WO2000032590A1 - SUBSTITUTED OXOAZAHETEROCYCLYL FACTOR Xa INHIBITORS - Google Patents

Abstract

This invention is directed to oxoazaheterocyclyl compounds which inhibit factor Xa, to pharmaceutical compositions comprising these compounds, to intermediates useful for preparing these compounds and to a method of inhibiting factor Xa.

Description

SUBSTITUTED OXOAZAHETEROCYCLYL FACTOR Xa INHIBITORS

FIELD OF THE INVENTION

This invention is directed to oxoazaheterocycyl compounds which inhibit factor Xa, to pharmaceutical compositions comprising these compounds, to intermediates useful for preparing these compounds and to a method of inhibiting factor Xa.

BACKGROUND OF THE INVENTION

Factor Xa and Factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) activates prothrombin to generate thrombin. Factor Xa is strategically located at the intersection of extrinsic and intrinsic pathways of the blood coagulation system. Thus, an inhibitor of Factor Xa inhibits the formation of thrombin and therefore is useful for preventing or treating disorders related to blood coagulation in mammals.

Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTC A), transient ischemic attacks, stroke, intermittent claudication and bypass grafting of the coronary (CABG) or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long- term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular 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 resulting in the formation of life-threatening clots throughout the microvasculature of several organ systems.

In addition to their use in anticoagulant therapy, Factor Xa inhibitors are useful in the treatment or prevention of other diseases in which the generation of thrombin has been implicated as playing a physiologic role. For example, thrombin has been proposed to contribute to the morbidity and mortality of such chronic and degenerative diseases as arthritis, cancer, atherosclerosis and Alzheimer's disease by virtue of its ability to regulate many different cell types through specific cleavage and activation of a cell surface thrombin receptor, mitogenic effects, diverse cellular functions such as cell proliferation, for example, abnormal proliferation of vascular cells resulting in restenosis or angiogenesis, release of PDGF and DNA syntheses. Inhibition of Factor Xa will effectively block thrombin generation and therefore neutralize any physiologic effects of thrombin on various cell types.

The representative indications discussed above include some, but not all, of the possible clinical situations amenable to treatment with a Factor Xa inhibitor.

Oxoazaheterocyclyl Factor Xa inhibitors are disclosed in International Patent Numbers PCT/US98/07158, published Oct. 22, 1998; PCT/US98/07159, published Oct. 22, 1998; PCT/US98/07160, published Oct. 22. 1998; PCT/US98/07161 , published Oct. 22, 1998; and PCT/US96/09290, published Dec. 19, 1996. Oxoazaheterocyclyl fibrinogen antagonists are disclosed in International Patent Application Number PCT/US92/09467, published May 13, 1993.

SUMMARY OF THE INVENTION

This invention is directed to oxoazaheterocycyl compounds as orally active inhibitors of factor Xa of the formula (I)

wherein

R¹ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl. alkoxy, aminoalkyl, -CH_:OZ, or - CH(CH_?)OZ; R² is hydrogen, optionally substituted alkyl, aryl, aralkyl, heteroaryl, or heteroarylalky;

R³ is hydrogen or methyl. X is N or O; Z is lower alkyl. or alkoxycarbonylalkyl; Cy, is an optionally substituted six-membered aryl group, or optionally substituted heteroaryl; and

Cy₂ is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclenyl, optionally substituted fused arylcycloalkyl, optionally substituted fused arylcycloalkenyl, fused arylheterocyclyl, optionally substituted fused arylheterocyclenyl, optionally substituted fused heteroarylcycloalkyl, optionally substituted fused heteroarylcycloalkenyl, optionally substituted fused heteroarylheterocyclyl or optionally substituted fused heteroarylhetercyclenyl; or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable prodrug thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.

In another aspect, this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I and a pharmaceutically acceptable carrier.

In another aspect, this invention is directed to a method of treating a physiological disorder capable of being modulated by inhibiting Factor Xa comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Patient" includes both human and other mammals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkyl" means about 1 to about 4 carbon atoms in the chain which may be straight or branched. The alkyl may be substituted with one or more "alkyl group substituents" which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, amino, carbamoyl, acylamino, aroylamino, carboxy. alkoxycarbonyl, aralkyloxycarbonyl and heteroaralkyloxycarbonyl. Representative alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl. t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl. "Alkenyl" means a straight or branched aliphatic hydrocarbon group containing a carbon-carbon double bond and having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. "Lower alkenyl" means 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 alkyl group substituents as defined herein. Representative alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl. 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, decenyl, and the like. "Alkylene" means a straight or branched bivalent hydrocarbon chain having from 1 to about 20 carbon atoms. The preferred alkylene groups are the lower alkylene groups having from 1 to about 6 carbon atoms. Alkylene may be substituted with 1 or more alkyl group substituents as defined herein. Representative alkylene groups include methylene, ethylene, and the like.

"Alkenylene" means a bivalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. The preferred alkenylene groups are the lower alkenylene groups having from 1 to about 6 carbon atoms. Alkenylene may be substituted by one or more alkyl group substituents as defined herein. Representative alkenylene include -CH=CH-, - CH₂CH=CH-, -C(CH₃)=CH-. -CH₂CH=CHCH -, and the like.

"Alkynylene" means a bivalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. Preferred alkynylene groups are the lower alkynylene groups having from 1 to about 6 carbon atoms. Alkynylene may be substituted by one or more alkyl group substituents as defined herein. Representative

lene include and the like.

I I ' '

— C - NHR -₁₂ "Amidino" or "amidine means a group of formula wherein R_π is selected from hydrogen,

cyano, optionally substituted lower alkyl, nitro or Y'Y²N- and

R₁₂ is selected from hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl and optionally substituted heteroaralkyl. Preferred amidino groups are those in which R_n is hydrogen, R^O, or optionally substituted lower alkyl and R₁₂ is as defined above. Most preferred amidino groups are those in which R_n and R,₂ are hydrogen.

"Basic nitrogen atom^" means an sp² or sp³ hybridized nitrogen atom having a non-bonded pair of electrons which is capable of being protonated. Examples of basic nitrogen atoms, which may be optionally substituted where possible, include those in heteroaryl, heterocyclyl, heterocyclenyl, fused arylheterocyclyl, fused arylheterocyclenyl, fused heteroarylcycloalkyl. fused heteroarylcycloalkenyl, fused heteroarylheterocyclyl, fused heterocyclylheterocyclenyl, imino. amino and amidino groups. "Cycloalkyl" means a non-aromatic mono- or multicyclic hydrocarbon ring system of about 3 to about 10 carbon atoms. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, cycloheptyl. and the like. Representative multicyclic cycloalkyl rings include decalinyl, norbornyl, adamantyl, and the like. The cycloalkyl group is optionally substituted with one or more cycloalkyl group substituents which may be the same or different, where "cycloalkyl group substituent" includes oxo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, amidino. amino, carbamoyl, or sulfamoyl. Preferred cycloalkyl group substituents are amino and amidino.

"Cycloalkenyl" means a non-aromatic monocyclic or multicyclic hydrocarbon ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms. The cycloalkenyl group is optionally substituted by one or more cycloalkyl group substituents as defined herein. Representative monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl, and the like. A representative multicyclic cycloalkenyl ring is norbornylenyl. Preferred cycloalkenyl group substituents are amino and amidino.

"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 ring atoms wherein the ring system contains one or more element(s) other than carbon. "Azaheterocyclyl" means heterocyclyl wherein one or more of the atoms in the ring system is/are nitrogen. Preferred heterocyclyl comprise about 5 to about 6 ring atoms wherein one or two of the ring atoms is/are independently selected from oxygen, nitrogen or sulfur. "Aza", "oxo^" or "thia", when used as a prefix before heterocyclyl means that the ring system contains at lease one nitrogen, oxygen or sulfur atom. The heterocyclyl is optionally substituted with one or more heterocyclyl group substituents which may be the same or different, where " heterocyclyl group substituent" includes oxo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aralkoxycarbonyl. acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl. heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, amino, carbamoyl. or sulfamoyl. Preferred heterocyclyl group substituents include amino, amidino, halogen, hydroxy, alkoxycarbonylalkyl and carboxyalkyl. Representative heterocyclyl include piperidyl, pyrrolidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, tetrahydrofuryl. morpholinyl, thiomorpholinyl, thiazolidinyl, 1.3-dioxolanyl. 1.4-dioxanyl, l J-dithianyl, l J,5-triathianyl, tetrahydrothienyl, tetrahydrothiopyranyl, quinuclidinyl, and the like. The thio or nitrogen moiety of the heterocyclyl may also be optionally oxidized to the corresponding S-oxide, S,S-dioxide or N-oxide. "Heterocyclenyl" means a heterocyclyl as defined herein which contains at least one carbon- carbon or carbon-nitrogen double bond. "Aza", "oxo" or "thia", when used as a prefix before heterocyclenyl means that the ring system contains at lease one nitrogen, oxygen or sulfur atom. The heterocyclenyl is optionally substituted with one or more heterocyclyl group substituents as defined herein. Representative heterocyclenyl include 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 2H-pyranyl, 1 ,2-dihydropyridyI, 1,4-dihydropyridyl, 1 ,2,3,4- tetrahydropyridyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. Preferred heterocyclyl group substituents include amino, amidino, halogen, hydroxy, alkoxycarbonylalkyl and carboxyalkyl. The thio or nitrogen moiety of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

"Aryl" means a 6 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system. The aryl is optionally substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aryldiazo, heteroaryldiazo, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, arylazo, heteroarylazo, amino, alkylamino, carbamyl and sulfamyl. Preferred aryl groups are optionally substituted phenyl or optionally substituted naphthyl. Preferred aryl group substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, CF₃S-, acylamino, alkylthio, alkylamino, amino, carbamyl, carbamylalkyl, thiocarbamyl alkoxyl, and amidino.

"Heteroaryl" means about a 5- to about a 10- membered aromatic monocyclic or multicyclic ring system wherein one or more of the atoms in the ring system is/are element(s) other than carbon. Preferred heteroaryl contain one to about 4 heteroatoms selected from oxygen, nitrogen and sulfur. "Aza", "oxo" or "thia", when used as a prefix before heteroaryl means that the ring system contains at lease one nitrogen, oxygen or sulfur atom. The heteroaryl is optionally substituted with one or more aryl group substituents as defined herein. Representative heteroaryl groups include pyrrolyl, pyrazinyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl. thiadiazolyl, thienopyridyl, pyrrolopyridyl, furanopyridyl, furazanyl, quinoxalinyl, quinazolinyl. quinolizinyl, imidazo[l,2-a]pyridyl, phthalazinyl, imidazo[2J-b]thiazolyl. benzofuranyl, indolyl, isoindolyl, indolizinyl, indazolyl, azaindolyl, benzimidazolyl, benzothienyl, benzisoxazolyl, benzothiazolyl, purinyl, benzotriazolyl, 1,8-naphthyridinyl, pteridinyl, quinolinyl, imidazolyl, isoquinolinyl. cinnolinyl, triazinyl, benzotriazinyl, and the like. Preferred heteroaryl group substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, CF₃S-, acylamino, alkylthio, alkylamino, amino, carbamyl, carbamylalkyl, thiocarbamyl alkoxyl, and amidino. When heteroaryl contains a nitrogen atom, the nitrogen atom may be oxidized to the N-oxide.

"Fused arylcycloalkyl" means a fused aryl and cycloalkyl as defined herein. Preferred fused arylcycloalkyls are those wherein the aryl thereof is phenyl and the cycloalkyl consists of about 5 to about 6 carbon atoms. Representative fused phenylcycloalkyl groups include 1,2,3,4-tetrahydronaphthyl, indanyl, and the like. The fused arylcycloalkyl is optionally substituted with one or more fused arylcycloalkyl group substituents selected from, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aryldiazo, heteroaryldiazo, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl. aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl. alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, arylazo, heteroarylazo, amino, alkylamino, carbamyl and sulfamyl. The cycloalkyl moiety is further optionally substituted with oxo. Preferred fused phenylcycloalkyl group substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino. carbamyl, thiocarbamyl and amidino.

"Fused arylcycloalkenyl^" means a fused aryl and cycloalkenyl as defined herein. Preferred fused arylcycloalkyenl are those wherein the aryl thereof is phenyl and the cycloalkenyl consists of about 5 to about 6 carbon atoms. The fused arylcycloalkenyl is optionally substituted with one or more fused arylcycloalkyl group substituents as defined herein. Representative fused phenylcycloalkenyls include 1 ,2-dihydronaphthylenyl, inden l. and the like. The cycloalkyl moiety is further optionally substituted with oxo. Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino. "Fused arylheterocyclyl^" means a fused aryl and heterocyclyl as defined herein. Preferred fused arylheterocyclyl are those wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms wherein one or two of the ring atoms is/are independently selected from oxygen, nitrogen and sulfur. "Aza", "oxo^" or "thia", when used as a prefix before the heterocyclyl portion of the fused arylheterocyclyl means that the heterocyclyl contains at lease one nitrogen, oxygen or sulfur atom. Representative preferred fused phenylheterocyclyl ring systems include indoiinyl,

1,2,3,4-tetrahydroisoquinolinyl. 1,2,3,4-tetrahydroquinoiinyl, lH-2J-dihydroisoindolyl, 2,3-dihydrobenz[f]isoindolyl, l J.3,4-tetrahydrobenz[g]isoquinolinyl, and the like. The fused phenylheterocyclyl is optionally substituted with one or more fused phenylcycloalkyl group substituents as defined herein. The heterocyclyl moiety is further optionally substituted with oxo. Preferred substituents include hydrogen, alkyl, aryl, heteroaryl. hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino. carbamyl, thiocarbamyl and amidino. The nitrogen or sulphur atom of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. "Fused arylheterocyclenyl" means a fused aryl and heterocyclenyl as defined herein. "Aza",

"oxo" or "thia", when used as a prefix before the heterocyclenyl portion of the fused arylheterocyclenyl means that the heterocyclenyl contains at lease one nitrogen, oxygen or sulfur atom. Preferred fused arylheterocyclyl are those wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms wherein one or two of the ring atoms is/are independently selected from oxygen, nitrogen and sulfur. Representative preferred fused arylheterocycloalkenyl ring systems include

3H-indolinyl, l

l. 2HJ-oxoisoquinolyl, and the like. The fused arylheterocyclenyl is optionally substituted with one or more fused arylcycloalkyl group substituents as defined herein. The heterocyclyl moiety is further optionally substituted with oxo. Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydrox\ . acyl, aroyl, halo, nitro. cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl. thiocarbamyl and amidino. The nitrogen or sulphur atom of the heterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

"Fused heteroarylcycloalkyl" means a fused heteroaryl and cycloalkyl as defined herein. "Aza", "oxo" or "thia", when used as a prefix before the heteroaryl portion of the fused heteroarylcycloalkyl means that the heteroaryl contains at lease one nitrogen, oxygen or sulfur atom. Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms in which one or two of the ring atoms are independently selected from oxygen, nitrogen and sulfur and the cycloalkyl consists of about 5 to about 6 ring atoms. Representative preferred fused heteroarylcycloalkyl include 5.6.7,8-tetrahydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4.5.6,7-tetrahydro-l H-benzimidazolyl, 4.5,6,7-tetrahydrobenzoxazolyl, lH-4-oxa-l,5-diazanaphthalen-2-onyl, l,3-dihydroimidizole-[4,5]-pyridin-2-onyl, and the like. The fused heteroarylcycloalkyl is optionally substituted with one or more fused phenylcycloalkyl group substituents as defined herein. The cycloalkyl moiety is further optionally substituted with oxo. Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy. acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino. The nitrogen atom of the heteroaπ.1 portion of the fused heteroarylcycloalkyl is optionally oxidized to the N- oxide.

"Fused heteroarylcycloalkenyl" means a 5- or 6-membered heteroaryl fused with a cycloalkenyl ring. "Aza", "oxo" or "thia". v. hen used as a prefix before the heteroaryl portion of the fused heteroarylcycloalkenyl means that the cycloalkenyl contains at lease one nitrogen, oxygen or sulfur atom. Preferred fused heteroarylcycloalkenyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms in which one or two of the ring atoms are independently selected from oxygen, nitrogen and sulfur and the cycloalkenyl consists of about 5 to about 6 ring atoms. Representative preferred fused heteroarylcycloalkenyl include 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-l H-benzimidazolyl, 4,5-dihydrobenzoxazolyl, and the like. The fused heteroarylcycloalkenyl is optionally substituted with one or more fused phenylcycloalkyl group substituents as defined herein. The cycloalkenyl moiety is further optionally substituted with oxo. Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro. cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkyl is optionally oxidized to the N-oxide.

"Fused heteroarylheterocyclyl" means a fused heteroaryl and heterocyclyl as defined herein. "Aza", "oxo^" or "thia", when used as a prefix before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl means that the heteroaryl or heterocyclyl contains at lease one nitrogen, oxygen or sulfur atom. Preferred fused heteroarylheterocyclyls are ring systems wherein one or two of the ring atoms of the heteroaryl are independently selected from oxygen, nitrogen and sulfur and the heterocyclyl portion consists of about 5 to about 6 ring atoms in which one or two of the ring atoms are independently selected from oxygen, nitrogen and sulfur. Representative fused heteroarylheterocyclyl include 2,3-dihydro-lH pyrrol[3J-b]quinolin-2-yl, 1 ,2,3,4-tetrahydrobenz [b][l ,7]naphthyridin-2-yl, 1 ,2,3,4-tetrahydrobenz [b][l,6]naphthyridin-2-yl, l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2yl, l,2,3,4-tetrahydro-9H-pyrido[4J-b]indol-2yl, 2,3,-dihydro-l H-pyrrolo[3J-b]indol-2-yl, lH-2,3,4.5-tetrahydroazepino[3J-b]indol-2-yl, lH-2,3,4,5-tetrahydroazepino[4J-b]indol-3-yl, lH-2,3,4,5-tetrahydroazepino[4.5-b]indol-2 yl, 5,6,7,8-tetrahydro[l ,7]napthyridinyl, l,2,3-4-tetrhydro[2,7]naphthyridyl, 2,3-dihydro[l,4]dioxino[2,3-b]pyridyl, 2,3-dihydro[l,4]dioxino[2,3-b]pyridyl, 3,4-dihydro-2H-l-oxa-4,6-diazanaphthalenyl,

4,5,6,7-tetrahydro-3H-imidazo[4.5-c]pyridyl, 6,7-dihydro-5,8-diazanaphthalenyl, and the like. The fused heteroarylheterocyclyl is optionally substituted with one or more fused arylcycloalkyl group substituents as defined herein. The heterocyclyl moiety is further optionally substituted with oxo. Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino. The nitrogen atom of the heteroaryl portion is optionally oxidized to the N-oxide. The nitrogen or sulphur atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

"Fused heteroarylheterocyclenyl" means a fused heteroaryl and heterocyclenyl as defined herein. "Aza", "oxo^" or "thia^". when used as a prefix before the heteroaryl or heterocyclenyl portion of the fused heteroarylheterocyclenyl means that the heteroaryl or heterocyclenyl contains at lease one nitrogen, oxygen or sulfur atom. Preferred fused heteroarylcycloalkenyls are ring systems wherein the heteroaryl portion thereof consists of about 5 to about 6 ring atoms in which one or two of the ring atoms are independently selected from oxygen, nitrogen and sulfur and the heterocyclenyl portion consists of about 5 to about 6 ring atoms in which one or two of the ring atoms are independently selected from oxygen, nitrogen and sulfur. Representative fused heteroarylheterocyclenyl include

7,8-dihydro[l ,7]naphthyridinyl, l,2-dihydro[2,7]naphthyridinyl, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl, and the like. The fused heteroarylheterocyclenyl is optionally substituted with one or more fused arylcycloalkyl group substituents as defined herein. The heterocyclenyl moiety is further optionally substituted with oxo. Preferred substituents include hydrogen, alkyl, aryl, heteroaryl, hydroxy, acyl, aroyl. halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, alkylamino, amino, carbamyl, thiocarbamyl and amidino. The nitrogen atom of the heteroaryl portion is optionally oxidized to the N-oxide. The nitrogen or sulphur atom of the heterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. "Aralkyl" means an aryl-alkyl- group in which the aryl and alkyl are as defined herein. Preferred aralkyls contain a lower alkyl moiety. Representative aralkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.

"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as defined herein. Preferred heteroaralkyls contain a lower alkyl moiety. Representative heteroaralkyl groups may contain thienylmethyl, pyridylmethyl, imidazolylmethyl and pyrazinylmethyl.

"Aralkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein. Preferred aralkenyls contain a lower alkenyl moiety. An representative aralkenyl group is 2-phenethenyl.

"Heteroaralkenyl" means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as defined herein. Preferred heteroaralkenyls contain a lower alkenyl moiety. Representative heteroaralkenyl groups may contain thienylethenyl, pyridylethenyl, imidazolylethenyl and pyrazinylethenyl.

"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is defined herein. Preferred hydroxyalkyls contain lower alkyl. Representative hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Caboxyalkyl" means a HOOC-alkyl group in which alkyl is defined herein. Representative carboxyalkyl groups include carboxymethyl. "Acyl" means an H-CO- or alkyl-CO- group in which alkyl is defined herein. Preferred acyls contain a lower alkyl. Representative acyl groups include formyl. acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.

"Aroyl" means an aryl-CO- group in which aryl is defined herein. Representative aroyl groups include benzoyl and 1- and 2-naphthoyl.

"Aryldiazo" means an aryl-N=N- group in which aryl is defined herein. Representative aryldiazo groups include pheny diazo and naphthyldiazo.

"Heteroaroyl" means an means a heteroaryl-CO- group in which heteroaryl is defined herein. Representative heteroaryl groups include thiophenoyl and pyridinoyl. "Heteroaryldiazo" means a heteroaryl-N=N- group in which heteroaryl is defined herein.

Representative heteroaryldiazo groups include pyridyldiazo and thienyldiazo.

"Alkoxy" means an alkyl-O- group in which alkyl is defined herein. Representative alkoxy groups include methoxy, ethoxy. n-propoxy, i-propoxy, n-butoxy and heptoxyΛ

"Alkoxyalkyl" means an alkyl-O-alkyl- group in which alkyl is defined herein. Representative alkoxy groups include methox} methyl, ethoxymethyl, n-propoxymethyl, i-propoxymethyl, n- butoxymethyl and heptoxymethyl.

"Aryloxy" means an aryl-O- group in which aryl is defined herein. Representative aryloxy groups include phenoxy and naphthoxy.

"Aralkyloxy" means an aralkyl-O- group in aralkyl is defined herein. Representative aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.

"Alkylthio" means an alkyl-S- group in which alkyl is defined herein. Representative alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.

"Arylthio" means an aryl-S- group in which the aryl group is defined herein. Representative arylthio groups include phenylthio and naphthylthio. "Aralkylthio" means an aralkyl-S- group in which aralkyl is defined herein. A representative aralkylthio group is benzylthio.

1 2 1 2

"Amino" means a group of formula Y Y N- herein Y and Y are defined herein. Preferred amino groups include amino (H N-), methylamino, dimethylamino, diethylamino, benzylamino, or phenethylamino.

1 2 1 2 "Aminoalkyl" means a Y Y N-alkylene- group wherein Y , Y and alkylene are defined herein.

"Alkoxycarbonyl" means an alkyl-O-CO- group wherein alkyl is defined herein. Representative alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, or t-butyloxycarbonyl. "Alkoxycarbonylalkyl^" means an alkyl-O-CO-alkylene- group wherein alkyl and alkylene are defined herein.

"Aryloxycarbonyl" means an aryl-O-CO- group wherein aryl is defined herein. Representative aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. "Aralkoxycarbonyl" means an aralkyl-O-CO- group wherein aralkyl is defined herein. A representative aralkoxycarbonyl group is benzyloxycarbonyl.

1 2 1 2

"Carbamyl" means a group of formula Y Y NCO- wherein Y and Y are defined herein.

Representative carbamyl groups are carbamyl (H₂NCO-) and dimethylaminocarbamyl (Me₂NCO-).

1 2 1 2

"Carbamylalkyl" means a group of formula Y Y NCO-alkyl- wherein Y , Y , and alkyl are defined herein. Representative carbamylalkyl groups are carbamylalkyl (H₂NCOCH₂-) and dimethylaminocarbamylmethv 1 (Me NCOCH₂-).

1 2 1 2

"Sulfamyl' means a group of formula Y Y NS0₂- wherein Y and Y are defined herein.

Representative sulfamyl groups are aminosulfamoyl (H₂NS0₂-) and dimethylaminosulfamoyl

(Me₂NS0₂-). "Acylamino" means an acyl-NH- group wherein acyl is defined herein.

"Aroylamino" means an aroyl-NH- group wherein aroyl is defined herein.

"Alkylsulfonyl" means an alkyl-S0₂- group wherein alkyl is defined herein. Preferred alkylsulfonyl groups are those in which the alkyl group is lower alkyl.

"Alkylsulfinyl" means an alkyl-SO- group wherein alkyl is defined herein. Preferred alkylsulfinyl groups are those in which the alkyl group is lower alkyl.

"Arylsulfonyl" means an aryl-S0₂- group wherein aryl is defined herein.

"Arylsulfinyl" means an aryl-SO- group wherein aryl is defined herein.

"Halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro. "Nitrogen protecting group^" means an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selective!} removable. The use of N-protecting groups is well known in the art for protecting groups against undesirable reactions during a sy nthetic procedure and many such protecting groups are known. CF, for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition. John Wiley & Sons, New York ( 1991 ). which reflects the level of understanding of the ordinary skilled artisan. Preferred N-protecting groups are acyl, including formyl- acetv 1, chloroacetyl, trichloroacetyl. o-nitrophenylaceK l. o-nitrophenox acetyl. trifiuoroacetv l. acetoacetv l. 4-chlorobιιt ryl. isobutyryl. o- nitrocinnamoyl. picolinoyl, acyl isothiocyanate, aminocaproyl, benzoyl and the like, and acyloxy including methoxycarbonyl,

9-fluorenyimethoxycarbonyl, 2.2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl (BOC), lJ-dimethylpropynyloxycarbonyl, benzyloxycarbonyl (CBZ), p-nitrophenylsulfinyl, p-nitrobenzyloxycarbony, 2,4-dichIorobenzyloxycarbonyl, allyloxycarbonyl (Alloc), and the like. "Oxo" means a carbonyl (>C=0) group.

"Compounds of the invention", and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. It is understood that the activity of individual compounds of formula (I) will vary depending on the individual compound and assay employed. Compounds of the invention as used herein includes all compounds of formula (I) having an in-vitro activity of greater than 10% at 3.9 ?M in the Factor Xa in vitro enzyme assay described herein. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.

"Prodrug" means a form of the compound of formula I which may or may not itself be biologically active but which may be converted, for example by metabolic, solvolytic, or other physiological means, to a biologically active chemical entity, and is suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use, including ketal, ester and zwitterionic forms. A prodrug is transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 which reflects the level of understanding of the ordinary skilled artisan.

