydrochloride and 7-methoxy-naphthalene-2-sulfonyl chloride in accordance with that prepared in Example 1, part J. After a similar treatment, the organic phase is concentrated in vacuo to give the title compound as a pale yellow solid which is used in this state in the subsequent step. : H NMR (CDCI3, 300 MHz) d 8.36 (s, ÍH), 7.87 (d, ÍH), 7.83 (s, ÍH), 7.77 (d, ÍH), 7.72 (dd, ÍH), 7.27 (dd, ÍH) ), 7.22 (s, •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 2H), 3.20 (m, 2H), 2.68 (t, 2H), 2.49 (, ÍH), 1.98 (, ÍH). H. Trifluoroacetate of. { 1- [2- (1H-benzoimidazol-5-yl) -ethyl] -2-oxopyrrolidin-3- (S) -yl} 7-methoxynaphthalene-2-sulfonic acid amide Is converted. { 1- [2- (4-amino-3-nitrophenyl) -ethyl} -2- oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid in the title compound according to that described in example 25, part HH. The crude product is purified by RP-HPLC eluting with a gradient of 10% • CH3CN / H20 (0.1% TFA) at 60% CH3CN / H: 0 (0.1% TFA), and the appropriate 5 product fractions are lyophilized to give the title compound as a white solid. XH NMR (DMSO-de, 300 MHz) d 9.38 (bs, 1H, 8.35 (s, ÍH), 8.13 (d, ÍH) 8.02 (d, ÍH), 7.93 (d, ÍH), 7.73 (d, ÍH) 7.69 (s, • 10 HH), 7.65 (,, HH), 7.55 (,, HH), 7.38 (,, HH), 7.32 (dD, HH), 3. 90 (m, 2H), 3.88 (s, 3H), 3.39 (, 2H), 3.11 (m, 2H) ^ 2.88 (t, 2H), 1.94 (m, ÍH), 1.47 (m, ÍH). FAB MS, [M + H] t = 465. Elemental analysis calculated with 1.4 mol of calculated H20. C = 51.68%, H = 4.65%, N = 9.27%; found C = 51.68%, H = 4.25%, N = 8.93%. EXAMPLE 27 Acetyl- [2-oxo-l- (2-pyrrolo [3,2- b] pipdm- • 1-yl-ethyl) -pyrrolidin-3- (S) -amide of 7-methoxy-naphthalene-2-trifluoroacetate -sulfon? co 20 A. lH-pyrrolo [3,2-c] pyridine The title compound is prepared from 3-picolm-N-oxide according to the procedure described in Tetrahedron 1993, 2885. The crude product obtained it is dissolved in EtOH and decolorizing carbon is added. The Mixture is filtered through a large column of Si02 gel eluting with EtOH to fuse the title compound as a beige solid. : H NMR (CDCI3, 300 MHz) d 10.92 (bs, ÍH), 8.98 (s, ÍH), 8.31 (d, ÍH), 7.36 (d, ÍH), 7.32 (d, 1H), 6.66 (d, ÍH) ). B. Pyrrolo [3, 2-c] pyridin-1-yl-acetic acid tert-butyl ester The title compound * is prepared from 1H-pyrrolo [3,2-c] pyridine in accordance with that described in Examples 18 and 19, part AA employing tert-butyl bromoacetate instead of methyl iodide. The crude product is purified by column chromatography eluting with a gradient of 3% MeOH / CH2CL2 at 6% MeOH / CH2CL2 1 to provide the title compound as an oil. E NMR (CDCI3, 300 MHz) d 8.93 (s, ÍH), 8.34 (d, ÍH), 7.18 (d, ÍH), 7.12 (d, ÍH), 6.65 (d, ÍH), 4.75 (s, 2H) , 1.45 (s, 9H). C. Pyrrolo [3, 2-c] pyridin-1-ii-acetic acid To a solution of pyrrolo [3,2-c] pyridin-1-yl-acetic acid tert-butyl ester (0.44 g, 1.89 mmol) in CH_.C12 (10 L) at a temperature of 10 ° C, trifluoroacetic acid (1 L) is added. After 15 minutes, the solution is allowed to warm to room temperature and is stirred for 18 hours. The reaction mixture is concentrated in vacuo and then subjected to azeotropy with toluene to provide 0.5 g of the title compound as a residue (wet with excess TFA) which is employed in this state in the subsequent step. lE NMR (CDCl 3 + CD 3 OD, 300 MHz) d 9. 09 (s, 1H), 8 34 (d, 1 ÍH), 7 91 (d, ÍH), 7. 71 (d, ÍH), 7. 08 (d, ÍH), 5. 18 (s, 2H). D. 2- (S) -benzyloxycarbonylamino-j.- (2-5-pyrrolo [3, 2-c] pyridin-1-yl-acetylamino) -butyric acid methyl ester Pyrrolo [3, 2-c] pyridine- 1-acetic acid (0.50 g, 1.89 min), 2-r (S) -benzyloxycarbonylamino-4-amino-butyric acid methyl ester trifluoroacetate (C.93 g, 2.45 mmol), 4-methylmorpholine 80.75 g, 7.41 mmol) , hydrate of 1- • 10 hydroxybenzotriazole (0.36 g, 2.65 mmol) is dissolved in DMF (11 mL) and the resulting mixture is cooled to a temperature of 0 ° C. 1- (3-dimethylaminopropyl) hydrochloride is added. 3-ethylcarbodiimide (0.80 g, 4.17 mmol) to the solution. The ice bath is removed and the reaction mixture is stirred to room temperature. After 18 hours, the solution is diluted with a saturated solution of NH.C1 and extracted twice with EtOAc. The combined organic layers are washed • with H20, saturated NaHCO 3 and saturated NaCl. The organic phase is dried over MgSO, filtered and concentrated in vacuo. The product The crude was purified by column chromatography eluting with a gradient of 3% MeOH / CH2Cl2 at 10% MeOH / CH2Cl2 'to give the title compound (0.33 g, 0.78 mmol) as a solid. XH NMR (CDCL3, 300 MHz) d 8.95 (s, ÍH), 8.35 (d, ÍH), 7.34 (m, 3H), 7.27 (m, 3H), 7.17 (d, ÍH), 6.73 (d, ÍH), 6.44 (bs, 1 ÍH), 5.45 (d, 1H), 4.93 (s, 2H), 4.78 (s) , 2H), 4.08 (m, ÍH) ,, 3.69 (s, 3H), 3.67 (m, ÍH), 2.90 (m, 1H), 2.03 (m, ÍH), 1.58 (m, ÍH). • E. Acetyl- [2-oxo-l- (2-pyrrolo [3, 2- 5 b] pyridin-1-yl-ethyl) -pyrrolidin-3 (S) -amide of 7-methoxynaphthalene acido- trifiuoroacetate 2-sulfonic acid To a solution of 2- (S) -benzyloxycarbonylamino-4- (2-pyrrolo [3,2-c] pyridin-1-yl-etu-acetylamino) -butyric acid methyl ester (0.51 g, 1.20 mmol ) in THF (5 mL) was added diborane (5 mL, 0.500 mmol, IM solution in THF). The resulting mixture is stirred at room temperature for 4 hours and then concentrated in vacuo. The residue is suspended in EtOAc (10 mL), treated with 10 drops of H20, 5 drops of NaOH IN and further quenched with a solution saturated with NH4CI. The mixture is concentrated in vacuo to approximately 1/2 volume, partitioned between EtOAc and 10% Na 2 CO 2 solution and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic phases are washed with saturated NaCl, dried over MgSO4, filtered and concentrated in vacuum. The crude product obtained is partially purified by column chromatography eluting with a gradient of 2% MeOH / CH2Cl2 at 10% MeOH / CH2Cl2 to provide benzyl ester of acid [2-oxo-l- (2-pyrrolo [3, 2-c] ] pyridin-1-yl-ethyl) -pyrrolidin-3- (S) -yl] -25-carbamic acid. FAB MS, [M + H] + = 379. To a solution of 1 benzyl ester of acid [2-oxo-l- (2-pyrrolo [3,2- c] pyridin-fL-yl-ethyl) -pyrrolidin- 3- (S) -yl] -carbamic acid in MeOH (10 L) and 'AcOH (3 mL) is added a catalytic amount of palladium at ip% in • activated carbon. The heterogeneous mixture is stirred at room temperature in a balloon of H; for 18 hours. The reaction mixture is filtered through a pad of Celite and washed with MeOH (3 times). The crude product is concentrated in vacuo and then subjected to azeotropy with toluene to provide 3- (S) -amino-1- (2- (10-pyrrolo [3, 2-c] pyridin-1-yl-ethyl) acetate) - pyrrolidin-2-one in the form of a residue (wet with excess HOAC). FAB MS, [M + H] + = 245. The title compound is prepared in CH; C12 instead of CH3CN in accordance with that described in example 1, part K using 3- (S) -amino- acetate. 1- (2-pyrrolo [3, 2- 15 c] pyridin-1-yl-ethyl) -pyrrolidin-2-one above in place of 7- (3- (S) -amino-2-oxopyrrolid? Nl hydrochloride -yl-methyl) -1- chloro-isoquinoline and 7-methoxynaphthalene-2-sulfonyl chloride • in accordance with that prepared in example 1, part J. The crude product is partially purified by chromatography in column eluting with a gradient of 3% MeOH / CH 2 Cl 2 at 5% MeOH / CH 2 Cl 2. The residue obtained is further purified by RP-HPLC eluting in a gradient of 10% CH3CN / H20 '(0.1% TFA) to 80% CH3CN / H20 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title in the form of a white solid.

X NMR (DMSO-de, 300 MHz) d 9.24 (s, ÍH), 8.58 (d, 1H), 8.48 (d, ÍH), 8.20 (d, ÍH) 8.08 (d, ÍH), 8.00 (d, ÍH), 7.9¡8 (s, ÍH), 7.75 (dd, ÍH), 7.61 (s, ÍH), 7.42 (dd, ÍH), 7.03 (d, • ÍH), 4.87 (m, ÍH), 4.56 (, 2H), 3.90 (s, 3H), 3.63 (m,? 2H), 5 3.30 (m, 2H), 2.27 (m, ÍH), 2.15 (s) , 3H), 2.04 (m, ÍH). FAB MS, [M + H] '= 507. EXAMPLE 28 [1- (4-Amino-quinazolin-6-yl-metii) -2-oxopyrrolidin-3- (S) -yl] -methylamide acid trifluoroacetate -methoxyaphthalene- W 10 2 -sulphonic A. 6-methyl-3H-quinazolin-4-one Sodium hydride (2.6 g) is added, 65 mmol, dispersion in 60% mineral oil) to dioxane (100 mL) at a temperature of 0 ° C. To the solution is added 2-amino-5-methyl-15-benzoic acid (7.6 g, 50 mmol) followed by [3- (dimethylamino) -2-azoprop-2-en-l-ylidene] dimethylammonium chloride (9.9 g, 60 mmol). After the addition, the solution is heated to reflux. The reflux continues for 16 hours. The reaction mixture is cooled to room temperature and added methanol (3 mL) followed by AcOH (10 mL). The solution is then refluxed for 3 hours. The solution is cooled to room temperature. The solution is concentrated. The resulting solid is diluted in water (60 mL). The pH of the resulting solution is adjusted to 7. The solution is filtered. He The resulting solid is dried under vacuum to provide the title compound (6.0 g, 38 mmol). X NMR (CDCL3, 300 MHz) d 8.03 (s, ÍH), 7.89 (s, ÍH), 7.57 (m, 2H), 2.41 (s, 3H). MS, [M + H] * = 507. B. 4-chloro-6-methyl-quinazoline 6-Methyl-3H-quinazoline-4-one (1.1 g, 6.9 mmoi) is dissolved in toluene (70 mL). To the solution is added triethylamine (1.82 g, 18 mmol) and P (0) C13 (1.06 g, 6.9 mmol). The sol ution is heated to reflux. After 3 hours, the solution is poured into water (100 mL). The solution is diluted with lEtOAc (200 mL). The layers are separated. ' The organic layer is washed with water, saturated NaHC03 (aqueous) and saturated NaCl (aqueous).

The organic layer is dried over MgSO4, filtered and concentrated.

The title compound is obtained in the form of an oil (0.75 g, 4.2 mmol). X NMR (CDCL3, 300 MHz) d 8.98 (s, ÍH), 8.04 (s, ÍH), 7.98 (d, ÍH), 7.82 (d, ÍH), 7.82 (d, ÍH), 2.62 (s, 3H) . C. 6-Bromomethyl-4-chloro-quinazoline The title compound is prepared according to that described in Example 1, part F by substituting l-chloro-7-methylisoquinoline for 4-chloro-6-methyl-quinazoline. The crude product is purified by column chromatography eluting with a gradient of "5% EtOAc / hexanes to 10% EtOAc / hexanes to provide the title compound as a white solid.

X H NMR (CDCl 3, 300 MHz) d 9.08 (s, HH), 8.23 (s, HH), 8.00 (dd, 2H), 4.68 (s, 2H). O (2-oxopyrrolidin-3- (S) -yl) -amide of acid; 7- • methoxynaphthalene-2-sulfonic acid To a solution of trifluoroacetic acid / CH; Cl; (20 mL) at a temperature of 0 ° C is added tert-butyl acid ester (2-oxopyrrolidin-3- (S) -yl) -carbamic acid (0.4 g, 2 mmol) prepared according to that described in the example 1, part G. The resulting solution is allowed to warm to • 10 room temperature and stir for 12 hours. Then the solution is concentrated. The resulting oil is reconcentrated from toluene. The oil is then diluted in CH3CN (6 mL). To the solution is added CH2C12 (6 mL). The resulting solution is cooled to 0 ° C and triethylamine (0.67) is added. g, 6.6 mmol) followed by 7-methoxynaphthalene-2-sulfonyl chloride (0.64 g, 2.5 mmol), prepared in accordance with that described in Example 1, part J. The solution is stirred • for 6 hours. After this time, the solution is concentrated. The resulting crude solid is triturated with EtOAc.

The crude solid is then further purified by column chromatography eluting with a 2.5% gradient.

MeOH / CH2CL2 at 5% MeOH / CH2CL2 to give the title compound (0.40 g, 1.25 mmol) as a white foam. f XH NMR (CDCL3, 300 MHz) d 8.35 (s, ÍH), 7.88 (d, ÍH), 7.78 (d, 2H), 7.28 (m, 2H), 5.65 (bs, ÍH), 5.34 (bs, ÍH), 3.94 (s, 3H), 3.67 (m, ÍH), 3.32 (m, 2H), 2.62 (m , ÍH), 2.21 (m, ÍH). E. Methyl- (2-oxo-pyrrolidin-3- (S) -yl) -amide of 7-methoxy-naphthalene-2-sulfonic acid • The title compound is prepared according to that described in Example 6, part A substituting (2- oxopyrrolidin-3- (S) -yl) -amide of 7-methoxynaphthalene-2-sulfonic acid by [1- (l-chloro-isoquinolin-7-yl-methyl) -2-oxopyrrolidin-3- (S ) 7-methoxynaphthalene-2-sulfonic acid amyl. The crude product is purified by chromatography column by eluting with a gradient of 40% EtOAc / CH 2 Cl 2 at 60% EtOAc / CH 2 Cl 2 - to give the title compound as a white solid. lE NMR (CDCl 3, 300 MHz) d 8.39 (s, ÍH), 7.90 (d, ÍH), 7.76 (m, 2H), 7.28 (m, 2H), 6.42 (bs, ÍH), 4.82 > 'm, ÍH), 3.92 (s, 3H), 3.32 (, 2H), 2.80 (s, 3H), 2.31 (m, ÍH), 2.05 (m, ÍH). F. [1- (4-Chloro-quinazolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl-7-methoxy-naphthalene-2-sulfonic acid ester To a solution of methyl- (2- 7-methoxynaphthalene-2-sulfonic acid oxopyrrolidin-3- (S) -yl) -amide (0.35 g, 1.04 mmol) in THF (7 mL) at a temperature of 0 ° C add LiN (SiMe3) 2 (1 L, 1 mmol, 1M solution in THF). The solution is stirred for 40 minutes at a temperature of 0 ° C. After this time, 6-bromomethyl-4-chloro-quinazoline (0.24 g, 0.94 mmol) is added. The resulting solution is stirred for 4 hours. The The reaction is quenched by the addition of a saturated solution of NH 4 Cl. The solution is diluted with EtOAc and water. The layers are separated. The organic layer is washed with water and brine. The organic layer is dried in MgSO4, filtered and • concentrated. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc / CH 2 Cl 2 at 40% EtOAc / CHCl 2 to provide the title compound (0.25 g, 0.49 mmol) as a white solid. lE NMR (CDCL3, 300 MHz) d 9.03 (s, ÍH), 8.40 (s, ÍH), 8.03 (m, 10 2H), 7.89 (d, ÍH), 7.81 (, 3H), 7.28 (m, 2H) , 5.00 (m, ÍH), 4.75 (AB, ÍH), 4.50 (AB, ÍH), 3.92 (s, 3H), 3.22 (m, 2H), 2.87 (s, 3H), 2.38 (m, ÍH) , 2.03 (m, ÍH). FAB MS, [M + H] + = 511. G. Trifluoroacetate of [1- (4-amino-quinazolin-6-ylmethyl) -2- 15 oxopyrrolidin-3- (S) -yl] -methylamide of acid 7-methoxynaphthalene-2-sulphonic A [1- [4-amino-quinazolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -methylamide of 7-methoxynaphthalene-2-sulfone? (0.05 g, 0.1 mmol) suspended in EtOH (10 mL) is added triethylamine (0.02 g, 0.2 mmol) and ammonium acetate (0.08 g, 1 mmol). The reaction is heated to a temperature of 80 ° C. The solution is concentrated. The residue is purified by RP-HPLC eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) to a gradient of 80% CH3CN / H20 (0.1% TFA) and the fractions Appropriate products are lyophilized to provide the title compound (0.03 g, 0.05 mmol) as a white solid. IE NMR (CDCL, 300 MHz) d 9.78 (bs, 2H), 8.78 (s, 1H), ¡8.36 (s, ÍH), 8.11 (s, ÍH), 8.02 (d, ÍH), 7.92 (d, ÍH) ), 7.83 (d, V5), 7.68 (m, 2H), 7.56 (s, ÍH), 7.49 (s, ÍH), 7.32 (dd, ¡ÍH), 4.93 (m, ÍH), 4.50 (AB, ÍH), 3.82 (s, 3H), 3.15 (m, 2H), 2.62 (s, 3H), 2.02 (m, ÍH), 1.78 (m, ÍH). FAB MS, [M + H] ~ = 492. EXAMPLE 29 [1- (4-Amino-thieno [2,3-d] pyrimidin-76-yl-10-methyl) -2-oxopyrrolidin-3- (S) -trifluoroacetate il] -amide of 7-methoxy-naphthalene-2-sulfonic acid A. 2-amino-5-methylthiophen-3-carboxylic acid methyl ester To a solution of methyl cyanoacetate (19.8 g, 200 'mmol) in DMF ( 25 mL) is added triethylamine (10.9 g, 108 mmol). To the solution is added sulfur (6.4 g, 200 mmol). The solution is heated to a temperature of 60 ° C. in a period of 20 minutes, propionaldehyde (11.6 g, 200 mmol) is added dropwise. After the addition, cooling of the room temperature solution is allowed for 1 hour. The solution is stirred for 16 hours. The reaction is poured into water (300 mL). The resulting solution is extracted with Et20 (2 x 200 mL) the combined Et20 extracts are washed with water and saturated NaCl (aqueous). The organic layer 5 is dried in MgSO 4, filtered and concentrated. The resulting crude product is recrystallized from MeOH / CH2Cl; , to provide the title compound (13.7 g, 80 mmol) as a yellow solid. P NMR (CDCl 3, 300 MHz) d 6.58 (s, ÍH), 5.78 (bs, 2H), 3.78 (s, 3H), 2.28 (s, 3H) B. 2-amino-5-methylthiophen-3-acid carboxylic acid To a solution of 2-amino-5-methylthiophen-3-carboxylic acid methyl ester (13.7 g, 80 mir.ol) in MeOH / H; 0 / THF (400 L, 1: 1: 1) LiOH H20 (16 g, 400 mmol) is added. The solution is heated to a temperature of 50 ° C. After 4 hours, the solution is concentrated. The resulting residue is dissolved in water. The pH of the solution is adjusted to a level between 5 and 6 using IN HCl. The precipitate is collected by filtration, washed with a small amount of water and dried in vacuum. The title compound (12 g, 76 mmol) is obtained in the form of a yellow solid. MS, [M] "= 157. C. 6-methyl-thieno [2,3-d] pyrimidin-4-ol The title compound is prepared according to that described in example 28, part A substituting 2 -amino-5-methylthiophen-3-carboxylic acid by 2-amino-5-methyl benzoic acid The crude product is purified by column chromatography eluting with a gradient of 2% MeOH / CH 2 Cl, to 6% MeOH / CH 2 Cl 2 to provide the compound of the title in the form of a solid.

MS, [M] * = 165. D. 4-Chloro-6-methyl-thieno [2,3-d] pyrimidine The title compound is prepared in accordance with • described in Example 28, part B substituting 6-methyl-3-thieno [2,3-d] pyrimidine-4-ol for 6-methyl-3H-quinazoline-4-one. The crude product is purified by column chromatography eluting with a gradient of CH2C1; to 5% EtOAc / CH2Cl2 to provide the title compound as a solid. X NMR (CDCL3, 300 MHz) d 8.84 (s, ÍH), 7.42 (s, ÍH), 2.6.8 (s, ™ 10 3H). E. 6-bromomethyl-4-chloro-thieno [2,3-d] pyrimidine The title compound is prepared according to that described in Example 1, part F by substituting 4-chloro-6-methyl-thieno [2, 3] d] irimidine by l-chloro-7-methylisoquinoline.

The crude product is purified by column chromatography eluting with a gradient of 70% CH2Cl2 / hexanes to 100% CH2C12 to give the title compound as a white solid. : H NMR (CDCL3, 300 MHz) d 8.84 (s, ÍH), 7.42 (s, ÍH), 4.72 (s, 2H). F. [1- (4-Chloro-thieno [2, 3-d] pyrimidin-6-yl-methyl) -2-oxopyrrolidin-3 (S) -yl] -carbamic acid tert-butyl ester The compound is prepared of the title according to that described in Example 1, part H substituting 6-bromomethyl-l-4-chloro-thieno [2,3-d] pyrimidine for 7-bromomethyl-l-chloroisoquinoline. The crude product is purified, by column chromatography eluting with a gradient of 20% EtOAc / CH2Cl2 at 30% EtOAc / CH2Cl2 to provide the compound • of the title in the form of a white foam. 5: H NMR (CDCl 3, 300 MHz) d 8.80 (s, ÍH), 7.31 (s, ÍH), 5.15 (bs, ÍH), 4.75 (AB, 2H), 4.18 (, ÍH), 3.36 (m, 2H ), 2.62 (m, ÍH), 1.96 (m, ÍH), 1.42 (s, 9H). G. [1- (4-chloro-thieno [2, 3-d] pyrimidin-6-ylmethyl) -2-oxopyrrolidin-3 (S) -yl] -7-methoxynaphthalene-2-sulphonic acid amide prepare the title compound according to that described in Example 1, part I by substituting [1- (4-chloro-thieno [2,3-d] pyrimidin-, 6-ylmethyl) tert-butyl ester] - 2-oxo-pyrrolidin-3 (S) -yl] -carbamic acid ester [l- (l-chloro-isoquinol-7-ylmethyl) -2-oxopyrrolidin-3 (S) -yl] - tert-butyl ester carbamic The resulting product is taken directly according to io described in Example 1, part K. The crude product is purified by column chromatography eluting with a gradient of 30% EtOAc / CH2Cl2 at 40% EtOAc / CH2Cl2 to give the title compound as a white solid. X NMR (CDCL3, 300 MHz) d 8.80 (s, ÍH), 8.32 (s, ÍH), 7.92 (d, ÍH), 7.76 (m, 2H), 7.24 (m, 3H), 5.51 (bs, ÍH) , 4.68 (s, 2H), 3.93 (s, 3H), 3.78 (m, ÍH), 3.32 (m, 2H), 2.62 (m, 1H), 2.12 (m, ÍH).

H. Trifluoroacetate [1- (4-amino-thieno [2, 3-d] pyrimidin-1-ethyl-ethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide-7-methoxynaphthalene-2-sulfonic acid It is prepared the title compound according to that described in example 28, part G substituting [l- (4-chloro-thieno [2,3-d] pyrimidin-6-yl-methyl) -2-oxopyrrolidin-3 (S) -l] 7-methoxynaphthalene-2-sulfonic acid amide by [1- (4-chloro-quinazolin-6-ylmethyl) -2-oxopyrrolidir.-3 (S) -yl] methylamide of 7-methoxynaphthalene- 2-sulfonic. The residue is purified by RP-HPLC eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) to 80% CH3CN / H20 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound in the form of a white solid. P NMR (DMSO-d6, 300 MHz) d 8.33 (m, 2H), 8.21 (d, ÍH) 8.02 (m, 2H), 7.91 (d, ÍH), 7.70 (dd, ÍH), 7.52 (s, ÍH) ), 7.43 (s, ÍH), 7.30 (dd, ÍH), 4.58 (AB, 2H), 4.05 (m, 2H), 3.93 (s, 3H), 3.17 (m, 2H), 1.98 (m, ÍH) , 1.55 (, ÍH). FAB MS ,? [M + H] t = 484. EXAMPLE 30 Trifluoroacetate [2- (6-amino-thieno [2,3-d] pyrimidin-j-6-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide of the acid -methoxyaphthalene-2-sulfonic acid A.-chloro-7-methyl-thieno [3,2-d] pyrimidine The title compound is prepared according to that described in example 28, part B by substituting 7-methyl-thieno [2]., 3-d] pyrimidin-4-ol by 6-methyl-3H-quinazolin-4rona. The crude product is purified by column chromatography eluting with a gradient of CH2C12 at 10% EtOAc / CH2Cl to give the title compound as a solid. XH NMR (CDC13, 300 MHz) d 9.02 (s, HH), 7.68 (s, HH), 2.5.1 (s, 3H). B. 7-Bromomethyl-4-chloro-thieno [3,2-d] pyrimidine The title compound is prepared according to that described in Example 1, part F by substituting 4-clqro-7-methyl-thieno [3, 2-d] pyrimidine by l-chloro-7-methylisoquinoline.

The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc / hexanes a, 10% EtOAc / hexanes to provide the title compound as a white solid. P NMR (CDCL3, 300 MHz) d 9.04 (s, ÍH), 8.08 (s, ÍH), 4.77 (s, 2H). C. [1- (4-Chloro-thieno! [3,2-d] pyrimidin-7-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid tert-butyl ester compound of the title according to that described in Example 1, part H, substituting 7-bromomethyl-1-chloromethyzoline [3, 2-d] pyrimidine for 7-bromomethyl-4-chloro-thieno [3, 2-d] pyrimidine. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc / CH2Cl2 at 30% EtOAc / CH2Cl2 to give the title compound as a white foam. X NMR (CDCL3, 300 MHz) d 8.95 (s, ÍH), 8.06 (s, ÍH), 5.18 (bs, ÍH), 4.76 (AB, 2H), 4.13 (m, ÍH), 3.44 (m, ÍH) , 3.37 (m, • ÍH), 2.64 (m, ÍH), 1.92 (, ÍH), 1.42 (s, 9H). D. [1- (4-chloro-thieno [3,2-d] pyrimidin-7-i1-methyl) -2-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid amide The title compound is prepared according to that described in Example 1, part I by substituting [1- (4-chloro-thieno [3,2-d] pyrimidin-7-ylmethyl] -butyl-10-butyl ester. ) -2-oxopyrrolidin-3- (S) -yl] carbamic acid ester [1- (4-chloro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl) tert-butyl ester ] carbamic. The resulting product is taken directly in accordance with what is described in Example 1, part K. The crude product is purified by column chromatography eluting with a gradient of 30% EtOAc / CH 2 Cl 2 at 40% EtOAc / CH 2 Cl: to provide the compound • of the title in the form of a white solid. X NMR (CDCL5, 300 MHz) d 8.92 (s, ÍH), 8.32 (s, ÍH), 7.96 (s, ÍH), 7.86 (d, ÍH), 7.74 (m, 2H), 7.28 (d, ÍH), 7.19 (d, 'ÍH), 5.64 (bs, ÍH), 4.71 (AB, 2H), 3.93 (s , 3H), 3.72 (m, ÍH), 3.44 (m, ÍH), 3.32 (m, ÍH), 2.52 (m, ÍH), 2.05 (m, ÍH). E. Trifluoroacetate [2- (4-amino-thieno [3,2-d] pyrimidin-7-yl-ethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 7-a methoxynaphthalene-2-sulfonic acid The title compound is prepared according to that described in example 28, part G substituting [l- (4-chloro-thieno [3,2-d] pyrimidin-6-yl-methyl) - 7-Oxopyrrolidin-3 (S) - yl] -7-methoxynaphthalene-2-sulfonic acid amide by [1- (4- (5-chloro-quinazol-6-yl-methyl) -2-oxopyrrolidin-3 (S) - il] 7-methoxynaphthalene-2-sulfonic acid methylamide. The residue is purified by RP-HPLC eluting in a gradient of 10% CHjCN / HsO (0.1% TFA) to 80% CH3CN / H20 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound. in the form of a white solid. XH NMR (DMSO-de, 300 MHz) d 8.55 (s, ÍH), 8.35 (bs, 3H), 8.14 (d, ÍH), 8.00 (m, 2H), 7.93 (d, ÍH), 7.68 (d, ÍH), 7.5.2 (s, ÍH), 7.32 (dd, ÍH), 4.49 (AB, 2H), 4.09 (m, ÍH), 3.90 (s, 3H), 3.18 (m, 2H), 1.96 (m, ÍH), 1.54 (m, ÍH). FAB, [M + H] * = 483. Elemental analysis calculated with 1.5 mol of H20 and 1.5 mol of • calculated trifluoroacetate. C = 44.75%, H = 3.83%, N = 10.44%; found C = 44.75%, H = 3.77%, N = 11.12%. EXAMPLE 31 Trifluoroacetate [1- (7-amino-thieno [2,3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-aide sulphonic acid A. 3-bromometi1-7-chloro-thieno [2, 3-c] pyridine The title compound is prepared according to that described in Example 1, part F by substituting 7-chloro-3-methyl-thieno [ 2, 3-c] pyridine by l-chloro-7-methylisoquinoline. The crude product is purified by column chromatography • eluting with a gradient of 5% EtOAc / hexanes to 10% EtOAc / hexanes to give the title compound as a white solid. H NMR (CDCl3, 300 MHz) d 8.38 (d, ÍH), 7.73 (s, ÍH), 7.71 (d, ÍH), 4.72 (s, 2H). B. [1- (7-Chloro-thieno [2, 3 • 10 c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] carbamic acid tert-butyl ester the title compound according to that described in Example 1, part H, substituting 3-bromomethyl-7-chloro-thieno [2, 3-c] pyridine for 7-bromomethyl-1-chloroisoquinoline. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc / CH2Cl2 at 40% EtOAc / CH2Cl2 to give the title compound as a white foam. • X NMR (CDCL3, 300 MHz) d 8.28 (d, ÍH), 7.74 (d, ÍH), 7.64 (s, 1H), 5.18 (bs, ÍH), 4.68 (AB, 2H), 4.17 (m, ÍH) ), 3.18 (m, 2H), 2.54 (m, ÍH), 1.86 (m, ÍH), 1.42 (s, 9H). C. [1- (7-chloro-thieno [2,3-c] pyridin-3-i1-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide-7-methoxy-naphthalene-2-sulfonic acid prepare the title compound in accordance with described in example 1, part I substituting [1- (7-chloro-thieno [2, 3-c] pyridin-, 3-ylmethyl) -2-oxopyrrolidin-3- (S) tert-butyl ester. ) -yl] carbamic ester, [1- (l-chloro-isoquinolin-7-yl-methyl) -2- • oxopyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester. The resulting product is taken directly in accordance with io described in Example 1, part K. The crude product is purified by column chromatography eluting with a gradient of 30% EtOAc / CH: Cl 2 at 40% EtOAc / CH 2 Cl 2 to provide the compound of the title in the form of a white solid. • 10 XH NMR (DMSO-de, 300 MHz) d 8.33 (s, ÍH), 8.30 (s, ÍH), 8.16 (d, ÍH), 8.07 (s, ÍH), 7.99 (d, ÍH), 7.92 ( d, ÍH), 7.78 (d, ÍH), 7.67 (d, ÍH), 7.51 (d, ÍH), 7.28 (dd, ÍH), 4.58 (AB, 2H), 4.08 (m, ÍH), 3.88 (s) , 2H), 1.89 (ir., ÍH), 1.48 (m "ÍH). D. Trifluoroacetate [1- (7-amino-thieno [2, 3-c] pyridin-3-yl-15-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amido-7-ethoxynaphthalene-2- acid sulphonic The title compound is prepared in accordance with • described in Example 28, part G substituting [l- (7-chloro-thieno [2,3-c] pyridin-3-yl-methyl) -2-oxopyrrelidin-3 (S) -yl]? amide of 7-methoxynaphthalene-2-sulfonic acid by [1- (4-chloroquinazolin-6-ylmethyl) -2-oxopyrrolidin-3 (S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid. The residue is purified by RP-HPLC eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) to 80% CH3CN / H20 (0.1% TFA) and the appropriate fractions of The product is lyophilized to provide the title compound as a white solid. : H NMR (DMSO-ds, 300 MHz) d 8.90 (bs, ÍH), 8.34 (s, ÍH), 8.16 (d, ÍH), 7.90 (d, ÍH), 7.82 (d, ÍH), 7.68 (d, ÍH), 7.62 (d, ÍH), 7.34 (m, 3H), 7.23 (dd, ÍH), 4.64 (AB, 2H), 4.08 (m, ÍH), 3.88 (s, 3H), 3.09 (, 2H), 2.11 (m, ÍH), 1.60 (m, 1 ÍH). FAB, [M + H] * = 483. EXAMPLE 32 Trifluoroacetate [1- (7-hydroxy-thieno [2, 3-c] pyridin-3-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] amide of acid 7-_ • 10-methoxynaphthalene-2-sulfonic acid A. Trifluoroacetate [1- (7-hydroxy-thieno [2,3-c] pyridin; -3-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] amide acid, 7- methoxynaphthalene-2-sulfonic acid The title compound is prepared in accordance with described in Example 28, part G substituting [l- (7-chloro-thieno [2,3-c] pyridin-3-yl-methyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide. -methoxyaphthalene-2-sulphonic acid by [1- (4-chloro- • qu? nazolm-6-yl-methyl) -2-oxopyrrolidin-3 (S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid. The residue is purified by RP-HPLC eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) to 80% CH3CN / H20 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a solid. White. : H NMR (DMSO-de, 300 MHz) d 8.36 (s, ÍH), 8.18 (d, 1H) "8.01 (d, ÍH), 7.92 (d, 1H), 7.86 (s, ÍH), 7.68 (d, ÍH), 7.52 (s, ÍH), 7.28 (m, 3H), 6.62 (d, ÍH), 4.42 (AB, 2H), 4.00 (m, 1H), 3.88 (s, 3H), 3.04 (m, 2H), 1.89 (, ÍH), 1.44 (m, ÍH). FAB, [M + H] * = 484. • EXAMPLE 33 5 Trifluoroacetate [1- (4-amino-thieno [3,2- c] pyridin-3-i1-met l) -2-oxopyrrolidin-3- (S ) -yl] 7-methoxynaphthaler.-2-sulphonic acid amide A. 3- (5-methyl-thiophen-2-yl) -acrylic acid methyl ester To 5-methyl-thiophene-2-carboxaldehyde (5g, 40) mmol) in CH2C1 * (100 m ^ r 10 L) is added methyl acetate (triphenylphosphoranylidene) (13.3 g, 40 mmol). The solution is stirred for 72 hours. After this time, the solution is concentrated. The residue is formed into a paste in Et20. The solution is filtered through a Celite bed. The collected liquid is concentrated. The residue is purified by column chromatography eluting with a gradient of 50% EtOAc / hexanes to 60% EtOAc / hexanes to give the title compound (4.5 g, 25 mmol) • in the form of an oil. P NMR (CDCL3, 300 MHz) d 7.69 (d, HH), 7.04 (d, HH), 6.71 (d, 20 HH), 6.11 (d, HH), 3.79 (s, 3H), 2.49 (s, 3H) ). B. 3- (5-Methyl-thiophen-2-yl) -acrylic acid The title compound is prepared according to that described in Example 29, part B by substituting 3- (5-methyl-thiophene) methyl ester. 2-yl) -acrylic ester Methyl 2-amino-5-methylthiophen-3-carboxylic acid. The title compound is obtained by filtration in the form of a white solid. lE NMR (CDCL3, 300 MHz) d 7.58 (d, ÍH), 7.24 (d, ÍH), 7.8¡2 (d, • ÍH), 5.98 (d, ÍH), 2.46 (s, 3H). C. 2-Methyl-5H-thieno [3, 2-c] pyridin-4-one The title compound of conformity ccr is prepared. as described in Example 1, part A substituting 3- (5-methyl-thiophen-2-yl) -acrylic acid for 3-p-tolyl-acrylic acid. The product is then treated according to example 1, • Part B, C, and D. The crude product is purified by column chromatography eluting with a gradient of 1% MeOH / CH2CL2 at 5% MeOH / CH2CL2 to give the title compound as a white solid. X NMR (CDCL3, 300 MHz) d 11.72 (bs, ÍH), 7.31 (s, ÍH), 7.18 (d, ÍH), 6.68 (d, ÍH), 2.58 (s, 3H). MS, [M] "= 165. D. 4-Chloro-2-methyl-thieno [3,2-c] pyridine The title compound of conformance is prepared as follows. • described in example 1, part E substituting 2-methyl-5H-thieno [3, 2-c] pyridin-4-one for 7-methyl-2H-isoquinol? N-l-one.

The crude product is purified by column chromatography eluting with a gradient of 70% CH 2 Cl 2 / hexanes at 100% HCl2 to provide the title compound as a white solid. XH NMR (CDCL3, 300 MHz) d 8.13 (d, ÍH), 7.58 (d, ÍH), 7.16 (d, HI), 2.61 (s, 3H).

E. 2-bromomethyl-4-chloro-thieno [3,2-c] pyridine The title compound is prepared according to that described in Example 1, part F by substituting 4-chloro-2- • methyl-thieno [3, 2 -c] pyridine by l-chloro-7-methylisoquinoline.

The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc / hexanes at 10% EtOAc / hexanes to give the title compound as a white solid. : H NMR (CDCl 3, 300 MHz) d 8.21 (d, HH), 7.63 (d, HH), 7.49 (s, 10 HH), 4.80 (s, 2H). F. [1- (4-Chloro-thieno [3, 2-c] pyridin-2-yl-methyl) -2-oxopyrrolidin-3 (S) -yl] carbamic acid tert-butyl ester compound of the title according to that described in Example 1, part H substituting 2-bromomethyl-l-4-chloro-thieno [3,2-c] pyridine for 7-bromomethyl-l-chloroisoquinoline. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc / CH2Cl2 at 30% EtOAc / CH2Cl2 to give the title compound as a white foam. 20 P NMR (CDCL3, 300 MHz) d 8.22 (d, ÍH), 7.63 (d, ÍH), 7.39 (s, ÍH), 5.13 (bs, ÍH), 4.78 (AB, 2H), 4.21 .m, ÍH ), 3.3¡3 (m, 2H), 2.62 (m, ÍH), 1.90 (m, 1H), 1.42 (s, 9H). G. 3- (S) -amino-1- (-chloro-thieno [3,2- c] pyridin-2-ylmethyl) -pyrrolidin-2-one hydrochloride. The title compound is prepared in accordance with that described in Example 1, part I substituting [1- (4-chloro-thieno [3,2- c] pyridin-2-methyl-2-oxopyrrolidin-3- (S) - tert-butyl ester] Figure imgf000038_0001] is selected from the group consisting of [1- (l-chloro-isoquinolin-7-yl-methy1) -2- 5-oxopyrrolidin-3- (S) -yl] -carbamic acid tert- butyl ester. The title compound is obtained in the form of a white solid. : H NMR (DMSO-ds, 300 MHz) d 8.50 (bs, 3H), 8.22 (d, ÍH), 3.06 (d, ÍH), 7.51 (s, ÍH), 4.81 (AB, 2H), 4.04 (m , 2H), 3.32 (m, 2H), 2.31 (, ÍH), 1.96 (m, ÍH). • 10 H_. [1- (4-Amino-thieno [3,2-c] pyridin-3-i1-methyl) -2-oxopyrrolidin-3- (S) -yl] -amide-3-methoxynaphthalene-2-sulfonic acid composed of the conformance title as described in example 1, part K substituting 3-aminc-l (4- 15 chloro-thieno [3,2- c] pyridin-2-yl-methyl) -pyrrolidin-2-one for 3- (S) -amino-1- (l-chloro-isoquinolin-7-yl-methyl) -pyrrolidin-2-one hydrochloride. The title compound is obtained in, form • of a white solid. : H NMR (DMSO-d., 300 MHz) d 8.36 (s, ÍH), 8.28 (d, ÍH) ,, 8.18 (d, ÍH), 8.02 (, 2H), 7.91 (d, ÍH) -, 7.69 (d, ÍH), 7.56 (d, ÍH), 7.42 (s, ÍH), 7.29 (dd, ÍH), 4.66 (AB, 2H), 4.10 (, ÍH), 3.88 (s, 3H), 3.14 (m, 2H), 1.97 (m, ÍH), 1.58 (m, 1H). I. Trifluoroacetate [1- (4-amino-thieno [3,2-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 7-methoxy-naphthalene-2-acid sulphonic The title compound is prepared according to that described in Example 1, part L substituting [l- (4-chloro-thieno [3,2- c] pyridin-3-ylmethyl) -2-oxopyrrolidin-3. (S) -yl] amide • of 7-methoxynaphthalene-2-sulfonic acid by [l- (l-chloro-5-isoquinolin-7-yl-methyl) -2-oxopyrrolidin-3 (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid . The resulting product is then treated according to that described in Example 1, part M. The residue is purified by RP-HPLC eluting in a gradient of 10% CH.CN/H20 (0.1% TFA), to 80% • CH3CN / H20 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid. X NMR (DMSO-d6, 300 MHz) d 8.58 (bs, 3H), 8.32 (s, ÍH), 8.26 (d, ÍH), 8.02 (d, ÍH), 7.92 (d, ÍH), 7.78 (s, ÍH), 7.69 (m, 15 2H), 7.49 (dd, 1H), 7.28 (dd, ÍH), 4.62 (AB, 2H), 4.02 (m, ÍH), 3.88 (s, 3H), 3.13 (m, 2H), 1.96 (m, ÍH), 1.58 (, ÍH). FAB MS, [M + H] = 483. • EXAMPLE 34 Trifluoroacetate [1- (4-hydroxy-thieno [3,2- c] pyridin-3-yl-20 methyl) -2-oxopyrrolidin-3- (S) -yl] 7-ethoxynaphthalene-2-sulfonic acid amide A. Trifluoroacetate [1- (4-hydroxy-thieno [3,2- c] pyridin-3-ylmethyl) -2-oxopyrrolidin-3- (S) -l] 7-methoxynaphthalene-2-sulfonic acid amide The title compound is prepared according to that described in Example 1, part L by substituting [l- (4-chloro-thieno [3,2-c] pyridine] 7-methoxynaphthalene-2-sulfonic acid-3-ylmethyl) -2-oxopyrrolidn-3 (S) -yl] -amide by [l- (l-chloro- • isoquinolin-7-yl-methyl) - 2-Oxopyrrolidin-3 (S) -yl] amide of 7-methoxynaphthalene-2-sulfonic acid. The resulting product is then treated in accordance with that described in Example 1, part M. The residue is purified by RP-HPLC eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) to 80% CH-CN / H20 (0.1% TFA) and the appropriate product fractions ^ 10 are lyophilized to give the title compound as a white solid. : H NMR (DMSO-ds, 300 MHz) d 11.32 (bs, 3H), 8.33 (s, 1H), 8.20 (d, ÍH), 8.02 (d, ÍH), 7.92 (d, ÍH), 7.69 (d , ÍH), 7. ^ 2 (d, ÍH), 7.46 (s, ÍH), 7.30 (m, 2H), 7.19 (m, ÍH), 6.71 (d, ÍH), 4.52 (AB, 2H), 4.06 (m, ÍH), 3.88 (s, 3H), 3.10 (, 2H), 1.90 (m, ÍH), 1.50 (m, ÍH). FAB MS, [M + H] "= 484. EXAMPLE 35 • Trifluoroacetate [1- (4-amino-thieno [3,2- c] pyridin-3-yl-methyl) -2-oxopyrrolidin-3- (S) -yl] benzo [b] thiophene-2-sulphonic acid amide A. [1- (4-chloro-thieno [3,2- c] pyridin-3-yl-methyl) -2-oxopyrrolidin-3- ( S) -yl] benzo [b] thiophene-2-sulfonic acid amide The title compound is prepared in accordance with described in Example 1, part K substituting 3-amino-l (4-chloro-thieno [3,2-c] pyridin-2-yl-methyl) -pyrrolidin-2-one for hydrochloride 3- (S) - amino-1- (1-chloro-isoquinolin-7-yl-methyl) -pyrrolidin-2-one and benzo [b] thiophen-2-sulfonyl chloride per • 7-methoxynaphthalene-2-sulfonyl chloride. The title compound is obtained in the form of a white solid. P NMR (CDCL3, 300 MHz) d 8.21 (d, HH), 7.96 (s, HH), 7.90 (m, 2H), 7.64 (d, HH), 7.49 (m, 2H), 7.39 (s, 1H) , 5.58 (bs, ÍH), 4. 76 (s, 2H), 3.97 (m, ÍH), 3.38 (m, 2H), 2.68 (m, ÍH), 2.18 (m, ÍH). 10 B. Trifluoroacetate [1- (4-amino-thieno [3,2-c] pyrid? N-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -benzoic acid amide [b] thiophen-2-sulfonic acid The title compound is prepared according to that described in Example 1, part L by substituting [1- (4-chloro-15-thieno [3,2-c] pyridin-3-yl-methyl) - Benzo [b] thiophene-2-sulfonic acid 2-oxo-pyrrolidin-3 (S) -yl] -amide by [l- (l-chloro-isoquinolin-7-yl-methyl) -2-oxopyrrolidin-3 (S) - il] amide of 7-methoxynaphthalene-2-sulfonic acid. The resulting product is then treated in accordance with that described in Example 1, part M. The residue is purified by RP-HPLC eluting in a gradient of 10% CH3CN / H; 0 (0.1% TFA) to 80% CH3CN / H20 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid. 25 XH NMR (DMSO-de, 300 MHz) d 8.70 (d, ÍH), 8.55 (bs, 2H), 8.07 (m, 3H), 7.78 (s, ÍH), 7.70 (d, ÍH), 7.49 (, 3H), 4.66 (AB, 2H), 4.16 (m, ÍH), 3.24 (m, 2H), 2.12 (m, ÍH), 1.72 (m, ÍH). FAB MS, [M + H] ~ = 459. • EXAMPLE 36 5 Trifluoroacetate [1- (4-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] 5-pyridine acid amide -4-yl-thiophen-2-sulphonic acid 4-thiophen-2-yl-pyridine 2-Bromothiophene (7.6 L, 78.5 mmol) is added dropwise to a flame and dried under vacuum in a bottom flask. round three-neck equipped with a condenser, a plug and magnesium (2 g, 82.3 mmol) in diethyl ether (70 mL). The resulting gray solution is stirred at reflux for 1.5 hours. Meanwhile, 4-bromopyridine hydrochloride is converted in the free base as follows: 4-bromopyridine hydrochloride (153 g, 78.7 mmol) is dissolved in water (100 mL) and cooled in an ice bath. Be add drop to • drop an equivalent of NaOH IN (approximately 100 mL) until a pH of approximately 5.6 is obtained. The aqueous solution Chilled on ice is extracted with hexane (3 x 150 mL) and the combined organic layers are dried over MgSO4 and filtered. Hexane is removed under vacuum (11 mm Hg) while cooling in an ice bath to a volume of about 30 mL. The resulting clear colorless solution is diluted with THF (150 mL) under N2. The Grignard reagent is then cooled to room temperature and added through a cannula to the NiCl solution: dppp (0.54 g, 1 mmol) and 4-bromopyridine in THF The resulting dark solution is refluxed • overnight. The reaction mixture is then vapiada in a saturated solution of NHC1 and extracted with diethylether (3 x 200 mL). The combined ether layers are acidified with 2N HCl (300 mL) and the aqueous layer is washed with diethyl ether. The aqueous layer is then cooled in an ice bath and neutralized with sodium bicarbonate. The cough coat The mixture is extracted with ethyl acetate (3 x 200 mL) and the combined organic layers are dried over MgSO 4, filtered and concentrated to give a brown solid. The crude solid is absorbed in hot hexanes and the yellow solution is separated from the insoluble black solid. The The hexane solution is concentrated and the procedure described above is repeated. As the hexane solution cools, solid yellow precipitates form. The yellow solid is collected to give the title compound (8.99 g, 55.8 mmol). 20 P NMR (CDCl 3, 300 MHz) d 8.60 (d, 2H), 7.51 (m, ÍH), 7.49 (d, 2H), 7.14 (dd, ÍH). The MS, [M] + = 161. B. 5-Pyridin-4-yl-thiophene-2-sulfonyl chloride To a solution of 4-thiophen-2-yl-pyridine (3.33 g, 20.7 mmol) in THF (137 mL) at a temperature of -78 ° C C BuLi is added (8.7 mL in a 2.5 M solution in hexanes, 21.7 mmol). After stirring for 15 minutes, a gas of S02 is bubbled through the solution for 30 minutes. The heating of the solution at room temperature is then allowed! and • stir during the night. The solution is concentrated to dryness and the resulting solid is suspended in hexanes (100 mL). Sulfuryl chloride (1.7 L, 21.7 mmol) is added to the ice-cooled solution. The ice bath is removed and the suspension is stirred for 2 hours. The mixture is then concentrated to dryness and diluted with ethyl acetate.

Ethyl and washed with saturated NaOH3 (aqueous), water and brine. The organic layer is dried over MgSO4, filtered and concentrated to give a yellow solid as the title product (3.39 g, 13.1 mmol) which is employed in a subsequent step without further purification. 15 X NMR (CDCL3, 300 MHz) d 8.75 (d, 2H), 8.60 (d, ÍH), 7.90 (d, ÍH), 7.51 (d, 2H) EI, [M] "= 259, 261 Cl pattern 5-pyridin-4-yl-thiophene-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide. 5-pyridin-4-ii-thiophene-2-sulfonyl at one solution of 3- (S) -amino-i- (1-chloro-isoquinolin-7-yl-methyl) -pyrrolidin-2-one hydrochloride (0.12g, 0.38 mmol) in pyridine (2 mL). The resulting mixture is stirred overnight and then concentrated to dryness. The residue is diluted with methylene chloride and washed with a solution saturated with NaHCO 3 and brine. The organic layer is dried over MgSO4, filtered and concentrated to give 105 mg of a crude solid. The crude product is purified by column chromatography eluting with 5% MeOH / CH2Cl2 to give the title product (0.026 g, 0.052 mmol) as a white solid. : H NMR (CDCl 3, 300 MHz) d 8.67 (d, 2H), 8.30 (d, 12H), '8.14 (s, ÍH), 7.83 (d, ÍH), 7.70 (d, ÍH), 7.57 - 7.61 ( m, 2H), 5.60 (bs, ÍH), 4.67 (AB, 2H), 3.98 (m, 1H), 3.29 (m, 2H), 2.68 (m, ÍH), 2.15 (m, ÍH). APCl MS, [M + H] "= 499, 501 standard Cl. D. Trifluoroacetate of [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of acid 5-pyridin-4-yl-thiophene-2-sulphonic Ammonium acetate (0.12 g, 1.56 mmol), phenol (0.049 g, 0.52 mmol), and [1- (l-chloro-isoquinolin-7-ylmethyl) are heated. 2-Oxopyrrolidin-3- (S) -yl] -amide of 5-pyridin-4-yl-thiophene-2-sulfonic acid (0.026 g, 0.052 mmol) at a temperature of 90 ° C for 6 hours and then The product is purified by RP-HPLC eluting with a gradient of 10% CH3CN / H20 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound (0.005 g, 0.007 mmol). in the form of a white solid: H NMR (DMSO-de, 300 MHz) delta 13.0 (bs, ÍH), 9.0 (bs, ÍH), 8.60-8.70 (m, 3H), 8.29 (s, ÍH), 7.91 (d, HH), 7.89 (d, HH), 7.71-7.80 (m, 4H), 7.66 (d, HH), 7.23 (d, HH), FAB MS, [M + H] ~ - 480. EXAMPLE 37 • [1- (l-aminoi trifluoroacetate soquinolin-7-ylmethyl) -2- 5-oxopyrrolidin-3- (S) -yl] -amide of 5-pyridin-3-yl-thiophene-2-sulfonic acid A. 3-thiophen-2-yl-pyridine It is prepared the title compound according to that described in example 36, part A using 3-bromopyridine • 10 instead of 4-bromopyridine hydrochloride. X NMR (CDC13, 300 MHz) delta 8.89 (dd, ÍH), 8.52 (dd, ÍH), 7.87 (ddd, ÍH), 7.38 (s, ÍH), 7.36 (d, ÍH), 7.31 (m, ÍH) , 7.12 (dd, ÍH). El, [M] t = 161. B. 5-Pyridin-3-yl-thiophene-2-sulfonyl chloride The title of the compound is prepared according to that described in example 36, part B using 3-thiophene 2-yl-pyridine in place of 4-thiophen-2-yl-pyridine. P NMR (CDCI3, 300 MHz) delta 8.95 (bs, ÍH), 7.95 (d, ÍH), 7.90 (d, ÍH), 7.45 (bs, ÍH), 7.44 (d, ÍH). The, [M] + = 259, 261, Cl pattern. C. [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 5-pyridin-3-yl-thiophene-2-sulfonic acid. Triethylamine (0.35 mL) is added. 2.5 mmol) dropwise to a solution of 5-pyridin-3-yl-thiofen-2-sulfonyl chloride (0.22 g, 0.85 mmol) and 3- (S) -amino-1- (1-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-one hydrochloride (0.22 g, 0.71 immol) in CHCN (5 mL ). The suspension is stirred at room temperature overnight and then concentrated to dryness ,. The residue is diluted with methylene chloride and washed with a saturated solution of NaHCO-, and brine. The organic layer is dried over MgSO4, filtered, concentrated, and then purified by column chromatography eluting with a gradient of 1% MeOH / CH2Cl2 at 5% MeOH / CH2Cl3 to provide the product (0.23 g, 0.45 mmol) as a solid white. : H NMR (CDC13, 300 MHz) delta 8.89 (d, ÍH), 8.63 (dd, ÍH), 8.30 (d, ÍH), 8.13 (d, ÍH), 7.82-7.89 (m, 2H), 7.70 (d , 1H), 7.57-7.68 (m, 2H), 7.33-7.40 (m, 2H), 5.45 (d, ÍH), 4.67 (AB, 2H), 3.95 (m, ÍH), 3.28 (m, 2H) , 2.75 (m, ÍH), 2.10 (m, ÍH). EM sputtering EM, [M + H] + = 499, 501, Cl pattern.

D. [1- (L-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 5-pyridin-3-yl-thiophen-2-sulfonic acid trifluoroacetate The title compound is prepared in accordance with that described in example 36, part D using [l- (l-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 5-pyridin-3-yl-thiophene-2-sulfonic acid in place of [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 5-pyridin-4-yl-thiophene-2-sulfonic acid and is heated to a temperature of 100 ° C at night. The crude product is purified by RP-HPLC eluting with gradient of 10% CH3CN / H20 (0.1% TFA) to 100% CH3CN. The appropriate product fractions are lyophilized to provide the compound • of the title in the form of a white solid. 5: H NMR (DMSO-de, 300 MHz) delta 12.9 (bs, ÍH), 8.90-9.05 (m, 2H), 8.55-8.65 (m, 2H), 8.31 (s, ÍH), 8.17 (m, ÍH) ), 8.9Í € (d, ÍH), 8.82 (d, ÍH), 7.70-7.72 (m, 2H), 7.65 (d, ÍH), 7.53 (dd, ÍH), 7.21 (d, ÍH), 4.60 ( AB, 2H), 4.30 (m, ÍH), 3.25 (m, 2H), 2.29 (m, ÍH), 1.78 (m, ÍH). FAB MS, [M + H] "= 480. ™ 10 EXAMPLE 38 [1- (4-Aminoquinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of benzothiophen-2-acid trifluoroacetate sulphonic A. 4-chloro-6-methylquinoline 15 Heat 5-methyl- (1H) -quinolin-4-one (1.57 g, 9.7 mmcl) in 20 mL of phosphorus oxychloride at a temperature of 110 ° C for 4 hours. The mixture is cooled to room temperature • environment and then diluted in ice water (approximately 200 mL) and the pH is adjusted to approximately 10 by NaOH addition N 10. The aqueous solution is extracted with methylene chloride (4 x 250 mL) and the combined organic layers are washed with brine, dried in Na, S0, filtered and concentrated. The crude residue is filtered through silica gel with 33% EtOAc / hexanes to provide the product (1.05 g, 5.9 mmol) as a yellow1.1o solid.

: H NMR (CDCl 3, 300 MHz) delta 8.69 (d, ÍH), 8.0 (m, 2H), 7.58 (dd, ÍH), 7.44 (d, ÍH), 2.58 (s, 3H). The MS, [M] t = 177, ¡179, pattern of Cl. • B. 6-bromomethyl-4-chloroquinoline 5 N-bromosuccinimide (1.1 g, 6.19 mmol) and 70% benzoyl peroxide (0.215 g, 0.62 mmol) are added to a solution of 4-chloro-6-methylquinoline (1.05 g, 5.93 mmol) in 35 M; l carbon tetrachloride. The resulting mixture is heated to reflux overnight and then cooled to room temperature Ü ^^ '10 environment and then diluted with methylene chloride. The organic layer is washed with IN NaOH, dried over Na 2 SO, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 33% EtOAc / hexanes1 to provide the product (0.915 g, 3.57 mmol) as a white solid. LH NMR (CDCl 3, 300 MHz) delta 8.73 (d, ÍH), 8.13 (d, ÍH), 8.07 (d, ÍH), 7.74 (dd, ÍH), 7.42 (d, ÍH), 4.67 (s, 2H) . Ion spray MS, [M + H] * = 256, 258, 260, Cl standard, Br. C. 3- (S) -amino-1- (4-chloroquinolin-6-ylme, tyl) hydrochloride - 20 pyrrolidin-2-one Sodium hydride (0.096 g, 2.4 mmol, 60% in peach) is added to a solution of tert-butyl acid ester! [2- oxopyrrolidin-3- (S) -yl] -carbamic acid (0.4 g, 2 mmol) in 15 mL of THA at a temperature of 0 ° C. The mixture is stirred for 25 30 minutes and then a solution is added slowly of 6-bromomethyl-4-chloroquinoline (0.513 g, 2 mmol) in 15 mL of THF. The resulting solution is heated at room temperature for 4 hours. The reaction mixture is poured # with a saturated solution of ammonium chloride and then diluted with EtOAc. The organic layer is separated, washed with brine, dried over Na 2 SO 4, filtered and concentrated. The residue is dissolved in ethyl acetate (50mL), and saturated with HCl gas at a temperature of 0 ° C. The solution is stirred at a temperature of 0 ° C for 15 minutes, and then the • The solution is heated to room temperature. After 4 hours at room temperature, the solid that is precipitated is collected, and washed with ether to give the title compound (0.44 g, 1.43 mmol) as a pale yellow solid. 15: H NMR (DMSO-dO, 300 MHz) delta 9.05 (d, ÍH), 8.78 (bs, '3H), 8.27 (d, ÍH), 8.23 (s, ÍH), 8.02 (d, ÍH), 7.96 (d, ÍH), 4.67 (AB, 2H), 4.12 (m, ÍH), 3.35 (m, 2H), 2.43 (m, ÍH), 2.09 (m, • ÍH). Ion Spray MS, [M + H] t = 276, 278. D. [1- (4-chloroquinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S -yl) -benzothiophene-2-sulfonic acid amide 3- (S) -amino-1- (4-chloroquinolin-6-ylmethyl) -pyrrolidin-2-one hydrochloride (0.12 g, 0.38 mmol) is suspended in 15 mL of CH3CN . To that solution is added triethylamine (110 mL, 0.79 mmol) followed by benzothiophene-2-sulfonyl chloride (0.094). g, 0.40 mmol). The mixture is stirred during the noPhe at room temperature, subjected to aqueous treatment and then concentrated to dryness. The crude product is purified by column chromatography eluting with 2-10% MeOH / CH2Cl2 • to provide the title compound (0.11 g, 0.23 mmol) 5 as an off-white solid. P NMR (CDC13, 300 MHz) delta 8.77 (d, ÍH), 8.08 (s, ÍH), 8.04"(s, ÍH), 7.97 (s, ÍH), 7.88 (m, 2H), 7.58 (dd, ÍH), 7.49 (m, 3H), 6.01 (bs, ÍH), 4.67 (AB, 2H), 4.03 (t, ÍH), 3.27 (m, 2H), 2.65 (m, 2H), 2.16 (, 1HJ.FAB MS, [M + H] "= 472, 474, IP 10 standard Cl. E. Trifluoroacetate of [1- (4-aminoquinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of benzothiophen-2-sulfonic acid It is treated [1- ( 4-chloroquinolin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl (S) -yl] -amide of benzothiophene-2-sulfonic acid (0.11 g, 0.23 mmol) with phenol (1 g) and ammonium acetate (0.22) g, 2.8 mmol) at a temperature of 110 ° C as previously described. ^ f After 5 hours, the mixture is cooled to room temperature and diluted with 100 mL of methylene chloride. The The organic solution is washed with IN NaOH (2X) and saline, dried over Na 2 SO 4, filtered and concentrated. The residue is purified by HPLC eluting with a gradient of 10 to 100% CH3CN / 0.1% TFA in water for 30 minutes. The fractions containing a pure product are lyophilized to provide The title compound was in the form of a white solid, (0.02 g, 0.044 mmol). P NMR (CD3OD, 300 MHz) delta 8.25 (d, ÍH), 8.13 (s, ÍH), 7.97 (s, ÍH), 7.85 (m, 2H), 7.80 (AB, 2H), 7.48 (m, 2H) 6.80 (d, ••••, 4.64 (s, 2H), 4.35 (t, ÍH), 3.31 (m, 2H), 2.48 (m, ÍH), 5 1.89 (m, ÍH). Ion spray MS, [M + H] * = 453 EXAMPLE 39 [1- (l-Amino-isoquinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide 6-trifluoroacetate -ciorobenzo [b] thiophene-2-sulphonic • 10 A. 1-phenoxy-6-bromomethyl-isoquinoline To l-chloro-6-methyl-isoquinoline (2.28 g, 13.3 mmol), which is prepared in accordance with described in Example 1, part E, substituting 6-methyl-2H-isoquinolin-1-one for 7- methyl-2H-isoquinolin-1-one, 20 g of phenol are added. The The solution is heated to a temperature of 80 ° C and KOH is added (3.73 g, 66.4 mmol). After the addition, the solution is stirred and heated to a temperature of 140 ° C. After 24 hours, the solution is cooled to room temperature, and dissolved in CH2C12. The organic solution is washed with H20.