"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates. and the like. "Hydrate" is a solvate wherein the solvent molecule(s) is/are H₂0. Where the compound of this invention is substituted with a basic moiety, acid addition salts may be formed. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although 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 as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention are those 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, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, sal icy late, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoates, gentisates, mesylates, isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. respectively. Acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid by the 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 aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution. Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial effects inherent in the free acid are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including for example alkali and alkaline earth metal salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonia, triethylammonia, ethylenediamine, n-methylglucamine, 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 may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating. Amine salts of compounds of the present invention may 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 acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared. The base addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.

As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.

Compounds of this invention may exhibit stereoisomerism by virtue of the presence of one or more asymmetric or chiral centers in the compounds. The present invention contemplates the various stereoisomers and mixtures thereof. Desired enantiomers are obtained by chiral synthesis from commercially available chiral starting materials by methods well known in the art, or may be obtained from mixtures of the enantiomers by resolution using known techniques.

Compounds of this invention may also exhibit geometrical isomerism. Geometrical isomers include the cis and trans forms of compounds of the invention having alkenyl or alkenylenyl moieties. The present invention comprises the individual geometrical isomers and stereoisomers and mixtures thereof.

Preferred Embodiments

Preferred compounds have formula I wherein Cy₂ contains at least one nitrogen atom and when

Cy₂ is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted fused phenylcycloalkyl or optionally substituted fused phenylcycloalkenyl, then said nitrogen atom is a basic nitrogen atom.

More preferred compounds have formula I wherein Cy₂ is optionally substituted azaheteroaryl.

More preferred compounds have formula I in which Cy₂ is optionally substituted azheteroaryl, wherein Cy₂ is optionally substituted benzamidines, optionally substituted thiopheneamidines, optionally substituted aminoquinazolines, optionally substituted aminoisoquinolines, optionally substituted aminoquinolines, optionally substituted azaindoles, optionally substituted aminopyridines, optionally substituted isoquinoline, optionally substituted quinazoline, optionally substituted thienopyrimidine, optionally substituted pyridothiophenes

More preferred compounds have formula I wherein Cy₂ is 4-aminoquinazolin-7yl.

Preferred compounds have formula I wherein R¹ is hydrogen, lower alkyl, aralkyl, -CH₂OZ, or - CH(CH₃)OZ.

Preferred compounds have formula I wherein R² is hydrogen, or lower alkyl.

Preferred compounds have formula I wherein R³ is hydrogen.

Preferred compounds have formula I wherein X is O.

Preferred compounds have formula I wherein Cy, is optionally substituted phenyl, or optionally substituted heteroaryl. Preferred compounds have formula I wherein Cy, is substituted with one or more groups selected from halo, lower-alkoxyl, CF₃S-, carboxyalkyl, carbamylalkyl, alkoxycarbonylalkyl, and alkyl.

More preferred compounds have formula I in which Cy, is a substituted phenyl, or a substituted heteroaryl. wherein Cy, is chlorophenyl, chlorothienyl, chloropyridinyl, chloropyrimidinyl, chloro- thiazinyl, amino-pyridine, amino-pyrimidine, amino-pyridazine, amino-pyrimidine, aminothiazole, or amino-thiophene.

Further preferred compounds have formula I wherein Cy₂ is 4-aminoquinazolin-7yl; RJs alkyl, -CH₂OCH₃. -CH₂OCH₂CH₃, or aralkyl; and

R² is hydrogen or lower alkyl.

Further preferred compounds also have formula I wherein Cy₂ is 4-aminoquinazolin-7yl; R¹ is alkyl, -CH₂OCH₃, -CH₂OCH₂CH₃, or aralkyl; R² is hydrogen or lower alkyl; and

Cy, is optionally substituted aryl or optionally substituted heteroaryl.

Compounds contemplated as falling within the scope of this invention, include, but are not limited to

20

22

More preferred is

Preparation of the Compounds of the Invention

A general route to the compounds of this invention wherein R¹. R², R³ X, Cy,, and Cy₂ are defined herein is outlined in Scheme 1.

Scheme 1

As shown in Scheme 1. coupling of a compound of formula II with an acid or an activated derivative thereof such as an anhydride or acid chloride in an appropriate solvent generates the compound of formula I. Amide formation can be conducted with acids and coupling reagents such as EDC or TBTU or with any variant of reactive acid derivatives and the use of an appropriate base additive such as triethylamine, N-methylmorpholine or diisopropylethylamine.

The preparation of the compound of formula II wherein R¹, R². X, and Cy₂, are defined herein is outlined in Scheme 2.

Scheme 2

II

As shown in Scheme 2. the compound of formula II is prepared by removing a nitrogen protecting group P from the compound of formula 1. In a preferred aspect, P is an alkyl, aralkyl or aryl carbamate moiety which is removed using strong acid, strong base or catalytic hydrogenation in an appropriate solvent such as methanol or ethanol. The preparation of the compound of formula 1 wherein R,, R₂, Cy₂, and P are defined herein is outlined in Scheme 3.

Scheme 3

As shown in Scheme 3, the compound of formula 1 is obtained by coupling a compound of formula 2 with an appropriate Cy₂-CH₂-LG group wherein LG is a leaving group such as chloro, bromo, iodo, or optionally substituted lower alkylsulfonyloxy or arylsulfonyloxy in an inert organic solvent such as THF, Et₂0 or DMF in the presence of a strong base such as NaH, lithium hexamethyldisilylazide or lithium diisopropylamine. In a preferred aspect, P is an alkyl, aralkyl or aryl carbamate group.

The preparation of intermediate compounds of formula 7 and 10 are outlined in Scheme 4.

Scheme 4

Ar = monocyclic aryl or heteroaryl

As shown in Scheme 4. reacting a compound of formula 3 with an appropriate malonic acid in a polar solvent such as pyridine or ethanol and a base such as piperidine or pyridine at reflux provides a compound of formula 4 wherein R is H. Alternatively, a compound of formula 3 may be reacted with a suitable Wittig or Horner-Emmons reagent in an inert solvent such as THF to give a compound of formula 4 wherein R is lower alkyl. When R is lower alkyl, the ester is hydrolyzed to the corresponding carboxylic acid (R is H) by an appropriate strong acid or alkali base. The corresponding acid is converted to the acid chloride using standard methods such as thionyl chloride or is converted to the mixed anhydride in a polar solvent such as acetone or THF to form an activated acyl compound. The activated acyl compound is then treated with a solution of NaN₃ in water at about -10 °C to about 25 °C to yield the corresponding acyl azide. The acyl azide compound is then heated slowly in an inert solvent such as benzene or toluene at about 60 °C to about 1 10 °C then concentrated in vacuo and heated in a higher boiling inert solvent such as 1 ,2-dichlorobenzene or phenyl ether at about 180 °C to about 240 °C with a catalyst such as iodine or tributylamine to obtain a compound of formula 5. Alternatively the acyl azide compound can be added directly to a high boiling inert solvent such as phenyl ether at about 190 °C to about 240 °C with a catalyst such as iodine or tributylamine to obtain the compound of formula 5. A compound of formula 8, prepared as described in S>n.. 739 ( 1975), which reflects the level of understanding of the ordinarv skilled artisan, or formula 5 above ma\ be chlorinated using standard methods such as POCl₃ or POCl,/PCl₅ and halogenated using standard conditions such as N- halosuccinimide and benzov l peroxide in an inert solvent such as carbon tetrachloride to give the corresponding chloro-halomethv l compounds 6 and 9. respectively.

The preparation of aminoquinazoline, quinazolinone or amino-thienopyrimidine intermediates is outlined in Scheme 5.

Scheme 5

Ar = monocyclic aryi or heteroaryl

As shown in Scheme 5. an aminoheteroaryl carboxylic acid or an aminoarylcarboxylic acid 1 1 in which the amino and carboxylic acid are adjacent is treated with formamidine under heat to form the corresponding quinazolinone or thienopyrimidinone 12. The quinazolinone or thienopyrimidinone 12 is then converted to the chloroquinazoline or chlorothienopyrimidine using a chlorinating reagent such as P(0)C1₃ and heat. The chloroquinazoline or chlorothienopyrimidine is brominated at the benzylic carbon using radical bromination conditions. Alternatively, a chloroquinazoline or chlorothienopyrimidine, containing a hydroxy-methylene group is converted to the corresponding bromide using CBr₄/PPh₃; or PBr₃ conditions. The bromide 13 is then reacted with the anion of the ring nitrogen of compounds of formula 2, formed using NaH. LiN(SiMe₃)₃, NaN(SiMe₃)₃, LDA, lithium alkoxides, sodium alkoxides or an appropriate base, in an inert solvent such as THF, DMF, ether, or DME. This yields compounds of formula 14 in which Cy₂ is a chloro-quinazoline or a chloro-thienopyrimidine. The chloro group is converted to an amino group using NH₃ in ethanol in the presence of a catalytic acid source. Alternatively, the chloro group is converted to a substituted amino using a primary or secondary amine in a solvent. Alternatively, the chloro group is converted to a hydroxy group using acetic acid in water with heating or using a hydroxide source. Alternatively, the chloro is converted to an alkoxy group using an alcoholic solvent with heated in the presence of a base.

An alternative synthesis of quinazolines and thienoquinazolines is outlined in Scheme 6.

Scheme 6.

19

17

Ar = monocN clic arvl or heteroaryl

As shown in Scheme 6, an amino-aryl nitrile or an amino heteroaryl nitrile 17 is treated with an aldehyde or ketone under imine forming conditions. The corresponding aryl or heteroaryl imine is brominated using radical bomination with NBS. The bromide is then reacted with the anion of the ring nitrogen of compounds of formula 2, formed using NaH, LiN(SiMe₃)₃, NaN(SiMe₃)₃, LDA, lithium alkoxides. sodium alkoxides or an appropriate base, in an inert solvent such as THF, DMF, ether, or DME. This yields compounds of formula 20 in which Cy₂ is an imino-aryl nitrile or an i ino heteroaryl nitrile. The imine is deprotected using an acid such as HCl to give the corresponding aniline. The aniline-aryi-nitrile or the aniline-heteroaryl nitrile is converted to the amino-quinazoline or thienopyrimidine using triazine or formamidine. The quinazolinone or thienopyrimidinone 21 is formed using formamide. The preparation of cinnoline (X¹ = N) and quinoline (X¹ = CH) intermediates is outlined in Scheme 7.

Scheme 7

As shown in Scheme 7. halogenated azaarenes exemplified by 4-chloro-7- trifluoromethylquinoline or cinnoline are treated with H,S0₄ (70 -95 %) at 180-220 °C for about 16 to 48 hours in a sealed reaction vessel. The solution is cooled, poured into water and neutralized with base to pH ~ 3-4. The product is dissolved in aqueous base and precipitated by acidification to yield 7-carboxy- 4-chloroquinoline or cinnoline. This material is converted to the alkyl ester (such as methyl or ethyl) by standard methods. 7-Alkyloxycarbonyl-4-chloroquinoIine or cinnoline is dissolved in an anhydrous, aprotic solvent (THF or ether). The solution is cooled (-60 to -95 °C) and treated with a reducing agent such as lithium aluminum hydride. The solution is warmed (approximately -40 to -50 °C) for about 15 to 30 minutes and quenched with a solvent such as ethyl acetate. Standard workup gives the product 7- hydroxymethyl-4-chloroquinoline or cinnoline. This material is treated with 45-50 % HBr and heated to about 100-140 °C for about 45 to 90 minutes. After cooling and standard workup 7-bromomefhyl-4- chloroquinoline or cinnoline is obtained. The preparation of pyrrolopyridine derivatives is outlined in Scheme 8.

Scheme 8

As shown in Scheme 8 pyrrolopyridine derivatives are prepared by alkylation of a suitably protected oxopiperazine with propargyl bromide in the presence of a base such as sodium hydride. The resulting alkyne is heated (100-120 °C) with a halopyridine optionally substituted with hydroxy, alkoxycarbonylamino, or sulflivdryl, a catalyst such as Pd(PPh₃)₂Cl₂. copper iodide and triethylamine in a suitable solvent such as acetonitrile in a sealed vessel or in DMF for 2-20 hours. When the pyridine is substituted with a hydroxyl moiety furopyridines are isolated directly. If the pyridine is substituted with an alkoxycarbonylamino moietv . additional treatment with DBU at about 60 °C in DMF yields pyrrolopyridines. Subsequent carbamate deprotection using transfer hydrogenation conditions such as Pd black in formic acid yields the desired oxopiperazine furopyridines or pyrrolopyridine- 1 -carboxylic acid alkyl ester derivatives. After further reaction with the L,-Cy, group, an additional deprotection step such as Boc removal using, for example, TFA, HCl is required for generating the oxopiperazine pyrrolopyridines.

The preparation of the compound of formula 40 are shown in Scheme 9.

Scheme 9

As shown in Scheme 9. compounds of formula 40 are prepared from an appropriately protected mono- or di- substituted amino-acid. To this is added an amino-acetaldehyde, protected as an acetal derivative, under standard peptide coupling procedures, employing activating reagents such as EDC, TBTU, or BOP. The resulting dipeptidyl moiety is subjected to conditions which remove the acetal, such as acidic conditions (TsOH). The resulting cyclic material is reduced using hydrogenating conditions to yield compounds of formula 40. This reduction, alternatively can be carried out using a reagent which acts as a hydride source.

The preparation of compounds of formula 45 is shown scheme 10.

Scheme 10.

As shown in Scheme 10. a protected amino acid is coupled to a beta-aminoalcohol using standard peptide coupling procedures as describe above. The alcohol is then oxidized to a ketone using, for example. Swern oxidation conditions. The protecting group is removed and the resulting compound is reduced under hydrogenation conditions to give the 2-piperidinone. The free amine can be reprotected and eantiomers are separated by chiral chromatographic methods, or in some cases by recrystallization of diastereomeric salts which may be formed.

A chiral synthesis of compounds of formula 45 is shown in Scheme 1 1.

Scheme 1 1

As shown in Scheme 1 1. an amino acid is protected as its trifluoroacetate derivative using trifluoroacetic anhydride and a base. An amino-alcohol is derivatized via reductive animation conditions using a benzaldehyde derivative, such as 2J-dimethoxybenzaldehyde. The resulting secondary amine is then coupled to an amino-acid protected as a trifluoroacetate using standard peptide coupling procedures. Ring closure is then accomplished by utilizing Mitsinobu conditions. The trifluoroacetate group is removed under basic conditions, and the amide of the ring is deproteced using an aqueous solution of potassium persulfate and sodium phosphate and heat. All possible enantiomers of piperazin-2-one can be made from the corresponding amino-alcohol and amino acid as shown in scheme 2c.

The preparation of the compound of formula 57 wherein R, and R₂ are hydrogen is shown in Scheme 12.

Scheme 12

As shown in Scheme 12, alkylating a compound of formula 54 with propargyl bromide in the presence of an amine base such as triethylamine provides the compound of formula 55. Coupling with bromoacetic acid using a standard reagent such as DCC gives the compound of formula 56 which can be cyclized using a non-nucleophilic strong base such as NaH in a solvent such as THF to yield the desired compound of formula 57.

The preparation of intermediate compounds of formula Cy,-CH₂ -X-C0₂H is outlined in Scheme

13.

Scheme 13

base

As shown in Scheme 13. the requisite Cy, acids as defined above can be obtained by alkylation of the appropriate alcohol with an alkylbromo acetate, followed by base hydrolysis to afford the equivalent acid derivative. Similarly, an amine can be converted to its corresponding amide, followed by reduction to the corresponding acid.

This invention is further exemplified but not limited by the following examples which further illustrate the preparation of the compounds of this invention. The starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods described herein or their obvious equivalents. Further examples which illustrate the preparation of the compounds of this invention are disclosed in International Patent Application No. US/99/01682; US Patent Application No. 09/363,196, 09/313,61 1 and US Provisional Application No. 60/072,707 and 60/1 10,012, which are incorporated herein by reference.

EXAMPLE 1. 6-Chlorobenzo[b]thiophene-2-sulfonyl chloride.

A. 1 -Chloro-3-(2,2-dimethoxyethylsulfanyl)benzene.

To a solution of 3-chlorothiophenol (2.4 g, 16.6 mmol) in THF (200 mL) at 0°C is added bromoacetaldehyde dimethyl acetal (2.8 g, 16.6 mmol). To the solution is added sodium hydride (60% mineral oil dispersion, 0.70 g. 17.4 mmol). The reaction is stirred for 16 hours, and then is quenched by the addition of saturated NH C1 (aq.). The solution is diluted with EtOAc. The organic layer is washed with a saturated NaCl (aq.). The organic layer is dried over MgS0₄, filtered and concentrated. The crude product is purified by column chromatography eluting with hexanes. The title compound (3.1 g, 15.9 mmol) is obtained as an oil. Η NMR (CDC1₃, 300MHz) δ 7.32 (m, 1 H), 7.25 (m, 1H), 7.12 ( , 1H), 447 (m, 1 H), 3.07 (s, 3H), 3.02 (s, 3H).

B. 4-Chlorobenzo[blthiophene and 6-Chlorobenzofblthiophene.

A solution containing polyphosphoric acid (8 g) and chlorobenzene (50 mL) is heated at reflux. A solution containing l-chloro-3-(2,2-dimethoxyethylsulfanyl)benzene (2.1 g, 1 1.6 mmol) in chlorobenzene (5 mL) is added dropwise to the refluxing polyphosphoric acid solution. After 6 hours, the solution is cooled to ambient temperature. The solution is diluted with CH₂CI₂ and washed with water and saturated NaCl (aq.). The organic layer is dried over MgS0 , filtered and concentrated. The crude product is purified by column chromatography eluting with hexanes to yield the title compounds (2.4 g, 9.0 mmol) as a 1 : 1 isomeric mixture. Η NMR (CDC1₃, 300MHz) δ 7.88 (m, 1H), 7.75 (m, 2H), 7.42 (m, 2H). MS (El): m/z 168. 170 (M+), Cl pattern.

C. 4-Chlorobenzo b1thiophene-2-sulfonyl chloride and 6-Chlorobenzorb1thiophene-2-sulfonyl chloride. To a solution of 4-chloro-benzo[b]thiophene and 6-chlorobenzo[b]thiophene (1 1.8 g, 88.1 mmol), in 400 mL of THF at -78°C is added n-BuLi (55 mL of a 1.6M solution in hexanes, 88.1 mmol).

After 15 minutes, the solution is added by cannula to a precooled (-78°C) solution of SO, (200 g) in 100 mL of THF. After addition, the solution is allowed to warm to ambient temperature. After 0.5 hour, the solution is concentrated. The residue is suspended in hexanes (400 mL) and is 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 NH C1 (aq.), H₂0 and saturated NaCl (aq.). The organic layer is dried over MgS0₄, filtered and concentrated. The crude product is dissolved in CH,C1₂ and filtered through a plug of silica gel. The crude product is purified by column chromatography eluting with hexanes to yield the title compound as well as 4- chlorobenzo[b]thiophene-2-sulfonyl chloride as white solids.

4-Chlorobenzo[b]thiophene-2-sulfonyI chloride: Η NMR (CDC1₃, 300MHz) δ 8.32 (m, 1H), 7.81 (m,

1H), 7.53 (m, 2H).

6-Chlorobenzo[b]thiophene-2-sulfonyl chloride: Η NMR (CDC1„ 300MHz) δ 8.1 1 (s, 1H), 7.88 (m, 2H), 7.50 ( , 1H).

EXAMPLE 2. 5'-Chloro-[2,2'lbithiophenyl-5-sulfonyl chloride.

A. 5-Chloro- 2J^'lbithiophene. The title compound is prepared from 2-chloro-thiophene according to the procedure described in Bull. Chem. Soc. Japan, 1979, 1 126. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes to afford a white solid. Η NMR (CDC1₃, 300MHz) δ 7.24 (m, 1H), 7.1 1 (d, 1 H), 7.03 (dd, 1 H), 6.94 (d, 1 H), 6.83 (d, 1 H). MS (El) [M+]= 200, 202, Cl pattern.

B. 5^,-Chloro-r2,2^,lbithiophenyl-5-sulfonyl chloride.

The title compound is prepared as described in Example 1 , Part C using 5-chloro- [2,2']bithiophene in place of 6-chloro-benzo[b]thiophene. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes to give a white solid. Η NMR (CDC1₃, 300MHz) δ 7.76 (d, 1 H), 7.14 (d, 1H), 7.09 (d, 1 H), 6.92 (d, 1 H). MS (El): m/z 298, 300 (M+), Cl pattern.

EXAMPLE 3. 2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl chloride.

A. 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid ethyl ester. n-Butyllithium (53.1 mL, 2.5M solution in hexanes) is added dropwise to a solution of ethylmethanesulfonate ( 12.9 mL, 0.12 mol) in THF (300 mL) at -78°C. The reaction mixture is stirred for 15 min then ethylchlorophosphonate (9.9 mL, 0.07 mol) is added dropwise. The solution is stirred at -78°C for 30 minutes and then heated to 50°C for 1 hour. The reaction mixture is then cooled to -78°C and stirred for 1 h then 5-chlorothiophenecarboxaldehyde (7.1 mL, 0.07 mol) is added dropwise. The reaction mixture is allowed to slowly warm to RT overnight. Water (30 mL) is added to the mixture and stirred for 15 min then concentrated in vacuo. The residue is taken up in CH₂Cl₂ and washed with water, brine, dried over MgS0₄, filtered and concentrated to dryness. The crude product is purified by column chromatography eluting with 5% EtOAc/hexanes to give title product (1 1.3 g, 0.04 mol) as an oil. Η NMR (CDC1₃, 300MHz) δ 7.51 (d, 1 H), 7.10 (d, 1 H), 6.91 (d, 1 H), 6.42 (d, 1 H), 4.20 (q, 2H), 1.40 (t, 3H).

B. 2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl chloride. Tetrabutylammonium iodide (16.3 g, (44.2 mmol) is added to a solution of 2-(5-chloro-thiophen-

2-yl)-ethenesulfonic acid ethyl ester (1 1.3 g, 40.2 mmol) in acetone (100 mL) at room temperature. The mixture is heated to reflux and stirred overnight then cooled to RT and conconcentrated in vacuo. The residue is taken up in CH₂Cl₂then washed with water and brine. The organic layer is dried over MgS0₄, filtered and concentrated to dryness to give an oil (18.74 g, 40.2 mmol) which is taken on to the next step without further purification. Sulfuryl chloride (7.1 mL, 88.5 mmol) is added to a solution of triphenylphosphine (21.0 g, 86.42 mmol) in CH₂Cl₂ at 0°C . The ice bath is then removed and the product (18.74 g, 40.2 mmol) from the above reaction is added. After 2 h, the reaction mixture is concentrated in vacuo and the product purified by column chromatography eluting with 10% EtOAc/Hexanes to give the title compound (6J g, 26J mmol) as an off-white solid. Η NMR (CDCl,, 300 MHz) δ 7.70 (d, 1H), 7.23 (d, 1H), 7.00 (d, 1 H), 6.91 (d, 1H).

EXAMPLE 4. 3-Chlorobenzyl sulfamyl catechol.

To a solution of 3-chlorobenzylamine (0.14 g, 1.0 mmol) in 3 mL of DMF is added Et₃N (0.10 g, 1.5 mmol). The solution is cooled to 0°C. Catechol sulfate (0.172 g, 1.0 mmol) is added. The solution is warmed to ambient temperatures. After 2.5 h, 30 mL of EtOAc is added. The solution is washed with 5% HCl, H₂0 and saturated NaCl. The organic layer is dried over MgS0 , filtered and concentrated to give the title compound (0.30 g. 0.97 mmol). Η NMR (d6-DMSO, 300 MHz) δ 9.94 (s, 1 H), 8.82 (m, 1 H), 7.41 (m. 4H), 7.19 (d, 1 H). 7.10 (m, 1 H), 6.95 (d, 1 H), 6.79 (m, 1 H), 4.32 (AB, 2H).

EXAMPLE 5. 2-Bromomethyl-6-chlorobenzorb1thiophene.

A. 6-Chlorobenzo b1thiophene-2-carboxaldehyde.

To a solution of 6-chlorobenzo[b]thiophene (1.0 g, 5.93 mmol) in THF (60 L) at -78°C is added a 1.6 M solution of n-BuLi in THF (3.9 mL, 6.23 mmol). After 10 minutes, 0.5 mL of DMF is added. The solution is stirred for 0.5 hours, then allowed to warm to ambient temperature. The solution is poured into a solution of saturated NH C1. The solution is diluted with ether and the layers are separated. The organic layer is washed with H₂0 and saturated NaCl. The organic layer is dried over MgS0₄, filtered and concentrated. The title compound is obtained as a white solid. MS (El): m/z 196 (M+).

B. 6-Chlorobenzo[blthiophen-2-yl)methanol.

To a solution of 6-chlorobenzo[b]thiophene-2-carboxaldehyde in THF at 0°C is added NaBH₄. After 1 hour, the solution is diluted with saturated NH₄C1 and ether. The organic layer is washed with H₂0 and saturated NaCl, dried over MgS0₄, filtered and concentrated. Η NMR (CDC1₃, 300 MHz) δ 7.82 (s, 1H). 7.60 (d, 1 H), 7.40 (m, 2H), 4.91 (AB, 2H).

C. 2-Bromomethyl-6-chlorobenzo[b1thiophene. To a solution of 6-chlorobenzo[b]thiophen-2-yl)-methanol (0.2 g, 1.01 mmol) in THF (10 mL) is added triphenyl phosphine (0J4 g. 1 J 1 mmol) followed by CBr₄ (0J2g, 1.26 mmol). After 3 hours, the solution is concentrated. The product is purified by column chromatography eluting in a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes. The product is obtained as a white solid (0.25 g, 0.53 mmol). Η NMR (CDC1₃, 300 MHz) δ 7.82 (s, 1H), 7.62 (d, 1H), 7.40 (m, 2H), 4.76 (s, 2H).

EXAMPLE 6. 5-Bromomethyl-5^,-chloro-r2,2^,lbithiophenyl.

To a solution of 5-chloro-[2,2']bithiophenyl (3.00 g, 14.9 mmol) in 30 mL of THF at 0°C is added n-BuLi (9.8 mL of a 1.6M solution in hexanes. 15.7 mmol) dropwise. DMF (2.30 mL, 30 mmol) is added dropwise and the resulting solution is heated at reflux for 1 hour. The solution is diluted with H₂0 and extracted with Et₂0. The organic layer is washed with H₂0 and saturated NaCl solution, then dried over MgS0₄, filtered and concentrated. The crude aldehyde is dissolved in 40 mL of anhydrous MeOH and sodium borohydride (0.85 g, 22.5 mmol) is added portionwise. The mixture is stirred at room temperature for 10 min. then quenched with water. The mixture is diluted with Et₂0 and the layers separated. The organic layer is washed with H₂0, then dried over MgS0 , filtered and concentrated to yield the title compound (2.23 g. 9.66 mmol) which is used in the subsequent step without further purification. Η NMR (CDC1,. 300MHz) δ 6.95 (d, 1 H). 6.90 (m, 2H). 6.86 (d, 1 H), 4.82 (s, 2H), 1.88 (bs, 1H).