The organic layer is washed with IN NaOH and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The resulting residue is dissolved in 50 mL of CCL. To the resulting solution is added NBS (2.01 g, 11.27 mmol) and benzoyl peroxide (0.6 g, 1.73 mmol). The solution is heated to reflux. After 16 hours, the solution is diluted with CH.C12. The organic layer is washed with 10% Na 2 CO 3 and saturated NaCl. The organic layer is dried in MgSO, filtered and concentrated. The residue is purified by column chromatography eluting with 5% EtOAc / hexanes and 10% EtOAc / hexanes. MS, [M] + = 313, 315, standard Br. B. Tert-Butyl acid ester [1- (l-chloro-isoquinolin-6-ylmethyl) -2-oxoprolididin-3- (S) - il] -carbamic acid To a solution of tert-butyl ester of (2- * 10-oxopyrrolidin-3- (S) -yl) -carbamic acid (0.15 g, 0.64 mmol) in 6 L of 10: 1 THF: DMF at 0 ° C a 60% dispersion of NaH (0.03 g, 0.71 mmol) is added followed by 1-phenoxy-6-bromomethyl isoquinoline (0.2 g, 0.64 mmol). After 16 hours, the solution is treated with 10 mL of saturated NHC1. The solution is diluted with CH2C12. The organic layer is washed with H20 and saturated NaCl. The resulting product is suspended in 5 g of NH 4 OAC and heated to 120 ° C. After 36 hours, the solution is cooled to room temperature. The solution is diluted with H; and CH2C12. The organic layer is washed with H20 and NaCl saturated. The organic layer is dried in MgSO4 / filtered and concentrated. The residue is purified by column chromatography eluting with 5% MeOH / CH 2 Cl 2 at 10% MeOH / CH 2 Cl 2 to give the product as a white solid (0.043 g, 0.11 mmol). 25 XH NMR (CDCl 3, 300 MHz) delta 8.41 (d, ÍH), 7.98 (d, ÍH), 7.63 (s), ÍH), 7.42 (m, 3H), 7.32 (, 4H), 7.22 (m, 5H), 5.40 (bs, ÍH), 5.14 (s, 2H), 4.64 (AB, 2H), 4.30 (m, ÍH ), 3.24 (m, 2H), 2.66 (m, ÍH), 1.92 (m, ÍH). FAB MS, [M + H] "= 391. • C. [1- (l-amino-isoquinolin-6-ylmethyl) -2- 5-oxopyrrolidin-3- (S) -yl] -amide of 6-trifluoroacetate -chlorobenzo [b] thiophene-2-sulphonic acid To a solution of [l- (l-chloroisoquinolin-6-ylmethyl) -2-oxopyrrolidin-3-S) -yl] -carbamic acid benzyl ester ( 0.043 g, 0.11 mmol) in 4 mL of MeOH is added 10% by weight of • 10 Pd / C (0.02 g). The atmosphere above the reaction is replaced by hydrogen. After 16 hours, the solution is filtered through Celite and Celite washed with MeOH. The solution collected is concentrated. The resulting residue is dissolved in 3 mL of CH2Cl2: EtOAc (2: 1). To the solution added Et3N (0.03 g, 0.11 mmol) and 6-chlorobenzo [b] thiophenesulfonyl chloride (0.03 g, 0.11 mmol). After 4 hours, the solution is concentrated. The residue is purified by • RP-HPLC eluting with a gradient of 10% CH_, CN / H20 (0.1% TFA) to 80% CH2CN / H20 (0.1% TFA). The appropriate fractions with lyophilized to provide the title compound as a white solid. X NMR (DMSO-de, 300 MHz) delta 8.95 (bs, 3H), 8.71 (d, ÍH), 8.46 (d, ÍH), 8.24 (s, 1H), 8.04 (m, 2H), 7.71 (s, ÍH), 7.63 (d, ÍH), 7.52 (m, 2H), 7.12 (d, ÍH), 4.52 (AB, 2H), 4.28 (m, ÍH), 3.17 (m, 2H), 2.12 (m, ÍH) ), 1.67 (m, 1H). FAB MS, [M + H] t = 487, 489, Cl pattern. EXAMPLE 40 • [2-Oxo-l- (1, 2, 3, 4-tetrahydro-isoquinolin-5-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 6-chlorobenzoic acid, trifluoroacetate [b] thiophene-2-sulphonic A. [1- (1- (1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3-yl] tert-butyl ester] -carbamic acid To a solution of tert-butyl acid ester [l- (l-chloro- ^^ -isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid (0.48 g, 1.28 mmol ) in 50 mL of AcOH: MeOH (1: 1) is added 5% by weight of PtO; / C (0.1 g) The atmosphere on the reaction is replaced by hydrogen.After 16 hours, the solution is filtered through of Celite and washed Celite with MeOH The organic solution is concentrated to give the product as a white foam MS, [M + H] "= 346. B. Tert-butyl ester of 7- (3-) acid tert-butoxycarbonyl-amin-2-oxopyrrolidin-l-ylmethyl) -3,4-dihydro-lH-isoquinoline-2-carboxylic acid To a solution of acid tert-butyl ester or [1- (1- (1, 2, 3, 4-tetrahydro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid (0.54 g, 1.58 mmol) in 50 mL of CH2C12 is added triethylamine (0.66 mL, 4.73 mmol) and chloroformate benzyl (0.39 mL, 1.89 mmol). The solution is stirred for 16 hours. After this time, the solution is diluted with CH2C12. The organic solution is washed with H20 and saturated NaCl. The residue is purified by chromatography on • column eluting with 20% EtOAc / CH2Cl2 • 5 X NMR (CDC13, 300 MHz) delta 7.35 (m, 5H), 7.08 (d, ÍH), 7.02 (d, ÍH), 6.95 (s, ÍH), 5.14 ( s, 2H), 5.10 (m, ÍH), 4.58 (s, 2H), 4.38 (m, 2H), 4.16 (m, ÍH), 3.68 (m, 2H), 3.18 (dd, 2H), 2.78 (, 2H), 2.59 (m, ÍH), 1.81 (m, ÍH), 1.42 (s, 9H). FAB MS, [M + H] + = 480. # 10 C. Benzyl ester of 7- [3- (6-chloro-benzo [b] thiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] - 3,4-dihydro-lH-isoquinoline-2-carboxylic acid To a solution of benzyl ester of 7- (3-tert-butoxycarbonylamin-2-oxopyrrolidin-1-ylmethyl) -3, -dihydro-1H-15-isoquinoline-2 -carboxylic acid (0.347 g, 0.72 mmol) in 8 mL of CH2C12 is added 2 mL of TFA. After 4 hours, the solution is concentrated. The residue is dissolved in CH, C12 and Et3N (0.30 mL, • 2.17 mmol) and 6-chlorobenzo [b] thiophenesulfonyl chloride (0.23 g, 0.87 mmol) is added. After 16 hours, the solution is concentrated. The residue is purified by column chromatography eluting with 10% ETOAc / CH2Cl. The product (0.25 g, 0.51 mmol) was obtained as a white solid. P NMR (CDCI3, 300 MHz) delta 7.91 (s, ÍH), 7.80 (m, 2H), 7.42 (d, ÍH), 7.34 (m, 5H), 7.08 (d, ÍH), 6.96 (d, ÍH), 6.88 (s, ÍH), 5.10 (s, 2H), 4.58 (s, 2H), 4.34 (s, 2H), 3.83 (m, ÍH), 3.68 (m, 2H), 3.18 (m, 2H), 2.77 (m, 2H), 2.59 (m, ÍH), 2.08 (m, ÍH). • D. [2-Oxo-l- (1, 2, 3, 4-tetrahydro-5-isoquinolin-7-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 6-chloro-benzoic acid [b] thiophene-2-sulfonic acid 7- [3- (6-Chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxopyrrolidyl-l-ylmethyl] -3-benzyl ester is added, 4-dihydro-lH-isoquinoline-2-carboxylic acid (0.25 g, 0.51 mmol) 10 in 5 mL of 30% HBr / AcOH at a temperature of 0 ° C. The solution is stirred for 30 minutes. After this time, 30 mL of Et20 is added. The resulting solid is collected by filtration. The crude solid is purified by RP-GPLC eluting with a gradient of 10% CH3CN / H20 (0.1% TFA) 15 to 80% CH3CN / H20 (0.1% TFA). The appropriate fractions are lyophilized to provide the title compound as a white solid. : H NMR (DMSO-de, 300 MHz) delta 8.95 (bs, 2H), 8.63 (dH), 8. 24 (s, ÍH), 8.00 (m, 2H), 7.51 (dd, ÍH), 7.16 (d, ÍH), 7.06 20 (m, ÍH), 6.96 (s, ÍH), 4.27 (s, 2H), 4.16 (m, 3H), 3.30 (m, 2H), 3.05 (m, 2H), 2.92 (m, 2H), 2.08 (m, ÍH), 1.60 (; ÍH). FAB MS, [M + H] + = 476, 478, chlorine standard. EXAMPLE 41 [1- (4-chloro-lH-pyrrolo [3,2-c] pyridin-2-ylmethyl) -2- 25 oxopyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [ b] thiophene-2-sulfonic acid A. l-Benzenesulfonyl-4-chloro-lH-pyrrolo [3,2-c] pyridine Benzenesulfonyl chloride (3 mL, 23.5 mmol) is added dropwise to a solution of tetrabutylammonium hydrogen sulfate. (0.53 g, 1.56 mmol), sodium hydroxide (1.56 g, 38.9 mmol) and 4-chloro-lH-pyrrolo [3,2-c] pyridine (2.33 g, 15.6 mmol) (prepared in accordance with Rasmussen, MJ Heet Chem. 1992, 29, 359) in CH2C12. The mixture is stirred at room temperature for 4 hours, then diluted with CH2C1 and washed with a saturated solution of NH4C1 and brine. The organic layer is dried in MgSO, filtered and concentrated1. The crude product is purified by column chromatography eluting with 1% MeOH / CH 2 Cl 2 at 2% MeOH / CK: Cl 2 to give the title product (3.21 g, 11 ol) as a white solid. X NMR (CDC13, 300 MHz) delta 8.25 (d, ÍH), 7.92 (m, ÍH), 7.90 (d, ÍH), 7.83 (dd, ÍH), 7.60-7.66 (m, 2H), 7.51 (m, 2H9, 6.80 (dd, ÍH) MS, [M] "= 292, 294, Cl. Pattern. B. L-benzenesulfonyl-4-chloro-lH-pyrrolo [3, 2-c] pyridin ethyl ester -2-carboxylic acid Lithium diisopropylamide (3.2 mL of a 1.5 M solution in THF, 4.80 mmol) is added to a solution of tetramethylethylenediamine (0.71 mL, 4.75 mmol) and 1-benzenesulfonyl-4-chloro-lH-pyrrolo [3, 2-c] pyridine (1 g, 3.42 mmol) in THF (13 mL) The resulting yellow solution is stirred at -78 ° C for 1 hour, and then ethyl chloroformate is added dropwise ( 0.78 mL, 8.16 mmol) The mixture is brought slowly to room temperature over a period of 3.5 hours The reaction is quenched with a saturated solution of Na 4 Cl and then diluted with ethyl acetate.The organic layer is washed with brine, dried in MgSO4, filtered and concentrated to give a solid of light brown color (1.46 g) as the product that is started in the subsequent step without • 10 additional purification. X NMR (CDC13, 300 MHz) delta 8.30 (d, ÍH), 8.12 (d, 2H9, 8.03 (d, ÍH), 7.70 (m, ÍH), 7.55 (m, 2H), 7.30 (s, ÍH), 4.45 (q, 2H), 1.46 (t, 3H), FAB MS, [M + H] "= 365, 367, Cl. C. l-benzenesulfonyl-4-chloro-lH-pyrrolo standard [3, 2- c] pyridin-2-yl) -15 methanol Lithium aluminum hydride (3.4 mL of a 1 M THF solution) is added dropwise to a solution of ethyl acid ester. • 1-Benzenesulfoni-1-4-chloro-lH-pyrrolo [3,2-c] pyridine-2-carboxylic acid (1.46 g, 3.42 mmol) in THF (27 mL) at a temperature of 0 ° C. After stirring for 1.5 hours at 0 ° C, the reaction is quenched with H20 and then diluted with ethyl acetate. The organic layer is washed with a saturated solution of NH 4 Cl and brine and then dried over MgSO 4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 1% MeOH / CH 2 Cl 2 at 3% MeOH / CH 2 Cl 2 to give the title product (0.73 g, 2.42 mmol) as a white solid. LH NMR (CDC13, 300 MHz) delta 8.25 (d, ÍH), 8.85-8.95 (m, 3H9, 7.64 (m, ÍH), 7.51 (m, 2H), 6.80 (s, 1H), 4.97 (d, 2H ), 2.85 5 (t, ÍH) The MS, [M] t = 322, 324, pattern of Cl. D.1-benzenesulfoni1-2-bromomethyl-4-chloro-1H-pyrrolo [3.2. C] pyridine Carbon tetrabromide (0.939 g, 2.83 mmol) is added to a solution of triphenylphosphine (1485 g, 5.66 mmol) and 1- 10-benzenesulfonyl-4-chloro-lH-pyrrolo [3,2-c] pyridin-2-yl. ) -methanol (0.914 g, 2.83 mmol) in CH2C12 (12 mL) at 0 ° C. The resulting yellow solution is stirred for one hour at a temperature of 0 ° C and then warmed to room temperature over a period of 1 hour. The mixture of The reaction is concentrated and then purified by column chromatography eluting with 1% MeOH / CH2Cl2 to give the title product (0.760 g, 1.97 mmol) as a • white solid. : H NMR (CDCI3, 300 MHz) delta 8.27 (d, ÍH), 7.91-8.00 (, ÍH), 7.67 (m, HH), 7.51 (m, 2H), 6.95 (s, HH), 4.94 (s, 2H). FAM MS, [M + H] "= 385, 387, 389, standard Cl. E. Tert-butyl acid ester [1- (1-benzenesulfonyl-4-chloro-1H-pyrrolo [3, 2-c] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid. Sodium hydride (0.081 g, 2.02 mmol, dispersion in 60% mineral oil) is added to a solution of tert-butyl ester of [2-oxopyrrolidin-3- (S) -yl] -carbamic acid (0.404 g, 2.02 mmol) in DMF (5 mL) at a temperature of 0 ° C. The mixture is • stirred for 10 minutes, then added through a cannula dropwise to a solution of l-benzenesulfonyl-2-bromomethyl-4-chloro-lH-pyrrolo [3,2-c] pyridine (0.74 g, 1.92 mmol ) in DMF (10 L) at a temperature of 0 ° C. The resulting yellow solution is stirred for 1 hour at 0 ° C, and then quenched with a saturated solution of sodium chloride. # 10 ammonium and diluted with EtOAc. The organic layer is washed with water and brine, then dried over MgSO4, filtered and concentrated. The solid product (0.94 g, 1.86 mmol) is used in the subsequent step without further purification. : H NMR (CDC13, 300 MHz) delta 8.25 (d, ÍH), 7.98 (m, 2H), 7.83 (d, ÍH), 7.68 (m, ÍH), 7.50 (m, 2H), 6.70 (s, 1H), 4.95 (AB, 2H), 4.20 (m, ÍH), 3.55 (m, 2H), 2.65 (m, ÍH), 2.03 (m, ÍH), 1.45 (s, 9H). FAB MS, [M + H] "= 505, 507, Cl standard. • F. 3- (S) -amino-1- (l-benzenesulfonyl-4-chloro-lH-pyrrolo hydrochloride [3, 2- c] pyridin-2-ylmethyl) -pyrrolidin-2-one The title compound is prepared according to that described in Example 1, part I using [1- (1-benzenesulfonyl-4-tert -butyl] -s-tert-butyl ester. chloro-lH-pyrrolo [3, 2-c] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid instead of tert-butyl ester of [1- (1-chloro -isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid and with stirring for 2 hours at a temperature of 0 ° C without heating to room temperature X NMR (CDC13, 300 MHz) delta 8.50 (d, ÍH), 8.28 (d, ÍH), 8.04 (m, 2H), 7.82 (m, ÍH), 7.65 (m, 2H), 6.83 (s, ÍH), 4.93 (s, 2H), 4.20 (, ÍH), 3.51 (, 2H), 2.41 (m, ÍH), 2.01 (m, ÍH), FAB MS, [M + H] + = 405, 407, pattern of Cl. G. [1- (1 -benzenesulfonyl- -chloro-lH-pyrrolo [3, 2-c] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 6-Chloro-benzo [b] thiophene-2-sulfonic acid The title compound is prepared according to that described in Example 1 part K, using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride and hydrochloride of 3-amino-1- (1-benzenesulfonyl-4-chloro-lH-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-2-one as starting material. The crude product is purified by column chromatography eluting with a gradient of 1% MeOH / CH 2 Cl 2 at 3% MeOH / CH: Cl 2 'to provide the product as a white solid. X NMR (CDCl 3, 300 MHz) delta 8.23 (d, ÍH), 7.96 (d, 1H), 7.90 (s, ÍH), 7.70-7.88 (, 3H), 7.55-7.61 (m, 2H), 7.40- 7.50 (, 3H), 6.51 (s, ÍH), 5.45 (bs, ÍH), 4.86 (s, 2H), 3.98 (m1, ÍH), 3.41 (m, 2H), 2.70 (m, 1H9, 2.18 (m , HH) FAB MS, [M + H] + = 635, 637, standard Cl. H ^ [1- (4-chloro-lH-pyrrolo [3,2-c] pyridin-2-ylmethyl) -2 6-chloro-benzo [b] thiophene-2-sulfonic acid-oxopyrrolidin-3- (S) -yl] -amide Ammonia gas is bubbled for 5 minutes in the solution of [1- (1-benzenesulfonyl-4-chloro -lH-pyrrolo [3,2-c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 6-oloro- • benzo [b] thiophen-2-sulfonic acid (0.14) g, 0.22 mmol) in MeOH (10 5 mL) The solution is refluxed overnight and then concentrated to dryness The crude product is purified by column chromatography eluting with 5% MeOH / CH2Cl2 to give the product (0.065 g, 0.13 mmol) as a white solid, 10 X NMR (DMSO-d6, 300 MHz) delta 11.95 (bs, ÍH), 8. 71 (d, ÍH), 8.30 (s, ÍH), 8.05 (m, ÍH), 7.91 (d, ÍH), 7.50 (d, ÍH), 7.35 (d, ÍH), 6.40 (s, ÍH), 4.50 (AB, 2H), 4.23 (, ÍH), 3.23 (m, 2H), 2.41 (m, ÍH), 1.78 (, ÍH). Ion spray MS, [M + H] * = 495, 497, Cl pattern. EXAMPLE 42 [2-oxo-l- (lH-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [b] thiophene-2-sulphonic palladium on carbon (0.01 g) is added to the solution of [1- (4-chloro-lH-pyrrolo [3,2- c] pyridin-2-ylmethyl) -2-oxopyridine-20 3- (S) -yl] -amide of 6-chloro-benzo [b] thiophene-2-sulfonic acid in 95% ethanol (5 mL) and charged with H2 gas. The mixture is heated to a temperature of 65 ° C overnight and I then cooled overnight and filtered through Celite The solvent is removed and the finished product is purified by RP-HPLC eluting with a gradient of 10% CH-_CN / H20 (0.1% TFA) to 100% CH3CN. The appropriate product fractions are lyophilized to provide the title compound as a white solid. • P NMR (DMSO-de, 300 MHz) delta 14.60 (bs, ÍH), 12.70 (bs, 5 ÍH), 9.15 (s, ÍH), 8.71 (d, ÍH), 8.38 (d, ÍH), 8.29 ( s, ÍH), 8.08 (s, ÍH), 8.00 (d, ÍH), 7.85 (d, ÍH), 7.52 (dd, ÍH), 6.88 (s, ÍH), 4.63 (AB, 2H), 4.21 (m , ÍH), 3.25 (, 2H), 2.10 (, ÍH), 1.75 (m, 1H). Ion Spray MS, [M + H] + = 461, '463, Cl. Standard. 10 EXAMPLE 43 [2-Oxo-l- (lH-pyrrolo [3,2-b] pyridin-2-ylmethyl trifluoroacetate] ) -pyrrolidin-3- (S) -yl] -amide of 7- methoxynaphthalene-2-sulfonic acid A.5-Chloro-lH-pyrrolo [3,2-b] pyridine 15 A mixture of pyrrolo [3, 2- b] pyridin-5-one (prepared according to the procedure described in J. Med. Chem. 1990, 33, 2087) (1.33 g, 9.91 mmol) and 20 L of phosphorus oxychloride are heated in a stainless steel vessel High pressure Parr sealed at a temperature of 180 ° C during 2.5 hours. After cooling, the excess phosphorus oxychloride is removed under vacuum. The residue is cooled in an ice bath and quenched with ice water. The resulting mixture is neutralized by adding a saturated solution of NaHCO 3 and extracted with EtOAc (3 times). The organic layers combined with dried MgSO4, filtered and concentrated in vacuo. The crude product (1.07 g, 7.01 mmol) is employed in the subsequent step without further purification. X NMR (CDC13 + CD3OD, 300 MHz) delta 7.71 (d, ÍH), 7.49 (d, • ÍH), 7.10 (d, ÍH), 6.59 (d, ÍH). MS, [M] + = 152, 154, 5 standard Cl. B. 1-Benzenesulfonyl-5-chloro-lH-pyrrolo [3,2-b] pyridine The title compound is prepared from 5-chloro -lH- pyrrolo [3, 2-b] pyridine in accordance with that described in example 41, part A. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc / hexanes at 20% EtOAc / hexanes to provide the title compound as a solid. X NMR (CDCl3, 300 MHz) D 8.23 (d, 1H9, 7.87 (d, 2H), 7.81 (d, ÍH), 7.632 (m, 1H9, 7.49 (m, 2H), 7.26 (d, 1H9, 6.81 ( d, ÍH).

C. Tert-butyl ester of l-benzenesulfonyl-5-chloro-lH-pyrrolo [3,2-b] pyridine-2-carboxylic acid The title compound is prepared from 1- • benzenesulfonyl-5-chloro- lH-pyrrolo [3, 2-b] pyridine in accordance with that described in example 41, part 3.

The crude product is purified by chromatography on citium eluting with a gradient of 10% EtOAc / hexanes at 33% EtOAc / hexanes to give the title compound as a solid. X H NMR (CDCl 3, 300 MHz) delta 8.41 (d, 1 H 9, 8.04 (d, 2 H), 7.66 (m, ÍH), 7.55 (m, 2H), 7.37 (d, ÍH), 7.21 (s, ÍH), 4.41 (q, 2H), 1. 40 (t, 3H). The MS, [M] + = 364, 366, Cl pattern. D. (l-Benzenesulfonyl-5-chloro-lH-pyrrolo [3,2- b] pyridin-2-yl) methanol The title compound is prepared from ethyl ester 5-l-benzenesulfonyl-5-chloro-lH- pyrrolo [3, 2] pyridine-2-carboxylic acid according to that described in example 41, part C. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc / hexanes at 50% EtOAc / hexanes to provide the title compound in the form of a solid. X NMR (CDC13, 300 MHz) delta 8.30 (d, ÍH), 7.81 (d, 2H), 7.63 (m, ÍH), 7.50 (m, 2H), 7.25 (d, ÍH), 6.80 (s, ÍH) , 4.97 (s, 2H), 2.99 (bs, ÍH). The MS, [M] t = 322, 324, Cl pattern. E.1-benzenesulfonyl-2-bromomethyl-5-chloro-lH-pyrrolo [3,2- 15 b] pyridine To a solution of (l-benzenesulfonyl-5-chloro-lH-pyrrolo [3, 2-b] pyridine -2-il) -methanol (0.156 g, 0.50 prmol) in 4 mL of • Et20 / CH2C12 (1: 1) at a temperature of 0 ° C is added phosphorus tribromide (0.023 mL, 0.25 mmol) dropwise. HE keeps the reaction vessel in the dark and is stirred at a temperature of 0 ° C for 1 hour, then at room temperature for 2 hours. The mixture is diluted with water and EtOAc and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with water, saturated NaHCO3 solution, and a saturated solution of NaCl, and then dried over MgSO4, filtered and concentrated. The crude product (0.16 g, 0.41 mmol) is used in the subsequent step without further purification. • X NMR (CDC13, 300 MHz) delta 8.83 (d, 1H), 7.87 (d, 2H), 7.64 5 (m, 1H9, 7.50 (m, 2H), 7.28 (d, ÍH), 6.93 (s, ÍH) ), 4.96 (s, 2H) F. [1- (l-Benzenesulfonyl-5-chloro-lH-pyrrolo [3,2- b] pyridin-2-ylmethyl) -2-oxop [beta] -tert-butyl acid ester rrolidin-3- (S) -yl] -carbamic acid ^ The title compound is prepared from (2-oxopyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester in accordance with that described in Example 1, part H using 1-benzenesulfoni1-2-bromomethyl-5-chloro-lH-pyrrolo [3,2-b] pyridine in place of 7-bromomethyl-1-chloro-isoquinoline The crude product is purified by column chromatography eluting with a gradient of 15% EtOAc / hexanes at 50% EtOAc / hexanes to give the title compound as a beige solid X NMR (CDCl 3, 300 MHz) delta 8.36 (d, 1H), 7.80 (d, 2H), 7.64 (m, ÍH), 7.50 (m, 2H), 7.25 (s, ÍH), 6.58 (s, ÍH), 5.13 (bs, ÍH), 4.93 (AB, 2H), 4.22 (, ÍH), 3.39 ( m, 2H9, 2.66 (m, HH), 1.95 (m, HH), 1.46 (s, 9H) G. 3- (S) -amino-1- (1-benzenesulfonyl-5-chloroH-) hydrochloride pyrrolo [3, 2-b] pyridin-2-ylmethyl) -pyrrolidin-2-one The title compound is prepared according to that described in Example 1, part I using tert-butyl acid ester [1-] (l-Benzenesulfonyl-5-chloro-lH-pyrrolo [3,2- b] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3- (S) -i] -l-carbamic acid as starting material. The title is obtained in the form of a white solid: H NMR (DMSO-de, 300 MHz) delta 8.51 (bs, 2H), 8.42 (d, ÍH), 8.00 (d, 2H), 7.78 (, ÍH), 7.64 (m, 2H9, 7.41 (d, ÍH), 6.96 (s, ÍH), 4.90 (AB, 2H), 4.16 (m, ÍH), 3.49 (, 2H), 2.47 (, ÍH), 2.10 (m, ÍH). ^ 10 H. [1- (l-Benzenesulfonyl-5-chloro-lH-pyrrolo [3,2- b] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of acid, 7- methoxy Naphthalene-2-sulfonic acid The title compound is prepared according to that described in Example 1, part K using 7- 15-methoxy-naphthalene-2-sulfonyl chloride and 3- (S) -amino-1- (1-) hydrochloride. benzenesulfonyl-5-chloro-lH-pyrrolo [3, 2-b] pyridin-2-ylmethyl) -pyrrolidin-2-one as starting materials. He • Crude product is used in the subsequent step without further purification. XH NMR (CDC13, 300 MHz) delta 8.37 (s, ÍH, 8.34 (d, ÍH), 7.92 (d, 1H9, 7.79 (m, 2H), 7.72 (m, 2H), 7.58 (m, ÍH), 7.45 (m, 2H), 7.31 (dd, ÍH), 7.24 (m, 2H), 6.48 (s, ÍH), 5.42 (s, ÍH), 4.85 (s, 2H), 3.96 (s, 3H), 3.76 (m, ÍH), 3.34 (m, 2H) 4 2.63 (, ÍH), 2.10 (m, ÍH). 25 I. [1- (5-chloro-lH-pyrrolo [3,2-b] pyridin-2 -ylmethyl) -2- oxopyrrolidin-3- (S) -yl] -amide of 7-methoxy-naphthalen-2-sulfonic acid The title compound is prepared from [1- (1- (benzenesulfonyl-5-chloro -lH-pyrrolo [3, 2-b] pyridin-2-ylmethyl) -2- 5-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene-2-sulfonic acid in accordance with that described in the example 41, part H. The crude product is purified by column chromatography eluting with a gradient of 1 ~: MeOH / CH2Cl2 at 6% MeOH / CH2Cl2 to provide the title compound in the form i ^ r 10 of a solid .X NMR ( CDC13, 300 MHz) delta 9.73 (bs, ÍH), 8.35 (s, ÍH), 7.70 (m, 3H), 7.49 (d, ÍH), 7.30 (dd, ÍH) , 7.20 (m, ÍH) ', 6.99 (d, ÍH), 6.75 (bs, ÍH), 6.48 (s, ÍH), 4.58 (m, 2H), 3. | 93 (, 1H), 3.90 (s, 3H), 3.35 (m, 2H), 2.48 (m, ÍH), 2.08 (m, ¡ÍH). J. [2-Oxo-l- (lH-pyrrolo [3,2- b] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 7- methoxynaphthalene-2-trifluoroacetate. sulphonic • Prepare the title compound from [1- (5? chloroH-pyrrolo [3,2- b] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (ls) -20 yl] - 7-methoxynaphthalene-2-sulfonic acid amide according to that described in example 42, at room temperature, using a catalytic amount of KOH in MeOH / benzene (1: 1) instead of EtOH solvent. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN / H2O (0.1% TFA) to 70% CH3CN / H20 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid. • X NMR (DMSO-de, 300 MHz) delta 12.65 (bs, ÍH), 8.60 (bs, ÍH), 5 8.43 (d, ÍH), 8.39 (s, ÍH), 8.26 (d, ÍH), 8.03 ( d, ÍH), 7.94 (d, ÍH), 7.71 (dd, ÍH), 7.56 (m, 2H), 7.32 (dd, ÍH), 6.80 (s, ÍH), 4.66 (AB, 2H), 4.17 (m , ÍH), 3.88 (s, 3H), 3.20 (m, 2H), 2.00 (m, ÍH), 1.60 (m, ÍH). FAB MS, [M + H] "= 451. EXAMPLE 44 ^ 10 (1-furo [3, 2-b] pyridin-2-ylmethyl-2-oxopyrrolid-n-3- (S) -yl) -amide of 6-chloro-benzo [b] thiophene-2-sulfonic acid A. Tert-butyl acid e (2-oxo-l-prop-2-in? l-pyrrole? din-3- (S) -yl) - The title compound is prepared from tert-butyl e of (2-oxopyrrolidin-3- (S) -yl) -carbamic acid in accordance with that described in Example 1, part H using propargyl bromide in place of 7-bromomethyl-l-chloro-isoquinoline The crude product is triturated from Et20 / hexanes to give the title compound in the form of a white solid X NMR (CDC13, 300 MHz) delta 5.09 (bs, 1H9) , 4.19 (m, ÍH), 4.15 (, 2H), 3.45 (m, 2H), 2.69 (m, ÍH), 2.29 (t, ÍH), 1.91 (m, 1H), 1.48 (s, 9H). Tert-butyl acid e (1-furo [3,2-b] pyridin-2-ylmethyl-2-oxopyrrolidin-3- (S) -yl) -carbamic acid A mixture of 2-iodo-3-hydroxy- pyridine (0.44 g, 2 mmol), acid tert-butyl e (2-oxo-l-prop-2-ynyl-pyrrolidin-3- (S) -yl) -carbamic acid (0.6 g, 2.5 mmol), bis (triphenylphosphine) -palladium (II) chloride (Pd (PPh3) 2C12) (50 mg), copper iodide (25 mg) and triethylamine (3 mL) in 3 mL of acetonitrile is heated in a sealed tube at a temperature of 120 ° C for 2 hours. After cooling, the reaction mixture is diluted with water and EtOAc and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and a saturated solution of NaCl, then dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 25% EtOAc / CH2Cl? to 90% EtOAc / CH2Cl2 to provide the title compound as a white solid. X NMR (CDC13, 300 MHz) delta 8.53 (d, 1H9, -7.72 (dd, ÍH), 7.21 (dd, ÍH), 6.86 (s, ÍH), 5.15 (bs, ÍH), 4.69 (AB, 2H) , 4.23 (m, 1H), 3.38 (m, 2H), 2.66 (m, ÍH), 1.91 (m, ÍH), 1.45 (s, 9H) C. Hydrochloride of 3- (S) -amino-1- (furo [3, 2-b] pyridin-2-ylmethyl) -pyrrolidin-2-one The title compound is prepared according to that described in Example 1, part I using tert-butyl acid e (1-furo). [3, 2-b] pyridin-2-ylmethyl-2-oxopyrrolidin-3- (S) -yl) -carbamic acid as starting material The title compound is obtained as a tan solid. ': H NMR (DMSO-ds, 300 MHz) delta 8.70 (bs, 2H), 8.65 (d, ÍH), • 8.35 (d, ÍH), 7.58 (dd, ÍH), 7.28 (s, ÍH), 4.77 (s, 2H), 4.10 5 (m, ÍH), 3.47 (m, 2H), 2.41 (m, ÍH) , 2.09 (, ÍH). 6-chloro-benzo [b] thiophene-2-sulfonic acid (1-furo [3, 2-b] pyridin-2-ylmethyl-2-oxopyrrolidin-3- (S) -yl) - is prepared the title compound according to that described in Example 1, part K using 6-f 10 chloro-benzo [b] thiophene-2-sulfonyl chloride and 3- (S) -amino-1- (furo [ 3, 2-b] pyridin-2-ylmethyl) -pyrrolidin-2-one as starting material. The crude product is purified by column chromatography eluting with a gradient of 25% EtOAc / CH 2 Cl 2 at 90% EtOAc / CHCl 2 to provide the compound of the title in the form of a white solid. X NMR (CDCI3 + CD3OD, 300 MHz) delta 8.49 (bs, ÍH), 7.92 (s, ÍH), 7.85 (s, ÍH), 7.81 (d, ÍH), 7.77 (d, ÍH), 7.41 (dd, ÍH), 7.24 (m, 1H), 6.85 (s, ÍH), 4.63 (AB, 2H), 4.03 (, ÍH), 3.41 (m, 2H), 2.63 (m, ÍH), 2.16 (m, ÍH) ). FAB MS, [M + H] "= 462, 464, pattern of Cl. EXAMPLE 45 (1-furo [3, 2-b] pyridin-2-ylmethyl-2-oxopyrrolidin-3- (S) -yl) -amide 6-chloro-benzo [b} thiophene-2-sulfonic acid A. 1-fluoro-3- (2,2-dimethoxy-ethyl-sulfanyl) -benzene The title compound is prepared according to that described in example 9, part A replaces 3-fluorothiophenol by 3-chlorothiophenol. The crude product is purified by column chromatography eluting with a • gradient of hexanes to 10% EtOAc / hexanes to give the title compound as an oil. ! H NMR (CDC13, 300 MHz) delta 7.21 (m, ÍH), 7.09 (m, 2H), 6.82 (m, 2H), 4.51 (m, ÍH), 3.09 (s, 31H), 3.07 (s, 3H ). B. 6-Fluoro-benzo [b] thiophene The title compound is prepared in accordance with ^ 10 described in Example 9, part B substituting l-fluoro-3- (2, 2-dimethoxy-ethyl-sulfanyl) -benzene for l-chloro-3- (2, 2-dimethoxy-ethyl-sulfanyl-benzene. The crude product is purified by column chromatography eluting with hexanes to give the title compound as a solid. white. MS, [M] + = 152. C. 6-Fluoro-benzo [b] thiophene-2-sulfonyl chloride • Prepare the title compound according to that described in Example 8, part A substituting 6-chloro - 20 benzo [b] thiophen by tianaphthalene. The crude product is purified by column chromatography eluting with hexanes to give the title compound as a white solid. : H NMR (CDCl 3, 300 MHz) delta 8.08 (s, ÍH), 7.94 (dd, ÍH), 7.58 (dd, ÍH), 7.23 (dt, ÍH).

D. (l-furo [3, 2-b] pyridin-2-ylmethyl-2-oxopyrrolidin-3- (S |) - i 1) - 6-fluoro-benzo [b] thiophene-2-sulfonic acid amide Prepared the title compound in accordance with • described in Example 1, part K using ide-5-fluoro-benzo [b] thiophene-2-sulfonyl chloride and! 3- (S) -amino-1- (furo [3,2-b] pyridine hydrochloride] -2-ylmethyl) -pyrrolidin-2-one as initial material. The crude product is purified by column chromatography eluting with 66% EtOAc / CH; Cl¿ to provide the title compound as a solid • 10 white. X NMR (CDCI3, 300 MHz) delta 8.46 (m, ÍH), 7.96 (s, ÍH), 7.91 (m, ÍH), 7.77 (d, ÍH), 7.58 (m, ÍH), 7.44 (s, ÍH) , 7.29 (m, 2H), 6.86 (s, ÍH), 4.65 (s, ÍH), 4.14 (m, ÍH), 3.42 (mj, 2H), 2.58 (m, ÍH), 2.09 (m, ÍH). FAB MS, [M + H] "= 446. EXAMPLE 46 [2-Oxo-l- (lH-pyrrolo [3,2- b] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -trifluoroacetate 6-chloro- • benzo [b] thiophene-2-sulfonic acid amide. 2-iodo-3-nitro-pyridine 20 To a solution of 2-amino-3-nitro-pyridine (8 g, 57.5 mmol) in 60 mL of 6N HCl cooled to 0 ° C is added dropwise a solution of sodium nitrite (6.35 g, 92 mmol) in 40 mL of water.The mixture is stirred at 0 ° C for 1.5 hours. add a solution of potassium iodide (22.9 g, 138 mmol) in 40 ml of water dropwise to the yellow solution. The resulting red mixture is stirred at a temperature of 0 ° C for 30 minutes and then heated to a temperature of 60 ° C for 45 minutes. After the • cooling, it becomes basic mixture by addition careful 3N NaOH. The aqueous layer is extracted with CH2C12 (4x) and the combined organic layers are washed with HC1 1N, Na; S03 diluted, and water. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude product (2.72 g, . 9 mmol) is used in the subsequent step without purification ^ 10 additional. X NMR (CDC13, 300 MHz) delta 8.65 (d, 1H), 8.25 (dd, 1H), 7. 48 (m, ÍH). IS MS, [M + H] + = 251. B .3-amino-2-iodo-pyridine To a solution of 2-iodo-3-nitro-pyridine (2.72 g, 10.9 mmol) In a concentrated solution of 10 ml of concentrated HCl, a solution of tin (II) chloride dihydrate (10.3 g, 45.7 mmol) in 12 mL of water is added dropwise. Concentrated HCl. The mixture is heated to • a temperature of 90 ° C for 15 minutes. The resulting mixture of red color is cooled to a temperature of 0 ° C and stirred for 2 hours during said period a precipitate forms. The solid is filtered, dissolved in water, and made basic by the addition of IN NaOH. The organic layer is extracted with CH2C12 (4x) and the combined organic layers are dried in MgSO4, filtered and concentrated in empty. The crude product (1.5 g, 6.82 mmol) is used in the subsequent step without further purification. : H NMR (CDCl 3, 300 MHz) delta 7.81 (m, 1H), 7.07 (m, 2H), 4.05 (bs, 2H). IS MS, [M + H] "= 221. • C. Tert-Butyl ester of (2-iodo-pyridin-3-yl) -5-carbamic acid Ethyl chloroformate (0.91 mL, 9.5 mmol) is added to a solution of 3-amino-2-iodo-pyridine (1.4 g, 6.36 mmol) in 15 mL of pyridine cooled to 0 ° C. The mixture is stirred at a temperature of 0 ° C for 2 hours and allowed to warm slowly at room temperature. At this time, excess pyridine is removed in vacuo. The residue is diluted with EtOAc and washed with water, IN HCl and saturated NaHCO 3. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by chromatography on Column eluting with 30% EtOAc / hexanes to give the title compound (1.2 g, 4.11 mmol) as a beige solid. X NMR (CDCl 3, 300 MHz) delta 8.51 (d, 1H), 8.07 (dd, ÍH), 7.25 (dd, ÍH), 7.1-6 (bs, ÍH), 4.28 (q, 2H), 1.38 (t, 3H) '. 20 D. 2- (3- (S) -tert-Butoxycarbonylamin-2-oxopyrrolidin-1-ylmethi) -pyrrolo [3,2- b] pyridine-1-carboxylic acid tert-butyl ester A mixture of ethyl ester (2-iodo-pyridin-3-yl) -carbamic acid (0.6 g, 2.05 mmol), tert-butyl acid ether (2-25 oxo-l-prop-2-ynyl-pyrrolidin-3- (S) - il) -carbamic acid (0.49 g, 2.05 mmol), Pd (PPh3) 2C12 (72 mg), copper iodide (12 g) and triethylamine (1.1 mL) in 4 mL of acetonitrile is heated in a sealed tube at a temperature of 100 ° C for 18 years. After cooling, the reaction mixture is diluted with MeOH and filtered through a pad of Celite. The filtrate is concentrated in vacuo. The residue is diluted with EtOAc and washed with water (4x). The combined aqueous layers are extracted with EtOAc (2x). The combined organic layers are washed with water, then dried over MgSO4, filtered and concentrated to provide the crude intermediate coupled with acetylene. IS MS, [M + H] ~ = 403. The crude acetylene intermediate is dissolved in 16 mL of DMF and treated with 1,8-diaza-bicyclo [5.4.0] undec-7-ene (DBU) '( 0.58 mL, 4.1 mmol). The mixture is heated to a temperature of 60 ° C for 2 hours. After cooling, the resulting mixture is diluted with water and EtOAc and the layers are separated. The organic layer is washed with water and then dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with 90% EtOAc / CH2Cl2 to provide the title compound (0.07 g, 0.22 mmol) as a beige solid. P NMR (CDC13, 300 MHz) delta 8.51 (d, ÍH), 8.35 (d, ÍH), 7.21 (dd, ÍH), 6.60 (s, ÍH), 5.34 (bs, ÍH), 4.95 (AB, 2H) , '4.55 (q, 2H), 4.30 (m, ÍH), 3.48 (m, 2H), 2.70 (m, ÍH), 2.05 (m, HI), 1.50 (t, 3H), 1.46 (s, 9H). IS MS, [M + H] + = 403.

E. 2- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -pyrrolo [3, 2-b] pyridine-1-carboxylic acid ethyl ester hydrochloride The title compound of conformity is prepared cpn described in Example 1, part I using, ethyl ester of 2- (3- (S) -tert-Butoxycarbonylamin-2-oxopyrrolidin-1-ylmethyl) -pyrrolo [3,2-b] pyridine-1-carboxylic acid as starting material. The title compound is obtained in foOrma from a beige solid. P NMR (DMSO-d6, 300 MHz) delta 8.70 (m, ÍH), 3.58 (m, 4H), ~ 10 7.50 (, ÍH), 6.91 (s, ÍH), 4.91 (, 2H), 4.51 (q, 2H), '4.01 (m, ÍH), 3.50 (m, 2H), 2.48 (m, ÍH), 2.10 (, ÍH), 1.43 (t, 3H). F. 2- [3- (S) - (6-Chloro-benzo [bl-thiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -pyrrolo [3,2- 15 b] pyridinyl ethyl ester 1-carboxylic acid The title compound is prepared according to that described in Example 1, part K using 6-chloro- • benzo [b] thiophene-2-sulfonyl chloride and 2- (3- (2-ethyl) ethyl ester hydrochloride. S) -tamino-2-oxopyrrolidin-1-ylmethyl-pyrrolo [3,2- 20 b] pyridine-l-carboxylic acid as the starting material, purify the crude product by column chromatography eluting with 60% EtOAc / CH 2 Cl 2 for give the title compound as a solid: X NMR (CDC13, 300 MHz) delta 8.49 (d, ÍH), 8.30 (d, ÍH) J 7.90 (s, ÍH), 7.78 (s, ÍH), 7.75 (d, ÍH), 7.48 (dd, ÍH), 7.20 (d, ÍH), 6.88 (bs, ÍH), 6.49 (s, ÍH), 4.81 (AB, 2H), 4.4.9 (q, 2H), 4.13 (m, ÍH), 3.39 (m, 2H), 2.61 (m, ÍH), 2.13 (m,? ÍH), 1.45 (t, 3H) . • G. [2-Oxo-l- (lH-pyrrolo [3, 2-b] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 6-chlorobenzo [trifluoroacetate]. b] thiophene-2-sulfonic acid To a solution of 2- [3- (S) - (6-chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -pyrroloic acid ethyl ester. [3, 2-b] pyridine-l-carboxylic acid (0.03 g, 0.06 mmol) in 3 • 10 mL of MeOH is added 4 drops of a solution of NaOH ION. The mixture is stirred at room temperature for one hour. The crude mixture is purified by RP-HPLC eluting in a gradient of 10% CH3CH / H20 (0.1% TFA) to 80% CH3CN / H; 0 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound (0.015 g, 0.026 mmol) as a white solid. P NMR (DMSO-ds, 300 MHz) delta 8.72 (d, 1H9, 8.58 (bs, ÍH), 8. 41 (d, ÍH), 8.27 (d, ÍH), 8.05 (s, ÍH), 8.02 (d, ÍH), 7.55 (m, 2H), 6.69 (bs, ÍH), 4.68 (AB, 2H), 4.25 (m, ÍH), 3.30 (m, 2H), 2.20 (, ÍH), 1.73 (m, ÍH). IS MS, [M + H] "= 461, 463, Cl pattern. Elemental analysis calculated with 1.6 mol of H20 calculated C = 43.76%, H = 3.54%, N = 9.28%, found C = 43.76%, H = 2.98%, N = 8.95%. EXAMPLE 47 25 [2-Oxo-l- (lH-pyrrolo [2, 3-c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide of 6-chloro-benzo [ b] thiophene-2-sulphonic A. 3- (S) -amino-l-prop-inyl-pyrrolidin-2-one hydrochloride The title compound of conformity cpn is prepared as described in Example 1, part I employing ester tert-butyl acid (2-oxo-l-prop-e-inyl-pyrrolidin-3- (S), - il) -carbámico as initial material. The title compound is obtained in the form of a beige solid. X NMR (CDC13 + DMSO-ds, 300 MHz) delta 8.75 (bs, 3H), 4.15 (AB, 2H), 3.90 (m, ÍH), 3.53 (m, 2H), 2.76 (t, ÍH), 2.59 ( m, 1H9, 2.19 (m, HH) B. (2-oxo-l-prop-2-ynyl-pyrrolidin-3- (S) -yl) -amide of 6-chloro-benzo [b] thiophene 2-sulphonic The title compound is prepared according to that described in Example 1, Part K using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride and 3- (S) -amino-1-hydrochloride. prop-2-ynyl-pyrrolidin-2-one as starting material The crude product is isolated in the form of a beige foam and used in the subsequent step without further purification X NMR (CDCl 3, 300 MHz) delta 7.90 (s, ÍH), 7.85 (s, ÍH), 7.80 (d, ÍH), 7.41 (dd, ÍH), 5.53 (bs, ÍH), 4.11 (AB, 2H), 3.91 (, ÍH), 3.42 (m, 2H ), 2.70 (m, ÍH), 2.27 (t, ÍH), 2.Í5 (m, ÍH) C. tert-Butyl ester of (4-iodo-pyridin-3-yl) -carbamic acid To a solution of tert-butyl acid ester (pyridin-3-yl) -carbamic acid (prepared in accordance with p procedure described in Tetrahedron Let t. 1994, 35, 9003) (2.2 g, 11.3 • mmol) in 20 mL of THF at a temperature of -78 ° C is added dropwise t-BuLi (15.4 mL of a 1.7 M solution in peritano, 26 mmol). After 15 minutes, the solution is heated at -10 ° C for 3 hours. The mixture is cooled to | a temperature -78 ° C and a solution of iodine (5.7 g, 22.4 mmol) in 20 L of THF is added through a syringe. The The resulting mixture is stirred at a temperature of -78 ° C for 1 hour, and then allowed to warm to room temperature and quenched with a saturated NH 4 Cl solution. The aqueous layer is extracted with EtOAc (2x). The organic layers combined with washed with IN HCl, water, Na2S20s diluted, saturated NaHC? 3, and saturated NaCl. The organic layer is then dried over MgSO4, filtered and concentrated. The crude product is purified by chromatography on cplumna eluting with a gradient of 5% EtOAc / CH 2 Cl 2 a 20% EtOAc / CH 2 Cl 2 to give the title compound (1.3 g, 4.06 mmol) in the form of a brown solid. X NMR (CDCl 3, 300 MHz) delta 19.17 (s, ÍH), 7.92 (d, ÍH), 6.69 (bs, ÍH), 1.58 (s, 9H). MS, [M] + = 320. D. 2- [3- (S) - (6-Chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl tert-butyl ester. ] - 25 pyrrolo [2, 3-c] pyridine-1-carboxylic acid A mixture of (4-iodo-pyridin-3-yl) -carbamic acid tert-butyl ester (0.85 g, 2.65 mmol), (2 6-Chloro-benzo [b] thiophene-2-sulfonic acid oxo-l-prop-2-ynyl-pyrrolidin-3- (S) -yl) (0.98 g, 2.65 mmol), Pd (PPh3) 2 Cl 2 (95 mg), copper iodide (18 mg) and triethylamine (1.45 mL) in 8 Ml of DMF at a temperature of 100 ° C for 1.5 hours. The reaction mixture is cooled to a temperature of, 50 ° C and DBU is added. The resulting mixture is heated to a temperature of 50 ° C for 1.5 hours. After cooling, the crude mixture is diluted with EtOAc and washed with a saturated solution of NH 4 Cl, water and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 1% MeOH / CH 2 Cl: at 4% MeOH / | cH 2 Cl 2 to give the title compound (0.73 g, 1.3 mmol) as a tan solid. X NMR (CDC13, 300 MHz) delta 9.28 (s, ÍH), 8.38 (d, ÍH), 7.88 (m, 2H), 7.68 (d, ÍH), 7.46 (, 3H), 6.31 (s, ÍH) , 4.93 (AB, 2H), 4.00 (, ÍH), 3.49 (m, 2H), 2.76 (m, ÍH), 2.26 (m, ¡ÍH), 1.60 (s, 9H). IS MS, [M] t = 561, 563, Cl pattern. E. [2-Oxo-l- (lH-pyrrolo [2, 3-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [b] -amide. ] thiophene-2-sulfonic acid The title compound is prepared from 2- [3- (S) - (6-chloro-benzo [b] thiophen-2-sulfonylamino) -2-oxopyrrolidin- tert -butyl ester. 1-ylmethyl] -pyrrolo [2,3-c] pyridine-l-carboxylic acid in accordance with that described in n ~ example 27, part C. The crude product is purified by RP- # HPLC eluting in a gradient of 10% CH3CN / H20 (0.1% TFA) at 5 80% CH3CN / H20 (0.1% TFA), and the appropriate product fractions are lyophilized to provide the title compound as a white solid. X NMR (DMSO-ds, 300 MHz) delta 13.07 (bs, ÍH), 9.07 (s, ¡ÍH), 8.74 (d, ÍH), 8.29 (s, ÍH), 8.27 (d, ÍH), 8.03 (m , 3H) ,? 7.52 10 (dd, ÍH), 6.79 (s, ÍH), 4.71 (AB, 2H), 4.27 (m, ÍH), 3.2¡9 (m, 2H), 2.20 (m, ÍH), 1.77 (m, ÍH) ), FAB MS, [M + H] + = 461, 463, Cl pattern. Elemental analysis calculated with 0.7 mol of H20 calculated C = 44.94%, H = 3.33%, N = 9.53%, found C = 44 ,. 92%, H = 2.91%, N = 8.91%. EXAMPLE 48 Ditrifluoroacetate [2-oxo-l- (lH-pyrrolo [2, 3-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of tiend [3,2-] b] pyridine-2-sulfonic acid thieno [3, 2-b] pyridine-2-sulfonyl chloride. The title compound is prepared according to that described in example 8, part A using tienp [3,2- b] pyridine (prepared according to the procedure described in J. Heteroeyelie Chem.1984, 21, 785) in tianaphthalene lug. The raw product is used in step i subsequent without further purification.

XH NMR (CDC13, 300 MHz) delta 8.93 (s, ÍH), 8.38 (d, 1H), 7.59 (m, ÍH). The MS, [M] + = 233, 235, Cl pattern. B. (2-Oxo-l-prop-inyl-pyrrolidin-3- (S) -yl) -amide of acid • thieno [3, 2-b] pyridine-2-sulphonic acid The title compound is prepared according to that described in Example 1, part K using thieno [3,2-b] pyridine-2-sulfonyl chloride and 3- (S) -amino-l-prop-2-ynyl-pyrrolidin-2-one hydrochloride as starting material. The crude product is isolated in the form of a white solid and • 10 is used in the subsequent step without further purification. X NMR (CDC13, 300 MHz) delta 8.81 (d, ÍH), 8.13 (s, ÍH) 1? l (m, ÍH), 6.05 (bs, ÍH), 4.10 (AB, 2H), 3.98 (m, ÍH), 3.48 (m, 2H), 2.70 (m, ÍH), 2.27 (t, 1H), 2.17 (my h) . C. [2-Oxo-l- (lH-pyrrolo [2, 3-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of thieno [3,2-b] ] pyridine-2-sulfonic acid The title compound is prepared from (2-oxo-l-prop-2-ynyl-pyrrolidin-3- (S) -yl) -amide of thien acid [3, 2-b] ] pyridine-2-sulfonic acid in accordance with the procedure described in Example 47, part D. The crude mixture is diluted with EtOAc and washed with a saturated solution of NH.C1, water and! Saturated NaCl. The aqueous layer is concentrated in vacuo to a residue. The salt residue is triturated with M¡eOH and CH2C12, filtered, washed with CH2Cl2 / MeOH and the filtrate yellow is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH, CN / H20 (0.1% TFA to 50% CH3CN / H20 (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound. in the form of a beige solid X NMR (DMS0-d3, 300 MHz) delta 13.00 (bs, 1H), 9.06 (s, ¡1H), 8.88 (d, 1H), 8.77 (, ÍH), 8.60 ( d, ÍH), 3.26 (d, ÍH), 8.12 (s, ÍH), 8.01 (d, ÍH), 7.52 (m, ÍH), 6.80 (s, ÍH), 4.71 '(AB, 2H), 4.35 ( m, ÍH), 3.30 (m, 2H), 2.22 (m, ÍH), 1.78 (m, 1H) .IS MS, [M + H] "= 428. Elemental analysis calculated coh 1.9 mol of calculated H20 C = 40.05 %, H = 3.33%, N = 10.15%, C = 40.06%, H = 2.82%, N = 9.87% EXAMPLE 49 Trifluoroacetate (2-oxo-l-thieno [3,2-cjpyridin-2-ylmethyl] benzo [b] thiophene-2-sulphonic acid pyrrolidin-3- (S) -yl) -amide A. 1- (Thieno [3,2-c] pyridin-2-ylmethyl) tert-butyl ester 2-oxopyrrolidin-3- (S) -yl] -carbamic acid To a solution of tert-butyl ester of l- (4-chloro-ti) [3, 2-c] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid (0.46 g, 1.2 mmol), prepared as described in example 33, part F, in 20 L of MeOH, 10% erJ weight of Pd / C (0.1 g) and KOH (0.13 g, 2.4 mmol) are added. The atmosphere above the reaction is replaced by hydrogen and the solution is heated to 50 ° C. After 16 hours, the solution is filtered through Celite and washed with Celite with MeQH. The crude material is purified by column chromatography eluting with a gradient of 30% EtOAc / CH2Cl at 40% EtOAc / CH2Cl2 to give the product as a white solid (0.2 g, 0.7 mmol). X NMR (CDC13, 300 MHz) delta 9.00 (s, ÍH), 8.44 (d, ÍH), '7.70 (S, ÍH), 7.31 (s, ÍH), 5.12 (bs, ÍH), 4.72 (AB, 2H ), 4.1¡8 (m, ÍH), 3.32 (m, 2H), 2.62 (m, ÍH), 1.88 (m, ÍH), 1.42 (s, | 9H). FAB MS, [M + H] + = 348. B. (2-Oxo-l-thieno [3,2-c] pyridin-2-ylmethyl-pyrrolidin-3- (S) -yl) -amide trifluoroacetate. benzo [b] thiophene-2-sulfonic acid To the solution of tert-butyl ester of 1- (tiend [3, 2-c] pyridin-2-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic (0.1 g, 0.35 mmol) in 4 mL of CH2C1 is added EtN (0.08 g, 0.78 mmol) and benzo [b] thiophenesulfonyl chloride (0.08 g, 0.35 mmol). After six hours, the solution is diluted with CH2C12 and washed with 10% Na2CO3 and saturated NaCl. The residue is purified by RP-HPLC eluting with a gradient of 10% EtOAc / CH 2 Cl 2 at 80% EtOAc / CH 2 Cl 2. The appropriate fractions are lyophilized to provide the title compound as a white solid. lE NMR (DMSO-d3, 300 MHz) delta 9.25 (bs, HH), 8.63 (d, 1 HH), 8.50 (m, 1H), 8.39 (m, HH), 7.99 (m, 4H), 7.61 (s) , HH), 7.46 (m, 2H), 4.70 (s, 2H), 4.14 (m, HH), 3.11 (m, 2H), 2.08 (m, HH), 1.62 (m, HH). FAB MS, [M + H] + = 444.

EXAMPLE 50 [1- (1H-Imidazo [4, 5-c] pyridin-2-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide of 7-methoxynaphthalene-2-sulphonic acid 5-trifluoroacetate A. [3- (S) -amino-2-oxo-cyclopentyl] -acetic acid benzyl ester hydrochloride Sodium hydride (0.13 g, 3.3 mmol, 60% by weight) is added to a tert-butyl ester solution of [2- oxopyrrolidin-3- (S) -yl] -carbamic acid (0.6 g, 3 mmol) in THF (30 mL) at a temperature of 0 ° C. The mixture is stirred for 390 minutes and then 2-bromo-acetate (0.76 g, 3.3 mmol) is added. The resulting solution is heated to room temperature and stirred for 1.5 hours. The reaction mixture is quenched with a saturated solution of ammonium and then diluted with methylene chloride. The organic layer is separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (0-3% MeOH / CH2Cl) and the isolated material is treated in ethyl acetate with HCl gas (from according to that described in example 1, part I) to provide the title compound (0.55 g, 1.9 mmol) as a pale yellow solid. P NMR (CD3OD, 300 MHz) delta 7.32 (m, 5H), 5.17 (s, 2H), 4.15 (d, 2H), 4.08 (m, ÍH), 3.54 (m, 2H), 2.54 (m, ÍH) , 2.0¡ 3 (m, 25 ÍH). The MS, [M] + = 248.

B_. 3- (S) - (7-Methoxy-naphthalene-2-sulfonylamino) -2-oxopyrrolidin-1-yl] -acetic acid. [3- (S) -amino-2-oxo-1-benzyl ester hydrochloride is suspended. cyclopentyl] -acetic (0.34 g, 1.2 mmol) in i CH3C1 (20 mL). To this mixture is added triethiamine (0.36 gl, 3.6 mmol) followed by 7-methoxy-naphthalene-2-sulfonyl chloride (0.31 g, 1.2 mmol). The mixture is stirred overnight at room temperature, subjected to aqueous treatment and then concentrated to dryness. The raw material is purified • 10 by flash chromatography (0-5% MeOH / CH2Cl2)? . Subsequent hydrogenolysis in MeOH / CH2Cl2 with 5% Pd / C at 17.577 kg / m2 (25 psi) for 1.5 hours gives the title compound (0.40 g, 1 mmol) as a white solid. : H NMR (CDC13, 300 MHz) delta 8.33 (s, ÍH), 7.80 (m, 3H) 7.23 (, 2H), 5.90 (br, ÍH), 3.95 (m, 6H), 3.38 (m, 2H), 2.40 (m, ÍH), 2.07 (, ÍH). MS from Ion Rossing, [M + H] "= 379. C ^ N- (3-.Amino-pyridin-4-yl) -2- [3- (S) - (methoxy-naphthalene-2- • sulfonylamino ) -2-oxopyrrolidin-l-yl] -acetamide Triethylamine (0.13 g, 1.3 mmol) and chloroformonate are added. isobutyl (0.18 g, 1.3 mmol) to a solution of ([3- (S) ~ (7-methoxy-naphthalene-2-sulfonylamino) -2-oxopyrrolidin-1-yl] -acetic acid (0.5 g, 1.3 mmol) in THF (15 mL) at a temperature of -10 ° C. The mixture is stirred for 20 minutes and then treated with a solution of 3,4-diamin pyridine (0.16 g, 1.5 25 mmol) in DMF (5 L). The resulting mixture is heated to room temperature and stirred for 3 hours. The reaction mixture is concentrated in vacuo and then diluted with methylene chloride. The organic layer is washed with brine, • dried in MgSO4, filtered and concentrated. The residue is purified by flash chromatography, 5-8% MeOH / GH2Cl2) to give the title compound (0.27 g, 0.58 mmol) as a solid. XH NMR (CDC13, 300 MHz) delta 8.88 (s, ÍH), 3.00 (s, 1HH 7.85 (d, 1H), 7.70 (m, 3H), 7.40 (d, ÍH), 7.20 (d, ÍH), 7.12 (s, 10 ÍH), 5.28 (s, 2H), 4.07 (m, 4H), 3.88 (3, 3H), 3.34 (m, 2H), 2.22 (m, ÍH), 1.90 (m, ÍH). ions, [M + H] "= 470. D. [1- (IH-imidazo [4, 5-c] pyridin-2-ylmethyl-2-oxopyrrolidin-3- (S) -yl] trifluoroacetate] 7-Methoxy-naphthalene-2-sulfonic acid amide N- (3-Amino-pyridin-4-yl) -2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxopyrrolidin- l-il] -acetamide (0.22 g, 0.47 mmol) in acetic acid (15 mL) at a temperature of 110 ° C overnight The resulting solution is concentrated to dryness. The residue is purified by HPLC eluting with a gradient of 10% to 100% CH3CN / 0.1% TFA in water for 30 minutes. Fractions containing pure product are lyophilized to provide the title compound as a white solid (0.24 g, 0.42 mmol). 25 X NMR (CDCl 3, 300 MHz) delta 9.30 (s, ÍH), 8.40 (d, ÍH) ', 8.28 (s, ÍH), 7.95 (d, ÍH), 7.70 (m, 3H), 7.40 (m, ÍH), 7.20 (m, 2H), 7.14 (s, ÍH), 4.92 (m, 2H), 4.46 (, ÍH), 3.82 (s, 3H), 3.38 (m, 2H), 2.20 (m, ÍH) ), 2.03 (m, ÍH). Roseate EM • ions, [M + H] + = 452. 5 EXAMPLE 51 [1- (2-am? No-3H-benzoimidazol-5-methyl) -2-oxopyrrolidin-3- (S) -yl] -amide trifluoroacetate of 7-methoxynaphthalene-2-sulfonic acid A. [1- (3,4-diam-nobenzyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxy-naphthalene-2-sulfonic acid 10% palladium on carbon (0.08 g) is added to a solution of [1- (4-amino-3-nitrobenzyl) -2-oxopyrrolidin-3- (S) -yl] -amido-7-methoxyamide. Naphthalene-2-sulfonic acid (0.22 g, 0.5 mmol) (prepared in accordance with that described in example 25, part F) in MeOH (40 mL) and CHC13 (3 mL) under a nitrogen atmosphere. The heterogeneous mixture is hydrogenated at room temperature in a Parr apparatus under 33,046 kg / m2 (47 psi) of • hydrogen for 5 hours. The catalyst is filtered, and the filtrate performed by TLC shows no initial material. He The filtrate is concentrated in vacuum and used in the subsequent step without further purification. X NMR (CD3OD, 300 MHz) delta 8.41 (s, ÍH), 7.93 (d, ÍH), 1 7.85 (d, ÍH), 7.73 (d, ÍH), 7.39 (d, ÍH), 7.25 (dd, ÍH) ), 7.02 (d, ÍH), 6.89 (s, ÍH), 6.79 (dd, ÍH), 4.30 (s, 2H), 4.13 (t, ¡ÍH), 3.95 (s, 3H), 3.13 (m, 2H), 2.14 (m, ÍH), 1.70 (m, ÍH). Ion Rostrate MS [M + H] "= 441. B. [1- (2-amino-3H-benzoimidazole-5-methyl] -2-oxopyrrolidin-3- (S) -yl] - trifluoroacetate 7-methoxmaphthalen-2-sulfonic acid amide 5 Triethylamine (0.063 mL, 0.45 mmol) is added to a solution of [1- (3,4-diaminobenzyl) -2-oxopyrrolidin-3- (S) -yl] - amide of 7-methoxmaphthalen-2-sulfonyl acid (0.205 g, 0.47 mmol) in MeOH (8 mL) under nitrogen Cyanogen bromide (0.19 mL of a 3 M solution, 0.56 mmol) is added dropwise to the ßP 10 mixture of the reaction at 0 ° C. After stirring for 5 minutes at a temperature of 0 ° C., the reaction is carried out at room temperature and stirred overnight.The clear solution is then concentrated under vacuum and the residue crude is purified using column chromatography eluting with a gradient of 9% MeOH / CH2Cl2 at 50% MeOH / CH2Cl2 to provide the product with a yield of 56%. The product is lyophilized in acetonitrile / TFA-water to • provide the title compound as a whitish solid. 20: H NMR (CD3OD, 300 MHz) delta 8.40 (d, ÍH), 7.90 (d, ÍH), 7.81 (d, ÍH), 7.75 (d, ÍH), 7.36 (d, ÍH), 7.25 (dd, ÍH), 7.15 (d, ÍH), 7.11 (d, ÍH), 6.92 (dd, ÍH), 4.41 (AB, 2H), 4.15 (t, HH), 3.91 (s, 3H), 3.10 (m, 2H), 2.10 (m, HH), 1.64 (, HH) - EM of Ion Rosette, [M + H] + = 466. 25 EXAMPLE 52 Hydrochloride 3- (S) -armino-1- (l-aminoisoquinolin-7-ylmethyl) -pyrrolidin-2-one A. 7-methyl-l-phenoxyisoquinoline • The title compound is prepared in accordance with described in Example 1, part L using l-chloro-7-methylisoquinoline as the starting material. The crude material is purified by column chromatography eluting with 20% EtOAc / hexanes to give the title compound as a pale yellow oil. ™ '10 X NMR (CDC13, 300 MHz) delta 8.22 (s, ÍH), 7.90 (d,' ÍH), 7.68-7.60 (m, ÍH), 7.60-7.52 (, ÍH), 7.50-7.40 (, 2H ), 7.30-7.20 (m, 4H), 2.57 (s, 3H). B. 7-Bromomethyl-1-phenoxyisoquinoline The title compound is prepared according to that described in Example 1, part F using 7-methyl-1-phenoxyisoquinoline as the starting material. The crude product is purified by column chromatography eluyendc with • 10% EtOAc / hexanes to give the title compound as a clear oil. 20 X NMR (CDC13, 300 MHz) delta 8.40 (s, ÍH), 7.95 (d, 1H), 7. 80-7.65 (m, 2H), 7.50-7.40 (m, 2H), 7.30-7.20 (m, 4H), 4.65 (s, 2H). C. [1- (1-Phenoxyisoquinolin-7-yl ethyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid benzyl ester The title compound is prepared according to that described in Example 1 , part H, employing 7-bromomethyl-1-phenoxyisoquinoline and benzyl ester of [2- ^ fc-oxopyrrolidin-3- (S) -yl] -carbamic acid as the starting materials. The crude product is purified by column chromatography eluting with 70% EtOAc / hexanes to give the title product as a clear oil. X NMR (CDC13, 300 MHz) delta 8.25 (s, ÍH), 7.97 (d, ÍH), 7.79 (d, ÍH), 7.60 (d, ÍH), 7.48-7.40 (m, 2H), 7.38-7.20 ( m, 9H), 5.40 (bs, 1H), 5.15 (s, 2H), 4.75 (AB, 2H), 4.30 (m, ÍH), • 10 3.30 (m, 2H), 2.67 (m, ÍH), 1.90 (m, ÍH). D. [1- (1-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid benzyl ester The title compound is prepared in accordance with that described in Example 1, part M using benzyl ester [1- (1-phenoxyisoquinol-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid as the starting material. The reaction mixture is diluted with methylene chloride and washed with 3N NaOH and brine. The organic layer is dried over MgSO, filtered and concentrated in vacuo. The crude product is purified by Column chromatography eluting with 10% MeOH / CH2Clc to form the title compound as a foamy yellow solid. X NMR (CDCl 3, 300 MHz) delta 7.95-7.87 (m, 2H), 7.70 (d, ÍH), 7.45 (d, ÍH), 7.40-7.30 (, 5H), 7.00 (d, ÍH), 5.75-5.55 (m, 3H), 5.20-5.15 (m, 4H), 4.3-4.1 (m, ÍH), 3.25 (m, 2H), 2.55 (m, ÍH), 2.27 (m, ÍH). E. 3- (S) -amino-1- (l-aminoisoquinolin-7-t-ylmethyl) -pyrrolidin-2-one hydrochloride. 10% palladium on carbon (0.089 g) is added to a 5-solution of benzyl ester. of [1- (1-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid (0.33 g, 0.84 mmol) in ethanol. The heterogeneous mixture is hydrogenated at room temperature in a Parr apparatus under a hydrogen pressure of 31.639 kg / m "(45 psi) for 3 hours.

The reaction mixture was through a pad of Celite, washed with ethanol and the filtrate was concentrated in vacuo to give the product (0.2 g, 0.78 mmol) as a foamy solid. The product is dissolved in diethyl ether and cooled to a temperature of 0 ° C. Chloride gas is bubbled of hydrogen through the solution to provide the product in the form of a hydrochloride salt. X NMR (DMSO-ds, 300 MHz) delta 8.95-8.50 (b, 2H), 8.0 ^ 5 (s, ÍH), 7.75-7.70 (m, 2H), 7.53 (d, 1H), 7.30-7.10 (b , 2H), 6.93 (d, ÍH), 4.57 (AB, 2H), 3.40 (m, ÍH), 3.15 (, ÍH), 2.37 (m, 20 1H), 2.02 (m, ÍH). FAB MS: [M + H] * = 257. F. [1- (1-aminoisoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide acid trifluoroacetate -methoxyaphthalene-2-sulphonic. The title compound can be prepared by an alternative route using 3- (S) -amino-1- (1-aminoisoquinolin-7-ylmethyl) -pyrrole-din-2-one hydrochloride and 7-methoxy-naphthalene-2-hydrochloride. -sulfon? as the initial material and continuing in accordance with that described in example 1, • part K. 5 EXAMPLE 53 Chloride of 6-chloroteno [2, 3-b] pyridine-2-sulfonyl A. 2-bromo-6-chlorothieno [2,3-b] pyridine The title compound is prepared starting from 2-brdmo-5-acetylthiophene in accordance with the procedure described in J. Chem. Soc., Perkin Trans. I, 1981, 1531. The crude product is purified by column chromatography eluting 2% EtOAc / hexanes to give a white solid -H NMR (CDC13, 300 MHz) delta 7.89 (d, 1H), 7.28 (d, 1H) - 7.27 (d, ÍH). B. Chloride of 6-chlorothieno [2, 3-b] pyridin-2-sulfonyl The title compound is prepared in accordance with that described in Example 1, part D using 2-broman-6-chlorothieno [2, 3 -b] pyridine in place of tianaphthalene. The crude product is obtained in the form of a white solid and has a sufficient purity to be used in the subsequent step. : H NMR (CDC13, 300 MHz) delta 8.22 (d, ÍH), 8.09 (s, ÍH), 7.52 (d, • ÍH). The MS, [M] + - 267, 269, Cl pattern. EXAMPLE 54 25 6-Fluorobenzo [b] thiophene-2-sulfonyl chloride The title compound is prepared according to that described in example 9, parts A-C using 3-fluorothiophenol instead of 3-chlorothiophenol. EXAMPLE 55 6-Chlorotino [3, 2-b] pyridine-2-sulfonyl chloride The title compound is prepared according to that described in example 48, part A using 6-chlorotier.o [3, 2-b] pyridine (prepared in accordance with the procedure described in J. Het &Jroci Chem.1984, 21, 785) in place of tianaphthalene. The crude product is used, in the subsequent step without further purification. Other compounds prepared in accordance with the procedures indicated above include the compounds encompassed by the following formula: It is selected within the group of formulas consisting of • 10 R-_, X5, and A are in accordance with what is defined here; and R; is selected within the group of formulas that consists of i_rb- 4o or ioo M ^^^^^^ M • 10 :40 fifteen • 20 MHkaMi EXAMPLE 56 [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrroli-di-n-3 - (S-) -yl] -amide of thieno acid [3, 2 b] pyridine-2-sulphonic • A. [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -5-yl] -amide of thieno acid [3, 2-b] pyridine-2-sulfonic acid To a solution of 3- (S) -amino-1- (1-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-one hydrochloride (0.15 g, 0.48 mol) suspended in CH3CN (2.5 L) triethylamine (0.23 L, 1.6 mmol) is added followed by thieno [3, 2-b] pyridin-2-sulphonyl chloride (0.14 g, 0.55 mmol). The mixture is stirred overnight and then concentrated. The residue is diluted with CH2C12 and washed with saturated NaHCO3 and brine. The organic layer is dried in MgSO, filtered and concentrated to dryness. The crude product is purified by chromatography in column eluting with 5% MeOH / CH; Cl; to provide the title compound (0.076 g, 0.16 mmol) in the form of a light yellow solid. : H NMR (CDC13, 300 MHz) delta 8.85 (d, ÍH), 3.32 (d, ÍH) [8.27 (d, ÍH), 8.15 (s, 2H), 7.85 (d, ÍH), 7.58- ~ .65 (m, 2H) f 7.45 (dd, ÍH), 5.60 (bs, ÍH), 4.68 (AB, 2H), 4.00 (, ÍH); 3.31 (m, 2H), 2.72 (m, ÍH), 2.20 (, ÍH). MS, [M] + = 472. B. [1- (l-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide of thieno acid [3, 2-b] pyridine-2-sulfonic acid [1- (1-chloro-isoquinolin-7-ylmethyl) -2-25-oxopyrrolidin-3 (S) -yl] -amide of thieno acid [3, 2-] is fused together b) pyridin-2-sulfonic acid (1.36 g, 2.88 mmol) and phenol (2.22 g, 23.6 mmol with stirring at a temperature of 70 ° C for 5 minutes.) Ammonium acetate (2.71 g, 28.8 mmol) is added and the reaction mixture is heated to a temperature of 90 ° C and stirred overnight.Additional ammonium acetate (0.50 g, 5.31 mmol) is added and the reaction is heated for an additional 20 hours.The reaction is cooled and the reaction is The residue is purified by RP-HPLC yielding in a gradient of 10% CH3CN / H ?0 (0.1% TFA) to 100% CH3CN.The appropriate product fractions ^^ 10 are lyophilized to provide the title compound as a solid. The enantiomeric purity is 90.5% ee in accordance with what is determined by r RP-HPLC Chiralpak AS analytical. X NMR (CDSO-de, 300 MHz) delta 12.90 (bs, ÍH), 9.00 (bs, 1 ÍH), 8.88 (d, ÍH), 8.79 (dd, ÍH), 8.60 (dd, ÍH), 8.30 (s, ÍH), 8.13 (s, ÍH), 7.95 (d, ÍH), 7.79 (dd, ÍH), 7.65 (d, ÍH), 7.53 (dd ÍH), 7.23 (d, ÍH), 4.50 (AB, 2H), 4.38 (m, ÍH), 3.21 (m, 2H), 2.20 (m, ÍH), 1.81 ( my h) . Ion spray, [M + H] "= 454. EXAMPLE 57 [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of thienic acid [2, 3-b] pyridine-2-sulphonic A. Thieno [2,3-b] pyridine-2-sulfonyl chloride N-Butyl (6.0 mL of a 1.6M solution in hexanes, 9.6 mmol) is added to a thieno [2, 3-b] pyridine solution (1.18 g, 8.7 mmol) (J. Org. Chem. 1969, 34 (2), 347) in THF (30 mL) at a temperature of -78 [deg.] C. After 40 minutes, the solution is added to a pre-cooled solution (-78 ° C) of SO; (approximately 6 mL) in Et0 (30 mL) through a • cannula. After the addition, the solution is stirred for 30 minutes, and then allowed to warm to room temperature. After 2 hours the solution is concentrated to give a brown solid. The residue is suspended in hexanes (30 mL) and S02C12 (0.6 mL, 7.5 mmol) 1 and added dropwise at room temperature. After stirring for one hour, the solution is concentrated and then diluted with methylene chloride and a saturated solution of NaHCO 3. The organic layer is separated and dried in MgSO 4, filtered and concentrated. The crude product is purified by column chromatography eluting with 20% EtOAc / hexanes to give a white solid with the title product. H NMR (CDC13, 30O MHz) delta 8.81 (dd, ÍH), 8.30 (dd, 1H), 8.12 (s, ÍH), 7.50 (dd, 1H). MS, [M] * = 233, 235, standard of Cl. 20 B. [1 (l-Chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-5- (S) -yl] -amide of thieno [2, 3-b] pyridine-2-sulfonic acid The title compound is prepared according to that described in example 56, part A using thieno [2,3-b] pyridine-2-sulfonyl chloride and hydrochloride of e- (S) -25 amino-1- (l-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-one as starting materials. The crude product is purified by column chromatography eluting with 5% MeOH / CH2Cl2 to give the title compound as a white solid. : H NMR (CDC13, 300 MHz) delta 8.72 (dd, ÍH), 8.31 (d, ÍH), 8.22 (dd, ÍH), 8.13 (d, ÍH), 7.92 (s, ÍH), 7.81 (d, 1H ), 7.60 (d, ÍH), 7.58 (d, ÍH), 7.43 (dd, ÍH), 5.89 (d, ÍH), 4.70¡ (AB, 2H), 4.05 (m, ÍH), 3.31 (m, 2H), 2.68 (m, ÍH), 2.13 (m, ¡ÍH). Ion spray, [M + H] ~ = 473, 475, Cl pattern. C. [1- (-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrole-din-3? - (S) -yl] -amido of thieno [2, 3-b] pyridine-2-sulfonic acid The title compound is prepared according to that described in example 56, part B using [l- (l-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of thieno [2, 3-b] pyridine-2-sulfonic acid as starting material. The crude product is purified by RP-HPLC eluting with a gradient of 10% CH3CN / H20 (0.1% TFA) to 100% CH3CN. The appropriate fractions are lyophilized to provide the title compound as a white solid. : H NMR (CDSO-dβ, 300 MHz) delta 12.90 (bs, ÍH), 9.00 (bs,! ÍH), 8.80 (d, ÍH), 8.72 (dd, ÍH), 8.42 (dd, ÍH), 8.27 ( Yes H) , 8. 08 (s, ÍH), 7.95 (d, ÍH), 7.79 (d, ÍH), 7.65 (d, ÍH), 7.58 (d, IH), 7.21 (d, ÍH), 4.50 (AB, 2H), 4.35 (m, ÍH), 3.2.5 (m, 2H), 2.21 (m, ÍH), 1.80 (m, ÍH). Ion spray, [M + H] t =? 454. EXAMPLE 58 [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 4-pyridin-3-yl-thiofen-2-sulfonic acid A. Chloride of 4-pyridin-3-yl-thiofen-2-sulfonyl The title compound is prepared according to that described in Example 57, part A using 2-bromo-4-p-ridin-3-yl- thiophene (J. Het, Chem. 1995, 32, 435) instead of thieno [2, 3-b] pyridine and carrying out the reaction at a temperature of -100 ° C instead of at -78 ° C. C. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc / hexanes to 20% EtOAc / hexanes to give the pale yellow solid. : H NMR (CDC13, 300 MHz) delta 8.87 (dd, ÍH), 8.65 (dd "ÍH), 8.3 (d, ÍH), 7.98 (d, ÍH), 7.90 (, ÍH), 7.42 (m, ÍH) . MS, [M] "= 259, Cl. B. standard. [1- (1-Chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 4 pyridin-yl-thiophene-2-suphonic The title compound is prepared according to that described in example 56, part A using 4-pyridin-3-yl-thiophene-2-sulfonyl chloride and 3-hydrochloride. (S) -amino-1- (l-chloro-isoquinolin-7-ylmethyl) -pyrrolidin-2-one as starting materials The crude product is purified by column chromatography eluting with a gradient of 2% MeOH / CH 2 Cl a 4% MeOH / CHCl2 to provide the title compound as a white solid.