B. 5-Bromomethyl-5^'-chloro- .2']bithiophenyl.

To a solution of (5'-chloro-[2,2']bithiophenyl-5-yl)-methanol (2.23 g, 9.66 mmol) in 65 L of CH₂C1₂ is added bromotrimethv lsilane (3.82 mL, 29.0 mmol). After 4 h. the solution is concentrated in vacuo. The crude product is stirred in hot hexanes and filtered. The filtrate is concentrated and the title compound (1.67 g, 5.69 mmol) is obtained as a green solid. Η NMR (CDC1₃, 300MHz) δ 7.00 (d, 1H), 6.94 (m, 2H), 6.85 (d, 2H), 4.71 (s, 2H).

EXAMPLE 7. 7-Bromometh\ l-4-chloroquinazoline.

A. 7-Methyl-3H-quinazolin-4-one.

A solution of 2-amino-4-methylbenzoic acid (31.6 g, 206 mmol) in formamide (60mL) is heated to 130°C for 1 hour, then at 175°C for 3 hours. The solution is poured into 500 mL of ice water. The resulting solid is collected by filtration and further dried under reduced pressure. The title compound (26.2 g, 170 mmol) is obtained as a white solid. MS (El): m/z 159 (M+).

B. 4-Chloro-7-methyl-quinazoline. To a solution of 7-methyl-3H-quinazolin-4-one (10.6 g, 69 mmol) in toluene (350mL) is added triethylamine (17.5 g, 173 mmol) followed by phosphorous oxychloride (12J g, 80 mmol). The resulting solution is heated to 80°C. After 4 hours, the solution is cooled to ambient temperature. The reaction mixture is poured into 500 mL of water. The layers are separated and the organic layer is washed with H₂0, saturated NaHC0₃, and saturated NaCl, dried over MgS0 , filtered and concentrated. The resulting crude product is purified by recrystallization from EtOAc. The title compound is obtained as a white solid ( lOg, 56 mmol). Η NMR (CDC1₃, 300 MHz) δ 9.02 (s, 1 H), 8.16 (d, 1H), 7.87 (s, 1H), 7.55 (d, 1 H). 2.62 (s, 3H).

C. 7-Bromomethyl-4-chloroquinazoline. To a solution of 4-chloro-7-methylquinazoline (7.0 g, 39 mmol) in carbon tetrachloride (140 mL) is added N-bromosuccinimide (8.0 g, 45 mmol), and benzoyl peroxide (0.8 g, 3.3 mmol). The solution is refluxed for 8 hours. After this time, the solution is filtered. The filtrate is concentrated and the residue is stirred with ether to give the title compound as an off-white solid (5.1 g, 20 mmol). 'H NMR (CDC1₃, 300 MHz) δ 9.10 (s, 1 H), 8.30 (d, 1 H), 8.10 (s, 1 H), 7.82 (d, 1 H), 4.68 (s, 2H). MS (El): m/z 237 (M+).

EXAMPLE 8. 3-Bromomethyl-7-chloro-l H-quinolin-2-one.

A. N-(3-Chlorophenyl)-2-methyl-3-phenylacrylamide.

To a solution of 3-chloroaniline (0.98 mL, 9.3 mmol) in CH₂C1₂ (25 mL) at 0°C is added pyridine (0.78mL, 9.5 mmol). To the resulting solution is added dropwise a solution of α-methyl cinnamic acid chloride (1.6 g, 9.3 mmol) in CH₂C1₂ (8 mL). After 3 hours, the solution is concentrated. The crude product is purified by column chromatography eluting with 5%EtOAc/hexanes to 10%EtOAc/hexanes. The title compound is obtained as a solid (2.5 g, 9.2 mmol). 'H NMR (CDC1₃, 300 MHz) δ 7.95 (m, 1H), 7.73 (s, 1H), 7.46 (m, 1H), 7.33 (m, 6H), 7.22 (m, 1 H), 7.03 (m, 1H), 2.13 (s, 3H).

B. 7-Chloro-3-methyl- 1 H-quinolin-2-one.

To a solution of N-(3-chlorophenyl)-2-methyl-3-phenylacrylamide (2.5 g. 9.2 mmol) in chlorobenzene (50 L) is added A1C1₃ (6.2 g, 46 mmol). The solution is heated to 120°C. After 4 hours, the solution is poured onto ice. The solution is filtered. The organic layer is washed with IN HCl, H₂0 and saturated NaCl. The crude product is purified by column chromatography eluting with 2% MeOH/CH₂Cl₂. The title compound is obtained as a white solid (1.5 g, 7.74 mmol). 'H NMR (d6- DMSO, 300 MHz) δ 1 1.82 (bs, IH), 7.73 (s, IH), 7.52 (m, IH), 7.21 ( , 2H), 2.08 (s, 3H).

C. 3-Bromomefhyl-7-chloro-l H-quinolin-2-one.

The title compound is prepared as described in Example 7, Part C, substituting 7-chloro-3- methylJH-quinoline-2-one for 7-methyl-4-chloroquinazoline. The title compound is obtained as a white solid. 'H NMR (d6-DMSO, 300 MHz) δ 12.00 (bs, I H), 8.17 (s, l H), 7.72 (d. I H), 7.29 (m, 2H), 4.58 (s, 2H).

EXAMPLE 4. 6-Bromomethyl-2-chloro-quinoline.

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 triturated in Et₂0/hexanes and filtered to give the title compound as a beige solid. Η NMR (DMSO-d₆, 300 MHz) δ 1 1.60 (bs, IH), 7.82 (d, I H), 7.41 (s, IH), 7J0 (d, I H), 7.18 (d, I H), 6.45 (d, IH), 230 (s, 3H).

B. 2-Chloro-6-methylquinoline, 6-Methyl-lH-isoquinolin-2-one (14.6 g, 91.7 mmol) in phosphorus oxychloride ( 160 mL) is heated at 60°C for 17 hours. The mixture is cooled to room temperature, then concentrated to a beige residue. The residue is diluted w ith ice water and the pH is adjusted to about 8 by slow addition of 10 N NaOH. The crude product is precipitated out during neutralization of the aqueous solution and the solid is filtered, washed with water and dried. The solid is recrystallize from MeOH to afford the title compound (12.0 g, 67.5 mmol) as a beige solid. Η NMR (CDCI₃, 300 MHz) δ 8.02 (d, IH), 7.92 (d, IH), 7.60 (s, IH), 7.58 (d, IH), 7.33 (d, IH), 2.53 (s, 3H).

C. 6-Bromomefhyl-2-chloro-quinoline.

N-Bromosuccinimide (12.9 g, 72.5 mmol) and benzoyl peroxide (0.33 g, 130 mmol) are added to a solution of 2-chloro-6-mefhyl-quinoline (12.0 g, 67.5 mmol) in carbon tetrachloride (300 mL). The mixture is heated at reflux for 6 hours. At this time, the resulting mixture is cooled to room temperature, filtered, washed with CH₂C1₂ and concentrated in vacuo. The crude residue is recrystallized from 50% EtOAc/hexanes to yield the title compound (8.80 g, 34.3 mmol) as a beige crystalline solid. Η NMR (CDC1₃, 300 MHz) δ 8.08 (d, I H), 8.02 (d, I H), 7.83 (s, I H), 7.77 (dd, I H), 7.40 (d, I H), 4.65 (s, 2H). MS (El): m/z 256, 258 (M+). Cl pattern.

EXAMPLE 10. 3-Bromomethyl-] .7-dichloro-2H-isoquinoline.

A. 3-(4-Chlorophenyl)-2-methyl-acryloyl azide.

To a solution of 3-(4-chlorophenyl)-2-methyl-acrylic acid (1 1.2 g, 57 mmol) in 500 mL of acetone at 0°C is added triethyl amine (9.6 mL, 68 mmol) followed by ethyl chloroformate (6.2 mL, 63 mmol). The solution is allowed to warm to ambient temperatures. After 2 h, sodium azide (5.6 g, 86 mmol) in 35 mL of H₂0 is added. After addition, the solution is stirred for 2 hours. The solution is diluted with H₂0 (100 L). The resulting solid is collected by filtration giving the title compound as a white solid (1 1.1 g, 50mmol). Η NMR (CDC1₃, 300 MHz) δ 7.67 (s, I H), 3.38 (m, 4H), 2.10 9s, 3H).

B. 7-Chloro-3-methyl-2H-isoquinoline-l-one. 3-(4-Chlorophenyl)-2-methyI-acryloyl azide ( 1 1.0 g, 50 mmol) is dissolved in 80 mL of diphenyl ether. The solution is added dropwise to a solution of tributyl amine (1 1.8 mL, 50mmol) in 170 mL of diphenyl ether at 210°C. After 4 hours., the solution is cooled 50°C and diluted with 1.5 L of hexanes. The resulting solid is collected bv filtration giving the title compound as a white solid (7.2 g, 37 mmol). Η NMR (d6-DMSO, 300 MHz) δ 1 1 A (bs, 1 H), 8.02 (s, 1 H), 7.67 (d, 1 H), 7.55 (d, 1 H). 6.34 (s, 1 H), 2.18 (s, 3H).

C. 1 J-Dichloro-3-methyl-isoquinoline.

A solution of 7-chloro-3-methyl-2H-isoquinoline- l-one (7.1 g, 36.7 mmol) in 100 mL of phosporous oxychloride is heated to 100°C. After 5 h, the solution is concentrated to dryness. The residue is dissolved in CH₂C1_:. The solution is washed with H₂0. The organic layer is dried over

MgS0₄, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 3%EtOAc/hexanes to 5% EtOAc/hexanes. The title compound is obtained as a white solid (6.0g, 28 mmol). Η NMR (CDCF„ 300 MHz) δ 8.23 (s, IH), 7.68 (m, I H), 7.63 (m, I H), 7.40 (s, I H). 2.64 (s, 3H).

D. 3-Bromomefhyl-l,7-dichloro-2H-isoquinoline.

The title compound is prepared as described in Example 7, part C, substituting l ,7-dichloro-3- methyl-isoquinoline for 4-chloro-7-methylquinazoline. Η NMR (CDC1₃, 300 MHz) δ 8.29 (s, IH), 7.82 (m, IH), 7.76 (m, 2H), 4.68 (s. 2H). EXAMPLE 1 1. 3-Bromomethyl-7-chloroisoquinoline.

A. 7-Chloro-3-methyl-isoquinoline. To a solution of lJ-dichloro-3-methyl-isoquinoline (0.50 g, 2.36 mmol), Example 10, part C, in

5.5 mL of 9: 1 acetic acid:H₂0 at 75°C is added zinc (0.23 g, 3.54 mmol) After 75 minutes, the solution is cooled to ambient temperatures. The solution is diluted with a 4: 1 EtOAc:CH₂Cl₂ solution. To the solution is added lOOmL of a IN NaOH solution. The aqueous solution is extracted with 4: 1 EtOAc:CH₂Cl₂. The combined organic layers are washed with a saturated NaCl solution. The organic layer is dried over MgS0 , filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 5%EtOAc/hexanes to 15% EtOAc/hexanes. The title compound is obtained as a white solid (036 g, 1.97 mmol). Η NMR (CDCI₃, 300 MHz) δ 9.09 (s, 1 H), 7.89 (s, IH), 7.61 (d, IH). 7.55 (d. lH), 7.44 (s, IH) 2.68 (s, 3H). MS (El): m/z 177, 179 (M+), C1 pattern.

B. 3-Bromomethyl-7-chloroisoquinoline.

The title compound is prepared as described in Example 7, part C, substituting 7-chloro-3- methyl-isoquinoline for 4-chloro-7-methylquinazoline. Η NMR (CDC1₃, 300 MHz) δ 9.18 (s, 1 H), 7.97 (s, IH), 7.75 (m, 2H), 7.67 (m. I H), 4.71 (s, 2H).

EXAMPLE 12. 2-Bromometh l-6-chloronaphthalene.

A. 6-Chloro-3J-dihydro- 1 H-naphthalene-2-one.

To a solution of (4-chlorophenyl)-acetyl chloride (17.3 g, 92 mmol) in 50 mL of CH₂C1₂ at -20°C is added a solution of A1C1₃ (24J g, 184 mmol) in 200 mL CH₂C1₂ dropwise. After 20 minutes, ethylene (g) is bubbled through the solution for 30 minutes. The solution is stirred at -10°C for 15 minutes. The reaction mixture is poured into 300 g of ice. The layers are separated. The organic layer is washed with H₂0, saturated NaHC0₃ and saturated NaCl. The organic layer is dried over MgS0₄, filtered and concentrated. The resulting solid is triturated with pentane (2x20mL). The solid is then dried to give the title compound as a solid ( 15.2 g. 84.2 mmol). Η NMR (CDC1₃, 300 MHz) δ 7.28 (m, 2H), 7.06 (m, IH), 3.52 (s, 2H), 3.04 (m, 2H). 2.56 (m, 2H).

B. 6-Chloro-2-methyl-lJ.3,4-tetrahydronaphthalene-2-ol. To a solution of TiCl (95 mL, 1 M in toluene) at -45°C is added a solution of CH₃MgBr (4.2 mL 3M in THF). The solution is stirred for 20 minutes. After this time, 6-chloro-3J-dihydro-lH- naphthalene-2-one (1 13 g, 63 mmol) in 80 mL of CH₂C1₂ is added dropwise over 15 minutes. The reaction is stirred for an additional 15 min at -45°C. The solution is warmed to 0°C. After 2 h, the solution is diluted with H₂0 and CH₂C1₂. The organic layer is dried over MgS0₄, filtered and concentrated. The title compound is obtained as an oil (1 1.3 g, 57.5 mmol). Η NMR (CDC1₃, 300 MHz) δ 7.10 (m, 2H), 6.97 (m, I H), 3.02 (m, 2H), 2.80 (s, 3H), 1.85 (m, 2H), 1.80 (m, 2H).

C. 2-Chloro-6-methyl naphthalene. A solution of 6-chloro-2-methyl-l,2,3J-tetrahydronaphthalene-2-ol (1 1.3 g, 57.5 mmol) and

Ph₃COH (16.5 g, 63 mmol) in 80 mL of TFA is stirred for 2.5 days. After this time, the solution is concentrated to dryness. The residue is dissolved in CH₂C1₂. The organic layer is washed with H₂0, saturated NaHC0₃, and saturated NaCl. The organic layer is dried over MgS0₄, filtered and concentrated. The crude product is purified by column chromatography eluting with hexanes. The title compound is obtained as a white solid (4.05 g, 22.9 mmol). Η NMR (CDC!₃, 300 MHz) δ 7.78 (s, IH), 7.69 (m, 2H), 7.58 (s, I H), 7.50 (m, 2H), 2.49 (s, 3H).

D. 2-Bromomethyl-6-chloronaphthalene.

The title compound is prepared as described in Example 7, part C. substituting 2-chloro-6-methyl naphthalene for 4-chloro-7-methylquinazoline. Η NMR (CDC1₃, 300 MHz) δ 7.82 (m, 2H), 7.78 (s, IH), 7.76 (m. 2H), 7.52 (d, IH), 7.42 (d, IH), 4.62 (s, 2H).

EXAMPLE 13. 2-(Benzhydrylidene-amino)-4-bromomethyl-benzonitrile.

A. 2-(Benzhydrylidene-amino)-4-methyl-benzonitrile.

To a solution of 2-amino-4-methyl benzonitrile (20 g, 151 mmol) in l OOOmL of dichloroethane is added benzophenone imine (30g, 166mmol). The solution is refluxed for 48 hours After this time, the solution is cooled to ambient temperatures. The solution is washed with sat. NaHC0₃, water and sat.

NaCl. The organic layer is dried over MgS0₄, filtered and concentrated under vacuum. The product is further purified by recrystallization from t-butyl ether. The title compound (25.5g, 1 18mmol) is obtained as a yellow solid. Η NMR (CDC1,, 300MHz) δ 7.88 (m, 2H), 7.42 (m, 3H), 7.32 (m, 7H), 6.79 (d, I H),

6.58 (s, lH). 2.23 (s, 3H).

B. 2-(Benzhvdrylidene-amino)-4-bromomethyl-benzonitrile. To a solution of 2-(benzhydrylidene-amino)-4-methyl-benzonitrile ( 1 1.2g, 37.8mmol) in 500mL of CC1 is added N-bromosuccinimide (7.06g, 39Jmmol), and benzoyl peroxide (0.92g, 3.8mmol). The solution is heated to reflux for 16 hours. After this time, the solution is filtered and the organic solution is concentrated under vacuum. The residue is purified by column chromatography eluting with a gradient of 20%t-butyl ether/hexanes to 25% t-butyl ether/hexanes. The product is obtained as an oil containing a mixture of the desired monobromide, dibromide and unreacted starting material. The mixture is assayed by proton NMR and is found to have a purity between 60-75%. 'H NMR (CDC1₃, 300MHz) δ 7.82 (m, 2H), 7.42 (m, 9H), 6.92 (d, I H), 6.81 (s, I H), 4.29 (s, 2H).

EXAMPLE 14. 7-Bromomethyl-4-chloroquinoline.

A. 7-Methyloxycarbonyl-4-chloroquinoline.

4-Chloro-7-trifluoromethylquinoline (5.0 g, 21.6 mmol) in 100 mL 80% H₂S0 is heated to 200°C for 24 hours in a sealed tube. The solution is cooled, poured into water and neutralized with sodium hydroxide to pH ~ 3-4. The precipitated solid is collected, washed with water and dissolved in 2 N sodium hydroxide. The aqueous solution is washed with ethyl acetate then acidified to pH~3-4. The precipitate is collected, washed with water and dried in a vacuum oven overnight to yield 7-carboxy-4- chloroquinoline as 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 DMF (2 mL) and 2 M oxalyl chloride in methylene chloride (14.5 mL, 29 mmol). The resulting suspension is stirred at room temperature for 2 h then treated with methanol (10 mL). After stirring 30 minutes the solution is concentrated and the residue is taken up in methylene chloride. The solution is washed with saturated sodium bicarbonate and dried (sodium sulfate) and concentrated to yield the title compound as a solid (2.1 g, 9.5 mmol). MS m/z: M⁺ = 221 ; Η NMR (CDC1₃, 300 MHz) ? 8.6 (s, IH), 8.2 (s, IH), 7.9 (d, I H), 7.65 (d, I H), 7.45 (s, IH), 3.95 (s. 3H).

B. 7-Hydroxymethyl-4-chloroquinoline.

7-Methyloxycarbonyl-4-chloroquinoline (2.1 g, 9.5 mmol) is dissolved in anhydrous THF (25 mL) and anhvdrous ether (200 mL). The solution is cooled in a dry ice/acetone bath and treated 1M lithium aluminum hydride in THF (1 1.0 mL, 1 1 mmol). The solution is warmed (approximately -45°C) for 20 minutes and quenched with ethyl acetate. The solution is diluted with ether (100 mL) and treated with water (36 mL), 15% NaOH (36 mL) and water (36 mL) in succession. The mixture is filtered and evaporated to yield the title compound as a residue (2.0 g, 9.1 mmol) which is dried under vacuum and used without further purification. MS m/z: M⁺ = 193; Η NMR (CDC1₃, 300 MHz) ? 8.65 (d, IH), 8.15 (d, IH), 8.0 (d. I H), 7.6 (d, I H). 7.45 (d, I H), 4.8 (s, 2H). C. 7-Bromomethyl-4-chloroquinoline.

7-Hydroxymethyl-4-chloroquinoline (0.2 g, 0.97 mmol) is treated with 48 % HBr and heated to 120°C for 1 hours. The resulting solution is cooled with ice, diluted with water and treated with ethyl acetate and sodium bicarbonate until basic to pH paper. The layers are separated and the organic layer is washed with water, dried (Na₂S0₄) and concentrated to give 7-bromomethyl-4-chloroquinoline (0.23 g, 0.9 mmol). MS m/z: M⁺ = 255: 'H NMR (CDC1₃, 300 MHz) ? 8.75 (d, l H), 8.25 (d, IH), 8.1 (s, IH), 7.7 (d, IH), 7.5 (d, lH), 4.7 (s. 2H).

EXAMPLE 15. 7-Bromomethvl-4-chlorocinnoline.

A. 4-methyl-2-nitrophenylethanone.

4-Fluro-3-nitrotoluene (7.5 g, 48.4 mmol) is treated with a solution of nitroethane (15.2 mL, 200 mmol) in ethyl acetate (100 mL) and DBU (21 mL, 145 mmol) and stirred overnight at ambient temperature. The solution is concentrated under vacuum, diluted with methanol, treated with 30% H₂0₂ (25 mL) and 10% sodium bicarbonate (25 ml) and stirred overnight at ambient temperature. The reaction mixture is concentrated in vacuo, acidified with 5% HCl and extracted with methylene chloride. The organic layer is dried (sodium sulfate) and chromatographed (35% ethyl acetate/hexane) to give the title compound (7.2 g, 40.2 mmol). MS m/z: M⁺ = 279; Η NMR (CDC1₃. 300MHz) ? 7.8 (s, IH), 7J8 (d, IH), 7.32 (d, I H), 2.5 (s, 3H). 2.4 (s, 3H).

B. 2-Amino-4-methylphenylethanone.

A solution of 4-methyl-2-nitrophenylethanone (5.0 g, 28 mmol) in methanol (100 mL) is treated with ammonium formate (9.6 g. 140 mmol) and 5% palladium on carbon (1.5 g). The mixture is heated to 60°C for 6 h then stirred at ambient temperature for 16 hours. The reaction mixture is filtered through Celite and the filtrate is concentrated in vacuo. The concentrate is treated with sodium bicarbonate and partitioned between water and ethyl acetate. The organic layer is separated, dried with sodium sulfate and concentrated to give crude title compound (4.5 g, 30.2 mmol) which is used without further purification. MS m/z:M⁺ = 149: 'H NMR (CDCI₃, 300MHZ) ? 8.05 (d, I H), 7.4 (d, IH). 7.25 (s, IH), 2.8 (s, 3H), 2.45 (s, 3H).

C. 7-Methyl-l-H-cinnolin-4-one.

A solution of 2-amino-4-methylphenylethanone (5.0 g, 33.6 mmol) in concentrated HCl (100 mL) is treated, in portions, w ith a solution of sodium nitrite (5.7 g, 82.6 mmol) in water (- 10 mL). The resulting solution is stirred at 60°C for 2 hr, cooled to ambient temperature and diluted with a saturated solution of sodium acetate (~ 200 mL). Solid sodium acetate is added portionwise until the solution tested basic to pH paper. Upon stirring, the title compound precipitated as a white solid which is collected and air dried (2.3 g, 143 mmol). MS m/z: [M+H]⁺ = 161; Η NMR (CDC1₃, 300MHz) δ 8.1 (d, IH), 7.85 (s, IH), 7.45 (s, IH) 7.3 (d, IH), 2.55 (s, 3H).

D. 4-Chloro-7-methylcinnoline.

7-Methyl-l -H-cinnolin-4-one (1.3 g, 8.1 mmol) is treated with about 80 mL of chlorobenzene and heated until the solid dissolves. The resulting solution is cooled and treated with pyridine (0.16 mL, 2 mmol) and POCl₃ (1.13 mL, 12.2 mmol). The solution is heated to reflux for 1 h then concentrated to dryness. The residue is chromatographed (20 % ethyl acetate/hexane) to yield the title compound as a tan solid (~ 1 g, 5.6 mmol). MS m/z (M+=178); Η NMR (CDC1₃, 300MHz) δ 9.3 (s, IH), 835 (s, I H), 8.1 (d, IH), 1.1 (d, I H). 2.68 (s, 3H).

E. 7-Bromomethyl-4-chlorocinnoline.

A solution of 4-chloro-7-methylcinnoline (0.6 g, 337 mmol) in carbon tetrachloride (30 mL) is treated with N-bromosuccinimide (0.64 g, 3.4 mmol) and a catalytic amount of 70 % benzoyl peroxide (0.22 g, 0.63 mmol). The solution is heated to 80 °C overnight, then filtered. The filtrate is concentrated in vacuo and the resulting residue is chromatographed (20 % ethyl acetate/ methyl chloride) to give the title compound (0.3 g, 1.2 mmol) and some unreacted starting material (0.1 g, 0.56 mmol). MS m/z:

[M+H]⁺= 257; Η NMR (CDC1₃. 300MHz) δ 9.35 (s, IH), 8.55 (s, IH). 8.2 (d, I H), 8.85 (d, I H), 4.75 (s, 2H).

EXAMPLE 16. 6-Bromomethyl-3-chloro-l-(toluene-4-sulfonyl)-lH-indole.

A. lH-Indole-6-carboxylic acid methyl ester.

To a solution of 6-indole carboxylic acid (0.91 g, 5.67 mmol) in 33 mL of 2: 1 THF/MeOH is added (trimethylsilyl)diazomethane (5.0 mL of a 2.0M solution in hexanes, 10.0 mmol). The mixture is stirred for 3 h and concentrated in vacuo to give the title compound (0.87 g, 4.97 mmol). The crude product is used in the next step without further purification. Η NMR (CDC1₃, 300 MHz) ? 8.70 (bs, 1 H), 8.20 (s, IH), 7.82 (dd, IH), 7.67 (d, IH), 7.45 (m, IH), 6.60 (m, IH), 3.95 (s, 3H).

B. 3-Chloro-l H-indole-6-carboxylic acid methyl ester. To a solution of lH-indole-6-carboxylic acid methyl ester (5.86 g. 33.5 mmol) in 30 mL of CH₂C1₂ is added N-chlorosuccinimide (0.58, 4.33 mmol) portionwise over 1.5 hours. The mixture is stirred for 2 h, then diluted with water. The layers are separated and the organic phase is washed with water and saturated NaCl solution. The organic layer is dried over MgS0₄, filtered and concentrated in vacuo to give the title compound (5.74 g, 27.3 mmol). The crude product is used in the next step without further purification. Η NMR (CDC1₃, 300 MHz) ? 8.46 (bs, 1 H), 8.19 (s , 1 H), 7.90 (dd, 1 H), 7.69 (d, lH), 7.36 (d, lH), 3.97 (s, 3H).

C. 3-Chloro-l-(toluene-4-sulfonyl)-l H-Indole-6-carboxylic acid methyl ester. To a solution of 3-chloro- l H-indole-6-carboxylic acid methyl ester (3.00 g, 17.1 mmol) in 40 mL of THF at -78°C is added LDA(8.55 mL of a 2.0M solution in hexanes, 17.1 mmol) dropwise. The solution is stirred at -78°C for 30 minutes p-Toluenesulfonyl chloride (3.43 g, 18.0 mmol) in 15 mL of THF is added dropwise and the resulting solution is stirred at -78°C for 3 hours. The mixture is warmed to 0°C , quenched with saturated NaHC0₃ solution and diluted with H₂0 and Et₂0. The layers are separated. The organic phase is washed with saturated NaHC0₃ solution, H₂0 and saturated NaCl solution, then dried over MgS0₄. filtered and concentrated. The crude residue is purified via flash column chromatography eluting with a gradient of 10% EtOAc/hexanes to 30% EtOAc/hexanes to provide the title compound (3.64 g, 10.0 mmol). Η NMR (CDC1₃, 300MHz) δ 8.70 (s, I H), 8.01 (dd, IH), 7.80 (d, 2H), 7.70 (s, IH), 7.60 (d, IH), 7.38 (m, 2H), 4.00 (s, 3H), 2.49 (s, 3H).

P. [3-Chloro- 1 -(toluene- 1 -sulfonyl)- 1 H-indol-6-yll-methanol.

To a solution of 3-chloro-l-(toluene-4-sulfonyl)-lH-Indole-6-carboxylic acid methyl ester (3.10 g, 8.53 mmol) in 50 mL of toluene at -78°C is added DIBAL (13.8 L of a 1.5M solution in toluene, 20.8 mmol) dropwise. The mixture is stirred at -78°C for 2 h, then warmed to room temperature and stirred for 2 hours. The reaction mixture is quenched by the addition of MeOH and washed with saturated disodium tartrate solution. The aqueuos layer is extracted with Et₂0. The combined organics are washed with saturated disodium tartrate solution, water and saturated NaCl solution. The organic phase is then dried over anhydrous MgS0₄, filtered and concentrated to give the title compound (2.88 g). The crude product is used in the next step without further purification. Η NMR (CDC1₃, 300 MHz) ? 8.01 (s, IH). 7.79 (d. 2H), 7.56 (s, I H), 7.53 (d, I H), 731 (d, IH), 7.25 (d, 2H), 4.84 (s, 2H), 2.37 (s, 3H), 1.88 (bs, IH).

E. 6-Bromomethyl-3-chloro- 1 -(toluene-4-sulfonyl)- 1 H-indole. To a solution of [3-chloro-l -(toluene- l-sulfonyl)J H-indoI-6-yl]-methanol (0.45 g, 134 mmol) in 13 mL of Et₂0 at 0°C is added phosphorous tribromide (0.04 mL, 0.40 mmol). The mixture is stirred at 0°C for 15 min, then at room temperature for 2 hours. The mixture is quenched by the addition of water/ice and diluted with Et₂0. The layers are separated and the organic phase is washed with saturated NaHC0₃ solution, water and saturated NaCl solution. The organic layer is dried over anhydrous MgS0₄, filtered and concentrated to provide the title compound (0.47 g, 1.18 mmol) as an oil. The crude product is used in the subsequent step without further purification. Η NMR (CDC1₃, 300 MHz) ? 8.09 (s, IH), 7.79 (d, 2H), 7.59 (s, IH), 7.50 (d. IH), 7.35 (d, IH), 7.27 (m, 2H), 4.66 (s, 2H), 2.39 (s, 3H).

EXAMPLE 17. 2-(3-Bromo-(E)-propenyl)-5-chloro-thiophene.

A. 3-(5-Chloro-thiophen-2-yl)-(E)-acrylic acid methyl ester.

To a solution of 5-chloro-2-thiophene-carboxaldehyde (5.10 g, 34.8 mmol) in 100 mL of dry CH₂C1₂ is added methyl (triphenylphosphoranylidene)acetate (1 1.8 g, 35.3 mmol). The resulting brown- green mixture is stirred for 19 h at room temperature. The mixture is filtered through a Celite pad, concentrated in vacuo and triturated with hexane. The white precipitate (triphenylphosphine oxide) is filtered off and the filtrate is concentrated. The crude residue is purified via flash column chromatography eluting with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes to provide the title compound (6.20 g, 30.6 mmol) as a yellow solid. Η NMR (CDC1₃, 300MHz) δ 7.65 (d, 1 H), 7.05 (d, IH), 6.89 (d, I H), 6.10 (d, IH), 3.80 (s, 3H).

B. 3-(5-Chloro-thiophen-2-yl)-prop-2-(E)-en-l-ol.

To a solution of 3-(5-chloro-thiophen-2-yI)-(E)-acrylic acid methyl ester (5.00 g, 24.7 mmol) in 80 mL of CH₂C1₂ at 0°C is added slowly a solution of DIBAL (36.2 mL of a 1.5M solution in toluene, 54.3 mmol). The mixture is stirred at 0°C for 15 min, then quenched by the addition of 6 mL of MeOH. The mixture is allowed to warm to room temperature, diluted with water/ice and stirred for 15 minutes. The mixture is filtered through a pad of Celite and washed with CH₂C1₂. The layers are separated and the aqueous layer is extracted with CH₂C1₂. The combined organics are washed with saturated NaCl solution, dried over anhydrous Na₂S0 , filtered and concentrated. The residue is purified via flash column chromatography eluting with a gradient of 15% EtOAc/hexanes to 25% EtOAc/hexanes to afford the title compound (4.18 g, 23.9 mmol) as an oil. Η NMR (CDC1₃, 300 MHz) ? 6.77 (d, IH), 6.71 (d, IH), 6.60 (d. I H), 6.10 (m, IH). 4.30 (d, 2H), 1.79 (bs, I H).

C. 2-(3-Bromo-(E)-propenyl)-5-chloro-thiophene. To a solution of 3-(5-chloro-thiophen-2-yl)-prop-2-(E)-en-l-ol (4.18 g, 23.9 mmol) in 140 mL of Et₂0 at 0°C is added phosphorous tribromide (134 mL, 14.3 mmol) in 10 mL of Et₂0. The mixture is stirred at 0°C for 45 min, then at room temperature for 1.5 hours. The mixture is quenched by the addition of water/ice and diluted with Et₂0. The layers are separated and the organic phase is washed with water until neutral (3x) and once with saturated NaCl solution. The organic layer is dried over anhydrous MgS0₄, filtered and concentrated to provide the title compound (5.46 g, 23.0 mmol) as an oil. The crude material solidified upon storage in the freezer and can be used in the subsequent step without further purification. Η NMR (CDC1₃, 300 MHz) ? 6.80 (m, 2H), 6.65 (d, lH), 6J 0 (m, lH), 4.10 (d, 2H).

EXAMPLE 18. 3-(4-Bromo-furan-2-yl)-(E)-propenal.

To a solution of 4-bromo-2-furfuraldehyde (0.5 g, 2.86 mmol) in 30 mL of dry CH₂CI₂ is added (triphenylphosphoranylidene)acetaldehyde (0.87 g, 2.86 mmol). The resulting mixture is stirred for 16 h at room temperature. The crude mixture is concentrated in vacuo and the residue is purified via flash column chromatography eluting with CH₂C1₂ to provide the title compound (0.15 g, 0.75 mmol) as a white solid. 'H NMR (CDC1₃. 300 MHz) ? 9.62(d, I H), 7.59 (s, I H), 7.18 (d, I H), 6.81 (s, I H), 6.60 (m, IH).

EXAMPLE 19. Acetic acid 3-(6-methoxy-pyridin-3-yl)-(E)-allyl ester. To a solution of 3-(6-methoxy-pyridin-3-yl)-prop-2-(E)-en-l -ol (0.39 g, 2.36 mmol, prepared as described in PREPARATION MB from 6-methoxy-pyridine-3-carbaldehyde (j. Org. Chem. 1990, 72)) in 8 mL of CH₂C1₂ at 0°C is added triethylamine (0.66 mL, 4.72 mmol). DMAP (0.05 g, 0J0 mmol) and Ac₂0 (0.33 mL, 3.54 mmol). The mixture is stirred at 0°C for 45 min, then at room temperature for 16 hours. The mixture is diluted with Et₂0 and washed with IN HCl, water, saturated NaHC0₃ solution and saturated NaCl solution. The organic layer is dried over anhydrous MgS0₄, filtered and concentrated. The residue is purified via flash column chromatography eluting with a gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to afford the title compound (0.25 g, 1.21 mmol) as an oil. Η NMR (CDC1₃, 300 MHz) ? 8.12 (d, I H), 7.68 (dd, IH), 6.72 (d, IH), 6.60 (d, IH), 6.18 (dt, IH), 4.73 (d, 2H), 3.95 (s, 3H), 2.10 (s, 3H).

EXAMPLE 20. 2-(3-Bromo-prop-l -ynyl)-5-chloro-thiophene.

A. 3-(5-Chloro-thiophen-2-yl)-prop-2-yn- 1 -ol. Nitrogen (g) is bubbled through a solution of 5-bromo-2-chloro-thiophene (1.00 g, 5.06 mmol) in 8 mL of piperidine. After 5 min, propargyl alcohol (032 mL, 5.56 mmol), tetrakis(triphenylphosphine) palladium(O) (0.06 g) and Cul (catalytic amount) are added to the solution. The mixture is heated at 80°C for 1 h in a sealed glass vessel. At this time, the mixture is cooled and diluted with EtOAc/Et,0. The organic layer is washed 3N HCl, water, saturated NaHC0₃ solution and saturated NaCl solution. The organic layer is dried, filtered and concentrated. The crude residue is purified via flash column chromatography eluting with a gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to give the title compound (0.8 g, 0.46 mmol) as an oil. Η NMR (DMSO-d₆, 300 MHz) ? 6.99 (d, I H), 6.80 (d, IH), 4.49 (s, 2H), 1.90 (bs, I H). El MS, [M]⁺=172, 174 (Cl pattern).

B. 2-(3-Bromo-prop- 1 -ynyl)-5-chloro-thiophene.

The title compound is prepared as described in EXAMPLE 17, Part C, using 3-(5-chloro- thiophen-2-yl)-prop-2-yn-l-ol in place of 3-(5-chloro-thiophen-2-yl)-prop-2-(E)-en-l-ol. The crude product is used in the subsequent step without further purification. Η NMR (CDC1₃. 300 MHz) ? 7.04 (d, IH), 6.80 (d, I H), 4.98 (d, 2H).

EXAMPLE 21. 2-Bromomethyl-5-chloro-indole-l -carboxylic acid tert-butyl ester.

A. 5-Chloro-2-methyl-indole-l -carboxylic acid tert-butyl ester. A solution containing 5-chIoro-2-methyIindole (4.0 g, 24.1 mmol) and DMAP (295 mg, 2.42 mmol) in anhydrous THF (100 mL) is cooled to 0°C. A solution containing (Boc),0 (5.27 g, 24.1 mmol) in anhydrous THF (100 mL) is then added over a 20 min period. The reaction mixture is stirred for 2 h at 0°C and then at ambient temperature for 16 hours. The reaction mixture is concentrated and the crude residue is purified by flash silica gel chromatography (2% EtOAc/hexane to 5% EtOAc/hexane) to provide 5.2 g (81 %) of title compound as a pale yellow solid. 'H NMR (300 MHz, CDC1J δ 1.67 (s, 9H), 2.57 (s, 3H), 6.24 (t, J = 0.9 Hz, I H), 7.16 (dd, J = 8.8, 2.1 Hz, I H), 7.38 (d, J = 2.1 Hz, IH), 8.01 (d, J = 8.8 Hz. IH) ppm; MS (El): m/z 265 (M+).

B. 2-Bromomethyl-5-chloro-indole-l -carboxylic acid tert-butyl ester. A solution containing 5-chloro-2-methyl-indole-l -carboxylic acid tert-butyl ester (3.0 g, 1 1.3 mmol), NBS (1.33 g, 1 1.3 mmol), and benzoyl peroxide (0.4 g, 1.13 mmol) in CC1₄ (100 mL) is heated at 80°C for 3 hours. An additional portion of NBS (0.65 g, 5.65 mmol), and benzoyl peroxide (0.2 g, 0.56 mmol) is then added and the reaction mixture is heated for an additional 3 hours. After cooling to ambient temperature, the reaction mixture is filtered. The filtrate is concentrated to a brown oil which is triturated with hexane to remove residual succinimide, filtered, and concentrated. The resultant oil (4.5 g, >100%) is used directly in the next reaction without further purification. Η NMR (300 MHz, CDC1₃) δ 1.72 (s, 9H), 4.88 (s, 2H), 6.63 (s, IH), 7.27 (dd, J = 9.0, 2.0 Hz, IH), 7.46 (d, J = 2.0 Hz, IH), 8.09 (d, J = 9.0 Hz, IH) ppm; MS (El): m/z 343 (M+).

EXAMPLE 22. 3-Bromomethyl-5-iodo-2-methoxy-pyridine

A. 5-Iodo-3-methyl-2-methoxy-pyridine.

To a solution containing 2-bromo-5-iodo-3-methyl-pyridine (4.80 g, 16.0 mmol) in DMSO (15 L) is added methanolic NaOMe (3.33 M, 53 mL, 17.7 mmol) at 0 °C. The solution is allowed to warm to ambient temperature and then heated at 70°C for 1 hour. The reaction mixture is diluted with diethyl ether (300 mL) and water (200 mL) and the layers are separated. The organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude product is purified by silica gel flash column chromatography (hexane/diethyl ether, 19:1) to provide 2.86 g (71%) of the title compound as a white solid. Η NMR (300 MHz, CDC1J δ 2.12 (s, 3H), 3.90 (s, 3H), 7.60 (d, J = 2.1 Hz, IH), 8.14 (d, J = 2.1 Hz, IH) ppm; MS (El): m/z 249 (M+).

B. 3-Bromomethyl-5-iodo-2-methoxy-pyridine.

A solution containing 5-iodo-3-methyl-2-methoxy-pyridine (1.00 g, 4.00 mmol) and NBS (0.78 g, 4.40 mmol) in CC1₄ (20 mL) is warmed to reflux. AIBN is added in 5 mg portions (0.03 mmol) every hour. After 3 h, the reaction mixture is cooled and then concentrated in vacuo. The residue is dissolved in EtOAc (150 mL) and washed successively with aqueous Na₂S₂0₃ (100 mL), water (100 mL), brine then dried over anhydrous Na₂S0₄, filtered and concentrated. The crude product ispurified by silica gel flash column chromatography (hexane/diethyl ether, 19: 1) to provide 0.72 g (55%) of the title compound as a white solid. Η NMR (300 MHz, CDC1₃) δ 3.97 (s, 3H), 4.38 (s, 2H), 7.83 (d, J = 2.2 Hz, IH), 8.27 (d, J = 2.2 Hz, I H) ppm; MS (El): m/z 327 (M+).

EXAMPLE 23. 5-Bromomethyl-6-methoxy -nicotinic acid methyl ester.

A. 6-Methoxy-5-methyl-nicotinic acid methyl ester.

A solution containing 5-iodo-3-methyl-2-methoxy-pyridine (10.0 g, 40.0 mmol), Et₃N (8.0 g, 80.0 mmol). and (Ph₃P)₄PdCl₂ (2.80 g, 4.00 mmol) in 1 : 1 DMF/MeOH (100 mL) is cooled to 0°C. Carbon monoxide is bubbled into the cooled solution for approx. 5 min at which time the reaction mixture is sealed under a balloon of CO. The reaction mixture is allowed to warm to ambient temperature and then stirred for 16 hours. The reaction mixture is concentrated in vacuo and the residue is partitioned between water (300 mL) and EtOAc (300 mL) and the layers are separated. The organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude product is purified by silica gel flash column chromatography (hexane/diethyl ether, 19: 1) to provide 4.10 g (57%) of the title compound as a white solid. 'H NMR (300 MHz, CDC1J δ 2.20 (s, 3H), 3.88 (s, 3H), 4.00 (s, 2H), 7.96 (d, J = 2.2 Hz, IH), 8.65 (d, J = 2.2 Hz, IH) ppm; MS (ISP loop): m/z 182 (M+H).

B. 5-Bromomethyl-6-methoxy -nicotinic acid methyl ester.

A solution containing 6-methoxy-5-methyl-nicotinic acid methyl ester (4.00 g, 22.1 mmol), NBS (5.1 1 g, 28.7 mmol), and AIBN (0.90 g, 5.5 mmol) in CC1₄ ( 100 mL) is warmed to reflux. After 5 h, the reaction mixture is cooled and then concentrated in vacuo. The residue is dissolved in EtOAc (500 mL) and washed successively with aqueous Na₂S₂0₃ (300 mL), water (100 L), brine then dried over anhydrous Na₂S0₄, filtered and concentrated. The crude product is purified by silica gel flash column chromatography (hexane/diethyl ether, 9:1 ) to provide 3.10 g (54%) of the title compound as a white solid. Η NMR (300 MHz, CDC1J δ 3.90 (s, 3H), 4.07 (s, 3H), 4.46 (s, 2H), 8.19 (d, J = 2.2 Hz, IH), 8.79 (d, J = 2.2 Hz, IH) ppm: MS (El): m/z 259 (M+).

EXAMPLE 24. 5-Chloro-2-thienyloxyacetic acid.

A. 2-Hydroxy-thiophene.

Thiophene (42g, 500mmol) is dissolved in ether (250mL). To the solution is added n-BuLi (200mL of a 2.5N solution in hexanes, 500mmol) at a rate which maintains a gentle reflux. After addition, the solution is stirred for 0.5 hour. The solution is then cooled to -78°C and triethyl borate (102 g, 700mL) is added dropwise. The solution is stirred for 3 hours. The cold bath is removed and 130mL of a 30%> H₂0₂ is added dropwise with rapid stirring. After addition, the solution is allowed to refluxed for an additional 20 minutes. The solution is then cooled to 0°C and acidified to pH=3 with 6N HCl. The resulting solution is extracted with ether. The organic solution is washed with 10% ferric ammonium sulfate, water and saturated NaCl. The solution is dried over MgS0₄, filtered and concentrated under vacuum. The title compound (32g, 320mmol) is obtained as an oil. 'H NMR (CDC1₃, 300MHz) δ 7.60 ( , 1H),6.35 (m, 1H), 4.12 (d, 2H).

B. Ethyl 2-thienyloxyacetate.

To a solution of 2-hydroxy-thiophene (32g, 320 mmol) in CHC1₃ (500mL) is added ethyl bromoacetate (53.4 g, 320 mmol). To the resulting solution is added a solution containing n-Bu NHS0₄ (25g, 74mmol) and NaOH ( 15.8g, 394 mmol) in water (500mL). After addition, the solution is stirred vigorously using mechanical stirring. The reaction is stirred for 12 hours. After this time, the layers are separated. The aqueous layer is extracted with CHC1₃. The combined organic layers are washed with water and saturated NaCl. The organic layer is dried over MgS0 , filtered and concentrated under vacuum. The resulting crude product is purified by column chromatography eluting with a gradient of 30%CH₂Cl₂:hexanes to 60%CH₂Cl₂:hexanes. The title compound (1 1.5g, 62mmol) is obtained as an oil. Η NMR (CDC1₃, 300MHz) δ 6.68 (dd, lH), 6.60 (d, lH), 6.22 (d, I H), 4.62 (s, 2H), 4.30 (q, 2H), 1.31 (t, 3H).

C. Ethyl 5-chloro-2-thienyloxyacetate.

To a solution of ethyl 2-thienyloxyacetate (l . l g, 5.9mmoI) in acetic acid (15mL) is added N- chlorosuccinimide (0.78g. 5.9mmoI). The solution is stirred for 1.5 hour. After this time the solution is concentrated. The resulting oil is dissolved in ether and washed with IN NaOH, water and sat. NaCl.

The organic layer is dried over MgS0₄, filtered and concentrated under vacuum. The title compound (1.26g, 5.7mmol) is obtained as an oil. 'H NMR (CDC1₃, 300MHz) δ 6.52 (d, l H), 6.06 (d, IH), 4.60 (s,

2H), 4.24 (q. 2H). 1.31 (t, 3H).

D. 5-Chloro-2-thienyloxyacetic acid.

To a solution of ethyl 5-chloro-2-thienyloxyacetate (039g, 1.77mmoI) in 9mL of a 1 : 1 : 1 mixture of CH₃OH:THF:vvater is added LiOH (0.38g, 9.0 mmol). The solution is stirred for 16 hours. After this time, the solution is concentrated to 1/3 its volume. The resulting solution is acidified to pH=3 with IN HCl. The aqueous solution is extracted with CH₂C1₂. The organic layer is dried over MgS0₄, filtered and concentrated under vacuum. The title compound (032g, 1.66mmol) is obtained as a white solid. Η NMR (CDC1₃, 300MHz) δ 6.50 (d, IH), 6.07 (d, I H), 4.66 (s, 2H).

EXAMPLE 25. 3-(5-Chloro-thiophen-2-yl)-(E)-acrylic acid.

To a mixture of 3-(5-chloro-thiophen-2-yl)-(E)-acrylic acid methyl ester (0.60 g, 2.96 mmol) in 15 mL of 1 : 1 : 1 THF/MeOH/H₂0 at 0°C is added lithium hydroxide onohydrate (0.62 g, 14.7 mmol). The mixture is stirred at 0°C for 1 h, then at room temperature for 1 h and concentrated in vacuo. The residue is diluted w ith EtOAc and washed with IN HCl. The aqueous layer is extracted with EtOAc and the combined organics are washed with water (2x), dried, filtered and concentrated to provide the title compound (0.54 g. 2.86 mmol) as a white solid. The crude material can be used in the subsequent step without further purification. Η NMR (CDC1₃, 300MHz) δ 7.65 (d. IH), 7.05 (d, IH), 6.90 (d, IH), 6.10 ( , IH). EXAMPLE 26. 3-(4-Chloro-thiophen-2-ylHE)-acrylic acid.

A. 4-Chloro-2-thiophene-carboxaldehyde. To a solution of 2-thiophene-carboxaldehyde (6.33 g, 56.4 mmol) in 100 mL of CHC1₃ at 0°C is added aluminum trichloride (16.8 g, 126 mmol) portionwise over a few minutes. In a separate vessel, chlorine gas (4.00 g) is bubbled for about 2 min into 100 mL of CC1₄ at 0°C and then added to the former mixture slowly at 0°C . The resulting mixture is stirred at 0°C for 45 min, then allowed to warm to room temperature and stirred overnight. After 16 h, the reaction mixture is poured slowly into 6N HCl at 0°C , then stirred at room temperature for 2 hours. The layers are separated. The aqueous layer is extracted with CHC1₃. The combined organic layers are washed with H₂0 and saturated NaCl solution, then dried over MgS0 , filtered and concentrated. The crude product is purified by column chromatography eluting with 10% EtOAc/hexanes to yield the title compound (6.70 g, 45.9 mmol). Η NMR (CDC1₃, 300 MHz) δ 9.87 (s, IH), 7.64 (s, IH), 7.63 (s, IH).

B. 3-(4-Chloro-thiophen-2-yl)-(E)-acrylic acid methyl ester.

The title compound is prepared as described in EXAMPLE 1 , Part A from 4-chloro-2-thiophene- carboxaldehyde. Η NMR (CDC1₃, 300 MHz) δ 7.69 (d, I H), 7.15 (s, I H), 7.1 1 (s, I H), 6.25 (d, IH), 3.82 (s, 3H).

C. 3-(4-Chloro-thiophen-2-yl)-(E)-acrylic acid.

The title compound is prepared as described in EXAMPLE 1 , Part B from 3-(4-chloro-thiophen- 2-yl)-(E)-acrylic acid methyl ester. Η NMR (CDC1₃, 300 MHz) δ 7.77 (d, 1 H), 7.19 (d, 2H), 6.25 (d, IH).

EXAMPLE 27. (5-Chloro-thiophen-2-yl)-acetic acid.

A. r2-(5-Chloro-thiophen-2-yl)-l-dimethylaminovinyπphosphonic acid diethyl ester.

To a suspension of sodium hydride (0.25 g, 6.25 mmol, 60% mineral oil dispersion) in 10 mL of THF is added slowly a solution of tetraethyl dimethylaminomethylenediphosphonate (2.03 g, 6.14 mmol, prepared according to the procedure described in Psaume, Montury, and Cosmetic Comm. 1982, 12, 415) in 10 mL of THF. After stirring 1 h, a solution of 5-chloro-2-thiophene carboxaldehyde (0.90 g, 6.14 mmol) in 10 mL of THF is added. The resulting mixture is heated at reflux for 1 h, then cooled to room temperature. The reaction mixture is partitioned between Et₂0 and water. The organic layer is washed sequentially with IN HCL water and saturated NaCl, then dried over MgS0₄, filtered and concentrated. The crude product is purified via flash column chromatography eluting with a gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound ( 1.52 g, 4.69 mmol) as an oil. 'H NMR (CDC1₃, 300 MHz) δ 7.20 (d, 1 H), 6.95 (d, 1 H), 6.82 (d, 1 H), 4.15 (m, 4H), 2.62 (s, 6H), 1.60 (t, 6H).

B. (5-Chloro-thiophen-2-yl)-acetic acid.

A mixture of [2-(5-chloro-thiophen-2-yl)-l-dimethylaminovinyl]phosphonic acid diethyl ester (1.52 g. 4.69 mmol) and 30 mL of 6N HCl is heated at reflux for 2 hours. After cooling to room temperature, ice water is added and the mixture is partitioned between Et₂0 and water. The organic layer is washed with water (2x). dried over MgS0₄, filtered and concentrated to give the title compound (0.62 g, 3.51 mmol) as a brown solid. The crude material can be used in the subsequent step without further purification. Η NMR (CDCI₃. 300 MHz) δ 8.30 (bs, IH). 7.79 (d. I H), 6.71 (d. I H). 3.81 (s, 2H).

EXAMPLE 28. 3-(5-Chloro-thiophen-2-yl)-propionic acid.

A. 3-(5-Chloro-thiophen-2-yl)-propionaldehyde.

To a mixture of Pd(OAc)₂ (0.12 g, 0.53 mmol). NaHC0₃ (0.52 g, 6.19 mmol) and Nal (0.28 g, 1.87 mmol) in 5 mL of HMPA is added 5-bromo-2-chloro-thiophene (1.00 g. 5.06 mmol) and allyl alcohol ( 1.03 mL, 15.2 mmol). The mixture is heated to 90°C and stirred for 16 hours. The reaction mixture is cooled to room temperature, diluted with Et₂0 and washed with water. The organic layer is dried over MgS0₄, filtered and concentrated in vacuo. The crude residue is purified by flash column chromatography eluting with a gradient of 10% Et₂0/hexanes to 20% Et₂0/hexanes to provide the product (0.18 g. 1.03 mmol) as an oil. Η NMR (CDC1₃, 300 MHz) δ 9.81 (s, IH), 6.71 (d, l H). 6.58 (d, IH). 3.07 (t, 2H), 2.81 (t. 2H).

B. 3-(5-Chloro-thiophen-2-yl)-propionic acid.

Silver nitrate (1 17 mg, 0.69 mmol) in 1 mL of H₂0 is added to 1.36 mL of IN NaOH at 0°C and stirred for 5 minutes. To the brown suspension is added 3-(5-chloro-thiophen-2-yl)-propionaldehyde (60 mg, 0.34 mmol) and the resulting mixture is allowed to warm to room temperature over 2 hours. The precipitate is filtered and washed with hot water (2x). The combined aqueous layers are acidified with 6 N HCl and extracted with EtOAc (2x). The combined organic layers are washed with water (2x). then dried over MgSOzj. filtered and concentrated in vacuo to give the title compound (50 mg, 0.26 mmol) as a beige solid. The crude material can be used in the subsequent step without further purification. 'H NMR (CDC1₃, 300 MHz) δ 6.72 (d, IH), 6.60 (d, IH), 3.07 (t, 2H), 2.71 (t, 2H).