? NMR (CDCI3, 300 MHz) delta 8.88 (d, ÍH), 8.31 (d, lH), 'd.l4 (s, ÍH), 7.95 (d, 1H), 7.88 (m, ÍH), 7.82 (d, ÍH), 7.79 (d, ÍH), 7.55-7.60 (m, 2H), 7.38 (m, ÍH), 5.45 (d, ÍH), 4.63 '(AB, 2H), 3.95 (m, ÍH), 3.29 ( m, 2H), 2.68 (m, 1H), 2.14 (m, 1H), 1.6 (s, 9H). Ion spray, [M + H] * = 499, 501. C. [1- (l-amino-isoquinolin-7-ylmethyl) -2-oxo-p-rrolidin-3- (S) -yl] -amide of 4-pyridin-3-l-thiophene-2-suphonic acid The title compound is prepared according to that described in Example 56, part B using [1- (1-chloro-isoquinolin-7-ylmethyl) -2-Oxo-pyrrolidin-3- (S) -yl] -amide of 4-pyridin-3-yl-thiophene-sulfonamide as initial material. The crude product is purified by RP-HPLC eluting with a gradient of 10% CH3CN / H20 (0.1% TFA) to 100% CH3CN.The appropriate fractions are lyophilized to provide the title compound as a white solid. 'H NMR (DMSO-ds, 300 MHz) delta 12.98 (bs, 1H), 9.00 (bs, 2H), 8.48-8.57 fm, 2H), 8.39 (s, ÍH), 8.27 (s, ÍH), 8.15- 8.21 (, 2H), 7.92 (d, ÍH), 7.78 (d, ÍH), 7.61 (d, IH), 7.43 (m, ¡lH), 7.21 (d, ÍH), 4.56 (AB, 2H), 4.39 (, ÍH), 3.20 (m, 2H), 2.20 (m, ÍH) ', 1.73 (m, ÍH). Ion spray, [M + H] "= 480. EXAMPLE 59 [2-oxo-l- (lH-pyrrolo [3,2- c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] 5'-chloro- [2, 2 '] bituiophenyl-5-sulphonic acid amide A. 4-amino-3-iodo-pyridine A solution of potassium iodide (19.4 g, 117.4 mmol) and iodine (18.37 g, 72.3 mmol) in water (77 mL) is added dropwise through an addition funnel to a refluxing solution of 4-aminopyridine (9.21 g, 97.8 mmol) and sodium carbonate. • (6.12 g, 57.5 mmol) in water (35 mL). After finishing the addition, the mixture is stirred for 2 hours at reflux and then cooled to room temperature and extracted with ethyl acetate. The combined organic layers are washed with a saturated solution of sodium thiosulfate (x3) and brine and then dried over MgSO, filtered and concentrated • 10 to provide the title product (8.37 g, 38.0, mmol) and a trace of di-diode compound as a yellow / orange solid. This material was used in the subsequent step without further purification. : H NMR (CDC13, 300 MHz) delta 8.70 (s, ÍH), 8.10 (d, ÍH); 6.55 (d, ÍH), 4.60 (bs, 2H). B. (3-iodo-pyridin-4-yl) -carbamic acid tert-butyl ester • Di-tert-butyl dicarbonate (20.7 g, 94.81 mmol) is added to a solution of 4-amino-3-iodo- pyridine (19.0 g, 86.41 mmol) in THF (86 L). The resulting solution is stirred for 2 hours at room temperature and then concentrated to dryness. The residue is diluted with ethyl acetate, and washed with a saturated solution of sodium bicarbonate and brine. The organic layer is dried in MgSO4, filtered and concentrated to dryness. The residue is purified by column chromatography eluting with 1% EtOAc / CH2Cl2 | to provide the title compound and a small amount of di-iodine compound protected by BOC. The crushing of the • mixing with ether / hexane removes the undesired compound leaving 5 the title product in the solution. Filtration of the solid and concentration of the filtrate gives the title product (18.95 g, 59.2 mmol). - NMR (CDCl ,, 300 MHz) delta 8.75 (s, ÍH), 3.35 (d, 1H), 8.1 (d, ÍH), 7.0 (bs, ÍH), 1.55 (s, 9H). ^ 10 C. Tert-butyl acid ester (2-oxo-l-prop-2-phenyl-pyrrolidin-3- (S) -yl) -carbamic acid. Sodium hydride (1.11 g, 27.7 mmol, dispersion in mineral oil) is added. 60%) to a solution of [2-oxopyrrolidin-3- (S) -yl] -carbamic acid benzyl ester (6.20 g, 26.4 mmol) in THF / DMF (88 mL, 3/1 volume / volume) at a temperature of 0 ° C. The mixture is stirred for 5 minutes, then propargyl bromide (4.4 L, 49.4 mmol) is added dropwise. . The resulting solution is stirred for 1 hour and then brought to room temperature and stirred for 2 hours. hours. The reaction is quenched by a saturated solution of ammonium chloride and then diluted with ethyl acetate and washed with water (x4) and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The residue is purified by column chromatography eluting with 5% MeOH / CH 2 Cl 2 to give the product (7.20 g, 26.4 mmol) as a white solid. : H NMR (CDCl 3, 300 MHz) delta 7.35 (m, 5H), 5.30 (bs, ÍH), 5.12 (s, 2H), 4.21 (m, ÍH), 4.13 (s, 2H), 3.43 (m, 2H) ), 2.73 (m, H), 2.25 (s, ÍH), 1.95 (m, ÍH). D. 2- [3R (S) -Benzyloxycarbonylamin-2-oxo-pyrrolid-n-ylmethyl) -pyrrolo [3, 2-c] pyridine-1-carboxylic acid tert-butyl ester Pd (PPh ^ 2Cl2 ( 0.49 g, 0.70 mmol), Cul (0.08 g, 0.42 mmol) followed by triethylamine (7.8 mL, 56.0 mmol) to a solution of benzyl ester of acid (2-oxo-l-prop-2-ynyl-pyrrolidin-3-). (S) -yl) -carbamic acid (3.81 g, 13.9 mmol) and (3-iodo-pyridin-4-yl) -carbamic acid tert-butyl ester (4.48 g, 14.0 mmol) in DMF (50 mL) at room temperature The mixture is heated to a temperature of 100 ° C and stirred for 1.5 hours.The reaction mixture is then cooled to a temperature of 50 C and DBU (4.2 mL, 28.1 mmol) is added after 30 minutes. the solution is cooled to room temperature, diluted with ethyl acetate and washed with saturated ammonium chloride, water and brine.The organic layer is dried over MgSO4, filtered and concentrated to dryness in vacuo.The resulting solid is purified by chromatography in column eluting with a gradient of 2% MeOH / CH2Cl2 at 5% MeOH / CH2Cl2 to provide the probuct (4.79 g, 10.3 mmol) as a white solid. ? MR (CDCl 3, 300 MHz) delta 8.80 (s, ÍH), 8.48 (d, ÍH), 7.90 (d, ÍH), 6.51 (s, 1H), 7.39 (m, 5H), 5.45 (d, ÍH), 5.19 (s, 2H), 4.90 (7AB, 2H), 4.30 (m, 1H), 3.49 (m, 2H), 2.75 (mj ÍH), 2. 10 (m, ÍH), 1.78 (s, 9H). Ion spray EM, ^ 465. E. 2-, 3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -pyrrolo [3, 2-c] pyridin-1 tert -butyl ester. carboxyl Tert-butyl ester to 2- [3- (S) -benzyloxycarbonylamino-2-oxo-pyrrolidin-1-ylmethyl) -pyrrolo [3, 2-c] pyridine-1-carboxylic acid (2.8 g, 6.0 mmol) in fl 10 HC02H / MeOH (30 mL, 4.4% solution) through a canula to a solution of palladium black (2.0 g, 13.8 mmol) in water (1 mL). After about 40 minutes, the catalyst is filtered through Celite and a saturated solution of sodium bicarbonate becomes basic. The filtering is Concentrate in vacuo to remove methanol.ol and then the resulting solution is extracted with methylene chloride. The organic layer is washed with brine, dried in MgSO-, • filtered and concentrated to dryness. The resulting white solid can be used in the subsequent step without additional purification. The title compound was purified in the following manner to prepare a focused sulfonamide library. The crude solid was purified by RP-HPLC eluting with a gradient of 10% CH3CN / H20 (0.1% TFA) to 100% CH3CN. The appropriate fractions are combined and neutralized with a saturated solution of sodium bicarbonate and then concentrated to remove CH3CN. The aqueous layer is extracted with methylene chloride (x4) and the organic layers are washed with brine, sedated MgSO, filtered and concentrated to provide the title compound as a white solid. P NMR (CDC13, 300 MHz) delta 8.80 (s, 1H), 8.43 (d, ÍH), 7.90 (d, ÍH), 6.41 (s, ÍH), 4.88 (AB, 2H), 3.65 (m, ÍH), 3.45 (m, 2H), 2.55 (, ÍH), 1.90 (, ÍH), 1.75 (s, 9H). Ion spray MS, [M + H] * = 331. F. 5-chloro- [2,2 '] bismophenyl The title compound is prepared from 2-chloro-thiophene according to the procedure described in Bull. Chem. Soc. Japan, 1979, 1126. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc / hexanes at 10% EtOAc / haxanes to give a white solid. : H NMR (CDC13, 300 MHz) delta 7.24 (, 1H), 7.11 (d, ÍH), 7.03 (dd, ÍH), 6.94 (d, ÍH), 6.83 (d, ÍH). MS, [M] "= 200, 202, standard Cl. G. Chloride 5'-chloro- [2, 2 '] bitiofeniI-5-sulfonyl The title compound is prepared according to what described in the example 57, part A employing 5-chloro- [2, 2 'jibothiophenyl in place of thieno [2, 3-b] pyridine!) The crude product is purified by chromatography eluting with a gradient of 5% EtOAc / hexanes at 10% EtOAc hexanes to give a white solid: H NMR (CDCl 3, 300 MHz) delta 7.76 (d, 1H), 7.14 (d, 1H), '7.09 (d, ÍH), 6.92 (d, ÍH). [M] '= 298, 300, pattern of C'l.

• H. 2- [3- (S) - (5'-Chloro-5 [2, 2 '] bit ofhenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-yl ester. ethyl] pyrrolo [3, 2-c] pyridine-1-carboxylic acid The title compound is prepared according to that described in example 56, part A, using 5'-chloro- [2, 2 '] biphenyphenyl- 5-sulfonyl and tert-butyl ester of 2-10- [3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -pyrrolo [3, 2-c] pyridine-1-carboxylic acid as starting material . The crude product can be purified by column chromatography eluting with 5% MeOH / CH2Cl2 to give the title compound as a white solid or can be used in the subsequent step after an aqueous treatment 'without further purification. Ion spray MS, [M + H] * = 593, 595, Cl pattern. • I. [2-Oxo-l- (lH-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 5'-chloro- [2, 2] '] Bituiophenyl-5-sulphonic acid Trifluoroacetic acid (1.0 L, 13.0 mmol) is added dropwise to a paste of tert-butyl ester of 2- [3- (S) - (5'-chloro- [2, 2 '] bromo-phenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] pyrrolo [3,2-c] pyridine-1-carboxylic acid (0.13 g, 0.22 mmol) in CH2C12 (2 mL) at a temperature of 0 ° C. After 30 minutes, the ice bath is removed and the solution is stirred at room temperature for 4 hours. The reaction mixture is concentrated to dryness and the product is • is purified by RP-HPLC eluting in a gradient of 10% 5 CH3CN / H20 (0.1% TFA) to 100% CH3CN. The appropriate product fractions are lyophilized to provide the title compound as a white solid. : H NMR (DMSO-d6, 300 MHz) delta 14.60 (bs, ÍH), 12.78 (s, 1H), 9.18 (s, ÍH), 8.55 (d, ÍH), 8.40 (d, ÍH), 7.88 (d , ÍH), 7.61 (d, ÍH), 7.38 (d, ÍH), 7.36 (d, ÍH), 7.21 (d, ÍH), 6.91 (s, ÍH), 4.70 (AB, 2H), 4.21 (, ÍH), 3.30 ( m, 2H), 2.25 (m, ÍH), 1.75 (, ÍH). Ion spray MS, [M + H] + = 493, 495, Cl standard. EXAMPLE 60 15 [2-oxo-l- (lH-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidine -3- (S) -yl] -amide of 2- (5-chloro-thiophen-2-yl) -etensulfonic acid A. 2- (5-Chloro-thiophen-2-yl) -ettensulfonic acid ethyl ester n-Butyllithium (1.6 mL) is added dropwise to a solution of 2.5 M in hexanes, 4.0 mmol) to a solution of ethyldiethylphosphorylmethanesulfonate (1.0 g, 3.8 mmol), prepared in accordance with that described in Tetrahedrom, 1987, 43 (21), 5125, at a temperature of -78 ° C in THF (15 mL). The mixture is stirred for 20 minutes then 5-25 chloro-2-thiophenecarboxaldehyde (0.45 mL, 4.2 mmol) is slowly added. The yellow mixture is stirred at -78 ° C for 1 hour and then allowed to warm to room temperature overnight. Most of the solvents are evaporated and the residue is treated with water (2 mL) 5 and extracted with CH2C12. The organic layer is washed with brine, dried in MgSO, washed and concentrated. The crude product is purified by column chromatography eluyendb with CH2C12 to give the title compound as a yellow solid. 10 X NMR (CDC13, 300 MHz) delta 7.55 (d, ÍH), 7.11 (d, ÍH), 6.90 (d, ÍH), 6.41 (d, ÍH), 4.20 (q, 2H), 1.39 (t, 3H). Ion spray MS, [M + H] "= 253. B. 2- (5-cyclo-thiophene-2? -yl) -ethene tetra-n-butylammonium sulfonate 15 2- (5-) ethyl ester chloro-thiophene-2-yl) -etensulfonic (0.92 g, 3.2 mmol) in acetone (16 L) is treated with tetrabutylammonium iodide (1.3 g, 3.5 mmol) and heated at reflux for 19 hours. The mixture is concentrated to dryness and then diluted with CH2C12 and washed with water and brine. The organic layer is washed in MgSO2, filtered and concentrated! to provide an oil / solid that is absorbed in the next step without further purification. X NMR (CDCI3, 300 MHz) delta 7.28 (d, ÍH), 6.81 (d, ÍH), 6.77 (d, ÍH), 6.73 (d, ÍH), 3.29 (t, 8H), 1.65 (, 8H), 1.4'5 (m, 5 8H), 1.00 (t, 12H).

C. 2- (5-Chlorothiophen-2-yl) -etensulfonyl chloride. Sulphoryl chloride (061 mL, 7.6 mmol) is added to a solution of triphenylphosphine (1.8 g, 6.9 mmol) in CH2C12 '(8.6 mL) at a temperature of 0 ° C. The ice bath is removed and 2- (5-chloro-thiophen-2-yl) -ethene tetra-n-butylammonium sulfonate (1.6 g, 3.4 mmol) in CH2C12 (17 L) is added to the reaction mixture through a cannula. . The resulting yellow solution is stirred for 1.5 hours and then hexane / ether (1: 1, volume / volume, 2Q0 L) ^ P '10 is added until the solution is no longer cloudy and until the formation of two layers. The solution is sung and the lower oily layer is discarded. The solution is concentrated to dryness and the product is purified by column chromatography eluting with CH2C12 to give the title compound as a pale yellow solid. X NMR (CDC13, 300 MHz) delta 7.71 (d, ÍH), 7.25 (d, ÍH), 7.00 (d, ÍH), 6.91 (d, ÍH). The MS, [M] '= 242, 244, 246, pattern of • Cl. D. 2- Tertiary butyl ester. { 3- (S) - [2- (5-Chloro-thiophen-2-yl) -etensulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl} - pyrrolo [3, 2-c] pyridine-1-carboxylic acid The title compound is prepared according to that described in example 56, part A using 2- (5-chlorothiophen-2-yl) -etensulfonyl chloride and ester tert-butyl 2- [3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -pyrrolo [3, 2-c] pyridine-l-carboxylic acid as starting materials. The crude product can be purified by column chromatography eluting with 5% MeOH / CH2Cl to provide the • composed of the title in the form of a white solid or? either can be used in the subsequent step after an aqueous treatment without further purification. "H NMR (CDC13, 300 MHz) delta 8.75 (s, ÍH), 8.46 (d, ÍH), 7.85 (d, ÍH), 7.48 (d, ÍH), 7.05 (d, ÍH), 6.85 (d, ÍH) ), 6.67 (d, ÍH), 6.40 (s, ÍH), 4.90 (AB, 2H), 4.15 (m, ÍH), 3.49 (, 2H), 2.71 (m, 1H), 2.21 (m, ÍH), 1.7 (s, 9H). Ion spray MS, [M + H] + = 537, 539, Cl. E. Standard. [2-Oxo-l- (lH-pyrrolo [3, 2-c] pyridin-2-ylmethyl) -pyrrolidin- 3- (S) -yl] -amide of 2- (5-chloro-thiophen-2-yl) -ettensulfonic acid. The title compound is prepared according to that described in example 59, part I using tertiary ester. butyl acid 2-. { 3- (S) - [2- (5-chloro-thiophen-2-yl) -ethersulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl} -pyrrolo [3, 2- c] pyridine-l-carboxylic acid as starting material. The product crude is purified by RP-HPLC eluting with a gradient of % CH3CN / H20 (0.1 &TFA) to 100% CH3CN. The appropriate fractions are lyophilized to provide the title compound as a white solid. '"H NMR (DMSO-de, 300 MHz) delta 9.19 (s, ÍH), 8.48 (d, ÍH), 7.91 (d, ÍH), 7.88 (d, ÍH), 7.50 (d, ÍH), 7.43 (d, ÍH), 7.20 (d, ÍH), 7.02 (d, ÍH), 6.90 (s, ÍH), 4.71 (AB, 2H), 4.12 (m, ÍH), 3.21 (m, 2H), 2.42 (m, ÍH), 1.85 (m, ÍH). MS, [M] * = 436, 433, Cl pattern. • EXAMPLE 61 5 [1- (l-amino-isoquininoin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - 5'-chloro- [2, 2 '] -bothiophenyl-5-sulfonic acid amide A. [1- (1-chloro-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] 5'-chloro- [2, 2 '] biphenyphenyl-5-sulfonic acid amide The title compound is prepared in accordance with • 10 described in Example 56, part A employing 5'-chloro- [2, 2 '] bithiophenyl-5-sulfonyl chloride and 3- (S) -amino-1- (1-chloro-isoquinoline-7-hydrochloride. -ylmethyl) -pyrrolidin-2-one as starting material. The crude product is purified by column chromatography eluting with 5% MeOH / CH2Cl_j for provide the title compound in the form of a white solid. E NMR (CDC13, 300 MHz) 3 8.30 (d, ÍH), 8.15 (s, ÍH), 7.82 (d, ÍH), 7.52-7.60 (m, 3H), 7.01-7.09 (, 2H), 6.88 (d , ÍH), 5.41 (s, ÍH), 4.68 (AB, 2H), 3.90 (m, ÍH), 3.29 (m, 2H), 2.61 (m, ÍH), 2.11 (m, ÍH). Ion spray MS, [M + H] = 538, 540, Cl. B. standard. [1- (l-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl ] - 5'-chloro- [2, 2 '] bithiophenyl-5-sulfonic acid amide The title compound is prepared according to that described in example 56, part B using [1- (1-chloroisoquinoline -7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide, of 5'-chloro- [2, 2 '] bithiophenyl-5-sulfonic acid as starting material. The crude product is purified by RP-HPLC eluting • with a gradient of 10% CH2CH / H20 (0.1% TFA) to 100% CH3CN. The appropriate 5 fractions are lyophilized to provide the title compound as a white solid. X NMR (DMSO-de, 300 MHz) delta 9.03 (bs, 2H), 8.58 (d, 1 HH), 8.31 (s, HH), 7.95 (d, HH), 7.81 (d, HH), 7.69 (d , ÍH), 7.61 (d, ÍH), 7.30-7.41 (m, 2H), 7.29-7.25 (m, 2H), 4.60 (AB, 2H), 4.25 (m, ÍH), 3.23 (m, 2H), 2.20 (m, ÍH), 1.75 (m, ÍH). MS ion spray, [M + H] * = 519, 521, Cl pattern. EXAMPLE 62 [1- (l-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl ] 2- (5-Chloro-thiophen-2-yl) -etensulfonic acid amide The title compound is prepared according to that described in example 56, part B using [1- (1-chloroisoquinol- 2- (5-chloro-thiophen-2-yl) -etensulfonic acid 7-oxo-pyrrolidin-3- (S) -yl] -amide as starting material. The crude product is purified by RP-HPLC eluting with a gradient of 10% CH3CN / H20 (0.1% TFA) to 100% CH3CN- The appropriate fractions are lyophilized to give the title compound as a pale pink ~ H solid. P NMR (DMSO-de, 300 MHz) delta 9.00 (bs, 2H), 8.32 (s, ÍH), 7.90-7.98 (m, 2H), 7.80 (d, ÍH), 7.63 (d, ÍH), 7.50 (d, ÍH), 7.48 (d, ÍH), 7.25 (d, ÍH), 7.18 (d, ÍH) ), 7.00 (d, ÍH), '6.73 (d, ÍH), 4.52 (AB, 2H), 4.20 (m, 1H), 3.23 (m, 2H), 2.4 3! (m, ÍH), 1.88 (m, ÍH). EM ion spray, [M + H] t = 463, 465, ^ 0 Cl pattern. EXAMPLE 63 [1- (4-Amino-quinazolin-6-yl-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 6-chlorobenzo [b] thiophen-2-trifluoroacetate The title compound is prepared according to the P10 described in Example 28, parts E, F, G using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride. X NMR (DMSO-de, 300 MHz) delta 9.83 (bs, 2H), 8.86 (m, 2H), 8. 25 (s, ÍH), 8.11 (s, ÍH), 8.00 (m, 3H), 7.85 (m, 2H), 7.55 (m, ÍH), 4.50 (AB, 2H), 4.15 (m, ÍH), 3.14 (m, 2H), 2.17 (? a, 15 ÍH), 1.72 (m, ÍH). FAB MS, [M + H] "= 488, 490; Cl pattern. EXAMPLE 64 [1- (4-Amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxopyrrolidin trifluoroacetate -3- (S) -yl] -6-chlorobenzo [b] thiophene-2-sulfonic acid amide The title compound is prepared according to that described in example 29, parts F, G, and H using 6-chloro-benzo [b] thiophene-2-sulfonyl chloride, X NMR (DMSO-de, 300 MHz) delta 8.78 (m, 2H), 8.28 (m, 2H), 8. 04 (m, 2H), 7.82 (m, 2H), 7.51 (d, 1H), 7.40 (s, 1H), 4.58 25 (AB, 2H), 4.13 (m, ÍH), 3.19 (m, 2H), 2.17 (m, ÍH), 1.68 (m, 1H). FAB MS, [M + H] t = 494, 496; Cl pattern. EXAMPLE 65 [1- (4-Amino-thieno [3,2-d] pyrimidin-7-yl- • methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate 6-Chloro-5-benzo [b] thiophene-2-sulfonic acid The title compound according to cpn is prepared as described in example 30, parts D, E using chloride 6-chloro-benzo [b] thiophen-2-sulfonyl. X NMR (DMSO-de, 300 MHz) delta 8.52 (m, 2H), 8.20 (m, ÍH), • 10 8.11 (s, ÍH), 7.91 (m, 2H), 7.71 (s, 1H), 7.42 (m, ÍH), 7.30 (, 2H), 4.58 (AB, 2H), 4.15 (m, ÍH), 3.21 (m, 2H), 2.20 (m, ÍH), 1. 72 (m, 1H). FAB MS, [M + H] + = 494, 496; Cl pattern. EXAMPLE 66 [1- (4-Amino-thieno [3,2-d] pyrimidin-7-yl-15-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide 5'-chloro trifluoroacetate - [2,2 '] Bithiophenyl-5-2-sulfonic acid The title compound of conformity is prepared as described in example 30, parts D, E, using '-chloro- [2,2 '] bromo-phenyl-5-sulfonyl. 20 X NMR (DMSO-de, 300 MHz) delta 9.30 (m, 2H), 8.70 (m, ÍH), 8. 44 (m, ÍH), 8.20 (m, ÍH), 7.55 (m, ÍH), 7.21 (m, 2H), 7.00 (m, ÍH), 4.57 (AB, 2H), 4.15 (m, ÍH), 3.20 (m, 2H), 2.19 (m, ÍH), 1. 70 (m, ÍH). FAB MS, [M + H] + = 526, 528; Cl pattern. EXAMPLE 67 25 2- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -pyrrolo [3,2-b] pyridine-1-carboxylic acid tert-butyl ester A. Tert-butyl ester of (2-bromo-pyridin-3? -yl) -carbamic acid To a solution of 3-amino-2-bromopyridine (1.5 g, 8.7 mm'ol) and di-tert-butyl dicarbonate (2.0 g, 9.2 mmol) in THF (15 mL) is added with 1.0 M sodium bis (trimethylsilyl) amide in THF (18 mL, 18 mmol) at a temperature of 0 ° C. it is stirred at room temperature for 4 hours, and then concentrated, quenched with saturated NHC1, diluted with EtOAc, and washed with water. The organic layer is dried in MgSO, treated with charcoal, filtered and concentrated to dryness. The title compound is obtained in the form of a light yellow solid (2.1 g, 7.7 mmol). : H NMR (CDC13, 300 MHz) delta 8.44 (d, ÍH), 8.03 (d, ÍH), 7.20 15 (, 1H), 7.02 (bs, ÍH), 1.50 (s, 9H). MS, [M + H] t = 273, 275. B. 2- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -pyrroloic acid tert-butyl ester [3, 2- b] pyridine-1-carboxylic acid The title compound is prepared from 1-tert-2-butyl ester of (2-bromo-pyridin-3-yl) -carbamic acid (1.6 g, 5.9 mmol) and benzyl acid ester ( 2-oxo-l-prop-2-ynyl-pyrrolidin-3- (S) -yl) -carbamic acid (1.6 g, 5.9 mmol) in accordance with the methods described in example 59, parts C, D and E. compound of the title is obtained in form of a white solid (0.29 g, 0.88 mmol).

: H NMR (CDCl 3, 300 MHz) delta 8.45 (d, ÍH), 8.27 (d, 1H), 1 7.18 (dd, ÍH), 6.50 (s, ÍH), 4.90 (AB, 2H), 3.64 (m, ÍH), 3.45 (m, 2H), 2.52 (m, ÍH), 1.85 (m, ÍH), 1.70 (s, 9H). The MS [M + H] "= 331. EXAMPLE 68 6-Chloro-1H-benzimidazole-2-sulfonyl chloride A mixture of 4-chloro-l, 2-phenylenediamine (4.3 g, 30 mmol), potassium hydroxide (1.9 g, 34 mmol), carbon disulfide ( 2.1 ml, 34 mmol), ethanol (30 ml) and water (4.5 ml) is heated at reflux for 3 hours. Norit is added, the mixture is refluxed for 10 minutes, and then filtered. The hot filtrate is diluted with water (30 ml, 50-75 ° C) followed by aqueous acetic acid (7.5 ml, 33%) with stirring. A brown solid forms, and the mixture is cooled with an ice bath. 6-Chloro-1H-benzimidazole-2-thiol (4.2 g, 2.3 mmol) is collected, washed with water and dried in vacuo. X NMR (DMSO-de, 300 MHz) delta 12.6 (d, 2H), 7.1 (s, 3H). MS, [M] ~ = 184, 186. A suspension of 6-chloro-lH-benzimidazole-2-thiol (1.0 g, 5.4 mmol) in 20% AcOH (30 mL) is cooled in an ice bath; C12 gas is bubbled through the mixture for 40 minutes. The resulting solid is collected by filtration, washed with water and air dried to provide the title compound as a light brown solid. X NMR (CDCl 3, 300 MHz) delta 7.75 (m, 2H), 7.50 (d, H) L EXAMPLE 69 Thieno [2,3-b] pyridine-2-sulfonyl chloride Thieotho [2, 3-b] pyridine (1.18 g, 8.7 mmol) to the • transfer sequence described in Example 8, part A. A flash chromatography (20% EtOAc / hexanes) of the crude product gives the title compound (0.59g, 2.5 mmol): -H NMR (CDC13, 300 MHz) delta 8.78 (dd, ÍH), 8.26 (dd, ÍH), 8. 10 (s, ÍH), 7.47 (dd, ÍH). MS Mt = 233, 235. EXAMPLE 70 ^ 10 6-Chloro-thieno [2, 3-b] pyridine-2-sulfonyl chloride 6-chloro-thieno [2,3-b] pyridine (0-73) is subjected g, 4.3 mmol) to the three step sequence described in Example 8, part A. Flash chromatography (15% EtOAc / Hexanes) of the crude product gives the title compound (0.75 g, 2.8 mmol): 15 X NMR ( CDCI3, 300 MHz) delta 8.19 (d, ÍH), 8.07 (s, ÍH), 7.47 (d, ÍH). MS M + = 267, 269, 271. The compounds of Examples 71-74 are synthesized using # method and reagents analogous to those described here. EXAMPLE 71 [1- (1, 6-diamino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of thieno [3, 2-b] pyridin-2 -amide. sulphonic The MS, [M] * = 469. EXAMPLE 72 [1- (l-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -25-yl] -amide of 2- ( 5-chloro-thiophen-2-yl) -etensulfonic ESI MS, [M + H] t = 463, 564 (Cl standard) EXAMPLE 73 [1- (l-Amino-isoquinolin-7-ylmethyl) -2-oxo - Ridolidin-3- (S) - • il] -amino-2-chloro- [2, 2 '] bithiophenyl-5-sulphonic acid The MS, [M + H] * = 519, 521 (Cl standard) EXAMPLE 74 [2-Oxo-l- (lH-pyrrol [3, 2-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 2- (5-chloro-thiophene) 2-il) -etensulfóhico MS, [M + H] + = 436, 438 (Cl standard). EXAMPLE 75 3- (R) -5-Chlorothiophen-2-yl) -ettensulfonic acid [1- (4-aminoquinino-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate Part A : 7-methyloxycarbonyl-4-chloroquinoline. Heat 4-chloro-7-trifluoromethylquinoline (5.0 g, 21.6 mol) in 100 mL of 80% H2SO4 at a temperature of 2001 C for 24 hours in a sealed tube. The solution is cooled, drained in water and neutralized with sodium hydroxide to a pH of about 3-4. The precipitated solid is collected, washed with water and dissolved in 2N sodium hydroxide. The aqueous solution is washed with ethyl acetate and then acidified to a pH of about 3-4. The precipitate is collected, washed with water, and dried in a vacuum oven overnight to provide 7-carboxy-4-chloroquinoline in the form of a solid (5.1 g, 24.6 mmol). A portion of this material (2.0 g, 9.6 mmol) is treated with anhydrous THF (200 mL and 200 mL) and DMF (2 mL) and 2M oxalyl chloride in methylene chloride (14.5 mL, 29 mmol). The resulting suspension is stirred at a medium temperature 2h then treated with methanol (10 mL). After stirring for 30 minutes, the solution is concentrated and the residue is absorbed in methylene chloride.

The solution is washed with saturated sodium bicarbonate and dried (sodium sulfate) and concentrated to give the title compound as a solid (2.1 g, 9.5 mmol). 10 MS m / z: M + = 221; X NMR (CDC13, 300 MHz) delta 8.6 (s, ÍH), 8. 2 (s, ÍH), 7.9 (d, ÍH), 7.65 (d, ÍH), 7.45 (s, ÍH), 3.95 (s, 3H). Part B: 7-hydroxymethyl-4-chloroquinoline Dissolve 7-methyloxycarbonyl-4-chloroquinoline (2.1 g, 9.5 mmol) in anhydrous THF (25 mL) and anhydrous ether (200 mL) The solution is cooled in a dry ice bath Acetone and treated with lithium aluminum hydride, ÍM THF (11.0 Ml, 11 mmol) The solution is heated (approximately -45 ° C) for 20 minutes and quenched with ethyl acetate.

The solution is diluted with ether (100 L) and treated with water (36 mL), 15% NaOH (36 mL) and water (3 times 36 mL), successively. The mixture is filtered and evaporated! to provide the title compound in the form of a residue (2.0 g, 9.7 mmol) which is dried in vacuum and used without further purification. MS m / z: M + = 193; 'P NMR (CDC13, 300 I MHz) delta 0.00, 8.65 (d, ÍH), 8.15 (d, ÍH), 8.0 (d, ÍH), 7.6 (d, 1H), 7.45 (d, ÍH), 4.8 (s, 2H). Part C: 7-bromomethyl-4-chloroquinoline • Treat 7-hydroxymethyl-4-chloroquinoline (0.2 g, 0.97 mmol) 5 with 48% HBr and heat at a temperature of 20 ° C for 1 hour. The resulting solution is cooled with ice, diluted with water and treated with ethyl acetate and sodium bicarbonate until reaching the basic level of pH paper. The layers are separated and the organic layer is washed with water, dried P 10 (Na 2 SO 4) and concentrated to give 7-bromomethyl-4-chloroquinoline (0.23 g, 0.9 mmol). MS m / z: M "= 255; HH NMR (CDC13, 300 MHz) 8.75 (d, HH), 8.25 (d, HH), 8.1 (s, HH), 7.77 (d, HH), 7.5 (d) , HI), 4.7 (s, 2H) Part D: 3-amino-1- (4-chloro-quinolin-7- 15-ylmethyl) -2-oxo-pyrrolidinone hydrochloride Dissolves 3- (R) - (t -butylcarbamyl) -2-oxo-pyrrolidinone (1.0 g, 5.0 mmol) in THF (70 L), cooled in an ice bath, and treated with tetrabutylammonium iodide (0.18 g) and 60% sodium hydride ( 0.24 g, 6.0 mmol) The reaction mixture is stirred at the temperature of 0 ° C for 30 minutes, and then treated dropwise with a solution of 7-bromomethyl-4-chloroquinoline (1.3 g, 5.1 mmol) in THF (50 MI). The resulting solution is stirred at a temperature of 0 ° C for 2 hours and then quenched with a solution of ammonium chloride and concentrated. Dilution with ethyl acetate is followed by a wash with water; the organic layer is dried (sodium sulfate) and concentrated. The residue is subjected to chromatography (3% methanol / methyl chloride) to • provide solid 3- (R) - (t-butylcarbamyl) -1- (4-chloro-quinolin-7- 5-ylmethyl) -2-oxo-pyrrolidinone (1.33 g, 3.3 mmol). This material is treated with a saturated solution of hydrogen chloride in ethyl acetate and stirred for two hours at room temperature. The solid is filtered, washed with ethyl ether and dried with air to provide the title compound. • 10 title (0.95 g, 3.0 mmol) MS m / z: M + =; : H NMR (CD30D, 300 MHz) 9. 0 (d, ÍH), 8.5 (d, ÍH), 8.15 (s, ÍH), 8.0 (d, ÍH), 7.9 (d, ÍH), 4.9 (q, 2H), 4.2 (t, 1H), 3.4 (m, 2H), 2.65 (m, ÍH), 2.1 (my h) . Part E: 3- (R) -5-Chloro-thiophen-2-yl) ethersulfonic acid [1- (4-chloro-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide] 3-Amino-1- (4-chloro-quinolin-7-ylmethyl) -2-oxo-pyrrolidine hydrochloride (40.0 g, 0.12 mmol) is treated with DMF (2 • ml), acetonitrile (8 mL), triethylamine (1.2 mL, 8.4 mmol) and a solution of 5-chloro-thiophen-2-yl) -etensulfonyl chloride 20 (30.0 mg, 0.12 mmol) in acetonitrile (2.0 mL) at a temperature of 0 ° C. After 2 hours, the solution is emptied, and extracted with ethyl acetate. The organic layer is washed with water, dried is sodium sulfate and concentrated to provide the title compound (28 mg, 0.5 mmol). 25 MS m / z: 481; [M + l] +; X NMR (CDC13, 300 MHz) delta 8.8 (d, ÍH), 8.15 (d, ÍH), 7.9 (d, 2H;, 7.85 (s, ÍH), 7.4-7.5 (m, 2H), 6.7 (d, ÍH), 6.6 (d, ÍH), 6.5 (d, ÍH), 5.8-5.9 (m, ¡1H), 4. 75 (q, 2H), 4.2 (t, ÍH), 3.3-3.4 (m, 2H), 2.6 (m, ÍH), 2.0 • (my h) . 5 Part F: [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 3- (R) -5-chloro-thiophene-2-yltrifluoroacetate ) -enesulfonic acid [3- (4-chloro-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 3- (R) -chloro-thiophen-2-yl) -etensulfonic acid (20) mg), ^ 10 ammonium acetate (0.5 mg), and phenol (1.0 g) are heated in a sealed tube at a temperature of 120 ° C for 1.5 hours. The contents of the containers are diluted with ethyl acetate and washed with IN NaOH (4 X 100 ml), water, concentrated and purified by HPLC (20% acetonitrile in TFA). aqueous 0.1% to 100% acetonitrile) and lyophilized to give the title compound 2.0 mg: MS m / z: 463 [M + H] X NMR (CD3OD, 300 MHz) S.3 (m, 1H) 7.7 (s, ÍH), 7.6 # (d, ÍH), 7.5 (d, ÍH), 7.2 (d, 1H), 7.0 (s, ÍH), 6.9 (d, 'lH), 6.8 (d, ÍH), 4.9 (q, 2H), 4.25 (t, ÍH), 3.5 (, 2H), 2., 6 (m, ÍH), 2.05 (, ÍH). The compounds of Examples 76-81 are synthesized using the analogous reagents described herein. EXAMPLE 76 2- (S) - [[1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] - (6-chlorobenzo [b]) methyl ester trifluoroacetate ] thiophen-2-sulfonyl) -amino] -acetic ESI MS, [M + H] t = 559, 561. EXAMPLE 77 [1- (4-Amino-quinolin-7-ylmethyl) -2-oxo- trifluoroacetate 5-pyrrolidin-3-yl] -amide of 2- (S) -6-chloro-benzo [b] thiophen-2-sulfonic acid ESI MS, [M + H] t = 487, 489. EXAMPLE 78 Trifluoroacetate [1 - (4-amino-qu? Nolin-7-ylmet? L) -2, -oxo- ^ 10 pyrrolidin-3-yl] -amide of 2- (s) - (5-chloro-thiophen-2-yl) ) - ESI MS ESS, [M + H] * = 463, 465. EXAMPLE 79 [1- (4-Ap? ino-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) ditrifluoroacetate. -yl] -thieno [3, 2-b] pyridine-2-sulphonic acid amide ESI MS, [M + H] x = 454. • EXAMPLE 80 N- (3-amino-pyridin-4-yl) -2- [3- (7-methoxy-naphthalene-2-sulphonylamino) -2-oxo-pyrrolid? Nl-yl] -acetamide MS, [M + H] "= 470. EXAMPLE 81 2- [3- ( 7-Methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -Np iridin-4-yl-acetamide 25 MS, [M + H] + = 455.