EXAMPLE 29. 3-Fluorophenoxy-acetic acid.

A. 3-Fluorophenoxy-acetic acid ethyl ester.

To a solution of 3-fluorophenol (1.2g, 1 l .δmmol) in 20mL of DMF at 0°C is added sodium hydride (0J7g, l OJmmol). After stirring for 10 minutes Ethyl bromoacetate (1.2g, 10.7 mmol) is added dropwise. The reaction is allowed to warm to ambient temperatures and is stirred for 16 hours. To the - reaction is added a saturated solution NH₄C1 (aq.). The resulting mixture is diluted with EtOAc and H₂0. The layers are separted. The organic layer is washed with H₂0 and a saturated solution NaCl (aq.). The organic layer is dried over MgS0₄, filtered and concentrated to give the product (2g, l Ommol) as an oil. Η NMR (CDC1₃, 300MHz) δ 7.22 (m, IH), 6.65 (m, 3H), 4.61 (s, 2H), 4.27 (q, 2H), 1.24 (t, 3H).

B. 3-Fluorophenoxy-acetic acid.

To a solution of ethyl 3-fluorophenoxy-acetate (2g, l Ommol) in 24mL of a 1 : 1 : 1 solution of MeOH:H₂0:THF is added lithium hydroxide monohydrate (2.25g, 54mmol). The solution is stirred for 16 hours. After this time, the solution is concentrated under reduced pressure to 1/3 of its volume. The remaining solution is acidified to pH=3 with IN HCl (aq.). The aqueous solution is extracted with EtOAc. The organic layer is washed with a saturated solution NaCl (aq.). The organic layer is dried over MgS0₄, filtered and concentrated to give the product (1.65g, 9.7mmol) as a white solid. Η NMR (CDC1₃, 300MHz) δ 9.8 (bs. I H), 7.28 (m, I H), 6.69 (m. 3H), 4.70 (s. 2H).

EXAMPLE 30. 2-Chloropyrdin-3-ylamino-acetic acid. To a solution of 3-amino-2-chloropyridine (l .Og, 7.8mmol) in 20mL of MeOH is added glyoxylic acid (0.86mL of a 50% by weight solution in H₂0, 7.8mmol). After stirring for 10 minutes, NaCNBH₃ (1.54 g, 23mmol) is added. The reaction is stirred for 16 hours., then is concentrated under reduced pressure. The resulting residue is dissolved in H₂0. The solution is acidified to pH=3 with IN HCl (aq.). The solution is extracted with EtOAc/CH₂Cl₂ (2: 1 ). The organic layer is dried over MgS0₄, filtered and concentrated. The resulting product is obtained as a white solid (0.95g, 5.1 mmol). 'H NMR (d6-DMSO, 300MHz) δ 12.7 (bs, I H), 7.62 (m, I H), 7.44 (m, I H), 6.90 (m, I H), 5.8 (bs, I H), 3.95 (AB, 2H).4.70 (s, 2H).

EXAMPLE 31. 5-Chlorothiophen-2-yl-sulfanyl acetic acid. A. Thiophen-2-yl-sulfanyl acetic acid ethyl ester.

To a solution of thiophene-2-thioI ( 1.49g, 1 l όmmol) in 40mL of CH,CN is added ethyl bromoacetate (2.14g, 167mmol) followed by K₂C0₃ (3.54g. 138mmol). The solution is stirred for 16 hours. After this time, the solution is filtered. The solvent is evaporate to give the product as an oil

(2.4g. 1 18mmol). Η NMR (CDC1₃, 300MHz) δ 7.37 (m, I H), 7.21 (m, I H). 6.94 (m, IH), 4.15 (q, 2H), 3.48 (s. 2H). 1.20 (t, 3H). MS (El): m/z 202 (M+).

B. 5-Chlorothiophen-2-yl sulfanyl acetic acid. To a solution of thiophen-2-yl-sulfanyl acetic acid ethy (0.52g, 2.6mmol) in 25 mL of CH₂CL is added N-chlorosuccinimide (035g. 2.6mmol). The solution is stirred for 10 minutes. After this time, 1 drop of TFA is added. The solution is stirred for 16 hours. The reaction mixture is then diluted with 25 mL of CH_:CI₂. The resulting solution is washed with IN NaOH and a saturated NaCl solution. The organic layer is dried over MgS0 . filtered and concentrated. The resulting product is obtained as an oil which is determined to contain 45% of the desired product. The oil is then dissolved in 60 mL of 1 : 1 : 1 THF:MeOH:H₂0. To the solution is added lithium hydroxide monohydrate (1.26g, 30mmol). The solution is stirred for 16 hours. After this time, the solution is acidified to pH=3 with IN HCl. The aqueous solution is washed with H₂0 and saturated NaCl solution. The solution is extracted with EtOAc/CH₂CI_: (2: 1 ). The organic layer is dried over MgS0₄. filtered and concentrated. The resulting crude product is purified by column chromatography eluting with 20% MeOH:Et₂0 to give the product as a white solid (0.4g. 1.9mmol). MS (El): m/z 208, 210 (M+), Cl pattern.

EXAMPLE 32. 5^'-Chloro-[2,2'lbithiophenyl-5-carboxylic acid.

A. 5^'-Chloro-r2.2^'1bithiophenyl-5-carbaldehyde.

To a solution of 5-chloro-[2,2']bithiophene (1.06 g, 5.28 mmol) in 12 mL of THF at -78°C is added n-BuLi (4.4 mL of a 1.6M solution in hexanes, 6.99 mmol). After 15 minutes, DMF (0.97 mL, 14 mmol) is added and the resulting solution is allowed to warm to 0°C. After 15 min, the solution diluted with EtOAc and quenched with saturated NaHC0₃ solution. The organic solution is washed with H₂0 and saturated NaCl solution, then dried over MgS0₄. filtered and concentrated. The crude product is purified by flash column chromatography eluting with a gradient of 10% Et₂0/hexanes to 20% Et₂0/hexanes to yield the title compound (0.89 g. 3.89 mmol) as a white solid. Η NMR (CDC1„ 300 MHz) δ 9.87 (s. I H). 7.70 (d, I H). 7.20 (d, I H). 7.15 (d, I H). 6.91 (d, I H). B. 5'-ChloroJ2,2'1bithiophenyl-5-carboxylic acid.

The title compound is prepared as described in EXAMPLE 28, Part B using 5'-chloro- [2,2']bithiophenyI-5-carbaldehyde. Η NMR (CDC1₃, 300 MHz) δ 7.69 (d, IH), 7.09 (d, IH), 7.06 (d, IH), 6.89 (d, I H). El MS, [M]⁺=243,245 (Cl pattern).

EXAMPLE 33. 7-Chloro-isoquinoline-3-carboxylic acid.

A. 7-Chloro-isoquinoline-3-carbaldehyde.

A 20mL of 80% H₂S0₄ is added 7-chIoro-3,3-dibromomethyl isoquinoline (0.69g, 2.06mmol) is heated to 150°C for 16 hours. The solution is then cooled to ambient temperatures and diluted with 40 L of H₂0. The resulting solution is basified to pH=l 1 with IN NaOH. The aqueous solution is extracted with CH₂C1₂. The organic solution is washed with H₂0 and a saturated NaCl solution. The organic layer is dried over MgS0₄, filtered and concentrated to give the product as an oil (0.25g, 1.3 mmol). 'H NMR (CDC1₃, 300MHz) δ 10.0 (s, IH), 9.30 (s, I H), 836 (s, IH), 8.07 (s, IH), 7.95 (d, IH), 7.78 (d, IH). MS (El): m/z 191 , 193 (M+), Cl pattern.

B. 7-Chloro-isoquinoline-3-carboxylic acid.

To 4.5 mL of a IN NaOH solution at 0°C is added a solution of AgN0₃ (0.3 lg, 1.8mmol) in 3 mL of H₂0, followed by a solution of of 7-chloro-isoquinoline-3-carbaldehyde (0.25g, 13mmol) in 3 mL of EtOH. The solution is stirred at 0°C for 10 minutes, then at room temp. For 3 hours. The solution is acidified to pH=3 with 1 H HCl. The resulting solution is extracted with CHC1₃. The organic layer is dried over MgS0₄, filtered and concentrated to give the product as a white solid (0.2g, 0.96mmol). Η NMR (CD₃OD, 300MHz) δ 9.18 (s, IH), 8..63 (s, IH), 8.18 (m, IH), 7.80 (m, 2H). 6.94 (m, IH), 4.15 (q, 2H), 3J8 (s, 2H), 1.20 (t, 3H). MS (El): m/z 208, 210 (M+), Cl pattern.

EXAMPLE 34. 2-Acetylamino-3-(5-chloro-thiophen-2-yl)-acrylic acid.

A. 4-(5-Chloro-thiophen-2-ylmethylene)-2-methyl-4H-oxazol-5-one.

A mixture consisting of 5-chlorothiophene-2-carboxaldehyde (1.00 g, 6.82 mmol), N- acetylglycine (0.96 g, 8.18 mmol), NaOAc (0.67 g, 8.18 mmol) in Ac₂0 (5 mL) is warmed at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and diluted with dilute aqueous NaOH (0.5 M, 100 mL) and CH₂C1₂ ( 100 mL). The layers are separated and the organic phase is washed with aqueous NaHC0₃, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to provide 1.5 g (100%) of the title compound as a colorless oil which is used without further purification in the next reaction. 'H NMR (300 MHz, CDC1J δ 2.39 (s, 3H), 6.94 (d, J = 4.0 Hz. I H), 7.21 (s, I H), 7.26 (d, J = 4.0 Hz, I H) ppm.

B. 2-Acetylamino-3-(5-chloro-thiophen-2-yl)-acrylic acid. To a solution containing 4-(5-chloro-thiophen-2-ylmethylene)-2-methyl-4H-oxazol-5-one (1.5 g,

6.82 mmol) in MeOH (18 mL) is added 1.0 M NaOH ( 12.0 mL, 12 mmol) at ambient temperature. After 3 h, the reaction mixture is diluted with water (100 mL) and CH₂C1₂ (100 mL) and the layers are separated. The basic, aqueous layer is washed with CH₂C1₂ and then acidified using 1.0 M HCl (20 mL) to provide a crude solid which is collected on a Buchner funnel. Drying in vacuo provided 1.2 g (75%) of the title compound as a pale brown solid which is used without further purification. Η NMR (300 MHz, DMSO-d₆) δ 2.00 (s, 3H), 7.14 (d, J = 4.01 Hz, I H), 7.38 (d, J = 4.01 Hz, IH), 7.63 (s, I H), 9.28 (s, 1 H), 12.73 (br s, 1 H) ppm: MS (El): m/z 245 (M+).

EXAMPLE 35. 2-Acetylamino-3-(5-chloro-thiophen-2-yl)-propionic acid. To a solution containing 2-acetylamino-3-(5-chloro-thiophen-2-yl)-acrylic acid (1.00 g, 4.08 mmol) and K₂C0₃ (1.70 g. 12.1 mmol) in DMF (20 mL) is added Mel (0.87 g, 6.12 mmol) at ambient temperature. After 2 h, the reaction mixture is diluted with water (100 mL) and EtOAc (100 mL) and the layers are separated. The aqueous layer is extracted with EtOAc (50 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0 . filtered and concentrated to provide 0.92 g (83%) of the methyl ester w hich is used without further purification. Η NMR (300 MHz, CDCIJ δ 2.19 (s, 3H), 3.77 (s, 3H), 6.86 (d. J = 4.02 Hz, IH), 6.99 (m, I H). 7.05 (d, J = 4.02 Hz, I H), 7.64 (s. I H) ppm.

A small Parr^® vessel is charged with the crude ester (0.85 g, 3.13 mmol) and (Ph₃P),RhCl (0.10 g, 0.10 mmol) in MeOH (50 mL). The vessel is pressurized to 50 PSI H₂ pressure and agitated for 7 h at ambient temperature. The reaction mixture is then filtered and concentrated to provide the desired compound, which is used ithout further purification. MS (El): m/z 261 (M+).

The above-prepared saturated ester is dissolved in a 1 : 1 : 1 solution of water/THF/MeOH ( 15 mL). LiOH monohydrate (0.14 g, 3.23 mmol) is added and the heterogeneous mixture is stirred for 16 hours. The reaction mixture is diluted ith water (100 mL) and EtOAc (100 mL) and the layers are separated. The aqueous layer is extracted with EtOAc (50 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0₄. filtered and concentrated to provide 0.62 g (81%) of the title compound as a colorless oil. Η NMR (300 MHz, CDC1J δ 2.02 (s, 3H), 3.30 (m, 2H), 4.81 (m. IH), 6.45 (br d, J = 6.45 Hz, IH), 6.58 (d, J = 3.68 Hz, I H), 6.71(d, J = 3.68 Hz, I H), 9.79 (br s, IH) ppm; MS (El): m/z 247 (M+). EXAMPLE 36. 3-(6-Amino-pyridin-3-yl)-acrylic acid.

A. N-(5-Bromo-pyridin-2-yl)-acetamide.

Triethylamine(17.7mL, 75 mmol) is added to a mixture of 2-amino-5-bromopyridine (5.0 g, 29 mmol) and acetic acid (7.1 mL, 75 mmol). The solution is heated to reflux for 48 hours. After this time, the solution is concentrated. The reside is dissolved in water and the pH is adjusted to 10 with IN NaOH. The solids are collected by filtration. The crude product is recrystallized from boiling water to give the title compound (2.6 g 12.0 mmol) as a white solid. Η NMR (300 MHz, CDC1J δ 10.62 (IH, bs), 8.42 (s, IH), 8.01 ( , 2H). 2.05 (s, 3H).

B. 3-(6-Acetylamino-pyridin-3-yl)-acrylic acid

To a mixture of N-(5-bromo-pyridin-2-yl)-acetamide (1.26 g. 5.86 mmol) and tri-n-butylamine in xylenes (10 mL)is added Pd(OAc)₂ (I J mg, 0.006 mmol) and triphenyl phosphine (15Jmg, 0.06 mmol). Acrylic acid (0.48 L. 7.03 mmol) is then added dropwise over 5 minutes. The mixture is heated to reflux for 5 hours. The solution is cooled to ambient temperatures. The mixture is diluted with water and the pH is adjusted to 4 with IN HCl. The solution is extracted with EtOAc/CH₂Cl₂ (2: 1 ). The resulting suspension is filtred to give the title compound (0.80 g, 3.88 mmol) as a white solid. MS (ion spray) 207, (M+H).

C. 3-(6-Amino-pyridin-3-yl)-acrylic acid

To 3-(6-acetylamino-pyridin-3-yl)-acrylic acid (0.80 g, 3.88 mmol) in ethanol ( 10 mL) is added IN NaOH (20mL). The solution is heated to reflux. After 16 h, the solution is concentrated to 1/3 its volume. The aqueous solution is diluted with water and acidified to pH=2 with 6N HCl. The solution is concentrated to dryness. The residue is dissolved in methanol. The solution is filtered. The organic solution is concentrated. The crude product is purified by RP-HPLC eluting with a gradient of

5%CH3CN/H20 (0.1% TFA) to 30% CH3CN/H20 (0.1%TFA) to give the product as a white solid (0.54 g, 1.93 mmol). Η NMR (300 MHz, CD₃OD) δ 8.34 (d, 1 H), 8.07 (s. 1 H), 7.54 (d, 2H), 7.06 (d, 1 H), 6.47 (d, IH). MS (ion spray) 165, (M+H).

EXAMPLE 37. 4-Chloro-benzyl isocyanate.

To a solution of triphosgene (0.54 g, 1.85 mmol) in 10 mL of dry CH₂C1₂ at 0°C is added 4- chloro-benzylamine (0.61 mL. 5.00 mmol) dropwise as a white precipitate forms. Et₃N (1.39 mL, 10.0 mmol) in 5 mL of CH₂C1₂ is added immediately and the resulting mixture is stirred at 0°C for 5 min, then at room temperature for 3 hours. The mixture is concentrated in vacuo and triturated with EtOAc. The white precipitate (triethylamine hydrochloride) is filtered off and the filtrate is concentrated. The title compound (6.20 g, 30.6 mmol) is isolated as a crude yellow residue and used in the subsequent step without further purification. Η NMR (CDC1₃, 300 MHz) δ 735 (d, 2H), 7.25 (d, 2H), 4.50 (s, 2H).

EXAMPLE 38. 5-Chloro-thiophene-2-carbonyl azide.

To a solution of 5-chloro-2-thiophene-carboxylic acid (5.00 g, 30.7 mmol ) in 130 L of acetone is added E-3N (4.29 mL, 30.7 mmol). The mixture is cooled to 0°C and ethyl chloroformate (3.23 mL, 33.8 mmol) is added. The mixture is stirred at 0°C for lh and sodium azide (3J0 g, 52.3 mmol) is added. The mixture is stirred at 0°C for 2 h, then poured into 300 mL of ice water and the aqueous layer is extracted with CH₂C1₂ (2x). The combined organics are washed with water (2x) and brine, then dried, filtered and concentrated. The crude residue is purified via flash column chromatography eluting with 10% EtOAc/hexanes to provide the title compound (3.00 g, 16.0 mmol) as a white solid. Η NMR (CDC1₃, 300 MHz) δ 7.67 (d, IH), 6.99 (d, I H).

EXAMPLE 39. 4-Nitro-2,3.5.6-tetrach1oropyridine.

Pentachloropyridine (80 g, 320 mmol) is treated with benzyl amine (104 mL, 96 mmol), dissolved in dioxane (1 L) and refluxed for 16 hours. The reaction mixture is cooled to ambient temperature and the precipitated white solid is removed by filtration. The filtrate is concentrated to a brown residue and triturated with 4 % ethyl acetate in hexane (3 X 250 mL) to give 4-benzyIamino- 2,3,5,6-tetrachloropyridine as an off-white solid (40 g, 124 mmol). This material is dissolved in chloroform (400 mL), cooled in an ice bath and treated with trifluoroacetic acid (500 mL) and 30% hydrogen peroxide (100 mL). The reaction mixture is warmed to room temperature overnight and treated with additional trifluoroacetic acid (500 mL) and 30% hydrogen peroxide (100 mL). After stirring 24 hours the reaction is treated with water (1L). The lower organic layer is separated and the aqueous layer is extracted with chloroform. The combined organic layers are concentrated to a solid residue and redissolved in ethyl acetate/hexane (30 L). The suspended orange solid is removed and the filtrate is loaded on a silica flash column. The column is eluted with hexane and the title compound is collected as a white solid (15.6 g, 60 mmol). El MS m/z 260, 262, 264 [M+].

EXAMPLE 40. 4-(tert-Butyloxycarbonyl)-piperazin-2-one

4-(Benzyloxycarbonyl)-piperazin-2-one (2.2 g, 9.4 mmol) and Boc anhydride (2.5 g, 1 13 mmol) are dissolved in methanol (100 mL), treated with 5% Pd /C and shaken 16 h under hydrogen gas (30 PSI). The reaction vessel contents are filtered through Celite and the filtrate is concentrated to yield 4- (tert-Butyloxycarbonyl)-2-oxopiperazine (1.9 g, 9.4 mmol) which is used without further purification. El MS m/z 200, M⁺; Η NMR (CDC1₃, 300 MHz) ? 6.17 (br, IH), 4.20 (s, 2H), 3.55 (t, 2H), 338 ( , 2H), 1.48 (s, 9H).

EXAMPLE 41. 2-Methoxymethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

A. N-Cbz-O-methylserine-aminoacetaldehyde dimethyl acetal.

To a solution of N-Cbz-O-methylserine (10.8g, 41.8mmol) in 500mL of CH₂C1₂ is added Et₃N (12.7 g, 125mmoI). The solution is cooled to 0°C and TBTU (13.5g, 42mmol) and aminoacetaldehyde dimethyl acetal (4.83g, 46mmoI) are added. The solution is stirred for 16 hours. The solution is diluted with 500mL of ether. The resulting solution is washed with water, IN KHS0₄, and sat. NaCl. The title compound (13.7g, 41.8mmol) is obtained as a white foam. 'H NMR (CDC1₃, 300MHz) δ 7J0 ( , 5H),6.55 (bs, I H), 5.66 (bs, I H), 5.32 (m, I H), 5.13 (s, 2H), 4.32 (m, 2H), 3.79 (dd, I H), 3.44 (m, 2H), 3.40 (m, 9H).

B. N-Cbz-2-Oxo-3-(S)-methoxymethyl-(4,5-dihydro)piperazine.

To a solution ofN-Cbz-O-methylserine-aminoacetaldehyde dimethyl acetal (13.7g, 41.8mmol) in 300mL of toluene is added TsOH.H20 (0.80g, 4.2mmol). The solution is heated to 60°C. After 5h, the solution is diluted with ether. The resulting organic solution is washed with water, sat. NaHC03, and sat. NaCl. The organic layer is dried over MgS0₄, filtered and concentrated under vacuum. The resulting crude product is purified by column chromatography eluting with a gradient of 10%EtOAc:CH₂CI₂ to 20%EtOAc:CH₂Cl₂. The title compound (10.7g, 38mmol) is obtained as a white solid. Η NMR (CDC1₃. 300MHz) δ 736 (m, 5H), 6.45 and 6.30 (d, IH rotational isomers), 5.61 and 5.50 (d, IH rotational isomers), 5.20 (s, 2H), 4.92 and 4.83 (bs, IH rotational isomers), 3.63 (m, 3H), 3.32 and 3.20 (s, 1 H rotational isomers).

C. 2-Methoxymethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

To a solution ofN-Cbz-2-oxo-3-(S)-methoxymethyl-(4,5-dihydro)piperidine (10.7g, 38mmol) in 50mL of methanol is added Pt/C (lgm, 10% by weight). The atmosphere above the reaction is replaced by hydrogen. After 24h, the solution is filtered and the filtrate is washed with methanol. The collected organic solutions are concentrated under vacuum. The resulting crude product is purified by column chromatography eluting with a gradient of 2%MeOH/CH₂Cl₂ to 5%MeOH/CH₂Cl₂. The title compound (6.0g, 22mmol) is obtained as a white solid. Η NMR (CDC1₃, 300MHz) δ 7.35 (m, 5H),6.42 (bs, IH), 5.20 (AB. 2H), 4.58 ( , IH). 4.18 (m, I H), 3.95 (m, IH), 3.50 (m, 4H), 3.27 (s, 3H). EXAMPLE 42. 2-Butyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

The title compound is prepared as in EXAMPLE 41 , substituting Cbz-norleucine for Cbz-O- methyl-serine. Η NMR (CDC1₃, 300mHz) δ 7.32 ( , 5H), 5.13 (AB, 2H), 4.60 (m, lH), 4.13 (m, IH), 3.38 (m, 2H), 3.23 (m, 2H). 1.90 (m, IH), 1.66 (m, IH), 1.29 (m, 4H). 0.89 (m, 3H). MS (ion spray) m/z 291, (M+H).

EXAMPLE 43. 2-Ethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

The title compound is prepared as in EXAMPLE 41 , substituting Cbz-2-amino-butric acid for Cbz-O-methyl-serine. Η NMR (CDC1₃, 300mHz) δ 737 (m, 5H), 6.55 (bs, IH), 5.10 (AB, 2H), 4.57 (m, I H), 4.24 (m, lH), 3J2 (m, IH), 3.26 (m, 2H), 2.20 (m, IH), 1.81 (m, IH), 0.96 (m, 3H).

EXAMPLE 44. 2-Propyl-3-oxo-piperazine- l -carboxylic acid benzyl ester.

The title compound is prepared as in EXAMPLE 41 , substituting Cbz-norvaline for Cbz-O- methyl-serine. 'H NMR (CDC1₃, 300mHz) δ 7.32 (m, 5H), 7.00 (bs. IH), 5.12 (AB, 2H), 4.58 (m, I H), 4.21 (m, I H), 3J0 (m, I H). 3.19 (m, 2H), 1.88 (m, IH), 1.73 (m, I H), 137 (m, 2H), 0.91 (m, 3H). MS (ion spray) m/z 277, (M+H).

EXAMPLE 45. 2-Ethoxymethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

The title compound is prepared as in EXAMPLE 41 , substituting Cbz-O-ethyl-serine for Cbz-O- methyl-serine. 'H NMR (CDC1₃, 300MHz) δ 7.32 (m, 5H),6.96 (bs. IH), 5.17 (AB, 2H), 4.58 ( , I H), 4.18 (m, IH), 4.03 (m, I H). 3.66 (m, 2H), 3J4 ( , 3H), 3.27 (s, I H). 1.06 (m, 3H). MS (ion spray) m/z 293, (M+H).

EXAMPLE 46. 2-Methyl-3-oxo-piperazine-l -carboxylic acid benzyl ester. The title compound is prepared as in EXAMPLE 41 , substituting Cbz-alanine for Cbz-O-methyl- serine. Η NMR (CDC1₃. 300MHz) δ 7.34 (m, 5H),7.02 (bs, IH), 5.17 (AB, 2H), 4.65 (m, ! H), 4.17 (m, lH), 3J2 (m, l H), 3.23 (m. 2H), 1.41 (d, 3H). MS (El) m/z 248JM+).

EXAMPLE 47. 2-Benzyl-3-oxo-piperazine-l -carboxylic acid benzyl ester The title compound is prepared as in EXAMPLE 41, substituting Cbz-phenylalanine for Cbz-O- methyl-serine. Η NMR (CDC1₃, 300MHz) δ 7.22 (m, 10H), 7.00 (bs, I H), 5.10 (AB, 2H), 4.10 (m, I H), 3.27 (m, 2H), 3.10 (m, 2H). 2.55 (m, 2H). MS (El) m/z 324, (M+).

EXAMPLE 48. 2-( l -Metl.oxyethyl)-3-oxo-piperazine-l -carboxylic acid benzyl ester. The title compound is prepared as in EXAMPLE 41, substituting Cbz-O-methyl-threonine for Cbz-O-methyl-serine. Η NMR (CDC1₃, 300MHz) δ 7.52 (bs, IH), 7.22 (m, 5H), 5.12 (AB, 2H), 4.33 (m, IH), 4.05 (m, 2H), 3.60 (m, IH), 3.14 (s, 3H), 3.10 (m, IH), 2.82 (m, IH), 1.10 (d, 3H). MS (ion spray) m/z 293, (M+H).

EXAMPLE 49. 2-2-Dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

The title compound is prepared as in EXAMPLE 41, substituting Cbz-2-amino-isobutryic acid for Cbz-O-methyi-serine. Η NMR (CDC1₃, 300MHz) δ 736 (m, 5H).6.52 (bs, IH), 5.12 (s, 2H), 3.72 (m, 2H), 3.33 (m. 2H), 1.68 (s. 3H), 1.64 (s, 3H). MS (El) m/z 262, (M+).

EXAMPLE 50. 2-Isopropyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

The title compound is prepared as in EXAMPLE 41 , substituting Cbz-valine for Cbz-O-methyl- serine. 'H NMR (CDC1₃, 300MHz) δ 7.36 (m, 5H),5.88 (bs, I H), 5.10 (s, 2H), 4.35 (m, I H), 3.44 (m, IH), 327 (m, 2H), 2.31 (m, IH), 1.00 (d, 3H), 0.94 (d, 2H).

EXAMPLE 51. 2-Isobutyl-3-oxo-piperazine- l -carboxylic acid benzyl ester.

The title compound is prepared as in EXAMPLE 41, substituting Cbz-leucine for Cbz-O-methyl- serine. Η NMR (CDC1₃, 300MHz) δ 7.35 (m. 5H), 6.50 (m, I H), 5.15 (s, @H), 4.18 (m, I H), 3.42 (m, 2H), 3.21 (m. 2H), 1.50 (m, 3H). 0.90 (m, 6H).

EXAMPLE 52. 2-(2-Methox ethyl)-3-oxo-piperazine-l -carboxylic acid benzyl ester.

The title compound is prepared as in EXAMPLE 41, substituting Cbz-O-methyl-homo-serine for Cbz-O-methyl-serine. 'H NMR (CDC1₃, 300MHz) δ 7.32 (m, 5H), 6.85 (bs, I H), 5.14 (s, 2H), 4.75 (m, 2H), 4.20 (m, 2H). 3.42 (m, IH), 3.21 (m, 3H), 2J2 (m, 4H).

EXAMPLE 53. 2-Methoxymethyl-5-methyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

The title compound is prepared as in EXAMPLE 41, substituting 2-amino-propionaldehyde dimethyl acetal for aminoacetaldehyde dimethyl acetal. Η NMR (CDC1₃, 300MHz) δ 7.42 (m, 5H), 6.96 (bs, I H). 5.12 (AB, 2H). 4.52 (m, IH), 4.21 ( , I H), 3.92 (m, IH). 3.58 (m, 2H), 3.22 (s, 3H), 3.10 (m, IH), 0.95 (m, 3H).

EXAMPLE 54. 3-(R)-(tert-Butyl-dimethyl-silanyloxymethyl)-5-oxo-piperazine-l-carboxylic acid benzyl ester. A. 2-tert-Butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propionic acid. tert-Butyldimethylchlorosilane (32.3 g, 0.214 mol) in THF (50 mL) is added dropwise via cannula to a solution of BOC serine (20.0g, 0.098 mol) and imidazole (153 g, 0.224 mol) in THF (360 mL) at RT. The resulting slurry is stirred for 2.5 h then the solvent is removed in vacuo. The crude product is dissolved in MeOH (180 mL) and 5N NaOH (58 mL) is slowly added at RT. The mixture is stirred for 3 h then diluted with water (180 mL) after which time the aqueous layer is washed with ether (180 mLx2). The aqueous layer is acidified to pH 4-5 with 2N HCl and extracted with diethyl ether. The organic layer is washed with saturated NaHC0₃ and brine then dried over MgS0₄, filtered and concentrated to dryness. The crude product (12.67g, 0.040 mol) is used in the subsequent step without further purification. 'H NMR (CDC1₃, 300 MHz) ? 535 (bs, I H), 4.30 (bs, IH), 4.13 (dd, I H), 3.80 (dd, IH), 1.45 (s, 9H), 0.98 (s, 9H), 0.10 (s, 6H). El MS, [M+H]⁺=320.

B. [2-(tert-Butyl-dimethyl-silanyloxy)-l-(methoxy-methyl-carbamoyl)-ethyll-carbamic acid tert-butyl ester. N-N-Dimethylarninopyridine (2.60 g, 21.3 mmol) and BOP reagent (18.15 g, 41.0 mmol) are added to a solution of 2-tert-butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propionic acid (1237 g, 38.7 mmol), diisopropylethylamine (8.1 mL, 46J mmol) and N-O-dimethylhydroxylamine hydrochloride (4.53 g, 46.4 mmol) in THF (260 mL) at RT. The resulting suspension is stirred at RT overnight then concentrated to dryness. The residue is diluted with EtOAc and washed with saturated NH₄C1, saturated NaHC0₃and brine. The organic layer is dried over MgS0₄, filtered and concentrated in vacuo to give the crude product which is purified by flash chromatography eluting with 10-30% EtOAc/Hexanes to yield the title compound (1 1.86 g, 30.37 mmol) as an oil. Η NMR (CDCI₃, 300 MHz) ? 535 (bd, IH), 4.71 (bs, IH), 3.78-3.85 (m, 2H), 3.72 (s, 3H), 3.20 (s, 3H), 1.42 (s, 9H), 0.90 (s, 9H), 0.05 (s, 6H).

C. [l-(tert-Butyl-dimethyl-silanyloxymethyl)-2-oxo-ethyl1-carbamic acid tert-butyl ester.

A solution of [2-(tert-buty 1-dimethyl-silanyloxy)- 1 -(methoxy-methy 1-carbamoy l)-ethyl]- carbamic acid tert-butyl ester (1 1.86, 30.37 mmol) in Et₂0 (100 mL) is added dropwise to a 1.0M solution of LAH in ether (35.5 mL) at -5°C-0°C . The resulting mixture is stirred for 2.5 h then an aqueous solution of KHS0₄ is slowly added. The reaction mixture is stirred for 30 minutes and then washed with saturated NH₄C1. saturated NaHC0₃ and brine. The organic layer is dried over MgS0₄, filtered and concentrated in vacuo to give the crude product which is purified by flash chromatography eluting with 30% EtOAc/Hexanes to yield the title compound (6.04 g, 19.9 mmol) as an oil. Η NMR (CDC1₃, 300 MHz) ? 9.65 (s, IH), 5.30 (bs, IH), 4.20 (m, IH), 3.65 (4.90 (m, 2H), 1.48 (s, 9H), 0.90 (s, 9H), 0.05 (s, 6H). Ion spray MS, [M+H]⁺=304.

P. [2-tert-Butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propylamino1-acetic acid methyl ester.

Sodium cyanoborohydride (2.63 g, 41.9 mmol) is added to a solution of [l-(tert-butyl-dimethyl- silanyloxymethyl)-2-oxo-efhyl]-carbamic acid tert-butyl ester (6.04 g, 19.9 mmol) and glycine methyl ester hydrochloride (2.75 g, 32.9 mmol) in MeOH (500 mL). The mixture is stirred for 2 days at RT then concentrated to dryness. The crude product is purifed by flash chromatography eluting with 1-5% MeOH/CH₂Cl₂ to yield the title compound (3.06, 8.12 mmol) as a colorless oil. Η NMR (CDC1₃, 300 MHz) ? 5.00 (bs, IH), 3.75 (s, 3H), 3.60-3.70 (m, 4H), 3.40 (d, I H), 2.80 (dd, IH), 2.68 (dd, IH), 1 J0 (s, 9H), 0.90 (s, 9H), 0.05 (s, 6H). Ion spray MS, [M+H]⁺=377.

E. (Benzyloxycarbonyl-r2-tert-butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propyll-amino)- acetic acid methyl ester.

Benzylchloroformate (1.4 mL, 9.81 mmol) is added dropwise to a solution of N,N- dimethylaminopyridine (1.09 g, 8.93 mmol) and [2-tert-butoxycarbonyIamino-3-(tert-butyl-dimethyl- silanyloxy)-propylamino]-acetic acid methyl ester (3.06 g, 8.12 mmol) in CH,Cl₂ at RT. The resulting mixture is stirred overnight then concentrated to dryness. The crude product is purifed by flash chromatography eluting with 1% MeOH/CH₂Cl₂ to yield the title compound (3.52 g, 6.89 mmol) as a colorless oil. Ion spray MS, [M+H]⁺=511.

F. 3-(tert-Butyl-dimethyl-silanyloxymethyl)-5-oxo-piperazine-l -carboxylic acid benzyl ester

(Benzyloxycarbonyl-[2-tert-butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propyl]- amino)-acetic acid methyl ester ( 3.52 g, 6.89 mmol) is stirred in 50% TFA/CH₂C1₂ (40 mL) at RT for 40 minutes. The reaction mixture is concentrated in vacuo and the crude product is purifed by flash chromatography eluting with 1% MeOH/CH₂Cl₂ to yield the title compound (1.1 g, 2.9 mmol) as a colorless oil. Ion spray MS, [M+H]⁺=379.

EXAMPLE 55. 5-Oxo-piperazine-l,3(R or S)-dicarboxylic acid 1 -benzyl ester 3-methyl ester.

N.N-Dimethylaminopyridine (0J3 g, 3.5 mmol) and benzylchloroformate (0.55 g, 3.8 mmol) are added to a solution of methyl 6-oxopiperazine-2-carboxylate (0.50 g, 3.2 mmol) (Aebischer, B., Helv. Chim. Acta 1989, 72, 1043-1051 ) in CH₂C1₂ at RT. After 1 h, the reaction mixture is poured into EtOAc and washed with saturated NaHC0₃ and brine then dried over MgS0₄, filtered and concentrated to dryness to give a solid (0.90 g. 3.1 mmol) which is used in subsequent reactions without further purification. Η NMR (CDC1 1₃. 300 MHz) δ 7.40 (bs, 5 H), 6.32 (bs, IH), 5.15 (s, 2H), 4.00-4.30 (m, 3H), 4.23 (s, 3H), 3.70-3.80 (m. 2H). MS (El) m/z 292 (M+).

EXAMPLE 56. (S)-5-Oxo-piperazine-l ,3-dicarboxylic acid 1-allyl ester 3-methyl ester.

To a solution containing methyl (S)-6-oxopiperazine-2-carboxylate (132 g, 8.35 mmol), prepared by the method of Aebischer, in anhydrous dichloromethane (30 mL) at 0 °C is added triethylamine (1.26 g, 12.5 mmol) followed by allylchloroformate (1.20 g, 10.0 mmol). After 1 h, the reaction mixture is poured onto a 1 : 1 mixture of CH₂Cl₂/water (200 mL), acidified using 1 N HCl and the layers are separated. The organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is chromatographed on silica gel (CH₂C1₂ to 1 % MeOH/CH₂Cl₂) to provide 1.22 g (60%) of EXAMPLE 35 as a viscous oil. 'H NMR (300 MHz, CDC1J δ 6J3 (bs, I H), 5.90 (m, IH), 5.26 (m, 2H), 4.61 (m, 2H), 4.05-4.26 (m, 3H), 3.80 (s, 3H), 3.72 (m, 2H); MS (ISP loop): m/z 243 (M+H).

EXAMPLE 57. (2S, 6R)-4-(2.6-dimethyl)-3-oxo-piperazine-l -carboxylic acid benzyl ester. and

EXAMPLE 58. (2S, 6S)-2.6-dimethyl-3-oxo-piperazine- l -carboxylic acid benzyl ester.

A. (2RS, l S)-ri-(2-hydroxy-propylcarbamyl)-ethyll-carbamic acid tert-butyl ester

N-(tert-Butoxycarbonyl)-L-alanine (10.0 g, 52.8 mmol) is dissolved in 150 mL of THF. Once the triethylamine (1 1.0 ml, 79.2 mmol) is added, the solution is cooled to 0°C . Isopropyl chloroformate in toluene (1M) (52.8 ml, 52.8 mmol) is added slowly followed by the addition of (2RS) l-amino-2- propanol (6.1 ml, 79.2 mmol). After stirring overnight, the mixture is washed with IN sodium hydroxide and IN hydrochloric acid. Concentration of the organic solvent afforded (2RS, l S)-[l-(2-hydroxy- propylcarbamyl)-ethyI]-carbamic acid tert-butyl ester (9.92 g, 76% yield) as a clear oil.

B. (l S)-[l-(2-oxo-propylcarbamoyl)-ethyl1-carbamic acid tertbutyl ester

Dimethylsulfoxide (7.16 ml, 100.8 mmol) is added to a solution of oxalyl chloride (4.41 ml, 50.4 mmol) in 126 mL of methylene chloride at -78 °C . The mixture is left to stir for fifteen minutes, and a solution of (2RS, l S)-[l-(2-hydroxy-propylcarbamyl)-ethyl]-carbamic acid tert-butyl ester (9.92 g, 40.32 mmol) in 100 L of CH₂C1₂ is added dropwise. After stirring for 15 minutes at -78 °C , the reaction is quenched with triethylamine (28 mL, 381 mmol), and the temperature is allowed to rise to room temperature. The volatile solvents are removed, and the residue is purified by flash column (SiO,, 60% EtOAc/Hexane). The product (l S)-[l-(2-oxo-propylcarbamoyl)-ethyl]-carbamic acid tertbutyl ester (5.93 g, 60 %) is isolated as a white solid. MS C,,H₂₀N₂O₄ MS m/z: 245.

C: (3S, 5RS)-3,5-dimethyl-piperazin-2-one. (l S)-[l-(2-oxo-propylcarbamoyl)-ethyl]-carbamic acid tertbutyl ester (5.93 g, 24.3 mmol ) is stirred in a solution of 30 % trifluoroacetic acid in methylene chloride (100 mL) for three hours. The solvents are removed in vacuo. The residue is dissolved in 50 mL of MeOH and transferred to a par bottle. Palladium on carbon (10 % , 1.0 g) is added, and the mixture is hydrogenated under pressure for 24 hours. The catalyst is filtered off ; the MeOH is removed in vacuo to afford (3S, 5RS)-3,5-dimethyl- piperazin-2-one which is directly protected with a benzyl carbamate without further purification.

D: (2S, 6RS)-2,6-Dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

To a solution of (3S, 5RS)-3,5-dimethyl-piperazin-2-one (24.3 mmol) in 100 mL of methylenechloride is added triethylamine (8.45 L, 60.75 mmol) and N- (benzyloxycarbonyloxy)succinimide (12.1 g, 48.6 mmol). After stirring overnight, the CH₂C1₂ is removed, and the crude mixture is chromatographed (50 % EtOAc/Hexane). (2S, 6RS)-2,6-Dimethyl-3- oxo-piperazine-1 -carboxylic acid benzyl ester (3.3 g, 52 %> yield over three steps) is isolated as a white powder. MS C_I4H,₈N₂0₃ MS m/z: 263.

E. (2S, 6R)-2.6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester and (2S, 6S)-2.6-dimethyl-3- oxo-piperazine-1 -carboxylic acid benzyl ester

The two single enantiomers [(2S, 6R)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester and (2S, 6S)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester] can be seperated by column chromatography from (2S, 6RS)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester, which can also be used directly in combination or separation of its derivatives as shown below.

EXAMPLE 59. (2S. 6R)-4-(2J-Dimethoxy-benzyl)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

A. (2S, 2S)-N-(2. 4-dimethoxy-benzyl)-N-(2-hydroxy-propyl)-2-(2,2.2-trifluoroacetylamino)- propionamide.

To a slurry of (2S)-2-(2J,2-trifluoroacetylamino)-propionic acid (15.3 g, 53J mmol) in 120 L of methylene chloride is added triethylamine (5.6 mL, 40.0 mmol). The heterogeneous mixture is cooled to 0°C and isopropyl chloroformate (27 mL, 27.0 mmol) is added slowly. After stirring for 20 minutes at room temperature, a solution of the (2S)-l-(2J-dimethoxy-benzylamino)-propan-2-ol (6.0 g, 26.7 mmol, obtained from the reductive animation of the corresponding aldehyde and aminoalcohol) in 5mL of methylene chloride is added. The resulting mixture is left to stir overnight. Ethyl acetate (500 mL) is added, and the organic solution is washed with IN hydrochloric acid (50 mL) and IN sodium hydroxide (50 mL). The ethyl acetate is dried with magnesium sulfate, filtered and condensed. The resulting residue is chromatographed on silica gel (25% ethyl acetate/hexane) to give (2S, 2S)-N-(2,4-dimethoxy- benzyl)-N-(2-hydroxy-propyl)-2-(2,2,2-trifluoroacetylamino)-propionamide (6.29g, 60% yield) as a clear oil. MS C₁₇H₂₃F₃N₂0₅ MS m/z: 393.

B. (3S, 5R)-l -(2J-dimethoxy-benzyl)-3,5-dimethyl-4-trifluoroacetyl-piperazin-2-one. (2S, 2S)-N-(2J-Dimethoxy-benzyl)-N-(2-hydroxypropyl)-2-(2,2,2-trifluoroacetylamino)- propionamide (3.64 g, 9.29 mmol) is dissolved in 25 mL of tetrahydrofuran. Triphenylphosphate (3.65 g, 14.0 mmol) is added, and the resulting mixture is cooled to 0 °C before diethyl azodicarboxylate (2.2 L, 14 mmol) is added slowly. The resulting mixture is left to stir overnight. The reaction mixture is condensed, and the residue is purified by column chromatography (Si0₂, 25% ethyl acetate/hexane). The desired product, (3S, 5R)-l-(2J-dimethoxy-benzyl)-3,5-dimethyl-4-trifluoroacetyl-piperazin-2-one (1.5 g, 43% yield), is isolated as a clear oil.

C. (3S, 5R)-l-(2J-Dimethoxy-benzyl)-3,5-dimethyl-piperazin-2-one.

(3S, 5R)-l-(2J-Dimethoxy-benzyl)-3,5-dimethyl-4-trifluoroacetyl-piperazin-2-one ( 575 mg, 1.54 mmol) is dissolved in 30 mL of methanol and 3 mL of H₂0. Potassium carbonate (883 mg, 6.4 mmol ) is added to the solution, and the reaction is refluxed for one and half hours before concentration. Ethyl acetate (3x 50 mL) is used to extract the aqueous layer. Removal of Ethyl acetate afforded the crude amine (387 mg, 91% yield) as a clear oil. C₁₅H₂₂N₂0₃ MS m/z: 279.

D. (2S, 6R)-4-(2J-dimethoxy-benzyl)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester. Triethylamine (0.4 mL, 2.8 mmol) and N-(benzyloxycarbonyloxy)-succinimide (1.04 g, 4.2 mmol) is added to a solution of the above crude amine (387 mg, 1.4 mmol) in 15 L of methylene chloride. The reaction mixture is left to stir overnight. The residue after concentration is chromatographed on silica gel (30% ethyl acetate/hexane) to give (2S, 6R)-4-(2J-dimefhoxy-benzyl)- 2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (450 mg, 78 % yield) as a clear oil.

E. (2S, 6R)-2,6-Dimefhyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

(2S,6R)-4-(2J-Dimethoxy-benzyl)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (1.13 g, 2.74 mmol) is dissolved in 20 mL of acetonitrile. An aqueous solution of potassium persulfate (2.2 g, 8.23 mmol) and sodium phosphate (2.3 g, 16.5 mmol) in 12 mL of H₂0 is added, and the resulting mixture is heated to 95-100 °C for two hours. After cooling to room temperature, ethyl acetate (200 mL) is used to extract the aqueous layer and dried over magnesium sulfate. The residue after filtration and concentration is chromatographed (Si0₂, 60% ethyl acetate/hexane) to give (2S, 6R)-2,6-Dimethyl- 3-oxo-piperazine-l -carboxylic acid benzyl ester (480 mg, 67 % yield) as a yellow oil.

EXAMPLE 60. (2S, 6RS)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-l- carboxylic acid benzyl ester.

(2S,6RS)-2,6-Dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (380 mg, 1.45 mmol) is dissolved in 10 mL of THF and 1 mL of DMF. Sodium hydride (60%, 72 mg, 3.14 mmol) is added at 0 °C and left to stir at room temperature for thirty minutes before 7-bromomethyl-4-chloro-quinoline (257 mg, 1.0 mmol) is added. The reaction is stirred for four hours. Ethyl acetate is added to the mixture, and the reaction is quenched with 3 mL of H₂0. The two layers are separated and ethyl acetate (2x 30 ml) is used to extract before dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (60% EtOAc/Hexane) to give (2S, 6RS)-4-(4-chIoro-quinolin-7- ylmethyl)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (417 mg, 95 % yield).C₂₂H₂₀ClN₃O₃ MS m/z: 438, 440.

EXAMPLE 61. (3S,5RS)-lJ4-chloro-quinolin-7-ylmethyl)-3J-dimethyl-piperazin-2-one. and

EXAMPLE 62. (3S, 5R)-lJ4-chloro-quinolin-7-ylmethyl)-3.5-dimethyl-piperazin-2-one. and

EXAMPLE 63 (3S, 5S)-l-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.

(2S, 6RS)-4-(4-Chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine- 1 -carboxylic acid benzyl ester (417 mg, 1.0 mmol) is taken up in 7 L of acetonitrile, and iodotrimethyl- silane (0.43 mL, 3.0 mmol) is added. The resulting mixture is stirred for one hour at room temperature before quenched with methanol (1 mL). The residue after concentration is taken up in 2N hydrochloric acid (3 mL) and is extracted with ether (2x 30 mL). The aqueous layer is condensed to dryness and the residue is recrystalized from isopropanol and ether to give a mixture (1 :4 ratio) of (3S, 5RS)-l-(4-chloro-quinolin- 7-ylmethyl)-3,5-dimethyl-piperazin-2-one as a yellow solid (290 mg). The two epimers are separated using a flash column (Si0₂, 1% triethylamine/3% methanol/methylene chloride). C₁₆H|₈C1N₃0 MS m/z: 304, 306. The minor isomer (3S. 5R)-l-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.is (3S, 5R)-l-(4-chloro-quinoIin-7-ylmethyl)-3,5-dimethyl-ρiperazin-2-one while the major isomer is (3S, 5S)-l-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyI-piperazin-2-one. Alternatively, (3S, 5R)-l-(4- chloro-quinolin-7-ylmethyl)-3J-dimethyl-piperazin-2-one and (3S, 5S)-l-(4-chloro-quinolin-7- ylmethyl)-3,5-dimethyl-piperazin-2-one can be made via the same chemistry shown below from pure (2S, 6S)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester and (2S, 6RS)-4-(4-chIoro- quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester, respectively.

Alternative synthesis of (3S, 5R)-l-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.

A. (2S, 6R)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester. (2S, 6R)-2,6-Dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (750 mg, 2.86 mmol) is dissolved in 20 mL of THF and 2 mL of DMF. Sodium hydride (60%, 142.6 mg, 6.20 mmol) is added at 0 °C , and the reaction is left to stir at room temperature for thirty minutes at which time the 7- bromomethyl-4-chloro-quinoline (952 mg, 3.72 mmol) is added. The reaction is complete after stirring for four hours. Ethyl acetate (200 mL) is added to the mixture, and the reaction is quenched with 3 mL of H₂0 . The two layers are separated, and ethyl acetate (2x 30 mL) is used to extract and dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (60% EtOAc/Hexane) to give (2S,6R)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine- 1 - carboxylic acid benzyl ester (1.04 g, 83 %).

B. (3S, 5R)-l-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.

A 33 % solution of hydrogen bromide in acetic acid (10 mL) is added to (2S,6R)-4-(4-chloro- quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (1.04 g, 2.38 mmol).

The reaction is left to stir at room temperature for one hour. The reaction mixture is diluted with ethyl acetate and stirred vigorously to force the product to precipitate out of solution. The ethyl acetate is decanted off and the precipitate is purified on a silica gel column (1 % triethylamine/3 % methanol/methylene chloride) to 582 mg (81% yield) of (3S,5R)-l -(4-chloro-quinolin-7-ylmethyl)-3,5- dimethyl-piperazin-2-one as a white solid.

EXAMPLE 64. (3S, 5S)-lJ4-chloro-quinolin-7-ylmethly)-4-r3-(5-chloro-thiophen-2-yl)-allyll-3,5- dimethyl-piperazine-2-one. and

EXAMPLE 65. (3S, 5R)-l -(4-chloro-quinolin-7-ylmethly)-4-r3-(5-chloro-thiophen-2-yl)-allvn-3,5- dimethyl-piperazine-2-one. The crude (3S,5RS)-l-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (69 mg, 0.20 mmol) obtained from above is dissolved in 1 mL of DMF. Potassium carbonate (76 mg, 0.60 mmol) is added followed by the addition of 2-(3-bromopropenyl)-5-chloro-thiophene (56 mg, 0.24 mmol). The reaction is left to stir overnight. The potassium carbonate is filtered off, and the crude material is purified. The two epimers are separated at this stage by preparative thin layer chromatography (80 % EtOAc/hexane) to give a major epimer (3S, 5R)-l-(4-chloro-quinolin-7- ylmethly)-4-[3-(5-chloro-thiophen-2-yl)-allyl]-3,5-dimethyl-piperazine-2-one (25 mg, 26% yield) and a minor epimer (3 S, 5S)-l -(4-chloro-quinolin-7-ylmethly)-4-[3-(5-chloro-thiophen-2-yl)-allyl]-3,5- dimethyl-piperazine-2-one (7 mg, 7.5% yield).

EXAMPLE 66. 4-(2-Oxopiperazin-l-ylmethyl)benzamidine.

A. 4-(4-Cyanobenzyl)-3-oxopiperazine-l -carboxylic acid benzyl ester.

To a solution of 3-oxo-piperazine-l -carboxylic acid benzyl ester (3.0 g, 12.8 mmol) and 4- bromomethyl tolylnitrile (2.76 g, 14.1 mmol) in 135 mL of THF and 15 mL of DMF at 0°C is added a 60% dispersion in mineral oil of NaH (0.49 g, 12.8 mmol). After 5 hours, the solution is diluted with saturated NH C1 and EtOAc. The organic layer is washed with H₂0 and saturated NaCl. The organic layer is dried over MgS0 , filtered and concentrated. The crude product is purified by column chromatography over silcia gel eluting with 20%> EtOAc/CH₂Cl₂. The title compound is obtained as a white solid (4.01 g, 1 1.4 mmol). 'H NMR (CDC1₃, 300MHz) δ 7.62 (d. 2H), 7.39 (m, 7H), 5.14 (s, 2H), 4.68 (s, 2H). 4.27 (s, 2H), 3.73 (m, 2H), 3.30 (m, 2H).

B. 4-(4-Carbamimidoylbenzyl)-3-oxo-piperazine-l -carboxylic acid benzyl ester.

A solution of 4-(4-cyanobenzyl)-3-oxopiperazine-l -carboxylic acid benzyl ester (2.4 g, 6.87 mmol) in 30mL of pyridine and 3 ml of Et₃N is saturated with H₂S. The resulting mixture is sealed and stirred for 16 hours. After this time, the solution is concentrated. The residue is dissolved in 30 mL of acetone and methyl iodide (19J g, 137 mmol) is added. The solution is refluxed for 2 hours. After this time, the solution is concentrated. The residue is dissolved in MeOH (40 mL) and NH₄OAc (5.0 g, 65 mol) is added. The solution is reluxed for 3 hours. After this time, the solution is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of CH₃CN to 60% CH₃CN/H₂O(0.1 %TFA). The appropriate collected fractions are lyophilized to give the product as a white foam. MS (FAB) m/z 367, (M+H).

C. 4-(2-Oxopiperazin- 1 -ylmethyl)benzamidine. To a solution of 4-(4-carbamimidoylbenzyl)-3-oxopiperazine-l -carboxylic acid benzyl ester (2.0 g, 5.0 mmol) in 40 mL of MeOH and 4 mL of AcOH is added 10% Pd/C (0J g). The atmosphere above the reaction is replaced by hydrogen. After 4hours, the solution is filtered through a pad of Celite. The organic layer is concentrated. The resulting crude product is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1 %TFA) to 40% CH₃CN/H₂0 (0.1 % TFA). The title compound is obtained as a white foam. Η NMR (d⁶-DMSO, 300 MHz) δ 9.3 (bs, 4H), 9.1 (bs, 2H), 7.83 (d, 2H), 7.42 (d, 2H), 4.78 (s, 2H), 3.80 (s, 2H), 3.44 (m, 2H), 3.32 (m, 2H).