EXAMPLE 82 (2-Oxo-l- [2- (pyridin-4-yl-amino) -ethyl] -pyrrolidin-3- (S) -yl.}. - 6-chlorobenzo [6-chlorobenzo] acid trifluoroacetate ] thiophene-2-sulphonic Part A: [1- (2-Amino-ethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butylic ester Tert-butyl ether is dissolved of [2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid (4.0 g, 20 mmol) is THF (150 mL), cooled in an oil bath and treated with 60% hydride. sodium (0.95 g, 24 mmol) The reaction mixture is stirred for 30 minutes and then reacted with tetra-butylammonium iodide (0.16 g, 0.44 mmol) and bromoacetonitrile (1.7 mL, 24 mmol). The reaction is quenched with concentrated water, to a small volume and extracted with methylene chloride (4 times) The combined organic extracts are concentrated and the residue is subjected to chromatography (2% MeOH / CH2Cl2) to provide tert-butyl acid ester [l-Cyanomethyl-2-oxo-pyrrolidin-3- (S) -yl] carbamic (3.4 G, 14 mmol) MS m / z: 240, [M + 1] +; XE NMR (CDC13, 300 MHz), delta 5.08. This material (3.0 g, 12.6 mmol) is dissolved in ethanol (80 m_L) and treated with platinum oxide (0.8 g) at 35, 155 kg / m2 (50 psi) of hydrogen gas for 24 hours. The catalyst is removed by filtration and the solution is concentrated! to provide the title compound (2.9 g, 12 mmol). The MS m / z: 244, [M + l] "; X NMR (CDC13, 300 MHz) delta 5.13 (br, ÍH), 4.13 (m, ÍH), 3.34 (m, 5H), 2.85 (t, ÍH), 2.60 (m, 1H), 1.90 (m, 1H), 1.40 (s, 9H). Part B: tert-butyl ester. { 2-oxo-l- [2- (2, 3, 5, 6-tetrachloro- • pi idin-4-ylamine) -ethyl] -3- (S) -yl} -carbamic 5 [1- (2-Amino-ethyl) -2-oxo-pyrrolidin-3-yl] -carbamic tert-butyl ester (2.7 g, 11 mmol) in methylene chloride (100 mL) is dissolved and treated with 4-nitro-2, 3, 5-tetraploropyridine (3.2 g, 12 mmol) and N-methylmorpholine (2.6 mL, 24 mmol). The reaction mixture is stirred for 5 hours, concentrated P P and the residue is purified by chromatography (50-60% ethyl acetate / hexane) to afford the title compound (3.2 g, 7.0 mmol). The MS ra / z: 456, 458, 460 !, 462 [M] t; X NMR (CDC13, 300 MHz) delta 5.6 (br, ÍH), 5.07¡ (br, ÍH), 4.15 (, ÍH), 3.94 (m, 2H), 3.60 (m, 2H), 3.36 (m "2H) , 15 2.65 (m, ÍH), 1.98 (m, ÍH), 1.44 (s, 9H). Part Cj 3- (S) -amino-1- [2- (pyridin-4-ylamino) -ethyl] pyrrolidin-2-one Tert-butyl acid ester is dissolved. { 2-Oxo-l- [2- (2, 3,4,5,6-tetrachloro-pyridin-4-ylamino) -ethyl] -pyrrolidin-3-20 (S) -yl} -carbamic (0.42g, 0.92 mmol) in methanol (16 L) and treated with 0.5 M sodium methoxide in methanol (18 mL), 8 mmol). The solution is treated with 10% Pd / C and stirred under an oxygen gas pressure of 42,186 kg / m2 (60 psi) for 16 hours. The solvent is removed and the residue is treated with saturated NH 4 Cl and then with saturated NaHCO 3. The aqueous solution is extracted with methylene chloride (8 times). The methylene chloride layer is dried (MgSO) and concentrated to a white foam (0.19) • g, 5.9 mmol). MS m / z: 321, [M + l] ";: H NMR (CDC13, 300 MHz) 5 delta 8.20 (d, 2H), 6.45 (d, ÍH), 5.1 (br, ÍH), 4.1 (m , 1H), 3.7 (m, HH), 3.4 (m, 5H), 2.57 (m, HH), 1.96 (m, HH), 1.46 (s, 9H) .This material (0.14g, 0.44 mmol) is treated with 20% trifluoroacetic acid in methylene chloride (10 mL) at room temperature for 2 hours • 10 The concentration of the solution provides a clean product in the form of TFA salt.The free base (0.072g, 0.33 mmol) is obtained by applying the TFA salt on the silica gel column and by elution with NH 4 OH / MeOH / CH 2 Cl 2 (1:10:70). APCl MS m / z: 221, [M + 1] +; LH NMR (CDCl 3, 300 MHz) 8.17 (d, 2H), 6.40 (d, 2H), 4.90 (br, HH), 3.55 (m, 3H), 2.42 (m, HH), 1.80 (m, HH). Part D: Trifluoroacetate of. { 2-Oxo-l- [2- (pyridin-4-yl- • amino) -ethyl] -pyrrolidin-3- (S) -yl} 6-chlorobenzo [b] thiophene-2-sulphonic acid amide. 3- (S) -amino-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-2-one is dissolved ( 0.12 mmol) in MeCN (5 mL) and treated with 4-methylmorphine (0.035 mL, 0.32 mmol); 6-chlorobenzo [b] thiophene-2-sulfonyl chloride (0.033 g, 12 mmol) in MeCN (1 mL) is added dropwise. The reaction mixture is stirred to Room temperature for two hours and then subjected to purification by HPLC, to give the title compound as a white solid (0.060 g, 0.11 mmolj MS m / z: 451, 453 [M + 1]; NMR (CD3OD, 300 MHz) delta 8.15 (d, ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• m, 6H), 2.37 (m, ÍH), 1.83 (m, ÍH). The compounds of Examples 83-84 were synthesized using reagent methods analogous to those described herein. EXAMPLE 83 ^ 10. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} 5'-chloro- [2, 2 '] bituiophenyl-5-sulfonic acid MS, [M + H] ~ = 483, 485. EXAMPLE 84 Trifluoroacetate of. { 2-Oxo-l- [2- (pyridin-4-ylamino-ethyl] -5-pyrrolidin-3-yl] -6-chloro-thieno [2, 3-b] pyridine-2-sulphonic acid MS, [M + H] '= 452, 454. • EXAMPLE 85 Dichloroacetate of. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl-20-pyrrolidin-3-yl} -amide of thienic acid [3, 2-b] pyridine-2-sulfonic acid MS, [M + H] "= 418. EXAMPLE 86 {2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin- 3-yl.} -amide of 2- (5-chloro-thiophen-2-yl) -etensulfonic acid MS, [M + HT = 427, 429. EXAMPLE 87 Ditrifluoroacetate of. {1- 1- [2- ( 2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} -amide of (S) -5'-5-chloro- [2, 2 '] ] bituiophenyl-5-sulphonic MS, [M + H] "= 532, 534, 536. EXAMPLE 88 1- [2- (2-Amino-3-chloro-pyrid n-4-ylamino) -ethyl] ditrifluoroacetate] -2-oxo-pyrrolidin-3-yl.} - (-s) -6- ^ r-10-chloro-benzo [b] thiophene-2-sulfonic acid MS, [M + HG = 500, 502, 504 EXAMPLE 89 Methyl acid ester ((6-chloro-benzo [b] t] ofen-2-sulfonium lo) - {2-oxo-i- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino) -acetic To a solution in DMF (2 ml) of 6-chloro-benzo [b] thiophene-2-sulphonic acid is added. { 2-Oxo-l- [2- (pyridin-4-yl-amino) -ethyl] - • pyrrolidin- (S) -yl} amide (0.030 g, 0.066 mmol) and K2C03 (0.027 g, 0.2 mmol). After stirring at room temperature for 10 minutes, methyl bromoacetate (0.01 ml, 0.1 mmol) is added and the mixture is stirred for 3 hours. The solvent is removed and the residue is purified by chromatography using NHOH / MeOH / CH2Cl2 (1: 5: 95) as eluent. The title compound is obtained in form i of a white solid (0.011 g, 0.021 mmol). MS m / z: 523, 525 [M + 1] +: -H NMR (CDCL3, 300 MHz) delta 8.15 (d, 2H), 7.98 (s, 1H), 7.84 (s, ÍH), 7.80 ( d, ÍH), 7.41 (d, ÍH), 6.35 (d, 2H), 4.72 (br, ÍH), 4.55 (t, ÍH), 4.18 (d, ÍH), 3.85 (d, ÍH), 3.70 (s, ¡3H), • 2.55 (m, ÍH), 3.4 (m, 5H), 2.60 (m, ÍH), 2.35 (m, ÍH). The compounds of Examples 90-100 are synthesized by using a method and reagents analogous to those described herein. EXAMPLE 90 ((6-Chloro-benzo [b] thiophen-2-sulphonyl) -. {2- (pyidin-4-ylamino) -ethyl] -pyrrolidin-3-yl} - acid trifluoroacetate. ^ P 10 amino) -acetic MS, [M + H] t = 509, 511. EXAMPLE 91 Allyl-. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrole idin-3-yl} - 6-chloro-benzo [b] thiophene-2-sulfonic acid amide 15 MS, [M + H] + = 491, 493. EXAMPLE 92 Methyl-. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} - • 6-chloro-benzo [b] thiophene-2-sulfonic acid amide MS, [M + H] t = 465, 467. EXAMPLE 93 Trifluoroacetate of. { 1- [2 (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} (S) -2- (5-Chloro-thiophen-2-yl) -ethersulfonic acid amide, [M + H] + = 476, 478, 480. EXAMPLE 94 Ditrifluoroacetate of. { 1- [2 (2-ami-no-3-chloro-pyrid-1-in-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} -amino '(S) -thieno [3, 2-b] pyridine-2-sulfonic acid MS, [M + H = 467, 469. EXAMPLE 95 (2- (5-Chloro-thiophene) methyl ester 2? -yl) -ethersulfonyl] - {2-oxo-l- [2 (pyridin-4-ylamino) -ethyl-pyrrolidin-3-yl} -acetic MS, [M + H] * = 499 , 501 10 EXAMPLE 96 ([2- (5-Chloro-thiophen-2-yl) -etensulfonyl] -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] isopropyl ester - pyrrolidin-3-yl.} - acetic MS, [M + H] t = 527, 529. EXAMPLE 97 ([2- (5-Chloro-thiophen-2-yl) -ettensulfonyl] - trifluoroacetate]. {2-Oxo-l- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amino-acetic MS, [M + H] "= 485, 487. EXAMPLE 98 Trifluoroacetate of ( 2-methoxy-ethyl) -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl-pyrrolidin-3-yl} -amide of 2- (5-chloro-thiophene) 2-yl) -ethenesulfonic acid MS, [M + H] + = 485, 487. EXAMPLE 99 ([2- (5-Chloro-thiophen-2-yl) -etensulfonyl] - ethyl ester ethyl ester trifluoroacetate. 2-oxo-l- [2- (pyridin-4-ylamino) -e usefull] -pyrrolidin-3-yl} -acetic MS, [M + H] t = 513, 515. EXAMPLE 100 3- (5-Chloro-thiophen-2-yl) -N- [2-oxo-l- [2- (pyridin-4-) trifluoroacetate ilamino) -ethyl] -pyrrolidin-3-yl} acrylamide MS, [M + H = 390, 392. EXAMPLE 101 1- [1- (4-aminoquinazolin-7-methyl) -2-oxopyrrolidin-3- (S) -yl] -3- (4-) trifluoroacetate chlorophenyl) urea A. Tert-butyl acid ester (2-oxopyrrolidin-3- (S) -yl) -carbamic acid Na- (S) -tert-butoxycarbonyl-α-alpha, gamma-diaminobutyric acid (20 g) is suspended / dissolved. , 92 mmol) in THF (360 mL), and 1-hydroxybenzotriazole hydrate (15.5 g, 100 mmol) is added, followed by the addition of triethylamine (28 g, 280 mmol). The suspension is stirred at room temperature for 15 minutes under a nitrogen atmosphere, before the addition of 1- [3- (dimethylamino) -propyl] -3-ethylcarbodiimide hydrochloride (22 g, 115 mmol). The reaction mixture is heated at 60 ° C for 22 hours, cooled and the solids are removed by filtration through a plug of silica.

The solids and silica are washed with THF until more product is observed in the filtrate by TLC. The combined filtrate is concentrated and the residual yellow sticky solid remains under high vacuum during nbche. The residual material is crushed with ethyl acetate, (100 ML), removed by filtration and washed with ethyl acetate and ethyl ether, and then dried under high vacuum. The product is isolated in the form of colorless fine needles (12.2 g, 61 mmol). : H NMR (CDC13, 300 MHz) delta 6.18 (m, ÍH); 5.11 (m, ÍH); 4.15 (, ÍH); 3.35 (m, 2H); 2.70 (m, ÍH); 1.96 (m, ÍH); 1.45 (s, • 10 9H). ESI MS, [M + H] + = 201. B. 2-Benzylideneamino-4-methylbenzonitrile Benzaldehyde (8.9 g, 84 mmol) is added to a substance of 2-amino-4-methylbenzonitrile (10.0 g, 756 mmol) in heptane (250 mL), and the mixture is refluxed under nitrogen overnight. The hot solution is decanted into a preheated flask to leave the insoluble coffee-colored oil material and the solution is cooled to room temperature • after addition of ethyl acetate (2 L) The resulting residue is removed by filtration and washed with heptane: ethyl acetate = 100: 1 (2X25 mL), and dried under high vacuum to give a beige powder (12.54 g) 57 mmol). X NMR (CDCl 3, 300 MHz) delta 8.46 (H, s); 7.95 (dd, 2H); 7.50 (m, 4H); 7.07 (dd, ÍH); 56.97 (s, ÍH); 2.43 (s, 3H). C. 2-Amino-4- (bromomethyl) -benzonitrile. 2,2'-Azobisisobutyronitrile (AIBN) (1.31 g, 8 mmol) is added to a solution of N-bromosuccinimide (6.87 g, 38 mmol) and 2- benzylideneamino-4-methylbenzonitrile (7 g, 31.8 mmol) in carbon tetrachloride (250 mL), and the reaction mixture • it is subjected to reflux under nitrogen at night. The reaction mixture is cooled and filtered through a plug of Celite, and the Celite is washed with carbon tetrachloride (100 L). The combined filtrate is washed with NI HCl, NaHCO; saturated aqueous, dried in MsSO and concentrated in vacuo. The crude product is purified by chromatography on • 10 column on silica with 10-20% ethyl acetate / hexanes. The combined product fractions are concentrated and the resulting sticky solid is washed with ethyl ether / hexanes to give the product as a pale yellow solid (3.2 g, 15 mmol). X NMR (CDC13, 300 MHz) delta 7.36 (d, ÍH); 6.75 (m, 2H); 4.45 (brs, 2H). MS, [M + H] r = 212. D: [1- (3-amino-4-cyanobenzyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid tert-butyl ester Tert-butyl ester of tert-butyl acid -butylic acid (2-oxopyrrolidin-3-20 (S) -yl) carbamic acid (1 g, 5 mmol) in THF (100 mL) under nitrogen, and cooled to 0 ° C. Tert-butoxide (0.62) is added. g, 5.5 mmol) in one portion to the solution with vigorous stirring, followed by 18-crown-6 (10 mg, 0.038 mmol), and allowing the reaction mixture to warm to room temperature and stir during a hour. The solution is cooled to a temperature of 0 ° C and 2-amino-4- (bromomethyl) enzonitrile (1.16 g, 5.5 mmol) is added dropwise as a solution in THF (10 mL), before allowing the m zcla • The reaction is warmed to room temperature and stirred overnight. The reaction is quenched with 0.25 M HCl (20 L), then neutralized with saturated aqueous NaHCO 3, and brine is added. The solution is extracted with ethyl acetate, and the organic phase is dried over MgSO4, concentrated and purified by column chromatography on silica with 0.5-5% ^ k. 10 methanol / dichloromethane. The fractions of the product are combined, concentrated, and the oily semisolid residue triturated with hexanes / dichloromethane = 100/1 (25 mL),. The product is isolated in the form of a pale yellow powder (1.24 g, 3.75 mmol). X NMR (CDC13, 300 MHz) delta 7.35 (d, ÍH); 6.64 (dd, ÍH); 5.15 (brs, ÍH); 4.40 (m, 4H); 4.19 (, ÍH); 3.24 (, 2H); 2.60 (m, ÍH); 1.90 (, ÍH); 1.45 (s, 9H). ESI MS, [M + H] * = 331. • E: [1- (4-aminoquinazolin-7- 20-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid tert-butyl ester Combine [1- (3-amino-4-cyanobenzyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid tert-butyl ester (890 mg, 2.69 mmol) and 1,3,5-triazine (650 mmol) , 8 mmol) in ethanol (40 mL) and acetic acid (480 mg, 8 mmol) is added. The mixture of The reaction is refluxed under nitrogen overnight, cooled and pressurized directly on silica. The product is purified by column chromatography on silica with 5-20% methanol / dichloromethane (containing hydroxide). • aqueous ammonium from 0.5% to 28%). The product fractions are combined and concentrated and the residue is left under high vacuum at night. The product is isolated in the form of a pale yellow solid (0.50 g, 1.4 mmol). XH NMR (DMSO-d, 300 MHz) delta 9.90 (brs, 2H); 8.35 (s, ÍH); 8.16 (d, ÍH); 7.49 (d, ÍH); 7.31 (dd, ÍH); 7.22 (br d, ÍH); • 10 4.57 (d, ÍH); 4.44 (d, ÍH); 4.20 (m, ÍH); 3.18 (m, 2H); 2.23 (m, ÍH); 1.80 (m, ÍH); 1.93 (s, 9H). ESI MS, [M + H] t = 358. F: 3- (S) -apino-1- (4-aminoquinazolin-7- ylmethyl) pyrrolidin-2-one hydrochloride Tert-butyl acid ester [l] is dissolved - (4- 15 aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] carbamic (1.70 g, 5.15 mmol) in methanol (100 mL) and stirred at a temperature of 0 ° C while allowing the introduction of HCl bubbles, g) through the solution to saturation (the solution becomes cloudy). It allows the mixture of The reaction is at room temperature for 10 minutes, and then concentrated in vacuo. The residue is washed with ethyl acetate and ether, and dried under high vacuum to give the product as a pale yellow powder (1.33 g, 4 mmol). 25 X NMR (DMSO-de, 300 MHz) delta 8.81 (s, ÍH); 8.73 (br s, 2H); 8. 57 (d, ÍH); 7.87 (d, ÍH); 7.65 (dd, ÍH); 6.68 (br s, 2H); 4.73 (d, ÍH); 4.60 (d, ÍH); 4.13 (m, ÍH); 3.35 (m, 2H); 2.43 (m, ÍH); 2.10 (m, ÍH). ESI MS, [M + H] "= 258. • G: 1- [1- (4-aminoquinazolin-7-ylmethyl) -2- 5 oxopyrrolidin-3- (S) -yl] -3- (4) trifluoroacetate chlorophenyl) urea. 3- (S) -amino-1- (4-aminoquinazolin-7-methyl) pyrrolidin-2-one hydrochloride (50 mg, 0.15 mmol) and triethylamine are stirred at room temperature for 30 minutes. 40 mg, 0.40 mmol) in dimethylformamide (3 L), and 4- ^ 10 chlorophenyl isocyanate (25 mg, 0.16 mmol) is added as a solution in DMF (2mL), left at room temperature for one hour, and then The dimethylformamide is removed at a temperature of 45 ° C / 17,577 kg / m2 (25 psi) in a vortex blower, the residue is dissolved in 30% acetonitrile / water (2%). of trifluoroacetic acid) and purified by reverse phase HPLC preparation with gradient avoidance 15-45% acetonitrile / water (0.1% trifluoroacetic acid). The product fractions are combined, the acetonitrile is removed under vacuum, and the aqueous solution is lyophilized. to produce the product in the form of a whitish powder which is washed with acetonitrile (2 L) to provide a pure product in the form of a white powder (45 mg, 0.086 mmol). X NMR (DMS0-d6, 300 MHz) delta 9.60 (br s, 2H); 8.87 (s, ÍH); 8.80 (s, ÍH); 8.37 (d, ÍH); 7.62 (dd, ÍH); 7.58 (d, ÍH); 7.43 (d, 2H); 7.25 (d, 2H); 6.65 (d, ÍH); 4.64 (, 2H); 4.36 (m, ÍH); 3.28 (m, 2H); 2.40 (m, ÍH); 1.91 (m, ÍH). ESI MS, [M + H] r = 411. EXAMPLE 102 N- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -2- (5-chlorothiophen-2-trifluoroacetate iioxy) acetamide 15-minute hydrochloride of 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethylpyrrolidin-2-one (40 mg, 0.12 mmol) and diisopropylethylamine (130 mg, 1 mmol) are stirred for 15 minutes at room temperature. ) in dimethylformamide (1 mL) The solution mentioned above is added to a solution of 2- (5-chlorothiophen-2-yloxy) acetic acid (23 mg, 0.12 mmol), diisopropylethylamine (20 mg, 0.16 mmol) and 2- (5-chlorothiophen-2-yloxy) acetic tetramethyluronium tetrafluoroborate (TBTU) (39 mg, 0.12 mmol) in dimethylformamide (1 L), which has been stirred at room temperature for 5 minutes before addition. The reaction mixture is stirred at room temperature over the weekend.The dimethylformamide is removed at a temperature of 45 ° C / 17.577 kg / iirr (25 psi) in a vortex air blower, and the residue is dissolved in a vacuum. % acetonitrile / water (trifluoroacetic acid al 2%) and purified by reverse phase HPLC preparation with gradient elution 14-45% acetonitrile / water (0.1% trifluoroacetic acid). The product fractions are combined, the acetonitrile is removed in vacuo, and the aqueous solution is lyophilized to give the product as an off-white powder (34 g, 0.062 mmol). : H NMR (DMSO-de, 300 MHz) delta 9.62 (br s, 2H); 8.80 (s; ÍH); • 8.64 (d, ÍH); 8.34 (d, ÍH); 7.62 (dd, ÍH); 7.60 (d, ÍH); 6.78 5 (d, ÍH); 6.28 (d, ÍH); 4.59 (m, 5H); 3.27 (m, 2H); 2.32 (m, ÍH); 1.97 (m, ÍH). ESI MS, [M + H] ~ = 432. EXAMPLE 103 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-indo1-2-ylmethyl) amino trifluoroacetate] pyrrolidin-2-one • 10 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one hydrochloride (40 mg, 0.12 mmol) and potassium carbonate are dissolved / dissolved in powder (80 mg, 0.58 mmol) in DMF (1 L), and to this solution is added 2-bromomethyl-l-tert-butoxycarbonyl-5-chloroindole (41 mg, 0.12 mmol) as a a solution in DMF (1 mL). The reaction mixture is sonicated for 10 minutes and then stirred at room temperature overnight. The dimethylformamide is removed • a temperature of 45 ° C, 511 kg / m2 (25 psi) in a vortex air blower, and the residue is extracted in methanol (2 x 10 mL). The filtrate is diluted with methanol (30 mL), and cooled to 0 ° C while introducing dry HCl bubbles (g) through the solution to saturation. The reaction mixture is left overnight at room temperature. The resulting red solution is concentrated in vacuum and extracted in nitrile acid (2 mL), diluted with water (1% trifluoroacetic acid) and the insoluble solids are removed by filtration before purification of the crude material by preparative reverse phase HPLC with • gradient elution 20-60% acetonitrile / water (5% trifluoroacetic acid). The product fractions! are combined, the acetonitrile is removed in vacuo, and the aqueous solution is lyophilized to give a product in the form of an off-white powder (12 mg, 0.022 mmol). P NMR (DMSO-de, 300 MHz) delta 11.43 (s, 1H); 9.61 (br s, • 10 3H); 8.78 (s, ÍH); 8.36 (d, ÍH); 7.67 (s, 1K); 7.63 (d, ÍH); 7.59 (dd, ÍH); 7.46 (d, ÍH); 7.13 (dd, ÍH); 6.64 (d, ÍH); 4.70 (d, ÍH); 4.63 (d, ÍH); 4.51 (, 2H); 4.19 (m, ÍH); 3.34 (m, 2H); 2.45 (, ÍH); 2.07 (m, ÍH). ESI MS, [M + H] + = 421. ' EXAMPLE 104 15 1- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5- • chlorothiophen-2-ii) urea 'trifluoroacetate and trifluoroacetate 5-Chlorothiophen-2-carboxylic acid [1- (4-aminoquinazol? N-7-ylmethyl) -2-? Oxopyrrolidin-3- (S) -yl] -amide 3-Hydrochloride is dissolved in 3- (S) - amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one (40 mg, 0.12 mmol) and diisopropylethylamine in DMF (1 mL) and 5-chlorothiophene-2-carboxylic acid azide (23 mg , 0.12 mmol). The reaction mixture is heated to a temperature of 100 ° C for 20 minutes, cooled to room temperature and the dimethylformamide is removed at a temperature of 45 ° C / 17.577 kg / m2 (25 psi) in a vortex air blower. The residue is dissolved in 30% acetonitrile / water (2% trifluoroacetic acid) and purified by preparative reverse phase HPLC with gradient elution 15-30% acetonitrile / water (0.1% trifluoroacetic acid). The fractions of the two different products are combined separately, the acetonitrile is removed in vacuo, and the aqueous solutions are lyophilized to yield the products in the form of white powders: urea (9 mg, 0.017 mmol), amide (22 mg, 0.043 mmol ). Urea: X NMR (DMSO-d6, 300 MHz) delta 9.98 (s, ÍH); 9.59 (br s, 2H); 8.80 (s, ÍH); 8.38 (d, ÍH); 7.59 (, 2H); 6.88 (d, ÍH); 6.75 (d, ÍH); 6.24 (d, ÍH); 4.67 (d, ÍH); 4.59 (d, 'ÍH); 4.39 (m, ÍH); 3.27 (m, 2H); 2.40 (m, ÍH); 1.94 (m, ÍH). ESI MS, [M + H] + = 421. Amide: X NMR (DMSO-d, 300 MHz) delta 9.73 (br s, 2H); 9.02 (d, ÍH); 8.82 (s, ÍH); 8.40 (d, ÍH); 7.65 (m, 3H); 7.21 (d, ÍH); 4.68 (, 3H); 3.31 (m, 2H); 2.37 (m, 2H); 2.06 (m, ÍH). ESI MS, [M + H] t = 421. EXAMPLE 105 Acid methyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - [3- (5-chlorothiophen-2-yl) acryloyl] amino} acetic acid A. 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one Chromatograph 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) hydrochloride) pyrrolidin-2-one (600 mg, i 1.82 • mmol) on silica with 12% methanol / 2% ammonium hydrochloride 5 (28% aqueous) / 86% dichloromethane, and the product fractions are combined and concentrated to provide the free base in the form of a yellow powder pale (360 mg, 1.4 mmol). X NMR (DMSO-de, 300 MHz) delta 8.35 (s, ÍH); 8.16 (d, 1 H) 10 7.74 (br s, 2H); 7.29 (dd, ÍH); 4.55 (d, ÍH); 4.49 (d, ÍH) 3.95 (br d, 2H); 3.55 (t, ÍH); 3.18 (m, 2H); 2.27 (m, '1H) 1.69 (m, ÍH) .ESI MS, [M + H] + = 258. B: Trifluoroacetate of tert-butyl acid ester. { G 1- (- aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -15-yl] amino} acetic acid Tert-butyl bromoacetate (247 mg, 1267 mmol) in dimethylformamide (5 mL) is added dropwise to a solution of 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin- 2-oria (326 mg, 1267 mmol) and pyridine (100 mg, 1267 mmol) in dimethylformamide, stirring at room temperature. After 90 minutes, an additional equivalent of pyridine (100 mg, 1267 mmol) in dimethylformamide (2 mL) is added, followed by the dropwise addition of a second equivalent of tert-butyl bromoacetate (247 mg, 1267 mg). mmol) in dimethylformamide (5 mL). The reaction mixture is allowed to stand at room temperature for 180 minutes, diluted with dichloromethane (150 mL) and flash chromatographed on silica with dichloromethane nitrate, • then 20% methanol / 5% ammonium hydroxide (28% aqueous) / 75% 5 chloromethane. The crude product fractions are combined and concentrated to give the impure yellow solid which is dissolved in 15% acetonitrile / water (2% trifluoroacetic acid) and purified by preparative reverse phase HPLC with gradient elution 10-50% • 10 acetonitrile / water (0.1% trifluoroacetic acid). The combined product fractions are usually removed under vacuum, and the residue is left under high vacuum overnight. The product is isolated in the form of a pale pink powder (300 mg, 0.808 mmol). 15-NMR (DMSO-d 6, 300 MHz) delta 9.76 (br s, 3H); 8.82 (d, ÍH); 8.39 (d, ÍH); 7.68 (d, ÍH); 7.61 (dd, ÍH); 4.64 (m, 2H); 4.11 (m, 3H); 3.33 (m, 2H); 2.40 (m, ÍH); 1.47 (s, 9H). ESI MS, • [M + H] '= 372. C: Acid methyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - [3- (5-chlorothiophen-2-yl) acryloyl] amino} acetic The same coupling procedure as in example 102 is carried out except that the coupling species are acid tert-butyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -ylamino} acetic acid and 3- (5-chlorothiophen-2-yl) -acrylic acid. The residue of the concentration of the reaction mixture is dissolved in 40% acetonitrile / water (trifluoroacetic acid • 2%) and purified by preparative reverse phase HPLC with gradient elution 30-100% acetonitrile / water trifluoroacetic acid 0.1%). The product fractions are combined and the solvents are removed in vacuo to provide the tert-butyl ester intermediate product in the form of a white powder. This intermediate is dissolved in methanol and cooled to 0 ° C while a bubbling of HClg is introduced} dry through the solution 'until you reach saturation. The reaction mixture is left at room temperature overnight, then concentrated in vacuo, and the residue dissolved in 20% acetonitrile / water (acid % trifluoroacetic) and purified by preparative reverse phase HPLC with 10-100% gradient acetonitrile / water elution (0.1% trifluoroacetic acid). The • product fractions are combined, acetonitrile is removed in vacuum, and the aqueous solution is lyophilized to provide the product in the form of a white powder (9 mg, 0.015 mmol). X NMR (DMSO-de, 300 MHz): delta 9.78 (br s, 2H); 8.82 (2s, H); 7.62 (m, 3H); 7.36 (m, ÍH); 7.15 (m, ÍH); 6.88, 6.73 (2d, ÍH); 5.28, 4.17 (2t, ÍH); 4.40 (m, 3H); 3.64.3.59 (2s, 3H); 3.28 (m, 2H); 2.37 (m, ÍH); 2.10 (m, ÍH). ES MS, [M + H] + =, 500.

EXAMPLE 106 [1- (4-aminoquinazol? N-7-ylmet? Lj-2-oxopyrrolidin-3- (R) -amylamide 6-chloro-benzo [b] thiophene-2-sulphonic acid trifluoroacetate 5 A. ester tert -butyl acid (2-oxoprolidid-3- (R,) -ylcarbamic acid The same procedure as in Example 10LA is applied, but using the (R) -enantiomer as starting material instead of the (S) -enantiomer. fP 10 X NMR (CDC13, 300 MHz) delta 6.18 (m, 1H), 5.11 (m, HH), 4.15 (m, HH), 3.35 (m, 2H), 2.70 (m, HH), 1.96 (m, ÍH); 1.45 (s, 9H) ESI MS, [M + HT = 201. B. [1- (3-amino-4-cyanobenzyl) -2-oxopyrrolidin-3- (R) tert -butyl acid ester -il] carbamic 15 The same procedure is used as in Example 101D, but using the (R) enantiomer as starting material instead of the (S) enantiomer. • X NMR (CDCI3, 300 MHz) delta 7.35 (d, ÍH) 6.64 (d, ÍH), 6.58 (dd, ÍH), 5.15 (br, ÍH), 4.40 (m, 4H), 4.19 (m, ÍH), 3.24 (m, 2H); 2.60 (m, 1H); 1.90 (m, ÍH); 1.45 (s, 9H). ESI MS, [M + H] + = 331. C. [1- (4-aminoquinazolin-7- ylmethyl) -2-oxopyrrolidin-3- (R) -yl] carbamic acid tert-butyl ester The same is used procedure that in example 101E, but using the enantiomer (R) as starting material instead of the (S) enantiomer. X H NMR (CDCl 3, 300 MHz) delta 9.90 (br s, 2 H); 8.35 (s,? ÍH); 8.16 (d, ÍH); 7.49 (d, ÍH); 7.31 (dd, ÍH); 7.22 (br d, ¡ÍH); 4.57 (d, ÍH); 4.44 (d, ÍH); 4.20 (m, ÍH); 3.18 (m, 2H); 2.23 5 (m, ÍH); 1.80 (m, ÍH); 1.39 (s, 9H). ESI MS, [M + H] t = 358 '. D. 3- (R) -Amino-1- (4-aminoquinazolin-7-ylnrtethyl) pyrrolidm-2-one The same procedure as in Example 101F is used, followed by the procedure of Example 105A, but in each case • 10 using the enantiomer (R) as starting material instead of the (S) enantiomer. X NMR (CDCl 3, 300 MHz) delta 8.81 (s, ÍH); 8.73 (br s, 2H); 8.57 (d, ÍH); 7.87 (d, ÍH); 7.65 (dd, ÍH); 6.68 (br s "2H); 4.73 (d, ÍH); 4.60 (d, ÍH); 4.13 (m, ÍH); 3.35 (m, 2H); 2.43 15 (m, ÍH); 2.10 (m, ÍH). ESI MS, [M + H] t = 258. E. Trifluoroacetate of [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -6-chlorobenzoic acid amide [b] thiophen- • 2-sulfonic acid 3- (R) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one (36 mg, 0.14 mmol) and 6-chlorothiophene-2-sulfonyl chloride are dissolved. (40 mg, 0.35 mg) in dichloromethane (2 mL) and DMF (1 mL), and triethylamine (36 mg, 0.35 mg) is added. The reaction mixture is left under stirring overnight, at room temperature, before performing a concentration at 45 ° C / 17.577 kg / m2 (25 psi) in an air vortex blower. The residue is dissolved in 30% acetonitrile / water (2% trifluoroacetic acid) and purified by preparative reverse phase HPLC with gradient elution 20-60% acetonitrile / water (0? 1% trifluoroacetic acid). The product fractions are combined, the acetonitop is removed in vacuo, and the aqueous solutions are lyophilized to provide the product in the form of a white powder (9 mg, 0.015 mmol). : H NMR (CDC13, 300 MHz) delta 9.61 (br s, 2H); 8.75 (m, 2H); 8.34 (d, ÍH); 8.27 (s, ÍH); 8.05 (s, ÍH); 8.02 (d, 1H); 7.55 (m, 3H); 4.55 (m, 2h); 4.25 (m, ÍH); 2.99 (m, 2H); 2.18 (m, ÍH); 1.73 (m, ÍH). ESI MS, [M + H] + = 488. EXAMPLE 107 [1- (L-aminoisoquinolin-7-ylmethyl-l-2-oxo-pyrrolidin-3- (R) -yl] -amide-thieno-amide trifluoroacetate [3, 2 -b] pyridine-2-sulfonic acid [1- (l-chloroisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] carbamic acid tert-butyl ester The same procedure as in Example 101D, but using tert-butyl acid ester (2-oxopyrrolidm-3- (R) -yl) carbamic acid (312 mg, 1.56 mmol) and 7-bromomethyl-1-chloroisoquinoline (440 mg, 1.72 mmol) as starting materials The crude product is purified by column chromatography on silica with 50-100% ethyl acetate / hexanes The product fractions are combined and concentrated1 to give the product as a pale yellow powder (471 mg, 1.25 mmol ).: H NMR (CDC13, 300 MHz) delta 8.28 (d, ÍH); 8.14 (s, ÍH); 7.83 (d, ÍH); 7.67 (dd, ÍH); 7.55 (d, ÍH); 5.50 (br s, ÍH); 4.77 5 (d, ÍH); 4.65 (d, ÍH); 4.31 (m, ÍH); 3.27 (m, 2H); 2.60 (m, ÍH); 1.96 (m, ÍH); 1.47 (s, 9H). ESI MS, [M + HT = 376. B. 3- (R) -amino-1- (l-aminoisoquinolin-7-ylmethyl) pyrrolidin-2-one trifluoroacetate Tert-butyl ester of [1- ( 1-P-10-chloroisoquinolin-7-ylmethyl) pyrrolidin-3- (R) -yl] carbamic acid (384 mg, 1.02 mmol), phenol (962 mg, 10.2 mmol), and anhydrous ammonium acetate (1576 g, 20.4 mmol) in a sealed tube, and it is heated overnight at a temperature of 100 ° C. It is cooled, acetate nitrile (20 mL) and water (20 mL) are added and separate the phases. The aqueous phase is washed with ethyl acetate, and concentrated to dryness. The residue of the concentration is extracted in methanol, the solids are removed by filtration, and the filtrate is concentrated. The residue is dissolved in 10% acetonitrile / water (acid % trifluoroacetic) and purified by preparative reverse phase HPLC with gradient elution 10-30% acetonitrile / water (0.1% trifluoroacetic acid). The product fractions are combined, the solvents removed in vacuum, and the product dried in high vacuum. It is isolated in the form of a powder white (88 mg, 0.238 mmol).

: H NMR (DMSO-de, 300 MHz) delta 9.11 (br s, 2H); 8.43 (br s, 2H); 8.37 (s, ÍH); 7.93 (d, ÍH); 7.83 (dd, ÍH); 7.69 (d, ÍH); 7.24 (d, ÍH); 4.66 (d, ÍH); 4.59 (d, ÍH); 4.09 (m, ÍH); 3.34 (m, 2H); 2.38 (m, 1H); 1.96 (, ÍH). ESI MS, [M + H] t = 257. 5 C. Trifluoroacetate of [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] thienoamide [3, 2 -b] pyridine-2-sulfonic acid 3- (R) -amino-1- (1-aminoisoquinolin-7-ylmethyl) pyrrolidin-2-one trifluoroacetate (80 mg, 0.216 ^ 10 mmol) and diisopropylethylamine ( 140 mg, 1.08 mmol) in acetonitrile (12 mL), and stirred at room temperature for 15 minutes before adding thieno [3,2-b] pyridine-2-sulfonyl chloride dropwise as an acetonitrile solution. (8 mL). Leave the reaction mixture to At room temperature overnight, water (4 mL) is added, and the solution is concentrated in vacuo to remove the acetonitrile (approximately 4 mL of solution). It is added • 75% acetonitrile / water (4 mL), and the product is purified by reverse phase preparative HPLC with 10-20 gradient elution 40% acetonitrile / water (0.1% trifluoroacetate acid). The product fractions are combined, the acetonitrile is removed in vacuo, and the aqueous solution is lyophilized, to give the product as a white powder (52 mg, 0.092 mmol). 25 P NMR (DMSO-de, 300 MHz) delta 9.12 (br s, 2H); 8.86 (d, ÍH); 8. 77 (br d, ÍH); 8.59 (d, ÍH); 8.27 (s, ÍH); 8.12 (s, '1H); 7.92 (d, ÍH); 7.77 (dd, ÍH); 7.65 (d, ÍH); 7.51 (dd, 1H); 7.21 (d, ÍH); 4.61 (d, ÍH); 4.47 (d, ÍH); 4.36 (m, ÍH); 3.19 • (m, 2H); 2.21 (m, ÍH); 1.74 (m, ÍH). ESI MS, [M + H] + = 454 5 EXAMPLE 108 1- (4-aminoquinolin-7-ylmethyl) -3- (S) '- [(5-chloro-lH-indol-2-ylmethyl) amino trifluoroacetate ] pyrrolidin-2-one A. [1- '-chloroquinolin-7- ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester P The same procedure as in example 101D, but using 7-bromomethyl-4-chloroquinoline as the electrophile. The crude product is purified by column chromatography on silica with 1-20% methanol / ethyl acetate. The product fractions are combined and concentrated to provide a semi-solid / oil which is triturated with ether to provide the product in the form of a white powder. P NMR (DMSO-de, 300 MHz) delta 8.83 (d, ÍH); 8.17 (d, ÍH); 7.95 (s, ÍH); 7.74 (d, ÍH); 7.62 (dd, ÍH); 7.22 (d, ÍH); 4.66 (d, ÍH); 4.57 (d, ÍH); 3.20 (m, 2H); 2.23 (m, ÍH); l.S3 (m, 20%); 1.39 (s, 9H). ESI MS, [M + H] + = 376. B. 3- (S) -amino-1- (4-aminoquinolin-7-ylmethyl) pyrrolidin-2-one hydrochloride Tert-butyl acid ester [1] is combined - (4-chloroquinolin-7-ylmethyl-2-oxopyrrolidin-3- (S) -yl] carbamic acid (250 mg, 0.665 mmol), phenol (626 mg, 6.65 mmol), and anhydrous ammonium acetate (513 mg, 6.65 mmol) and heated at 100 ° C, with reflux apparatus, overnight under nitrogen. It is cooled to room temperature, and acetonitrile (20 mL) and water are added. • (20 mL). The solution separated into two gases (both, phases 5 containing the product), which are concentrated to dryness, and purified separately by reverse phase preparative HPLC with elution of 20-40% acetonitrile / water gradient (0.1% trifluoroacetic acid). The product fractions from each experiment are • 10 combined, the solvents are removed in vacuum, and the residue is dried under high vacuum overnight. The [l- (4-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] carbamic acid tert-butyl ester intermediate is dissolved in methanol and cooled to 0 ° C while introduced bubbling of HCl (g> dry through the solution to saturation) The reaction mixture was left at room temperature for 2 hours and then concentrated in vacuo The residue was washed with ether to provide the pure product in the form of a colorless powder (170 mg, 0.516 mmol). X NMR (DMSO-de, 300 MHz) delta 9.15 (br s, 2H); 8.75 (br s, 2H); 8.50 (d, ÍH); 8.35 (d, ÍH); 7.96 (s, ÍH); 7.53 (d, ÍH); 6.79 (d, ÍH); 4.71 (d, ÍH); 4.58 (d, ÍH); 4.11 (m, 1H); 3.11 (m, 2H); 2.45 (, ÍH); 2.13 (m, ÍH). ESI MS, [M + H] + = 257. 25 C. 1- (4-aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-indol-2-ylmethyl) amino trifluoroacetate ] pyrrolidin-2-one The same procedure as example 103 is used, except that 3- (S) -amino-1- (4-aminoquinolin-7-ylmethyl) pyrrolidin-2-one hydrochloride is used as starting material in instead of 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one hydrochloride: H NMR (DMSO-de, 3-00 MHz) delta 11.39 (s, ÍH); 9.73 (br s, ÍH), 8.97 (br s, 2H), 8.38 (, ÍH), 7.73 (s, ÍH), 7.62 (d, ÍH); 7.52 (d, ÍH); 7.45 (d, ÍH); 7.13 (dd, ÍH); 6.75 (d, ÍH); 6.64 (s, ÍH); 4.65 (m, 2H); 4.54 (d, ÍH); 4.46 (d, ÍH); 4.15 (m, ÍH); 3.32 (m, 2H); 2.46 (m, ÍH); 2.05 (m, 1H). ESI MS, [M + H] t = 420. EXAMPLE 109 1- (4-aminoquinazolin-7-ylmethyl-3- (S) - [3- (5-chlorothiophen-2-yl) allylamino] pyrrolidin-3 trifluoroacetate -one Dissolve / suspend in DMF (1 mL) 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one hydrochloride (40 mg, 0.12 mmol) and potassium carbonate in powder (80 mg, 0.58 mmol), and to this solution is added 3- (5-chlorothiophen-2-yl) allyl bromide (30 mg, 0.126 mmol) in the form of a solution of DMF (1 mL). The reaction mixture is sonicated for 10 minutes, and then stirred overnight.The dimethylformamide is removed at a temperature of 45 ° C, 511 kg / m2 (25 psi) in a vortex air blower, the residue is extracted in a methanol (2x10 mL), and the solids are removed by filtration, the filtrate is concentrated, and the crude material is purified by reverse phase preparative HPLC with gradient elution 20-60% acetonitrile / water (acid • 0.1% trifluoroacetic). The product fractions are combined, the acetonitrile is removed in vacuo, and the aqueous solution is lyophilized to give the product as an off-white powder (15 mg, 0.028 mmol). P NMR (DMSO-de, 300 MHz) delta 9.64 (br s, 3H); 8.79 (s "H); 7.68 (d, H); 7.59 (dd, H); 7.08 (d, H); 6.95 (d, H); 5.9.6 (m, 10 H); 4.71 (d, J); 4.64 (d, H); 4.25 (t, H); 3.87 (m, H); 3.37 (m, 2H); 2.47 (m, H); 2.05 (m, H). ESI MS, [M + H] ~ = 414. EXAMPLE 110 N- [1- (4-aminoquinazolin-7-ylmethyl) -1-trifluoroacetate 2. oxopyrrolidin-3- (S) -yl] -3- (5- chlorothiophen-2-yl) acrylamide The same procedure as example 102 is employed, but using 3- (5-chlorothiophen-2-yl) acrylic acid in place of 2- (5-chlorothiophen-2-yloxy) acetic acid. • ESI MS, [M + H] + = 428. EXAMPLE 111 20 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-benzimidazol-2-ylmethyl) trifluoroacetate) amino] pyrrolidin-2-one The same procedure is used as in example 103, but using a mixture of 2-chloromethyl-l-tert-butoxycarbonyl-5-chlorobenzimidazole and 2-chloromethyl-l-tert-butoxycarbonyl-6-25 chlorobenzimidazole instead of 2-bromomethyl-l-, tert-butoxycarbonyl-5-chloroindole. ESI MS, [M + H] + = 422. EXAMPLE 112 • Acid methyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] [2- (5-chlorothiophen-2-yl) etensulfonyl] amino} acetic The same procedure as in example 106E, | but using tert-butyl acid trifluoroacetate ester. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -F-10-yl] amino]} acetic acid instead of 3- (R) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one and 2- (5-chlorothiophen-2-yl) etensulfonyl chloride in place of chlorothiophen-2-sulfonyl. The tert-butyl ester intermediate is isolated by reverse phase preparative HPLC with elution of gradients 10-100% acetonitrile / water (0.1% trifluoroacetic acid). The product fractions are combined, the solvents are removed in vacuum, and the intermediate product is • drying during the night in high vacuum. The dry material is dissolved in methanol and cooled to a temperature of 0 ° C while bubbling of HCllg is introduced? through the solution until its saturation. It is stirred overnight at room temperature. The reaction mixture is concentrated to dryness in vacuo, and the residue is dissolved in 20% acetonitrile / water (2% trifluoroacetic acid) and purified by preparative reverse phase HPLC with elution of 20-100% acetonitrile / water gradient (0 | .i% trifluoroacetic acid). The product fractions are combined, the acetonitrile is removed under vacuum and the aqueous solution is lyophilized. • to provide the product in the form of a white powder. EXAMPLE 113 Acid methyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidir.-3- (S) -yl] (5-chloro-lH-indo1-2-ylmethyl) amino} acetic ^ r 10 The same procedure as example 103, 'but using trifluoroacetate of tert-butyl acid ester . { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] amino} acetic acid in place of 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one hydrochloride. 15 ESI MS, [M + H] + = 493. EXAMPLE 114 Trifluoroacetate methyl acid ester? . { [1- # (aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] [3- (5-chlorothiophen-2-yl) allyl] amino] acetic acid The same procedure is used as in example 103, but using acid tert-butyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] amino} acetic acid instead of 3- (S) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one and '3- (5-chlorothiophen-2-yl) allyl hydrochloride instead of 2-bromomethyl- l-Tert-butoxycarbonyl-5-chloroindole added. ESI MS, [M + H] t = 486. • EXAMPLE 115 5 Acid methyl ester trifluoroacetate. { ! - [,! - (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5-chlorothiophen-2-yl) ureido} acetic The same initial procedure as in Example 104 is employed, but using acid tert-butyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] amino} acetic acid instead of 3- (R) -amino-1- (4-aminoquinazolin-7-ylmethyl) pyrrolidin-2-one. Only urea-non-amide is observed. The intermediate tert-butyl ester is isolated by reverse phase preparative HPLC with elution of 10-100% acetonitrile / water gradient (0.1% trifluoroacetic acid). The product fractions are combined, the solvents are removed in vacuum and the intermediate product is dried overnight under high vacuum. The dried material is dissolved in methanol, and cooled to a ° C temperature while bubbles of 'HCl (g) are introduced through the solution to saturation. Stir at room temperature overnight. The reaction mixture is concentrated to dryness in vacuo, and the residue is dissolved in 20% acetonitrile / water (trifluoroabetic acid to 2%), and purified by preparative reverse phase HPLC with gradient elution 20-60% acetonitrile / water (0.1% trifluoroacetic acid). The product fractions are combined, the acetonitrile is removed in vacuo, and the aqueous solution is lyophilized to provide the product in the form of a white powder. ESI MS, [M + H] t = 489. EXAMPLE 116 N- [1- (4-aminoquinazolin- "7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -3- (5-) trifluoroacetate chlorothiophen-2-yl) acrylamide The same procedure is used as in example 110, but using the (R) enantiomer as starting material, instead of the (S) enantiomer. ESI MS, [M + H] + = 428. EXAMPLE 117 1- (4-aminoquinazolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate The same procedure is used as in example 103f but using the enantiomer (R) as starting material, instead of the (S) enantiomer. ESI MS, [M + H] t = 421. EXAMPLE 118 1- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -3- (5-chlorothiophene) trifluoroacetate -2-yl) urea- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -5-chlorothioophen-2-carboxylic acid trifluoroacetate The same is used procedure as in example 104, but using the (R) enantiomer as starting material, instead • of the enantiomer (S). Urea: ESI MS, [M + H] "= 417. Amide: ESI MS, [M + H]" = 402. EXAMPLE 119 Acid methyl ester trifluoroacetate. { [l- (4-aminoquinazolin-7-? memethyl) -2-oxopyrrolidin-3- (R) -yl] (5-chloro-l-indol-2-ylmethyl) amino] acetic • 10 A. Tert-butyl ester of acid. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] amino} acetic The same procedure as example 105 B is used, but using the (R) enantiomer as starting material, instead of the (S) enantiomer. It is not required to carry out the Purification by HPLC since a pure material is obtained from column chromatography. The product is isolated in the form of the free base. ESI MS, [M + H] "= 372. B. Acid methyl ester trifluoroacetate { [L- (4- 20 aminoquinazol n-7-ylmethyl-oxopyrrolidin-3- (R) -yl] (5- chloro-lH-indol-2-ylmethyl) amino] acetic The same procedure as example 113, i is employed but using tert-butyl acid ester { [l- (4-aminoquinazolin-7-ylmethyl) -2- oxopyrrolidin-3- (R) -25 il] amino] acetic acid instead of trifluoroacetate of tert-butyl ester of acid { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S ) -yl] amino.} acetic as the material . . . . initial • ESI MS, [M + H] + = 493. 5 EXAMPLE 120 1- (4-Aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-benzimidazol-2-ylmethyl) trifluoroacetate) amino] pyrroiidin-2-one The same procedure is used as in example 1C3, I but using 3- (S) -amino-1- (4-aminoquinino-7- p-10-ylmethyl) pyrrolidin-2-one hydrochloride as starting material instead of 3- (S) -amino-1- (4-aminoquinolin-7-ylmethyl) pyrrolidin-2-one hydrochloride; and a mixture of 2-chloromethyl-1-tert-butoxycarbonyl-5-chlorobenzimidazole and 2-chloromethyl-1-tert-butoxycarbonyl-6-chlorobenzimidazole instead of 2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole. ESI MS, [M + H] + = 421. The compounds of Examples 121 to 138 are synthesized • using method and reagents analogous to those described here. EXAMPLE 121 20 [- (4-Amino-quinazol-n-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide 5-chloro-benzo [b] thiophene-5-trifluoroacetate 2- sulfonic ESI MS, [M + H] = 487, 489, Cl pattern. EXAMPLE 122 [1- (4-Amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 2- (5-chloro) acid -thiophen-2-yl) -etensulfonic 470, 472, Cl. 5 standard. [1- (4-Amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - trifiuoroacetate 7-methoxy-naph alen-2-sulfonic acid amide ESI MS, [M + H] "= 477 EXAMPLE 124 10- [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin- trifluoroacetate 3- (S) -ii] -2- (5-chloro-thiophen-2 + yl) -ettensulfonic acid amide ESI MS, [M + H] t = 464, 466, Cl standard. EXAMPLE 125 15 Trifiuoroacetate of [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -6-chloro-benzo [b] thiophene-2-sulphonic acid ester ESI MS, [M + H] t = 488, 490, Cl pattern. EXAMPLE 126 20 (S) - [1- (4-Amino-thieno [3,2-d] pyrimid, in-6-ylmethyl) -2-oxo trifluoroacetate -pyrrolidin-3-yl] -amino-5-chlorobenzo [b] thiophene-2-sulfonic acid ESI MS, [M + H] + = 493, 395, Cl standard. EXAMPLE 127 25 Trifluoroacetate (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of thienol [3,2- b] pyridin-2 -amide sulphonic ESI MS, [M + H] + = 460. • EXAMPLE 128 5 (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo- trifluoroacetate pyrrolidin-3-yl] -amide of 6-chlorobenzo [b] thiophen-2-sulfonic acid ESI MS, [M + H] + = 493, 495, Cl pattern. EXAMPLE 129 • 10 (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5'- acid chloro- [2,2 '] bitiofeni1-5-sulfonic ESI MS, [M + H] t = 525, 527, Cl pattern. EXAMPLE 130 15 (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-yl-ethyl) -2-oxo-pyrrolidin-3-yl] -amide of 2- (3-amino) -amide 5-Chloro-thiophen-2-yl) -etensulfonic ESI MS, [M + H] + = 469, 471, Cl standard. EXAMPLE 131 20 [(S) -1 (4-amino-thieno [3]] trifluoroacetate 2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5-chlorobenzo [b] thiophen-2-sulfonic acid ESI MS, [M + H] + = 493, 495, Cl pattern. EXAMPLE 132 25 [(S) -1- (4-Amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrole-din-3-yl] -amide acid trifluoroacetate chlorobenzo [b] thiophene-2-sulphonic ESI MS, [M + H] t = 493, 495, Cl pattern. EXAMPLE 133 5 [(S) -1- (4-amino-thieno [2,3-d] pyrim? D | in-6-methylmethyl) -2-oxo-pyrrolidin-3-yl] -amide acid trifluoroacetate 5'c'loro- [2, 2 '] bitiofenil-5-sulfonic ESI MS, [M + H = 525, 527, Cl pattern. EXAMPLE 134 • 10 [(S) -1- (4-Amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrole-din-3-yl] -tridyloacetate] 3,2-b] pyridine-2-sulphonic ESI MS, [M + H] * = 460. EXAMPLE 135 15 [(S) -1- (4-amino-thieno [2,3] -d] pyrimidine trifluoroacetate 6-Chlorobenzo [b] thiophene-2-sulfonic acid 6-ylmethyl) -2-oxo-pyrrolidin-3-yl] amide # ESI MS, [M + H] ~ = 493, 495, Cl standard. EXAMPLE 136 20 [1- (4-Amino-thieno [2,3-d] pyrimidin-7-ylmethyl) -2-oxo-pyrroiidin-3 (S) -yl] -amide 5'-chloro trifluoroacetate - [2,2 '] bromo-phenyl-5-sulfonic ESI MS, [M + H] "= 525, 527, Cl standard. EXAMPLE 137 25 [1- (4-amino-thieno [2,3-d] trifluoroacetate] ] pyrimidin-7-ylmethyl) -2-oxo-pyrrolid? n-3- (S) -yl] -amide of thieno [3, 2-b] pyridine-2-sulfonic acid ESI MS, [M + HT = 460 • EXAMPLE 138 5 ((S) -1- (4-amino-thieno [2,3-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 6- chloro-benzo [b] thio in-2-sulphonic ESI MS, 493, 495, standard Cl. In a similar manner, the following compounds are synthesized ^ P 10 using methods and reagents analogous to those described above: 3- [[1- (4-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin methyl ester -3- (R) -yl] - (5-chloro-lH-indol-2-ylmethyl) amino] propionic; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) - (3-ethylbutyl) amino] pyrrolidin-2-one; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [benzyl- (5-chloro-lH-1 indol-2-ylmethyl) a] pyrrolidin-2-one; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl-thiazol-5-ylmethylamino] pyrrolidin-2-one; -aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) - (2H-pyrazol-3-ylmethyl)) amino] pyrrolidin-2-one; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorobenzo [b] thiophen-2-ylmethyl) amino] pyrrolidin-2-one; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorobenzo [2,3-25 b] pyridin-2-ylmethyl) amino] pyrrolidin-2-one; s1- (4-a-inkyquinazolin-7-ylmethyl) -3- (S) - [(1H-1-rolo [2,3- c] pyridin-2-ylmethyl) amino] pyrrolidin-2-one; 3-. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopi-rolidin-3-, (S) -ylamino] methyl} -lH-quinolin-2-one; 1- (7-aminothieno [3,2- b] pyridin-2-ylmethyl) -3-. R) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one; [2-Oxo-l- (lH-pyrrolo [3, 2-c] pyridin-2-ylmethi) pyrrolidin-3- (R) -yl] -amide-5-chlorothiophen-2-yl) -etensulfqmco; isopropyl ester of α ^ i.do. { [2- (5-chlorothiophen-2-yl) etensulfonyl] - [2-oxo-l- (lH-pyrrolo [3,2- c] pyridin-2-ylmethyl) pyrrolidin-3- (R) -yl] Not me} acetic; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indoyl-2-ylmethyl) amino] pyrrolidin-2-one; and [1- (4-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -amide of 5-chloro-lH-benzoimidazole-2-sulfonic acid. PREPARATION 1 • Reaction vessels are charged with a resin of 4-hydroxy-2, 3, 5, 6-tetraf lurobenzamidomethyl-copoii- (styrene | -l% -divinylbenzene) (0.20 g, 0.15 mmol). Each vessel is treated with methylene chloride (2 mL) for 10 minutes followed by aromatic sulfonyl chloride (0.45 mL) and diisopropylethylamine (0.104 mL, 0.60 mmol). The containers are sealed and stirred for approximately 16 hours. The reaction mixtures are individually filtered and washed sequentially with 20% Nal aqueous DMF (10 X), THF (5 X) and dichloromethane (5 X), and then dried in vacuo at room temperature overnight. By way of example, 6-chlorobenzothiophen-2-sulfonyl) oxy-2,3,5,6-tetrafluoro-benzamidomethyl-copoly- (styrene-1% -divinylbenzene) resin showed: : '-F-NMR d-144. 572, -145. 608; IR (cm-1) 1684 (segment, C = 0), 1391, (segment S02 asymmetric) 1195, 1177 (segment SO, asymmetric).

Reaction vessels are charged with arylsulfonyloxy-2,3,5,6-tetrafluro-benza idomethyl-copoly- (styrene-1% -divinylbenzene) resins (0.024 g, 0.012 mmol), • prepared in accordance with what is described above. The resins 5 are swollen with DMF, then treated with a 0.01 M solution of an amine (1 ml, 0.01 mmol) in DMF. The containers are covered with an aluminum foil and stirred for 72 hours. The progress of the reaction is monitored by TLC; in the case of slow reactions, a 1,5,7- ^ P 10 triazabicyclo [4.4.0] dec-5-ene resin is added. The reaction mixtures are individually filtered and the resins are washed | with ethanol The filtrates in concentrates with a nitrogen current. The waste is dissolved again in ethanol and reconcentrated twice more. The resulting waste is treated with 20% trifluoroacetic acid in methylene chloride (1 ml) and stirred overnight. The reaction mixture is concentrated by a stream of nitrogen. HE • add methylene chloride (1 ml); it is concentrated with a stream of nitrogen. Methanol (1 ml) is added; HE concentrates with the nitrogen stream. The final residues are analyzed by LC / mass spec; Evidence of the desired product is obtained in each case. By way of example, the reaction product of 6-chlorobenzothiophen-2-sulfonyl) oxy-2,3,5,6-tetrafluoro-benzamidomethyl-copolyol (styrene-1% -divinylbenzene) ester with tertiary ester butyl 2- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -pyrrolo [3, 2-b] pyridine-1-carboxylic acid and subsequent deprotection cor. 20% TFA in methylene chloride showed: M + H = 461. This material had an IC5. against factor Xa less than 500 nM. 5 Through the method described in this preparation, 2- (3- (S) -amino-2-oxopyrrolicin-1-ylmethyl) -pyrrolo [3, 2-b] pyridinyl tert-butyl ester. -carboxylic acid 2- (3- (S) -am-2-oxopyrrolidi-1-ylmethyl) -3-pyrrolo [3, 2-c] pyridine-l-carboxylic acid tert-butyl ester and tert-butyl ester butíüco de 2- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) -pyrrolo [3, 2-c] pyridine-1-carboxylic acid reacts with 14 arylsulfonyloxy-2, 3, 5, 6 resins -tetrafluoro-benzamidomethyl-copoly- (styrene-1% -divinylbenzene) to obtain, after deprotection, the compounds encompassed by the following formula: select between two points: Ri is H; and R2 is selected within the group of formulas consisting of: N-XI o - oX sC * "\ ~ otr oQ 5 N O O N-0 LCMS: M + H - 462 LCMS: M + H = 42» LCMS: M + H = 444 LCMS. M + H = 462 LCMS M * H = 493 LCMS: M + H ¿42? LCMS: M + H - 462 LCMS: M - H = 445 is selected among the points X = a • 10 R is H; and R2 is selected within the group of formulas consisting of: LCMS: M + H = 461 LCMS: M + H = 428 LCMS: M + H = 454 # twenty LCMS: M + H = 462 LCMS: M + H = 428 LCMS: M + H = 444 LCMS: M + H = 462 LCMS: M + H = 493 LCMS: M + H = 427 LCMS: M + H = 462 LCMS: M + H = 454 LCMS: M -r H = 475 LCMS: M + H = 462 LCMS: M + H = 445 is selected from: R-. it's H; and R2 is selected within the group of formulas consisting of: LCMS: M + H = 461 LCMS: M + H = 428 LCMS: M + H = 454 LCMS: M + H = 462 LCMS: M + H = 428 LCMS: M + H ^ 444 LCMS: M + H * 462 LCMS: M + H = 493 LCMS: M + H = 427 LCMS: M + H = 462 LCMS: M + H = 454 LCMS: M + H = 475 LCMS: M + H = 462 LCMS: M + H = 445 Through the methods described herein, compounds comprised by the following formula are also prepared: R: is H; and R2 is selected within the group of formulas consisting of: Q, T = H. CH3, F, Cl Q, T = H. CH3. F, Cl Through the methods described herein, compounds comprised by the following formula are also prepared: Ri is H; and R2 is selected from a group of formulas consisting of: LCMS: M + H = 451 LCMS: M + H = 418 LCMS: M + H = 444 twenty LCMS: M + H = 452 LCMS: M + H = 418 LCMS: M + H = 434 LCMS: M + H = 452 LCMS: M + H = 444 LCMS: M + H = 465 LCMS: M + H = 452 LCMS: M + H = 435 The molecules described here inhibit the coagulation of blood by virtue of its ability to inhibit the penultimate enzyme in the coagulation cascade, controlling the activity of factor Xa. Both the activity of free factor Xa and the activity of factor Xa assembled in the The prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by compounds of formula I. The inhibition of factor Xa activity is obtained by the direct formation of complexes between the inhibitor and the enzyme and therefore is independent of the cofactor plasma antithrombin III. An effective inhibition of factor Xa activity is achieved by administering the compounds either by oral administration, continuous intravenous infusion, intravenous administration of bolus or through any other parenteral route in such a manner that the desired effect is achieved. of preventing factor Xa induced thrombin formation from prothrombin. An anticoagulant therapy is indicated for the treatment and prophylaxis of various thrombotic conditions of both the P ^ veins and the arteries. In the arterial system, an abnormal thrombus formation is primarily related to the coronary, cerebral, and peripheral arteries. Diseases associated with thrombotic occlusion of these vessels mainly include acute myocardial infarction AMI), unstable angina, thromboembolism, acute vessel closure related to thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), ischemic attacks • Transients, stroke, intermittent claudication as well as coronary or peripheral artery bypass grafting (CABG). A chronic anticoagulant therapy may also be beneficial in preventing luminal narrowing of the vessel (restenosis) that frequently occurs after PTCA and CABG, and to maintain the vascular access opening in patients undergoing long-term hemodialysis. As for the veins, The pathological formation of thrombi occurs frequently in the veins of the lower extremities after abdominal, knee and hip surgery (deep vein thrombosis)., DVT). DVT also predisposes the patient to cover the highest level of pulmonary thromboembolism. A systemic, diseased intravascular coagulopathy (DIC) commonly occurs in both basilar systems during septic shock, certain viral infections, and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors which results in the formation of thrombin that threatens life in all the vessels of various organ systems. The indications discussed above include some of the possible clinical situations where anticoagulant therapy is warranted, but not all of these possible clinical situations. People! With experience in this field they know the circumstances that require either an anticoagulant or prophylactic water therapy or a chronic prophylactic anticoagulant therapy. The compounds of this invention can be used alone or in combination with other diagnostic agents, anticoagulants, antiplatelets, or fibrinolytics. For example, adjunctive administration of factor Xa activity inhibitors with standard heparin, low molecular weight hepariha, direct thrombin inhibitors (ie, hirudin), aspirin, fibrinogen receptor antagonists, streptokinase, urokinase and / or Tissue plasminogen activator may result in greater antithrombotic or thrombolytic efficacy or efficiency. The compounds described herein can be administered to treat thrombotic complications in various animals such as primates including humans. Inhibition of factor Xa is useful not only in the anticoagulant therapy of individuals who have thrombotic conditions but is also useful when the inhibition of blood coagulation ^^ 10 is required to prevent the coagulation of whole blood stored and to prevent coagulation in other biological samples for testing or storage. Thus, any inhibitor of factor Xa activity can be added or contacted with any medium containing the Factor Xa or of which is suspected to contain factor Xa and in which it is desired to inhibit blood coagulation. In addition to its use in anticoagulant therapy, 'inhibitors of factor Xa activity may be useful in the treatment of the prevention of other conditions physiological in which thrombin generation has been implicated as playing a pathological role! For example, it has been suggested that thrombin contributes to the morbidity and mortality of such chronic and degenerative diseases as arthritis, cancer, atherosclerosis, restenosis after coronary angioplasty and Alzheimer's disease by virtue of their ability to regulate many different cell types through dissociation and specific activation of a cell surface thrombin receptor.

• The inhibition of factor Xa activation effectively blocks the generation of thrombin and therefore neutralizes the pathological effects of thrombin on various cell types. In accordance with an additional feature of the invention, there is provided a method for the treatment of a human or an animal suffering from a physiological condition that can be improved by the administration of an inhibitor of factor Xa activity, for example, conditions such as those described above, comprising administering to the patient an amount therapeutically Effective of compound of the formula I or a composition containing a compound of the formula I. An "effective carity" refers to an amount of the compound of the • present invention which is carried out to inhibit the activity of factor Xa and consequently to produce the effect The desired therapeutic The present invention also includes within its scope pharmaceutical formulations comprising at least one of the compounds of the formula I in association with a pharmaceutically acceptable carrier or coating. In practice, compounds of the present invention may be administered generally parenterally, intravenously, subcutaneously, intramuscularly, in the colon, nasally, intraperitoneally, rectally or orally. • The products according to the present invention can be presented in forms that allow administration by the most appropriate route and the invention also refers to pharmaceutical compositions containing at least one product according to the invention that are suitable for their use in human or veterinary medicine. These compositions can be prepared according to the usual methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions can be in the form of tablets, pills, granules, suppositories such as powders, aqueous solutions or suspensions, injectable solutions, elixirs, or syrups, and may contain one or more agents selected from the group comprising sweeteners, flavors, colorants, or stabilizers with The object is to obtain pharmaceutically acceptable preparations. The choice of a vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the product, the particular way of administration and the standards to observe in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used to prepare tablets. For the preparation of a capsule, it is advantageous to use lactose as well as high molecular weight polyethylene glycols. When aqueous suspensions are used, they may contain emulsifying agents or agents that facilitate the suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixture thereof may also be emed. For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example, sesame oil, peanut oil or olive oil, or inorganic acid solutions such as water and propylene glycol , injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. Aqueous solutions which also comprise solutions of the salts in pure distilled water can be used for intravenous administration provided that the pH is suitably adjusted, that they are suitably buffered and isotonic turns with a sufficient amount of glucose or sodium chloride, and that sterilize 5 by application of heat, irradiation or microfiltration. Suitable compositions containing the compounds of the invention can be prepared by conventional means. For example, compounds of the invention can be dissolved or suspended in a suitable vehicle for use for example ^ P 10 in an atomizer, or an aerosol in suspension or solution, or they can be absorbed or adsorbed in a solid carrier suitable for Use in a dry powder inhaler. Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I. The percentage of active ingredient in the formulations of the invention may vary, it is necessary that it constitutes a • proportion such that an adequate dosage is obtained. Obviously, several dosage unit forms can administered approximately at the same time. The dose used will be determined by the doctor and will depend on the desired therapeutic effects, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally approximately 0.01 a About 100, preferably from about 0.01 to about 10, mg / kg of body weight per inhalation day, from about 0.01 to about 100, preferably from about 0.01 to 70, more especially from 0.05 to 10 mg / kg of weight per day per oral administration, and from about 0. O'l to about 50, preferably from 0.01 to 10 mg / kg of body weight per day in the case of intravenous administration. In each particular case, the doses will be determined in accordance with the distinguishing factors for patients to • 10 treat, for example, age, weight, general health and other characteristics that may influence the efficacy of the medical product. The products according to the invention can be administered as frequently as necessary with the object to obtain the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose and may find more maintenance doses • Adequate weak. In the case of other patients, it may be necessary to have long-term treatments at a rate of 1 to 4 doses per day, according to the physiological requirements of each particular patient. In general, the active product can be administered orally 1 to 4 times a day. It is evident that, in the case of other patients, it is necessary to prescribe no more than one or two doses per day. Compounds within the scope of the present invention present invention exhibit remarkable pharmacological activities in accordance with the tests described in the literature, said test results are correlated according to the pharmacological activity in humans and other mammals, as is believed. The following pharmacological test results are typical characteristics of the compounds of the present invention. Enzyme assays: A capacity of the compounds of the present invention! To act as inhibitors of factor Xa, thrombin, trypsin, tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), plasmin and activated protein C is evaluated by determining the concentration of inhibitor that resulted in a 50% loss of enzymatic activity (IC50) using purified enzymes. All enzyme assays are performed at room temperature in 96-well microtiter plates using a final enzyme concentration of 1 nM. The concentration of factor Xa and thrombin are determined by titration of active site and the concentrations of all other enzymes are based on the concentration of protein supplied by the manufacturer. Compounds according to the present invention are dissolved in DMSO, diluted with their respective buffers and tested at a final maximum concentration of DMSO of 1.25%. Dilutions of compound are added to wells containing buffer and enzyme and pre-equilibrated between 5 and 30 minutes. The enzymatic reactions • are initiated by the addition of substrate and the color 5 revolving from the hydrolysis of the peptide-p-nitroanilide substrates is continuously monitored for 5 minutes at 405 nm on a Vmax microplate reader (Molecular Deviices) . Under these conditions, less than 10% of the substrate is used in all the tests. The measured initial velocities 10 are used to calculate the amount of inhibitor that resulted in a 50% reduction of the control rate (IC50) • The apparent Ki values are then determined in accordance with the Cheng-Prusoff equation (IC50 = Ki [1+ [S] / Km]) assuming characteristics competitive inhibition kinetics. By way of example, trifluoroacetate of [1- (1,6-diaminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid has a Ki 'value of 80 nM. An additional in vitro assay can be used to evaluate the potency of the compounds according to the invention in normal human plasma. Activated partial thromboplastin time is a plasma-based coagulation assay that is based on the in situ generation of factor Xa, its assembly in the The prothrombinase complex and the subsequent generation of thrombin and fibrin eventually offer the formation of a clot as the endpoint of the assay. This essay is now being used chemically to monitor the ex-effects • live heparin, using commonly used anticoagulant, as well as direct-acting antithrombin agents undergoing clinical evaluation. Accordingly, the activity in this in vitro assay is considered as a surrogate marker for anticoagulant activity in vivo. Coagulation assay based on human plasma ^ P 10 Coagulation times are determined in activated partial thromboplastin in duplicate in an MLA Electra 800 instrument. A volume of 100 ml of coded normal human plasma (George King Biomedical) is added to a cover containing 100 ml of a compound in accordance with invention in Tris / NaCl buffer (pH 7.5) and placed in the instrument. After a warm-up period of 3 minutes, the instrument automatically adds 100 ml of # Activated cephaloplastin reagent (Actin, Dade) followed by 100 ml of CaCl; 0.035 M to start the reaction of coagulation. Coagulum formation is determined spectrophotometrically and measured in seconds. The potency in the compound is quantified as the concentration required to double the time of control coagulum formation measured with human plasma in the absence of the compound of according to the present invention.

Compounds according to the present invention can also be evaluated for their antithrombotic efficacy in vivo in two experimental models of • well-established animals with acute vascular thrombosis. A rabbit model of jugular vein thrombosis and a rat model of carotid artery thrombosis are employed! to demonstrate the antithrombotic activity of these compounds in different paradigms of animal models of human venous thrombosis and human arterial thrombosis, respectively. • 10 Model of experimental in vivo rabbit venous thrombosis It is a well characterized model of venous thrombosis rich in fibrin validated in the literature and shown as sensitive to several anticoagulant drugs including heparin (Antithrombotic Effect of Recombinant Truncated Tissue Factor Pathway Inhibitor (TFPI 1-161) in Experimental Venous Thrombosis-a Comparison with Low Molecular Weight Heparin, J. Holst, B. Lindblad, D. Bergqvist, O. Nordfang, P.B.