EXAMPLE 67. l-(2-Aminoquinolin-6-ylmethyl)piperazin-2-one.

A. 4-(2-Chloro-quinolin-6-ylmethyl)-3-oxo-piperazine- l -carboxylic acid benzyl ester.

To a solution of 3-oxopiperazine-l-carboxylic acid benzyl ester (4.65 g, 19.8 mmol) and 6- bromomethyl-2-chloroquinoline (5.40 g, 21.0 mmol) in 80 mL of a 3: 1 mixture of THF:DMF at 0°C is added sodium hydride (0.81 g, 20.2 mmol, 60% mineral oil dispersion). The resulting mixture is stirred for 1 hour at 0°C then at room temperature for 18 hours. The reaction mixture is quenched with saturated NH C1 solution, then diluted with EtOAc. The organic layer is washed sequentially with IN HCl, water, saturated NaHC0₃ and saturated NaCl, then dried over MgS0₄, filtered and concentrated. The crude product is triturated in Et₂0/hexanes/EtOAc and filtered to afford the title compound (6.96 g, 17.0 mmol) as a white solid. Η NMR (CDC1₃, 300 MHz) δ 8.08 (d, 1 H), 8.00 (d, 1 H), 7.69 (s, 1 H), 7.63 (dd, IH), 7.41 (d, IH), 7.35 (s, 5H), 5.15 (s, 2H), 4.78 (s, 2H), 4.28 (s, 2H), 3.70 (m, 2H), 3.32 (bs, 2H).

B. 4-(2-Phenoxyquinolin-6-ylmethyl)-3-oxopiperazine-l -carboxylic acid benzyl ester.

A mixture of phenol (15.1 g, 160 mmol) and 4-(2-chloroquinolin-6-ylmethyl)-3-oxopiperazine- 1 -carboxylic acid benzyl ester (6.60 g, 16.1 mmol) is melted together at 70°C until a homogeneous mixture is obtained. Potassium hydroxide (3J5 g, 56.1 mmol) is added and the resulting mixture is heated overnight at 120°C. After 24 hours, the brown/black residue is cooled to room temperature, diluted with CH2CI2 and stirred with IN NaOH (100 mL) for 30 minutes. The two layers are separated and the aqueous layer is extracted with CH₂CI₂. The combined organic layers are washed with IN NaOH, saturated NaCl, dried over Na₂S0₄, filtered and concentrated. The crude title compound (6.92 g, 14.8 mmol) is obtained as a beige foam and used in the subsequent step without further purification.

'H NMR (CDC1₃, 300 MHz) δ 8.07 (d, IH), 7.76 (d, I H), 7.63 (s, IH), 7.50 (dd, I H), 7.42 (m, 2H), 7.34 (m, 6H), 7.25 (m, 2), 7.09 (d, IH), 5.14 (s, 2), 4.75 (s, 2H), 4.27 (s, 2H), 3.66 (m, 2H), 330 (bs, 2H).

C. 4-(2-Aminoquinolin-6-ylmethyl)-3-oxopiperazine- l -carboxylic acid benzyl ester A mixture of ammonium acetate (18.7 g, 242 mmol) and 4-(2-phenoxyquinolin-6-ylmethyl)-3- oxopiperazine-1 -carboxylic acid benzyl ester (6.92 g. 14.8 mmol) is heated overnight at 150°C. After 21 hours, an additional 3 g of ammonium acetate is added and the heating is continued. After 5 hours, the mixture is cooled to room temperature, diluted with CH₂C1₂ and stirred with IN NaOH (100 mL) for 30 minutes. The two layers are separated and the aqueous layer is extracted with CH₂C1₂. The combined organic layers are washed with IN NaOH, saturated NaCl, dried over Na₂S0₄, filtered and concentrated. The crude mixture of the title compounds (5.50 g, 14.1 mmol) is obtained as a beige foam and used in the subsequent step without further purification.

Major component (4-(2-aminoquinolin-6-ylmethyl)-3-oxopiperazine-l -carboxylic acid benzyl ester): 'H NMR (CDC1₃, 300 MHz) δ 7.86 (d, I H). 7.63 (d, I H), 7.48 (d, I H), 7.45 (d, I H), 735 (s, 5H), 6.74 (d, IH), 5.14 (s, 2H), 4.79 (bs, 2H), 4.71 (s, 2H), 4.26 (s, 2H). 3.66 (s, 2H), 3.30 (s, 2H).

Minor component (3-oxo-4-(2-oxo- l ,2-dihydroquinolin-6-ylmethyl)piperazine-l -carboxylic acid benzyl ester): 'H NMR (CDC1₃. 300 MHz) δ 7.75 (d, I H), 7.48 (m, 2H). 7.37 (m, 6H), 6.70 (d, IH), 5.14 (s, 2H), 4.66 (s, 2H), 4.26 (s, 2H), 3.66 (s, 2H), 3.30 (s, 2H).

D. l-(2-Aminoquinolin-6-ylmethyl)piperazin-2-one.

To a solution of a mixture of 4-(2-aminoquinolin-6-ylmethyl)-3-oxopiperazine-l -carboxylic acid benzyl ester and 3-oxo-4-(2-oxo-l ,2-dihydro-quinolin-6-ylmethyl)piperazine-l-carboxylic acid benzyl ester (5.50 g, 14.1 mmol) in 100 mL of 10: 1 MeOH/HOAc is added a catalytic amount of 10% palladium on activated carbon. The heterogenous mixture is hydrogenated at room temperature under a balloon of H₂ for 18 hours. The reaction mixture is filtered through a pad of Celite. washed with MeOH, and the filtrate is concentrated in vacuo. The crude mixture of products is purified by RP-HPLC eluting in a gradient of 2% CH₃CN/H₂0 (0.1 % TFA) to 20% CH₃CN/H₂O(0.1 % TFA) and the appropriate product fractions are concentrated in vacuo to provide l -(2-aminoquinolin-6-ylmethyl)-piperazin-2-one ditrifluoroacetate (2.64 g. 5.45 mmol) as the major product in the form of a white solid. 'H NMR (d⁶- DMSO, 300 MHz) δ 8.78 (bs. 2H), 8.31 (d, IH), 7.80 (s, I H), 7.66 (m. 2H), 7.08 (d, IH), 4.70 (s, 2H), 3.84 (s, 2H), 346 (bs, 4H). MS m/z 256, [M+]. Elemental analysis calculated with 0.25 mol of H₂0 cal. C=44.25%, H=3.82%. N=l 1.47%, found C=44.23%, H=3.76%, N=l 1.23%. The minor by-product 6-(2-oxo-piperazin-l-ylmethyl)J H-quinolin-2-one(0.62 g, 1.28 mmol) is also isolated from the RP-HPLC separation as a white solid Η NMR (d⁶-DMSO, 300 MHz) δ 1 1.16 (bs, 1 H), 9.30 (bs, 2H), 7.85 (d, I H). 7.55 (s, I H), 7.42 (d, I H). 7.28 (d, I H), 6.50 (d, IH), 4.60 (s, 2H), 3.80 (s, 2H). 338 (bs, 4H). MS m/z 257, [M+]. Elemental analysis calculated with 0.5 mol of H₂0 cal. C=43.72%, H=3.68%- N=8.50%. found C=43.70%. H=3.62%, N=8.61%. EXAMPLE 68. l-(l-Aminoisoquinolin-6-ylmethyl)piperazin-2-one.

The title compound is prepared as described in EXAMPLE 67 substituting 6-bromomethyl-l - chloroisoquinoline for bromomethyl-2-chloroquinoline. Η NMR (d6-DMSO, 300 MHz) ? (9.18 (bs, 2H), 8.53 (d, I H), 7.81 (s, IH). 7.63 (m, 2H), 7.14 (d, IH), 4.77 (s, 2H), 3.88 (s, 2H), 3.50 (m, 4H).

EXAMPLE 69. 2-(2-Oxopiperazin-l-ylmethyl)pyrrolo[3,2-clpyridin-l -carboxylic acid tert-butyl ester.

A. 3-Iodopyridin-4ylamine.

A solution of potassium iodide (19.48 g, 1 17.4 mmol) and iodine (18.37 g, 723 mmol) in water (77 mL) is added dropwise via an addition funnel to a refluxing solution of 4-aminopyridine (9.21 g, 97.8 mmol) and sodium carbonate (6.12 g, 57.7 mmol) in water (35 mL). Upon complete addition the mixture is stirred for 2 hours at reflux then cooled to room temperature and extracted with ethyl acetate. The combined organic layers are washed with saturated sodium thiosulfate solution (3x) and brine then dried over MgS0₄, filtered and concentrated to give the title product (837 g, 38.0 mmol) and a trace of the di- iodo compound as an yellow/orange solid. This material is used in the subsequent step without further purification. Η NMR (CDC1₃. 300 MHz) ? 8.70 (s, 1 H), 8.10 (d, 1 H), 6.55 (d, 1 H). 4.60 (bs, 2H).

B. (3-Iodopyridin-4-yl)-carbamic acid tert-butyl ester.

Di-tert-butyl dicarbonate (20.7 g, 94.8 mmol) is added to a solution of 3-iodopyridin-4-ylamine (19.0 g, 86J mmol) in THF (86 mL). The resulting solution is stirred for 2 hours at room temperature then concentrated. The residue is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and brine. The organic layer is dried over MgSO.. filtered and concentrated. The residue is purified by column chromatography eluting with 1% EtOAc/CH₂Cl₂ to give the title product and a small amount of the BOC-protected di-iodo compound. Trituration of the mixture with ether/hexane removes the undesired compound leaving the title product in the solution. Filtration of the solid and concentration of the filtrate yields the title product (18.95 g, 59.2 mmol). 'H NMR (CDC1₃, 300 MHz) ? 8.75 (s, I H), 8.35 (d, IH), 8.1 (d, IH), 7.0 (bs, I H), 1.55 (s, 9H).

C. 3-Oxo-4-prop-2-ynylpiperazine-l -carboxylic acid benzyl ester.

Sodium hydride (0.82 g. 23.0 mmol, 60% mineral oil dispersion) is added to a solution of 4- benzyloxycarbonylpiperazin-2-one (5.13 g, 21.9 mmol) in THF/DMF (75 mL, 3/1 v/v) at 0°C . The mixture is stirred for 5 minutes, then propargyl bromide (3.1 mL, 41.5 mmol) is added dropwise. The resulting solution is stirred for 1 hour then brought to room temperature and stirred for 2 hours. The reaction is quenched with saturated ammonium chloride solution then diluted with ethyl acetate and washed with water (4x) and brine. The organic layer is dried over MgS0 , filtered and concentrated to dryness. The residue is purified by column chromatography eluting with 5% MeOH/CH₂Cl₂ to give the product (5.96 g, 21.9 mmol) as a white solid. 'H NMR (CDC1₃, 300 MHz) ? 7.3 (m, 5H), 5.12 (s, 2H), 4.25 (s,2H), 4.16 (s, 2H), 3.75 (m, 2H), 3.41 (m, 2H), 2.22 (s, IH).

P. 2-(4-Benzyloxycarbonyl-2-oxopiperazin-l-ylmethyl)pyrrolor3,2-clpyridin-l -carboxylic acid tertbutyl ester.

Pd(PPh₃)-Cl- (0.29 g, 0.41 mmol), Cul (0.05 g, 0.25 mmol) and triethylamine (4.6 mL, 32.9 mmol) is added to a solution of 3-oxo-4-prop-2-ynylpiperazine-l -carboxylic acid benzyl ester (2.24 g, 8.23 mmol) and (3-iodopyridin-4-yl)-carbamic acid tert-butyl ester (2.63 g, 8.23 mmol) in DMF (30 mL) at room temperature. The mixture is heated to 100°C and stirred for 1.5 hours. The reaction mixture is then cooled to 50°C and DBU (2.5 mL, 16.5 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 MgS0₄, filtered and concentrated in vacuo. The resulting solid is purified by column chromatography eluting with a gradient of 2% MeOH/CH₂Cl₂to 5% MeOH/ CH₂Cl₂to give the product (2.93 g, 6.31 mmol) as a white solid. Η NMR (CDC1₃, 300 MHz) ? 8.75 (s, 1 H), 8.4 (d, IH). 7.85 (d, IH), 7.35 (m, 5H), 638 (s, IH), 5.2 (s, 2H), 5.00 (s, 2H), 4.29 (s, 2H), 3.85 (m, 2H), 3.52 (m, 2H), 1.7 (s, 9H). Ion spray MS, [M+H]⁺= 465.

E. '2-(2-Oxopiperazin-l-ylmethyl)pyrrolor3,2-clpyridin-l -carboxylic acid tert-butyl ester. Palladium black (1.1 g, 10.3 mmol) is added to a solution of 2-(4-benzyloxycarbonyl-2-oxo- piperazin-l -ylmethyl)pyrrolo[3,2-c]pyridin-l -carboxylic acid tert-butyl ester (1.1 g, 3.1 mmol) in HCO-H/MeOH (45 mL, 4.4% solution). After 40 minutes the catalyst is filtered through Celite and washed with MeOH. The filtrate is concentrated in vacuo to remove methanol then the resulting solution is diluted with methylene chloride and washed with saturated sodium bicarbonate, and brine. The organic layer is dried over MgS0₄, filtered and concentrated to dryness. The resulting solid is purified by column chromatography eluting with a gradient of 5% MeOH/CH₂Cl₂ to 10% MeOH/CH₂Cl₂ to give the product (0.8 g, 2.5 mmol) as a pale yellow foamy solid. 'H NMR (CDC1₃, 300 MHz) ? 8.78 (s, 1 H), 8.40 (d, 1 H), 7.9 (d, 1 H), 6.48 (s, 1 H), 4.98 (s, 2H), 3.7 (s, 2H), 3.51 (t, 2H), 3 JO (t, 2H), 1.91 (bs, 1 H), 1.70 (s, 9H).

EXAMPLE 70. 2-(5-(±)-Methoxycarbonyl-2-oxo-piperazin-l-ylmethyl)-pyrrolo[3,2-clpyridine- carboxylic acid tert-butyl ester.

A. 2-Benzyloxycarbonylamino-3-(prop-2-ynylamino)-propionic acid methyl ester. Propargyl bromide (1.6 mL, 14J mmol) is added to a solution of 3-amino-2- benzyloxycarbonylamino-propionic acid methyl ester hydrochloride (4.0 g, 13.9 mmol) and triethylamine (4.1 L, 29J mmol) in THF (46 mL). The resulting mixture is heated to 50°C and stirred overnight then cooled to RT and concentrated in vacuo. The crude residue is diluted with methylene chloride, washed with saturated NaHC0₃ and brine then the organic layer is dried over MgS0₄, filtered and concentrated in vacuo. The crude material (4.0 g) is taken on to the subsequent step without further purification. Η NMR (CDC1₃, 300 MHz) ? 7.25-7.30 (m, 5H), 5.75 (bs, I H), 5.20 (s, 2H), 4.45 (bs, IH), 3.80 (s, 3H), 3.75 (m, IH), 3.31 (s, 2H), 3.08 (dd, lH), 2.98 (dd, lH), 2.20 (t, IH). El MS, [M+H]⁺=291.

B. 2-Benzyloxycarbonylamino-3-(bromoactyl-prop-2-ynyl-amino)-propionic acid methyl ester.

DCC (2.27 g, 1 1.0 mmol) and bromoacetic acid (1.48 g, 10.7 mmol) is added to a solution of 2- benzyloxycarbonylamino-3-(prop-2-ynylamino)-propionic acid methyl ester (3.10 g, 10.7 mmol) in CH₂CI₂ at RT. The mixture is stirred overnight then diluted with ether. The white solid which precipitates out is filtered and the filtrate is concentrated to give a yellow oil. The crude product is purified by chromatography eluting with a gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to yield the title product (2.1g, 5.12 mmol) as an oil. Η NMR (CDC1₃, 300 MHz) ? 7.30 (m, 5H), 5.70 (d, IH), 5.10 (s, 2H), 4.63 (m, IH). 4.15 (d, 2H), 4.00 (m, IH). 3.80 (s, 3H), 3.75 (s, 2H), 3.70 (dd, I H), 2.27 (bs, I H). Ion spray MS, [M+H]^~=41 1 , 413, Br pattern.

C. 5-Oxo-4-prop-2-ynyl-piperazine-l ,2-dicarboxylic acid 1-benzyl ester 2-methyl ester.

Sodium hydride (0.20 mg, 4.9 mmol) is added to a solution of 2-benzyloxycarbonylamino-3- (bromoactyl-prop-2-ynyl-amino)-propionic acid methyl ester (2.0 g, 4.8 mmol) in THF (50 L) at 0°C. The solution is stirred for 40 minutes then quenched with saturated NH₄C1 solution. The reaction mixture is concentrated in vacuo then diluted with CH₂Cl₂and washed with brine. The organic layer is dried over , filtered and concentrated in vacuo. The crude product is purified by chromatography eluting with 50% EtOAc/hexanes to give the title product (1.4 g, 4.1 mmol). Η NMR (CDC1₃, 300 MHz) ? 7.30 (m, 5H), 5.20 (s, 2H), 5.10 (m, I H), 4.30 (dd, I H), 4.25 (d, 2H), 4.08 (m, I H), 4.00 (dd, I H), 3.78 (dd, IH), 3.78 (s, 3H), 2.25 (t, IH).

P. 2-(5-(±)-Methoxycarbonyl-2-oxo-piperazin- 1 -ylmethyl)-pyrrolo[3,2-c1pyridine- 1 -carboxylic acid tert-butyl ester.

'H NMR (CDCl₃, 300 MHz) ??8.75 (s, I H), 8.41 (d, I H). 7.90 (d, lH), 6.42 (s, I H), 5.00 (AB, 2H), 3.85-3.93 (m, 2H), 3.78 (s. 3H), 3.70-3.81 (m, 3H), 1.65 (s, 9H). Ion spray MS, [M+H]⁺=389. EXAMPLE 71. 2-(2-(±)-Methoxycarbonyl-6-oxo-piperazin- 1 -ylmethyl)-pyrrolo^r3,2-clpyridine- 1 - carboxylic acid tert-butyl ester.

'H NMR (CPC1₃, 300 MHz) ? 8.81 (s, IH), 8.43 (d, IH), 7.90 (d, IH), 6.48 (s, IH), 5.63 (d, IH), 4.40 (d, lH), 4.20 (m, I H), 3.78 (s, 3H), 3.70 (d, l H), 3.52 (d, lH), 3.33 (dd, lH), 2.92 (s, I H), 1.55 (s, 9H). Ion spray MS, [M+HJY389.

EXAMPLE 72. l-(4-Aminoquinazoline-7-ylmethyl)piperazine-2-one.

A. 4-(4-Chloroquinazoline-7-ylmethyl)-3-oxopiperazine-l -carboxylic acid tert-butyl ester. To a solution of 3-oxopiperazine-l -carboxylic acid tert-butyl ester (3.93 g. 19.6 mmol) and 7- bromomethyl-4-chloroquinazoline, EXAMPLE 7, (5.0 g, 19.6 mmol) in 150 mL of THF and 15 mL of PMF at 0°C is added a 60% dispersion in mineral oil of NaH (0.79 g, 19.6 mmol). The solution is stirred at 0°C for 0.5 hours and then is allowed to warm to ambient temperature. After 4 hours, the solution is poured into a saturated solution of NH₄C1. The layers are separated and the organic layer is washed with H₂0, and saturated NaCl, dried ov er MgS0₄, filtered and concentrated. The title compound is obtained as a white solid (5.1 g, 13.4 mmol). MS (FAB) m/z 377, 379, (M+H), chlorine pattern.

B. 4-(4-Aminoquinazoline-7-ylmethyl-3-oxopiperazine-l -carboxylic acid tert-butyl ester.

A solution of 4-(4-chloroqtιinazoline-7-ylmethyl)-3-oxopiperazine-l-carboxylic acid tert-butyl ester (1.84 g, 4.9 mmol) in 120 mL of ethanol is saturated with NH₃ gas. To the resulting solution is added acetic acid (0.03 mL). The solution is heated to reflux. After 16 hours, the solution is concentrated. The resulting solid is dissolved in CH₂C1₂ and the inorganic salts are filtered off. The organic solution is concentrated. The resulting solid is triturated with EtOAc. The title compound is obtained a a white solid (1.59 g. 4.5 mmol). MS (FAB) m/z 356, (M+H).

C. l-(4-Aminoquinazoline-7-ylmethyl)piperazine-2-one.

A solution of 4-(4-aminoquinazoline-7-ylmethyl)-3-oxo-piperazine-l -carboxylic acid tert-butyl ester (1.92 g, 5.4 mmol) in EtOAc (200 mL) at 0 °C is saturated with HCl gas. The solution is stirred at 0°C for 4 hours. After this time, the solution is concentrated. The title compound is obtained as a white solid (1.19 g, 5.4 mmol). 'H NMR (d⁶-PMSO, 300 MHz) δ 9.9 (bs, 3H). 9.7 (bs, 2H), 8.8 (s. 1 H), 8.46 (d, I H), 7.72 (s, IH), 7.61 (d, IH). 4.78 (s, 2H), 3.83 (s, 2H), 3.4 (m, 4H).

Example 73. l-(4-Amino-thieno[23-d1pyrimidin-6-ylmethyl)-piperazin-2-one. A. l-(4-Amino-thienor2,3-d]pyrimidin-6-ylmethyl)-3-oxo-piperazine-l -carboxylic acid tert-butyl ester.

The title compound is prepared as described in EXAMPLE 72, Part A, substituting 6- bromomethyl-4-chlorothieno[2,3-d]pyrimidine. for 7-bromomefhyl-4-chloroquinazoline. Followed by treatment as described in EXAMPLE 72, Part B, the title compound is obtained. 'H NMR (CP₃OP, 300 MHz) δ 8.22 (s, I H), 7.35 (s, IH), 5.48 (s, 2H), 4.10 (s, 2H), 3.60 (m, 2H), 3.40 (m, 2H), 1.45 (s, 9H). MS (ion spray), 364, (M+H).

B. l-(4-Amino-thienor2,3-dlpyrimidin-6-ylmethyl)-piperazin-2-one.

The title compound is obtained by treatment of l-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)- 3-oxo-piperazine-l -carboxylic acid tert-butyl ester as described in EXAMPLE 72, Part C. MS (El), 2634, (M+).

EXAMPLE 72. 4J3-(2-Oxo-piperazin-l-yl)-propyl]-piperidine-l -carboxylic acid tert-butyl ester.

A. 4-[3-(l-tert-butoxycarbonv -piperidin-4-yl)-propyl1-3-oxo-piperazine-l -carboxylic acid benzyl ester. The title compound is prepared as described in EXAMPLE 72, Part A, substituting 3- oxopiperazine-1 -carboxylic acid benzyl ester for 3-oxopiperazine-l -carboxylic acid tert-butyl ester and 4-(3-bromopropyl)-piperidine-l -carboxylic acid tert-butyl ester for 7-bromomethyl-4-chIoroquinazoline. The title compound is obtained as a white foam. 'H NMR (CPC1₃, 300MHz) δ 738 (m, 5H), 5.12 (s, 2H), 4.18 (m, 4H), 3.73 (m, 2H). 333 (m, 4H), 2.66 (m, 2H), 1.58 (m, 6H), 1.42 (s, 9H), 138 (m, 3H).

B. 4-r3-(2-Oxo-piperazin-l-yl)-propyll-piperidine-l -carboxylic acid tert-butyl ester.

4-[3-( l-tert-butoxycarbonyl-piperidin-4-yl)-propyl]-3-oxo-piperazine-l -carboxylic acid benzyl ester is treated as described in EXAMPLE 67, Part P, to give the title compound as an oil.

EXAMPLE 75. 1 -(4-Amino-quinazoline-7-ylmethyl)-3-methoxymethyl-piperazine-2-one.

A. 2-Methoxymethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

To a solution of 2-oxo-3-(S)-methoxymethylpiperidine (536g, 193mmol), EXAMPLE 41 Jn 200mL of 10: 1 THF:DMF is added 2-(benzhydrylidene-amino)-4-bromomethyl-benzonitrile (12.6g,

60%purity. 19.3mmol), prepared as in EXAMPLE 13. The solution is cooled to 0°C. To the solution is added NaH (O.llg of a 60% dispersion in mineral oil, 193mmol). The solution is stirred for 16 hours. After this time, IN HCl is added until the pH=l . The solution is stirred for 1 hour. After this time, the solution is diluted with EtOAc. The organic layer is washed with water and sat. NaCl. The organic layer is dried over MgS0₄, filtered and concentrated under vacuum. The resulting crude product is purified by column chromatography eluting with a gradient of 20%EtOAc/CH₂Cl₂ to 40%EtOAc/CH₂Cl₂. The title compound (6.8g, 16.7mmol) is obtained as a white solid. 'H NMR (CDC1₃, 300MHz) δ 734 (m, 5H), 6.61 (m, 2H),5.13 (AB, 2H), 4.76 (m, IH), 4.40 (AB, 2H), 4.08 (m. 5H), 3.74 (m, 2H), 3.32 (m, IH), 3.30 (s, 3H), 3.10 (m, IH).

B. 4-(4-Amino-quinazolin-7-ylmethyl)-2-methoxymethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

To a solution of 2-methoxymethyl-3-oxo-piperazine- l -carboxylic acid benzyl ester (6.8g, 16.7mmol) in lOOmL of ethanol is added triazine (2.2g, 26Jmmol) and acetic acid (1.6g,26.4mmoI).

The solution is heated to a reflux. After 36h, the solution is concentrated. The resulting crude product is purified by column chromatography eluting with a gradient of 2%MeOH/CH₂Cl₂ to 5% MeOH/CH₂Cl₂. The title compound (5.8g, 13.3mmol) is obtained as a white solid. 'H NMR (CDC1₃, 300MHz) δ 8.55 (s, IH), 7.72 (m, 2H), 7.48 (m, IH), 735 (m, 5H), 6.40 (bs, 2H), 5.16 (AB, 2H), 5.06 (m, 1H),4.72 (m, IH), 4.59 (m, IH), 4.09 (m, 2H), 3.74 (m, 2H), 3.44 (m, I H), 3.30 (s, 3H), 3.12 (m, IH). MS (ion spray) m/z 436, (M+H).