• Ostergaard, J. G. L. Petersen, G. Nielsen and U. Hedner. Thrombosis and Haemostasis, 71, 214-219 (1994)). The purpose to use this model is to evaluate the ability of the compounds to prevent the formation of venous thrombi (clots) in vivo generated at the site of an injury and partial stasis of the jugular vein. White rabbits of the New Zeland breed males and females icon weight of 1.5 to 2 Kg are anesthetized with 35 mg / kg of ketamine and 5 mg / kg of xylazine in a volume of 1 ml / kg (i.m.). The right jugular vein is cannulated for anesthetic infusion (ketamine / xylazine 17 / 2.5 mg / kg / hour at a rate of approximately 0.5 ml / hr) and administration of test. The right carotid artery is cannulated to record arterial blood pressure and to collect blood samples. The body temperature is maintained at 39 ° C with GAYMAR T-PUMP. The left external jugular vein is isolated and all lateral branches along a segment of 10 to 2-3 cm of exposed vessel are tied. The internal jugular vein is cannulated, just above the bifurcation of the common jugular, and the tip of the cannula is advanced near the common jugular vein. A 1 cm segment of the vein is isolated with non-traumatic vascular staples and a relative stenosis by attaching a library around the vein with an 18G needle just below the most distant staple. This creates a region of reduced flow and • partial stasis at the site of the injury. The isolated segment is gently rinsed with a saline solution 2-3 times a through the cannula in the internal jugular. Then, the isolated segment is filled with 0.5 ml of 0.5% polyoxyethylene ether (W-1) for 5 minutes. W-1 is a detergent that disrupts the lining of endothelial cells of the segment, thus providing a thrombogenic surface for the initiation of clot formation. After 5 minutes, W-1 is removed from the segment, and the segment is rinsed again gently with a saline solution 2-3 times. The vascular staples are then removed! • restores blood flow through this position of the 5 vessel. Clot formation and growth is allowed for 30 minutes after which the vein is cut just below the stenotic ligation and checked to determine blood flow (absence of dangre flow is recorded as complete occlusion). The entire isolated segment of the vein is then ligated and the clot formed is removed and weighed (wet weight). The effect of the test agents on the final weights of the clots is used as the primary end point. The animals are kept for additional minutes to obtain a final measurement of the 15 pharmacodynamic characteristics of anticoagulation. Drug administration begins 15 minutes before vascular injury with W-1 and continues throughout the period of • formation and maturation of clots. 3 blood samples (3 ml each) are obtained for evaluation of hemostatic parameters: a sample just before administration of W-1; a second sample 30 minutes after the removal of the vascular staples and a third sample at the end of the experiment. The antithrombotic efficacy is expressed as a reduction of the final weight of the clot in preparations treated with a compound according to the present invention in relation to control animals treated with vehicle. Model of experimental in vivo rat arterial thrombosis • The antithrombotic efficacy of factor Xa inhibitors against an arterial thrombosis rich in platelets can be evaluated using a model of thrombosis induced by FeCl; of well-characterized rat carotid artery (Superior Activity of a Thromboxane Receptor Antagonist as Coij.pared with Aspirin in Rat Models of Arterial and Venous Thrombosis, • 10 W.A. Schumacher, C.L. Heran, T.E. steinbacher, S. Youssef and M.L. Ogletrre. Journal of Cardiovascular Pharmacology, 22, 526-533 (1993); Rat Model of Arterial Thrombosis Induced by Ferric Chloride, K.D. Kurtz, B.W. Main, and G.E. Sandusky. Thrombosis Research, 60, 269-280 (1990); The Effect of Thrombin Inhibition in a Rat Arterial Thrombosis Model R.J. Broersma, L.W. Kutcher and E.F. Heminger Thrombosis Research 64, 405-412 (1991). This model is widely used to • evaluate the antithrombotic potential of several agents including heparin and action thrombin inhibitors direct. Sprague Dawley rats weighing 375-450 g were anesthetized with sodium pentobarbital (50 mg / kg i.p.). Upon reaching an acceptable level of anesthesia, the ventral surface of the neck is shaved and prepared for surgical intervention. aseptic. Electrocardiogram electrodes are connected and conductor II is monitored throughout the experiment. The right femoral vein and artery are cannulated with PE-50 tube for the administration of a compound according to the invention and for obtaining blood samples and i for monitoring blood pressure, respectively. A midline incision is made on the ventral surface of the neck. The trachea is exposed and intubated with a PE-240 tube to ensure the opening of the airways! The right carotid artery is isolated and two 4-0 silk sutures are placed around the vessel to facilitate instrumentation. An electromagnetic flow probe (01.95-1 mm lumen) is placed around the vessel to measure blood flow. Distantly from the probe, a 4x4 mm parafilm strip is placed under the vessel to isolate it from the adjacent muscular bed. After performing the baseline flow measurements, a strip of 2x5 mm filtrp paper previously saturated in 35% FeCl2 is placed on top of the vessel downstream of the probe for 10 minutes and then removed. The FeCi is considered; it diffuses into the underlying segment of the artery and causes the desendothelialization resulting in a thrombus formation. After application of filter paper soaked in FeCl2, blood pressure, carotid artery blood flow and heart rate are monitored during a 60-minute observation period. After occlusion of the vessel (defined as obtaining a zero blood flow), or 60 minutes after the application of the filter paper if the opening is maintained, the artery is ligated near and far from the area of the injury and the vessel is removed. The thrombus is removed and weighed immediately and recorded as a primary endpoint of the study. After the surgical instrumentation, a blood sample of control (Bl) is extracted. All blood samples are collected from an arterial catheter and mixed with sodium citrate to prevent clot formation. After each blood sample, the catheter is rinsed with 0.5 ml of 0.9% saline. A compound according to the present invention is delivered intravenously (i.v.) starting 5 minutes before the application of FeCl.sub.2. The time between the application of FeCl? and the time in which the blood flow in the carotid reaches zero is recorded as the time to occlusion (TTO). In the case of vessels that are not occluded within a period of 60 minutes, a value of 60 minutes is assigned to TTO. Five minutes after the application of FeCl2, a second blood sample (B2) is withdrawn. After 10 minutes of exposure to FeCl2, the filter paper is removed from the beaker and the animal is monitored for the remainder of the experiment. Upon reaching a zero blood flow, a third blood sample (B3) is removed and the clot is removed and weighed. Measurements of tempering bleeding time are made on the front leg cushions at the same time • time that blood samples are obtained. The profiles of coagulation consisting of activated partial thromboplastin time (APTT) and prothrombin time (PT) are performed in all blood samples1. In some cases, a compound according to the invention can be administered orally. Rats are restricted ^ 10 manually using standard techniques and administered compounds by intragastric forced feeding using a 18-gauge curved dosing needle (volume of 5 ml / kg). 15 minutes after intragastric administration, the animal is anesthetized and the instruments described above. The experiments are then carried out according to the protocol described above. The present invention can be applied in other forms • specific without leaving their spirit or their main attributes. twenty

Claims (34)

1. CLAIMS 1. A compound of the formula the monocyclic containing at least one nitrogen atom, or a | bicyclic heteroaryl group including a first close ring attached on Z and a distal ring relative to said First ring, said distant ring includes at least one nitrogen atom; Z is alkenyl, - (CH2) X (O) NR "(CH2) s ~, - (CH;) SR" NC (O) (Of r-, - ^ * \ ww (CH;) NR "(CH; ) 3- or - (CH;) 3NR "(CH;), - Ri is hydrogen, optionally substituted alkyl, alkenyl Optionally substituted, optionally substituted aralkyl, optionally substituted heteroaralkyl, R'0 (CH2) x-, R'0; C (CH;) x-, R'C (O) (CH:) X-, YVNCÍO) ( CH;) X-, OR Y1Y: N (CH2) X-; R 'and R "are independently hydrogen, alkyl Optionally substituted, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkenyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; 5 R; is hydrogen, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl, optionally substituted heteroaralkenyl, R5R4NC (0) (CH2) x-, R3S (0) F- or R3R.NS (0) p-; R3 is hydrogen, optionally substituted alkyl, * optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl, or optionally substituted heteroaralkenyl, or R and R3 together with the portion -NS (0) p- or the portion -NS (0) p- NR- through which Ri and R3 are attached form an optionally substituted heterocycle of 5 to 7 members; And R 4 is hydrogen, optionally substituted alkyl, Optionally substituted cycloalkyl or optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or R3, and R4 together with the nitrogen to which R3 and R are attached form a 4 to 6 heterocyclyl. 7 members optionally substituted; Xi and ai are independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or X: and ia together form oxo; X; and X2a are H, or alternatively form oxo; X3 is H, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted P ^ heteroaryl, optionally substituted aralkyl, or, optionally substituted heteroaralkyl, or X3 and one of Xi and X? A together form a 4'-cycloalkyl. 7 members; Xi is H, optionally substituted alkyl, optionally substituted aralkyl, or hydroxyalkyl; Xs, Xsa and Xsb are independently selected from them between H, RsReN-, (hydroxy) HN-, (alkoxy) HN-, or (amin) HN-, • R70-, R5RsNC0-, R5R6NS0; -, R7C0-, halo cyano, nitro and Rs (0) C (CH2) q-, and is a bicyclic heteroaryl group, one of X5, sa and Xsb is a substituent that is alpha for a nitrogen of Said ring and is selected from the group consisting of H, hydroxy and H; N-, (optionally) substituted lower alkyl) HN (hydroxy) HN-, (alkoxy) HN-, or (amino) HN- substituting Y1 and Y "are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y1 and Y2 together with the N through which Y1 and Y2, are together they form a 4 to 7 membered heterocyclyl, R5 and R6 are independently H or optionally substituted lower alkyl, or one of R5 and R6 is H and the other of R5 and Re is Rs (0) CCH2- or lower acyl; R7 is H, optionally substituted lower alkyl, lower acyl or R8 (0) CCH-; Rs is H, optionally substituted lower alkyl, alkoxy or hydroxy; is O, 1, 2 or 3; p and r are, independently 1 or 2; q is 0 or 1, s is 0, 1 or 2; and x is 1, 2, 3, 4, or 5, or else a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.
2. 2 . A compound of the formula I a bicyclic heteroaryl group including a first close ring attached on Z and a ring distant relative to said first ring, said distal ring includes at least one nitrogen atom; Z is alkenyl; Ri is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, R'0 (CH;) and -, R'02C (CH2) x-, Y NCtO) (CH2) X-, O- YTN (CH :) .-; R 'is hydrogen, optionally substituted alkyl, optionally substituted alkyl or optionally substituted heteroaralkyl; R2 is R3S (0) p- or R3R4NS (0) p-; R3 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, • optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl, or optionally substituted heteroaralkenyl, or R- and R3 together with the -NS (0) p- portion or the -NS portion (0) ) p- NR4- through which Ri and R3 are attached form an optionally substituted heterocycle of 5-7 members; and R4 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or R3 and R4 together with the nitrogen to which R and R4 are attached form a heterocyclyl of 4 to 7 members optionally substituted; Xi and Xia are independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or else Xi and Xα together form oxo; 'X2 and X2a are H, or alternatively form oxo; X3 is H, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or | either optionally substituted heteroaralkyl, or X3 and one of Xi and X? a together form a cycloalkyl of 4 j to 7 members; X 4 is H, optionally substituted alkyl, optionally substituted aralkyl, or hydroxyalkyl; Xs, Xsa and Xsb are independently selected from among them H, R5R6N-, (hydroxy, alkoxy or amino) HN-, R70-, R5R5NC0-, R5RdNS02-, R7CO-, halo cyano, nitro or < all right • R8 (O) C (CH2) q-, and one of X5, X5a and XSD is a substituent that is alpha for a nitrogen of said distal ring of and is selected from the group consisting of H, 15 hydroxy or H; N-, (optionally substituted lower alkyl) HN (hydroxy) HN-, (alkoxy) HN-, or (amino) HN--; Y1 and Y2 are independently selected from hydrogen, • optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or! either optionally substituted heteroaralkyl, or Y ~ 'and Y2 together with the N through which Y1 and Y2 are nested form a 4 to 7 membered heterocyclyl; R5 and Re are, independently, H or optionally substituted lower alkyl, or one of R5 and R6 is H and the other 25 of R5 and Rβ is R8 (0) CCH; - or lower acyl; R7 is H, optionally substituted lower alkyl, lower acyl or R3 (0) CCH; -; R8 is H, optionally substituted lower alkyl, alkoxy or hydroxy; 5 m is 0, 1, 2 or 3; p is 1 or 2; q is 0 or 1, and x is 1, 2, 3, 4, or 5, or else a pharmaceutically acceptable salt thereof, an N- • 10 oxide thereof, a hydrate thereof or a solvate of the same. ism.
3. 3. The compound according to claim 1 from a monocyclic heteroaryl group containing at least one nitrogen atom.
4. 4. The compound according to claim 1 wherein Z is alkenyl, - (CH2) rC (O) NR "(CH2) s ~, - (CH2) SR" NC (O) (CH2) r-, - • ( CH2) rNR "(CH2) S- or - (CH2)? NR" (CH2) r-.
5. 5. The compound according to claim 1 where 20 R; is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, -R'0 (CH2)? -, R'02C (CH;) x-, R'C (0) 0 (CH2)? -, YVNCÍO) (CH2) X-, O 'well Y1Y2N (CH2)? -.
6. 6. The compound according to claim 1 wherein R_. is selected within the group consisting of 10
7. 7. The compound according to claim 1 wherein within the group consisting of 20 25
8. 8. The compound according to claim 1 wherein Ri is H, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally alkyl. • replaced.
9. 9. The compound according to claim 1 wherein R; is R3S (0) p-.
10. 10. The compound according to claim 9 wherein p is 2.
11. 11. The compound according to claim 9 wherein: R3 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thienyl, optionally substituted benzothienyl. optionally substituted thieniopyridyl, optionally substituted quinolinyl, or optionally substituted isoquinolinyl.
12. 12. The compound according to claim 1 wherein Z is methylenyl and m is 1.
13. 13. The compound according to claim 1 wherein • 2 and X? A together are oxo.
14. 14. The compound according to claim 1 wherein each of Xi, Xia, X3 and X4 is H.
15. The compound according to claim 1 wherein 0x - eess iisoquinolinyl optionally substituted.
16. 16. The compound according to claim 15 wherein Z is fixed on isoquinolinyl at the position 7. •
17. 17. The compound according to claim 1 wherein (r is optionally substituted quinolinyl
18. 18. The compound according to claim 17 wherein Z is attached to quinolinyl in theposition 7.
19. 19. The compound according to claim 1 wherein optionally substituted quinazolinyl.
20. 20. The compound according to claim 19 wherein Z is attached to quinazolinyl in the 7-position.
21. The compound according to claim 1 wherein is an optionally substituted portion of the formula and W and S, O or NRn, where Rn is H, alkyl, aralkyl, -25 heteroaralkyl, R8 (O) C (CH2) q-, and A is CH or N.
22. 22. The compound according to claim 21 wherein Z is attached to said portion through the 5-membered ring. •
23. 23. The compound according to claim 1 wherein one of Xs, Xsa and so is a substituent that is in the proximal ring of hydroxy and amino.
24. 24. The compound according to claim 2, one of Xs, Xsa and Xsb is hydroxy or amino.
25. 25. The compound according to claim 1 wherein Xsa and Xsb replacing the distant ring of the alpha position for a nitrogen thereof is H or (H, optionally substituted lower alkyl, hydroxy or amino) HN-.
26. 26. A compound according to claim 1 which is selected from methyl 3- [[1- (4-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] - (methyl) ester ( 5-chloro-1H-indol-2-ylmethyl) amino] propionic; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2? -? Ilmethyl) - (3-ethylbutyl) amino] pyrrolidin-2-one; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [benzyl- (5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) thiazol-5-ylmethylamino] pyrrolidin-2-na; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2- • 10-ylmethyl) - (2H-pyrazol-3-ylmethyl)) amino] pyrrolidin-2 -one; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorobenzo [b] thiophen-2-ylmethyl) amino] pyrrolidin-2-one; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(6-chlorothieno [2, 3-b] pyridin-2-ylmethyl) amino] pyrrolidin-2-one; 1- (-aminoquinazolin-7-ylmethyl) -3- (S) - [(IH-pyrrolo [2,3-c] pyridin-2-ylmethyl) amino] pyrrolidin-2-one; 3-. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) - • ylamino] methyl} -IH-quinolin-2-one; 1- (7-aminothieno [3,2- b] pyridin-2-ylmethyl) -3- (R) - [(5-chloro-lH-20 indol-2-ylmethyl) amino] pyrrolidin-2-one; 2- (5-chlorothiophen-2-yl) -ettensulfonic acid [2-oxo-l- (lH-pyrrolo [3, 2-c] pyridin-2-ylmethyl) pyrrolidin-3- (R) -yl] -amide; Isopropyl ester of acid. { [2- (5-chlorothiophen-2-yl) etensulfonyl] - [2-oxo-l- (lH-pyrrolo [3,2- c] pyridin-2-ylmethyl) pyrrolidin-3- (R) -yl] Not me} acetic; 1- (4-aminoquinolin-7-ylmethyl) -3- (R) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one; [1- (4-aminoquinplin-5-ylmethyl) -2-trifluoroacetate [1- (l-aminoisoquinolin-7-ylmethyl) -2- • oxopyrrolidin-3- (R, S) -yl] -idene] 5-Chloro-1H-benzoimidazole-2-sulfonic acid-7-methoxynaphtal ^ n-2-sulphonic acid-oxopyrrolidin-3- (R) -yl] amide; [1- (1-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3 < hydrochloride; S) -yl] 7-methoxynaphthalene-2-sulfonic acid amide; ^^ trifluoroacetate of 7-methoxynaphthalene-2-sulphonic acid [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -7-methoxynaphtali-2-sulphonic acid trifluoroacetate; [1- (1-hydroxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R, <S) -yl] -7-methoxynaphthalene-2-sulfonic acid; • [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R, S) -yl] methylamide of 7-methoxy-naphthalene-2-sulfonic acid trifluoroacetate; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] methylamide trifluoroacetate of 7-methoxynaphthalene-2-sulfonic acid; trifluoroacetate of benzo [b] thiophene-2-sulfonic acid [1- (l-aminoisoquinolin-7-ylmethyl) -2-, 25-oxo-pyrrolidin-3- (S) -yl] -amide; [1- (l-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -6-chloro-benzo [b] tiophen-2-sulfonic acid trifluoroacetate; [1- (1-amino-6-methoxyisoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -7-methoxy-naphthalene-2-sulfonic acid hydrochloride; [1- (6-methoxyisoquinolin-butylmethyl) -2-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; 4- (2-Chloro-6-nitrophenoxy) -benzenesulfonic acid [1- (1-amino-6-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide trifluoroacetate; [1- (1,6-diaminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (1,6-diaminoisoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate; [1- (2-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) yl] -amide-7-methoxy-naphthalene-2-sulfonic acid trifluoroacetate; 6-chloro-benzo [b] thiophene-2-sulfonic acid [1- (2-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide trifluoroacetate; [1- (2-aminoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -benzo [b] thiophene-2-sulphonic acid trifluoroacetate; [1- (2-aminoquinolin-7-ylmethyl) -2-5-oxopyrrolidin-3- (S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid trifluoroacetate; [1- (2-hydroxyquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid; [1- (2-aminoquinolin-5-ylmethyl) -2- (10-oxo-pyrrolidin-3- (S) -yl] -amide-7-methoxy-naphtha-2-sulfonic acid trifluoroacetate; [1- (2-aminoquinolin-5-ethylmethyl) -2-oxopyrrolidin-3- (S) -yl] methylamide of 7-methoxy-naphthalene-2-sulfonic acid trifluoroacetate; [1- (2-hydroxyquinolin-5-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] methylamide of 7-methoxynaphthalene-2-sulfonic acid; [1- (2-aminoquinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl jiamide • of 7-methoxynaphthalen-2-sulfonic acid; 7-methoxynaphthalene-2-sulfonic acid [1- (2-hydroxyquinolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -20-yl] -amide; trifluoroacetate of 7-methoxynaphthalene-2-sulfonic acid [1- (1H-benzimidazol-5-ylmethyl) -2- oxopyrrolidin-3- (S) -yl] -amide; [2- (lH-benzimidazol-5-ylethyl) -2- [25-oxopyrrolidin-3- (S) -yl] -7-methoxynaphthalene-2-sulphonic acid trifluoroacetate; [1- (4-aminoquinazolin-6-ylmethyl Dl -2-oxopyrrolidin-3- (S) -yl] -methyl-methylamide of 7-methoxynaphthyl-alen- • 2-sulphonic acid; [2, 3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide-7-methoxy-naphthalene-2-sulfonic acid trifluoroacetate of 2- (6-) [2, 3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -7-methoxy-naphthalene-2-sulfonic acid amide: [1- (7-aminothylene) -trifluoroacetate [2, 3-c] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide, 7-methoxy-naphthalene-2-sulfonic acid; [1- (7-hydroxy-tieno [trifluoroacetate]] 2, 3-c] pyridin-3-yl-15-methyl-2-oxopyrrolidin-3- (S) -yl] -amidoxinaphthalene-2-sulfonic acid amide; [1- (4-aminothieno [3]] trifluoroacetate. 2-C] pyridin-3-ylmethyl) -2-oxo-pyrrolidin-3- (R, S) -yl] -amide-7-methoxy-naphthalene-2-sulfonic acid; [1- (4-hydroxy-tiene) trifluoroacetate [3, 2-c] pyridin-3-yl-methyl) -2-oxopyrrolidin-3- (R, S) -yl] a acid measurement, 7- methoxynaphthalene-2-sulfonic acid; [1- (4-aminothieno (3, 2-c) pyridin-3-ylmethyl) -2-oxopyrrolidin-3- (R, S) -yl] -amide] benzo [b] thiophene acid trifluoroacetate 2-sulfonic; [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S-yl) -amide of thieno [3,2- b] pyridine-2-sulfonic acid; -amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S-il] -amide of thieno [2, 3-b] pyridine-2-sulfonic acid; 5 [1- (l-amino-isoquinolin 4-pyridin-3-yl-thiophene-2-sulfonic acid-2-oxo-pyrrolidin-3- (S-yl) -amide; [2-oxo-l- (lH-pyrrolo [3, 2 -c] pyridin-2-ylmethyl) -pyrrolidin-3 (S) -yl] -amide of 5 'chloro- [2, 2'] bithiophenyl-5-sulfonic acid; [2-oxo-l- (lH-pyrrolo [ 3, 2-c] pyridin-2-ylmethyl) -pyrrolidin -3- • 10 (S) -yl] 2- (5-chloro-thiophen-2-yl) -etensulforic acid amide; 5'-Chloro- [2, 2 '] -bothiophenyl-5-sulfonic acid-amino-3-oxo-pyrrolidin-3- (S) -yl] -amide; amino-isoquinolin-7-ylmethyl) -2- (5-chloro-thiophen-2-yl) -etensulfonic acid-2-oxo-pyrrolidin-3- (Si) -Il] -amide; 4-amino-quinazolin-6-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -acidic acid amide 6-cl oro-benzo [b] thiophen 2-sulfonic; • [1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [b] thiophene 2-sulfonic; [1- (4-Amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [b] thiophen-2-sulfonic acid; [1- (4-Amino-thieno [3,2-d] pyrimidin-7-yl-25-methyl) -2-oxo-pyrrolidin-3- (S) -yl] -5-chloro- [2-chloro] -acetic acid trifluoroacetate , 2 '] bitiofeni1-5-2 sulfonic; [3, 2-b] pyridine-2-sulfonic acid [1- (1, 6-diamino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; 2- (5-Chloro-thiophen-2-yl) -etensulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide; ! 5'-Chloro- [2, 2 '] bithiophenyl-5-sulfonic acid [1- (1-amino-isoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -yl] -amide; [2-oxo-l- (lH-pyrrolo [3, 2-c] iridin-2-ylmethyl) -pyrrolidin 3 (S) -yl] -amide of 2- (5-chloro-thiophen-2-yl) acid? -etensulfonic; 3- (R) -5-chlorothiophen-2-yl) -etensulfonic acid [1- (4-aminoquinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate; 2- (S) - [[1- (4-Amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] - (6-chloro-benzo [b] thiophene) methyl ester trifluoroacetate 2-sulfonyl) -amino] -acetic; [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 2- (S) -6-chloro-benzo [b] thiophene-2-trifluoroacetate -sulfonic; [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 2- (s) - (5-chloro-thiophen-2-yl) trifluoroacetate) -etensulfonic; [1- (4-amino-quinolin-6-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl [- thieno [3,2-b] pyridine-2-sulfonic acid ditrifluoroacetate; N- (3-amino-pyridin-4-yl) -2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -acetamide; 2- [3- (7-methoxy-naphthalene-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] -N-pyridin-4-yl-acetamide; trifluoroacetate. { 2-oxo-l- [2- (pyridin-4-ylamino) ethyl] -pyrrolidin-3- (S) -yl} 6-chlorobenzo [b] thiophene-2-sulfonic acid amide; [2-Oxo-l- [2- (pyridin-4-ylamino'-ethyl] -pyrrolidin-3-yl} -amide of 5'-chloro- [2, 2 '] -bitiofenyl-5-sulfonic acid; {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl} -pyrrolidin-3-yl} -amide of 6-chloro-thieno [2, 3-b] pyridine-2-sulfonic acid; {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide of thieno acid [3, 2-ditrifluoroacetate] b] pyridine-2-sulfonic acid;. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} -amide of 2- (5-chloro- thiophen-2-yl) -etensulphonic acid; .1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl.} ditrifluoroacetate. - (S) -5'-chloro- [2, 2 '] -bitiofenyl-5-sulfonic acid amide: {. 1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -tritrifluoroacetate ethyl) -2-oxo-pyrrolidin-3-yl.} - (S) -6-chloro-benzo [b] thiophene-2-sulphonic acid amide ((6-chloro-benzoyl) [b] thiophen-2-sulfonyl) -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidi n-3- (-yl.}. - amino) -acetic; ((6-chloro-benzo [b] thiophene-2-sulfonyl) -. {2-oxo-l- [2-pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl-trifluoroacetate} -amino) -acetic; 5 alil-. { 2-Oxo-1- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-11} - 6-chloro-benzo [b] thiophene-2-sulfonic acid amide; methyl-. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} - 6-chloro-benzo [b] thiophene-2-sulfonic acid amide; trifluoroacetate. { 1- [2- (2-amino-3-chloro-pyridin-4- (10-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} S-acid amide) -2- (5-chloro-thiophen-2-yl) -etensulfonic acid; ditrifluoroacetate. { 1- [2- (2-amino-3-chloro-pyridin-4-ylamino) -ethyl] -2-oxo-pyrrolidin-3-yl} - (S) -thieno [3, 2-b] pyridine-2-sulfonic acid amide; Methyl ([2- (5-chloro-thiophen-2-yl) -ethersulfonyl] -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-methyl ester -yl.}. -amino) -acetic; • ([2- (5-Chloro-thiophen-2-yl) -ethersulfonyl] -. {2-oxo-l [2- (pyridin-4-ylamino) -ethyl] -20-pyrrolidin-3 isopropyl ester -yl.}. -amino) -acetic; ([2- (5-Chloro-thiophen-2-yl) -ethersulfonyl] -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-trifluoroacetate il.}. -amino) -acetic; (2-methoxy-ethyl) trifluoroacetate -. { 2-Oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} 2- (5- ^ loro-thiophen-2-yl) -etensulfonic acid amide; ([2- (5-C-thiophene-2-yl) -etensulfonyl] -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidine ethyl ester trifluoroacetate -3-yl.} -amino) -acetic; 5-Trifluoroacetate 3- (5-chloro-thiophen-2-yl) -N- [2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-yl} acrylamide; 1- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (-chloro-enyl) -urea trifluoroacetate; N- [1- (4-aminoquinazolin-7-ylmethyl) -2- 9 ^^ 10 oxopyrrolidin-3- (S) -yl] -2- (5-chlorothiophen-2-yloxy) acetamide trifluoroacetate; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5-chlorothiophen-2-yl) urea trifluoroacetate and 15-Chlorothiophen-2-carboxylic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide trifluoroacetate; • acid methyl ester trifluoroacetate. { [1- (4-aminoquinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] - [3- (5-chlorothiophen-2-yl) acryloyl] amino} acetic; 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -amide trifluoroacetate; trifluoroacetate of [3, 2-b] pyridine-2-sulphonic acid [1- (l-aminoisoquinolin-7-ylmethyl) -2- [ox-2-oxopyrrolidin-3- (R) -yl] -amide; 1- (4-aminoquinolin-7-ylmethyl) -3- (S) | - [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [3- (5-chlorothiophen-2-yl) allylamino] pyrrolidin-2-one trifluoroacetate; N- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5-chlorothiophen-2-yl) acrylamide trifluoroacetate; 1- (4-aminoquinazolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; ^ F 10 acid methyl ester trifluoroacetate. { [L- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] [2- (5-chlorothiophen-2-yl) etensulfonyl] amino} acetic; acid methyl ester trifluoroacetate. { [l- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] (5-chloro-15 lH-indol-2-ylmethyl) amino] acetic; acid methyl ester trifluoroacetate. { [1- (aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] [3- (5-chlorothiophen-2-yl) allyl] amino} acetic; [l- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -3- (5-chlorothiophen-2-yl) ureido acid methyl ester trifluoroacetate} acetic; N- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -3- (5-chlorothiophen-2-yl) acrylamide trifluoroacetate; 1- (4-aminoquinazolin-7-ylmethyl) -3- (R) -25 [(5-chloro-lH-indol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; 1- [1- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -3- (5-chlorothiophen-2-yl) urea trifluoroacetate and trifluoroacetate of [1- (4 5-chloro-thiophene-2-carboxylic acid -aminoquinazolin-7-ylmethyl) -2- • oxopyrrolidin-3- (R) -yl] -amide; acid methyl ester trifluoroacetate. { [I- (4-aminoquinazolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] (5-chloro-l-indol-2-ylmethyl) amino] acetic; 1- (4-aminoquinolin-7-ylmethyl) -3- (S) - [(5- {0-chloro-lH-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one trifluoroacetate; [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide of 5-chloro-benzo [b] thiophene-2-sulphonic acid trifluoroacetate; [1- (4-Amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-5-pyrrolidin-3 (S) -yl] -amide of 2- (5-chloro-thiophene) 2-yl) -etensulfonic; [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 7-methoxy-naphthalene-2-sulphonic acid trifluoroacetate; iO trifluoroacetate of [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 2- (5-chloro-thiophen-2-yl) - Etensulfonic; [1- (4-amino-quinazolin-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [b] thiorfen-2-sulphonic acid trifluoroacetate; (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5-chlorobenzo [b] ] thiophene-2-sulfonic acid; • (S) - [1- (4-Amino-thieno [3,2- d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of thieno acid [3, 2- b] pyridine-2-sulfonic acid; (S) - [1- (4-Amino-thieno [3,2-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate and 6-chlorobenzo [b] acid ] thiophene-2-sulfonic acid; ^ 10 (S) - [1- (4-Amino-thieno [3,2- d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5'-chloro- . { 2,2 '] bitiopheni-5-sulphonic; (S) - [1- (4-amino-thieno [3,2- d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide trifluoroacetate of 2- (5-chloro-thiophene) -2- 15 il) -etensulfonic; [(S) -1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5-chloro- • benzo [3-amino-thieno [3,2-d] pyrimidin-7-ylmethyl] b] thiophene-2-sulfonic; [(S) -1- (4-amino-thieno [2,3-d] pyrimid-in-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5-chloro- benzo [b] thiophene-2-sulphonic; [(S) -1- (4-Amino-thieno [2,3-d] pyrimid-in-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 5'-ci-trifluoroacetate paro- [2, 2 '] bromo-phenyl-5-sulfonic acid; [(S) -1- (4-Amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of thieno acid [3, 2-trifluoroacetate] b] pyridine-2-sulfonic acid; [(S) -1- (4-amino-thieno [2,3-d] pyrimidin-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 6-cioro-5-benzoate [b] thiophene-2-sulphonic; [1- (4-Amino-thieno [3,2-d] pyrimidiLn-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -yl] -amide of 5'-c-gold- [1-trifluoroacetate] 2, 2 '] bitiofeni-1-5-sulphonic; [1- (4-Amino-thieno [3,2-d] pyrimidm-7-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of tienc [3,2-] b] pyridine-2-sulfonic acid; and [(S) -1- (4-amino-thieno [3,2-d] pyrimidin-7-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 6-chloro-benzo [b] thiophen-2-sulphonic.
27. 27. A compound according to claim 1 which is selected from trifluoroacetate of [1- (6-methoxyisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (S) -yl] -amide of 7-methoxynaphthalene acid -2- sulfonic; Trifluoroacetate 1- (4-aminoquinolin-7-ylmethyl) -3- (S) - [(5-chloro-lH-benzimidazol-2-ylmethyl) amino] pyrrolidin-2-one; [2-Oxo-l- (lH-pyrrolo [3,2-c] pyridin-2-ylmethyl) -pyrrolidin-3- (S) -yl] -amide of 2- (5-chloro-thiophen-2 -amide) il) -technical; [1- (4-amino-quinazolin-7-ylmethyl) -2-bxo-pyrrolidin-3- (S) -yl] -amide of 2- (5-chloro-thiophen-2-yl) trifluoroacetate - Etensulfonic; (S) - [1- (4-Amino-thieno [3,2-d] pyrimid-6-ylmethyl) -2-oxo-pyrrolidin-3-yl] -amide of 2- (5- chloro-thiophen-2-yl) -etensulfonic; 5-trifluoroacetate of [3, 2-b] pyridine-2-sulphonic acid [1- (1-aminoisoquinolin-7-ylmethyl) -2-oxopyrrolidin-3- (R) -yl] -amide; trifluoroacetate. { 2-oxo-l- [2- (pyridin-4-yl-amino) -ethyl] -pyrrolidin-3- (S) -yl} 6-chlorobenzo [b] thiophen-2- (10) sulfonic acid amide; methyl ester of ((6-chloro-benzo [b] thiophen-2-sulfo'nyl) -. {2-oxo-l- [2- (pyridin-4-ylamino) -ethyl] -pyrrolidin-3-methyl ester (-yl.} - amino) -acetic; ditrifluoroacetate of [2-oxo-l- (lH-pyrrolo [2,3-c] pyridin-2-yl-ylmethyl) -pyrrolidin-3- (S) -il ] thieno [3, 2-b] pyridine-2-sulfonic acid amide; [1- (l-ammo-isoquinolin-7-ylmethyl) -2-oxo- • pyrrolidin-3- (S) -yl trifluoroacetate] ] thieno [3, 2-b] pyridine-2-sulfonic acid amide; [1- (4-amino-quinolin-7-ylmethyl) -2-oxo-pyrrolidin-3 (S) -trifluoroacetate -yl] -amide acid 2 (S) -5- (5-chloro-t? ofen-2-yl) -etensulfonic acid and [1- (1,6-diamino-isoquinolin-7-ylmethyl) bistrifluoroacetate] ) -2-Oxo-pyrrolidin-3- (S) -yl] -amide of 6-chloro-benzo [b] thiophene-2-sulfonic acid.
28. 28. A compound according to claim 1 of the formula is a radical selected from the group consisting of twenty W is S, O or NRn, where Ru is H, alkyl, aralkyl, heteroaralkyl or Re (O) C (CH2) q-; A is CH or N; yi R2 is a radical selected from the group consisting of 25 25 25 - - ---- ** - - - - + ft • 10 25 10 25
29. 9. A compound according to claim 1 of the formula where s is Ri is H; and R is a radical selected from the group consisting of: oc otX c. • oo O t XiZ * r? O-. fifteen 25 R: is H; and R is a radical selected from the group, consisting of: Ri is H; and R; is a radical selected from the group consisting of: ; Ri is H; and R: it's a radical se! it consists of: 10 •
30. 30. A pharmaceutical composition comprising a pharmaceutically acceptable amount of a compound according to claim 1 and a pharmaceutical carrier "Acceptable.
31. 31. A method for the treatment of a patient suffering from a physiological disorder that can be modulated by the inhibition of a Factor Xa activity, which comprises administering to the patient a therapeutically effective amount of a compound according to the claim C 1.
32. 32. The method according to claim 31 wherein the physiological disorder is the abnormal formation of thrombi, acute myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy or 15 percutaneous transluminal coronary angioplasty, transient ischemic attacks, stroke, pathological thrombus formation that occurs in the veins of the lower extremities after abdominal, knee and hip surgery, risk of pulmonary thromboembolism or 20 well circulating systemic intravascular coagulopathy that occurs in vascular systems during septic shock, some viral infections or cancer.
33. 33. The method according to claim 31 wherein the physiological disorder is the abnormal formation of, thrombi, 25 acute myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy, transient ischemic attacks, restenosis later! of venous or coronary angioplasty, pathological formation of thrombi that occurs in the veins of the lower extremities after abdominal, knee and hip surgery or risk of pulmonary thromboembolism.
34. 34. The method according to claim 31 wherein the physiological disorder is stroke, luminal narrowing of vessels or disseminated systemic intravascular coagulopathy occurring in vascular systems during septic shock, certain viral infections or cancer.