C. l-(4-Amino-quinazoline-7-ylmethyl)-3-methoxymethyl-piperazine-2-one.

To a solution of 2-methoxymethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (5.8g, 133mmol) in 50mL of acetic acid is added dropwise, 20mL of a 30%HBr in AcOH solution. The solution is stirred for 1 hour. After this time, the solution is concentrated. The resulting crude product is purified by column chromatography eluting with CH₂Cl₂:MeOH:NH₄OH (20:5: 1 ). The title compound (2.0g. 6.6mmol) is obtained as a white solid. 'H NMR (d⁶-DMSO, 300MHz) δ 8.60 (s, IH), 7.72 (m, 2H).7.48 (d, IH), 5.60 (bs, 2H), 4.72 (AB, 2H), 3.87 (m, 2H), 3.71 (m, IH), 3,42 (m, IH), 3.40 (s, 3H), 3.19 (m, 2H), 3.02 (m, I H). MS (ion spray) m/z 302, (M+H).

EXAMPLE 76. 1 -(4-Aminoquinazoline-7-ylmethyl)-3-butyl-piperazine-2-one.

The title compound is prepared as described in EXAMPLE 75, substituting 2-butyl-3-oxo- piperazine-1 -carboxylic acid benzyl ester, Example 42, for 2-methoxymethyl-3-oxo-piperazine-l - carboxylic acid benzyl ester. 'H NMR (CD₃OD, 300MHz) δ 8.35 (s, I H), 8.09 (d, IH). 7.54 (s, I H), 7.41 (d, I H), 4.74 (s, 2H), 3.43 (m, 2H), 3.28 (m, lH), 3.09 (m, I H), 2.95 (m, IH). 1.92 (m, I H), 1.70 (m, I H), 1.39 (m, 4H), 0.93 (m. 3H). MS (ion spray) m/z 314, (M+H).

EXAMPLE 77. 1 -(4-Aminoquinazoline-7-ylmethyl)-3-ethyl-piperazine-2-one. The title compound is prepared as described in EXAMPLE 75, substituting 2-ethyl-3-oxo- piperazine-1 -carboxylic acid benzyl ester r, Example 43, for 2-methoxymethyI-3-oxo-piperazine-l- carboxylic acid benzyl ester. Η NMR (CD₃OD, 300MHz) δ 836 (s, I H). 8.1 1 (d, IH), 7.57 (s, IH), 7.42 (d, IH), 4.78 (s, 2H), 3.40 (m, 2H), 3.29 (m, 1H), 3.1 1 (m, lH), 2.98 (m, l H), 2.00 (m, IH), 1.77 (m, 1 H), 1.20 (m, 3H). MS (ion spray) m/z 286, (M+H).

EXAMPLE 78. 1 -(4-Aminoquinazoline-7-ylmethyl)-3-propyl-piperazine-2-one.

The title compound is prepared as described in EXAMPLE 75, substituting 2-propyl-3-oxo- piperazine-1 -carboxylic acid benzyl ester. Example 44, for 2-methoxymethyl-3-oxo-piperazine-l- carboxylic acid benzyl ester. 'H NMR (CD₃OD, 300MHz) δ 8.36 (s, I H), 8.13 (d, I H), 7.60 (s, IH), 7.47 (d, IH), 4.78 (s, 2H), 3.44 (m, 2H), 3.30 (m, I H), 3.1 1 (m, l H), 2.97 (m, IH), 1.98 (m, IH), 1.72 (m, IH), 1.50 (m, 2H), 0.97 (m. 3H). MS (ion spray) m/z 300, (M+H).

EXAMPLE 79. 1 -(4-Amino-quinazoline-7-ylmethyl)-3-ethoxymethyl-piperazine-2-one. The title compound is prepared as described in EXAMPLE 75, substituting 2-ethoxymethyl-3- oxo-piperazine-1 -carboxylic acid benzyl ester, Example 45, for 2-methoxymethyl-3-oxo-piperazine-l - carboxylic acid benzyl ester. 'H NMR (CD₃OD, 300MHz) δ 8.34 (s, I H), 8.07 (d, I H), 7.53 (s, I H), 7.40 (d, IH), 4.79 (AB, 2H), 3.90 (m, I H), 3.72 (m, I H), 3.68 (m. I H), 3.52 (m, 2H), 336 (m, 2H), 3.20 (m, IH), 3.00 (m, I H), 1.92 (m. 3H). MS (ion spray) m/z 316, (M+H).

EXAMPLE 80. l-(4-Amino-quinazoline-7-ylmethyl)-3-methyl-piperazine-2-one.

The title compound is prepared as described in EXAMPLE 75. substituting 2-methyl-3-oxo- piperazine-1 -carboxylic acid benzyl ester, Example 46, for 2-methoxymethyl-3-oxo-piperazine- l- carboxylic acid benzyl ester. Η NMR (CD₃OD, 300MHz) δ 8.36 (s, IH), 8.1 1 (d, IH), 7.57 (s, IH), 7.44 (d, IH), 4.79 (AB. 2H), 3.58 ( , l H), 3.47 (m, IH), 3.31 (m, lH). 3.12 (m, lH), 3.00 (m, IH), 1.41 (d, 3H). MS (ion spray) m/z 272. (M+H).

EXAMPLE 81. l-(4-Amino-quinazoline-7-ylmethyl)-3-benzyl-piperazine-2-one.

The title compound is prepared as described in EXAMPLE 75. substituting 2-benzyl-3-oxo- piperazine- 1 -carboxylic acid benzyl, Example 47, ester for 2-methoxymethyl-3-oxo-piperazine- 1 - carboxylic acid benzyl ester. Η NMR (CD₃OD, 300MHz) δ 8.35 (s, I H), 8.09 (d, I H), 7.57 (s, I H), 7.38 (d, I H), 7.27 (m, 5H), 4.74 (AB, 2H), 3.76 (m, I H), 3.47 (m. IH). 3.30 (m, 3H), 3.08 (m, I H), 2.96 (m, I H). MS (ion spray) m/z 348, (M+H). EXAMPLE 82. l-(4-Amino-quinazoline-7-ylmethyl)-3-(l -methoxyethyl)-piperazine-2-one.

The title compound is prepared as described in EXAMPLE 75, substituting 2-( 1 -methoxyethyl)- 3-oxo-piperazine-l -carboxylic acid benzyl ester, Example 48, for 2-methoxymethyl-3-oxo-piperazine-l- carboxylic acid benzyl ester. This compound is isolated as the bis hydrobromide salt. Η NMR (CD₃OD, 300MHz) δ 8.70 (s, IH), 8J0 (d, IH), 7.88 (s, IH), 7.71 (d, IH), 4.94 (AB, 2H), 430 (m, 2H), 3.76 (m, IH), 3.68 (m, 3H), 3.36 (s, 3H), 1.42 (d, 3H). MS (ion spray) m/z 316, (M+H).

EXAMPLE 83. l-(4-Amino-quinazoline-7-ylmethyl)-3,3-dimethyl-piperazine-2-one.

The title compound is prepared as described in EXAMPLE 75, substituting 2,2-dimethyl-3-oxo- piperazine-1 -carboxylic acid benzyl ester, Example 49, for 2-methoxymethyl-3-oxo-piperazine-l- carboxylic acid benzyl ester. 'H NMR (d⁶-DMSO, 300MHz) δ 8.34 (s. IH), 8.12 (d, IH), 7.72 (bs, 2H),

7.41 (s, IH), 7.26 (d, IH), 4.60 (s. 2H), 333 (m, 2H), 2.98 (m, 2H), 1.27 (s, 6H).

EXAMPLE 84. 1 -(4-Amino-quinazoline-7-ylmethyl)-3-isopropyl-piperazine-2-one. The title compound is prepared as described in EXAMPLE 75, substituting 2-isopropyl-3-oxo- piperazine- 1 -carboxylic acid benzyl ester, Example 50, for 2-methoxymethyl-3-oxo-piperazine-l- carboxylic acid benzyl ester. 'H NMR (d⁶-DMSO, 300MHz) δ 8.32 (s, IH), 8.12 (d, I H), 7.66 (bs, 2H),

7.42 (s, I H), 7.27 (d, I H), 4.60 (AB, 2H), 3.23 (m, 2H), 3.05(m, I H), 2.79 (m, I H), 2.34 (m, I H), 0.92 (s, 3H), 0.80 (s, 3H).

EXAMPLE 85. l-(4-Amino-quinazoline-7-ylmethyl)-3-isobutyl-piperazine-2-one.

The title compound is prepared as described in EXAMPLE 75, substituting 2-isobutyl-3-oxo- piperazine-1 -carboxylic acid benzyl ester, Example 51, for 2-methoxymethyl-3-oxo-piperazine-l- carboxylic acid benzyl ester. 'H NMR (d⁶-DMSO, 300MHz) δ 8.65 (s, IH), 7.70 (m, 2H), 7.48 (m, IH), 5.61 (m, 2H), 4.82 (m. IH), 4.65 (m, I H), 3.52 (dd, IH), 337 ( , I H), 3.18 (m, 2H), 2.98 (m, IH), 1.92

(m, 1 H), 1.76 (m, 1 H). 1.59 (m. 2H), 0.95 (m, 6H).

EXAMPLE 86, l-(4-Amino-quinazoline-7-ylmethyl)-3-(2-methoxyethyl) l-piperazine-2-one.

The title compound is prepared as described in EXAMPLE 75, substituting 2-(2-methoxyethyl)- 3-oxo-piperazine-l -carboxylic acid benzyl ester. Example 52, for 2-methoxymethyl-3-oxo-piperazine-l- carboxylic acid benzyl ester. Η NMR (d⁶-DMSO, 300MHz) δ 8.32 (s, IH), 8.13 (d, IH), 7.70 (bs, 2H), 7.42 (s, IH), 7.28 (m. I H), 4.60 ( . 2H), 3.32 ( , 8H), 3.1 1 (m, I H), 2.95 (m, IH), 2.78 (m, I H), 2.07 (m, IH), 1.72 (m, IH). EXAMPLE 87. 1 -(4-Amino-quinazoline-7-ylmethyl)-3-methoxymethyl-6-methyl-piperazine-2-one.

The title compound is prepared as described in EXAMPLE 75, substituting 2-methoxymethyl-5- methyl-3-oxo-piperazine-l -carboxylic acid benzyl ester, Example 53, for 2-methoxymethyl-3-oxo- piperazine-1 -carboxylic acid benzyl ester. 'H NMR (CD₃OD, 300MHz) δ 8.72 (s. IH), 8.32 (d, IH), 7.78 (m, 2H), 5.1 1 (m, IH), 4.81 (m, IH), 4.42 (m, IH), 4.13 (m, IH), 4.04 (m, IH), 3.74 (m, 2H), 3.52 (m, IH), 3.43 (s, 3H), 1.34 (d, 3H).

EXAMPLE 88. (3S,5RS)-l-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.

A. (2S,6RS)-4-f3-(benzhydryl-amino)-4-cyano-benzyll-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

To a solution of the (2S.6RS)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (1.98 g, 7.56 mmol in 20 mL of tetrahydrofuran and 2 mL of DMF is added sodium hydride (60%, 289 mg, 12.6 mmol) at 0°C. The reaction is stirred for one hour at room temperature and the 2- benzhydrylidene-amino)-4-bromomethyl-benonitrile (4.24 mg, 1 1.34 mmol), Example 13, is added.

After stirring at room temperature overnight, the tetrahydrofuran is removed. The residue is taken up in ethyl acetate. Excess sodium hydride is quenched with 5 mL of water, and normal aqueous work-up followed. The crude product is chromatographed on silica gel (50% EtOAc/Hexane ) to give (2S,6RS)- 4-[3-(benzhydryl-amino)-4-cyano-benzyI]-2,6-dimethyI-3-oxo-piperazine-l -carboxylic acid benzyl ester (2.6 g, 65%). C₃₅H₃₂N 0₃ MS m/z: 557.

B. (2S,6RS)-4-(3-amino)-4-cvano-benzyl)-2,6-dimethyl-3-oxo-piperazine- 1 -carboxylic acid benzyl ester.

(2S,6RS)-4-[3-(Benzhydryl-amino)-4-cyano-benzyl]-2,6-dimethyl-3-oxo-piperazine-l- carboxylic acid benzyl ester (2.6 g, 5.21 mmol) is dissolved in 100 L of ethyl acetate and cooled to 0°C. A 12N solution of hydrochloric acid (0.5 ml, 6.0 mmol) is added dropwise. The deprotection is complete in thirty minutes. The reaction mixture is washed with 10 % sodium bicarbonate. The ethyl acetate layer is dried with magnesium sulfate, filtered and condensed. The resulting residue is purified by flash colunm (Si0₂, 60 % ethyl acetate/hexane) to give the product (2S,6RS)-4-(3-amino)-4-cyano- benzyI)-2,6-dimethyl-3-oxo-piperazine-l-carboxylic acid benzyl ester (2.03 g, 99 %).

C. (2S,6RS)-4-(4-Amino-quinazolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine- 1 -carboxylic acid benzyl ester. Glacial acetic acid (0.9 ml, 15.54 mmol) and 1,3,5-triazine (840 mg, 1036 mmol) is added to a solution of (2S,6RS)-4-(3-amino-4-cyano-benzyl)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (2.03 g, 5.18 mmol) in ethanol. The resulting mixture is heated to reflux overnight. Replaced the ethanol with ethyl acetate and washed with saturated sodium bicarbonate (5 mL). The ethyl acetate layer is dried with magnesium sulfate, filtered and condensed. The resulting residue is purified by flash colunm (Si0₂, 20% methanol/methylene chloride) to give the product (2S,6RS)-4-(4-amino- quinazolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (1.85 g, 85%) as a yellow solid. C₂₃H₂₅N₅0₃ MS m/z: 420.

D. (3SJRS)-l -(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.

Palladium on carbon (10 %, 700 mg) is added to a solution of (2S,6RS)-4-(4-amino-quinazolin- 7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester (1.62 g, 3.87 mmol) in 20 mL of methanol and 2 mL of acetic acid. The reaction mixture is left to stir in an atmosphere of hydrogen for eight hours. The palladium is filtered off, and the volitale solvents are removed on the rotovap. The crude product (1.7 g, 95 %) is isolated as a white solid. The two epimers are separated on silica gel (1% triethylamine/15% methanol/methylene chloride). The minor epimer is assigned as (3S,5R)- l-(4-amino- quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one and the major epimer is assigned as (3S,5S)-l-(4- amino-quinazoliι.-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.

EXAMPLE 89. l -(4-Chloroquinolin-7-ylmethyl)-piperazin-2-one.

4-(Benzyloxycarbonyl)-piperazin-2-one (1.1 g, 4.6 mmol) is dissolved in THF (50 mL), cooled in an ice bath and treated with tretrabutylammonium iodide (0.18 g. mmol) and 60% sodium hydride (0.24 g, 6.0 mmol). The reaction mixture is stirred at 0 C for 30 minutes then treated dropwise with a solution of 7-bromomethyl-4-chloroquinoline (1.2 g, 4.6 mmol), Example 14, in THF (50 mL). The resulting solution is stirred at 0 C for 2 h then quenched with ammonium chloride solution and concentrated. Dilution with ethyl acetate is followed by a water wash; the organic layer is dried (sodium sulfate) and concentrated. The residue is chromatographed (4% methanol/methylene chloride) to yield solid

4-(benzyloxycarbonyl)-l-(4-chloroquinolin-7-ylmethyl)-piperazin-2-one (1.2 g, 2.9 mmol). A portion of this material (0.75 g, 1.8 mmol) is dissolved in acetonitrile (20 mL) and treated with iodo trimethylsilane (0.78 mL, 5.4 mmol) at room temperature for 3 hours. The reaction is quenched with methanol and concentrated to dryness. Methanol addition and concentration is repeated four times. The final residue is taken up is 2M aqueous HCl; the solution is washed with ether and concentrated. The residue is recrystallized from isopropanol and ether to yield the title compound (0.63 g, 2.3 mmol) MS m/z: M^~ = 275; 'HNMR (CD₃OD, 300 MHz) ? 9.1 (d, IH), 8.5 (d, IH), 8.2-8.3 (m, 2H), 8.0 (d, I H), 5.2 (s, 2H), 4.1 (s, 2H), 3.7-3.8 (m, 2H), 3.6-3.7 ( , 2H).

EXAMPLE 90. l-(4-Chlorocinnolin-7-ylmethyl)-piperazin-2-one. 4-(t-Butyloxycarbonv l)-piperazin-2-one (0.6 g, 3.0 mmol), EXAMPLE 40, is dissolved in THF

(80 mL), cooled in an ice bath and treated with tretrabutylammonium iodide (0.23 g, 0.62 mmol) and 60% sodium hydride (0.12 g. 3.0 mmol). The reaction mixture is stirred at °C for 40 minutes then treated dropwise with a solution of 7-bromomethyl-4-chlorocinnoline (10.7g. 2.1 mmol), Example 15, in THF (20 mL). The resulting solution is warmed to ambient temperature over 2 hours. The solution is evaporated to dryness and the residue is taken up in ethyl acetate and 10 % aqueous sodium bicarbonate solution. The organic layer is separated, washed with water, dried (sodium sulfate) and concentrated. The residue is chromatographed (ethyl acetate) to yield the title compound (0.6 g, 1.6 mmol). A portion of this material (0.21 g, 1.26 mmol) is dissolved in THF (~ 4 mL) and treated with a saturated solution of HCl in ethyl acetate (50 mL) at room temperature for 2 hours. The solution is filtered and concentrated to a residue (0.14 g, 0J mmol). MS m/z: M⁺ = 275; Η NMR (CD3OD, 300 MHz) ? 9.15 (d, IH), 8.5 (d, IH), 8.25 (s, I H), 8.15 (d, l H). 8.0 (d, I H), 5.0 (s, 2H), 4.1 (s, 2H), 3.7-3.8 (m. 2H), 3.6-3.7 (m, 2H).

EXAMPLE 91. lJ4-Chloroquinolin-7-ylmethyl)-3-(S)-methylpiperazin-2-one.

4-(Benzyloxycarbon\ l)-3-(S)-methylpiperazin-2-one ( 1 .0 g, 4.0 mmol), EXAMPLE 46, is dissolved in THF (60 mL), cooled in an ice bath and treated with tretrabutylammonium iodide (0.10 g, 0.27 mmol) and 60% sodium hvdride (0.18 g, 4.4 mmol). The reaction mixture is stirred at 0°C for 30 minutes then treated dropwise w ith a solution of 7-bromomethyl-4-chloroquinoline (1.12 g, 4.4 mmol), EXAMPLE 14, in THF (5 mL). The resulting solution warmed to room temperature over approximately 1 h then quenched with sodium bicarbonate solution and concentrated. The residue is partitioned between ethyl acetate and water; the organic layer is dried (sodium sulfate) and concentrated. The residue is chromatographed (5 % methanol/methylene chloride) to yield solid 4-(Benzyloxycarbonyl)-l-(4- chloroquinolin-7-ylmethyl)-3-(S)-methyl-piperazin-2-one (1.32 g, 3.1 mmol). A portion of this material (0.10 g, 0.23 mmol) is dissol ed in acetonitrile (6 mL) and treated with iodotrimethyl-silane (0.1 mL, 0.75 mmol) at room temperature for 2 hours. The reaction is quenched with methanol and concentrated to dryness. Methanol addition and concentration is repeated six times. The final residue is taken up is 2M aqueous HCl; the solution is washed with ether and concentrated to yield the title compound. MS m/z: M^' = 289; 'H MR (CD3θD. 300 MHz) ? 9.2 (d, IH), 8.6 (d, I H), 8.2-83 (m,2H), 8.0 (d, I H), 5.1 (q, IH), 4.3-4.4 (m, IH), 3.8-4.0 (m. 2H), 3.6-3.8 (m, 3H), 1.75 (d, 3H). EXAMPLE 92. l-[2-(Pyridin-4-ylamino)-ethyπ-piperazin-2-one.

A. 4-(tert-Butyloxycarbonyl> 1 -(2-aminoethyl)-piperazin-2-one.

4-(tert-Butyloxycarbonyl)-piperazin-2-one (8.0 g, 40 mmol), EXAMPLE 40, is dissolved in THF (160 mL), cooled in an ice bath and treated with 60 % sodium hydride (1.9 g, 48 mmol). The reaction mixture is stirred 40 minutes, then treated with tetra-butylammonium iodide (0.35 g, 0.95 mmol) and bromoacetonitrile (3J mL, 48 mmol). After 2 h the reaction is quenched with water, concentrated to a small volume and extracted with methylene chloride (3 X). The combined organic extracts are concentrated and the residue is chromatographed (50 % ethyl acetate/hexane) to give 4-(tert- butyloxycarbonyl)-l -cyanomethyl-piperazin-2-one (5.2 g, 21.7 mmol). This material is dissolved in ethanol (140 mL) and treated with platinum oxide (0.83 g) at 50 PSI of hydrogen gas for 24 hours. The catalyst is removed by filtration and the solution is concentrated to yield 4-(tert-butyloxycarbonyl)-l -(2- aminoethyl)-piperazin-2-one (5.2 g, 21.6 mmol). Η NMR (CDC1₃, 300 MHz) ? 4.08 (s, 2H), 3.62 (m, 2H), 3J4 (t, 2H), 3.38 (t, 2H). 2.89 (t, 2H).

B. 4-(tert-Butyloxycarbonyl)-l- 2-(2,3,5,6-tetrachloropyridin-4-ylamino)-ethyll- piperazin-2-one.

4-(tert-Butyloxycarbonv )-l-(2-aminoethyl)-piperazin-2-one (4.0 g, 16 mmol) is dissolved in methylene chloride (150 mL) and treated with 4-nitro-2,3,5,6-tetrachloro-pyridine (4.8 g, 18 mmol) and N-methylmorpholine (4.0 mL. 36 mmol). The reaction mixture is stirred for 5 h, concentrated and the residue is purified by chromatography (50% ethyl acetate/hexane) to give the title compound (4.8 g, 10.5 mmol). Fab MS m/z: 457, 469. 461 , [M+lf; 'H NMR (CDC1₃, 300 MHz) ? 6.00 (t. I H), 4.10 (s, 2H), 3.97 (m, 2H), 3.66 (m. 2H), 3.38 (m, 2H).

C. l-[2-(Pyridin-4-ylamino)-ethyll-piperazin-2-one. 4-(tert-Butyloxycarbonyl)-l-[2-(2J,5,6-tetrachloropyridin-4-ylamino)-ethyl-piperazin-2-one

(3.5 g, 7.6 mmol) is dissolved in methanol (20 mL) and 0.5 M sodium methoxide in methanol (150 mL, 75 mmol). The solution is treated with Pd/C (0.5 g) and agitated under 50 PSI of hydrogen gas for 16 hours. The solvent is removed and the residue is extracted with methylene chloride which is filtered. The filtrate is concentrated and loaded onto a silica flash column. The column is eluted with 5% MeOH/CH₂Cl₂ followed by NH₄OH/MeOH/CH₂Cl₂ (1 :5:95) and NH OH/MeOH/ CH₂C1₂ (1 : 10:70) to yield 4-(tert-Butyloxycarbonyl)-l-[2-(pyridin-4-ylamino)-ethyl]-piperazin-2-one as a white foam (1.5 g, 4.1 mmol). This material (1.5 g. 4.1 mmol) is treated with 20% trifluoroacetic acid in methylene chloride (1 l OmL) at ambient temperature for 2 hours. The solution is concentrated and the residue is treated with saturated bicarbonate solution and ammonium hydroxide until a basic solution is obtained. The solution is applied to a silica column and eluted with NH₄OH/MeOH/CH₂Cl₂ (1 : 10:60) and l-[2-(pyridin-4- ylamino)-ethyl]-piperazin-2-one is isolated as a mixture of desired product and inorganic salts (estimate 25 % by weight) El MS m/z: 220, M⁺; Η NMR (CD3OD, 300 MHz) ? 8.07 (d, 2H), 6.96 (d, 2H), 3.77 (s,

2H), 3,65 (m, 6H), 3.44 (t, 2H).

EXAMPLE 93. H2-{(Methyl)-(pyridin-4-yl)-amino}-ethyl^~l-piperazin-2-one trifluroacetate.

4-(tert-ButyloxycarbonyI)-l-[2-(2,3,5,6-tetrachloropyridin-4-ylamino)-ethyl]-piperazin-2-one (0.19 g, 0.41 mmol), Example 92, Part B, is dissolved in DMF (3 ml) and treated with 60 % NaH (20 mg, 0.5 mmol). After 10 minutes methyl iodide (0.025 ml, 0J0 mmol) is added and the yellow solution is stirred at r.t. overnight. The solution is diluted with EtOAc and washed with H₂0 (6 X). The organic layer is dried (MgS04) and concentrated to a residue (0.19 g, 0.40 mmol). The residue is dissolved in methanol (2 ml) and treated with 0.5 M NaOMe in MeOH (8 ml, 4.0 mmol)). The solution is treated with Pd/C and agitated under 60 PSI of hydrogen gas overnight and filtered. The filtrate is concentrated and extracted several times with CH₂C1₂; removal of solvent in vacuo gives 4-(tert-Butyloxycarbonyl)-l-[2- {(methyl)-(pyridin-4-yl)-amino}-ethyl]-piperazin-2-one as an amorphous residue (0.16 g). El MS m/z: 335, [M+lf; 'H NMR (CDC1₃, 300 MHz) ? 8.21 (d, 2H), 6.56 (d, 2H), 3.99 (s, 2H), 3.60 (t, 2H), 3.53 (t, 2H), 3.47 (t, 2H), 3.28 (t, 2H), 2.98 (s, 3H), 1.46 (s, 9H). Treatment of the above product with 20% TFA/CH₂C1₂ (10 mL) at r.t. for 1 h gives, after concentration, the title compound as a residue which is used without further purification. 'H NMR (CD₃OD, 300 MHz) ? 8.14 (d, 2H), 730 (br, I H), 7.00 (br, IH), 3.88-3.67 (m, 8H), 3.53 (t, 2H), 2.26 (s, 3H).

EXAMPLE 94. l-[^"2-(3-Methylpyridin-4-yl-amino)-ethyll-piperazin-2-one.

A. 4- 2-(3-Methylpyridin-4-ylimino)-ethyll-3-oxo-piperazine-l-carboxlic acid benzyl ester. 4-(Benzyloxycarbonyl)-piperazin-2-one (4.1 g, 20 mmol) is dissolved in THF (50 mL) and treated with 1.5M LDA (20 mL. 30 mmol) at 0°C. The reaction mixture is treated with condensed ethylene oxide (3 mL, 40 mmol) and stirred at r.t. overnight. The mixture is neutralized with 2N HCl, concentrated, and extracted with EtOAc. The EtOAc layer is washed with H₂0 and concentrated to a crude residue. Further extraction of the crude with Et₂0 and concentration of the ethereal layer gives an oil (1.5 g). The above oil is dissolved in CH₂C1₂ (25 L) and added to the solution of 2M oxalyl chloride (7.5 mL, 15 mmol) and DMSO (2.3 mL, 29.7 mmol) in CH₂C1₂ (25 mL) at -60°C. After 15 minutes. Et₃N (2.1 ml. 15 mmol) is added. The mixture is stirred at -50 °C for 10 minutes then warmed to r.t for 10 minutes. The reaction is quenched with 0.5 N HCl and extracted with CH₂C1₂. The CH₂C1₂ layer is washed with 0.5 N HCl. brine (2 X), H₂0, and concentrated to a residue. The residue is purified by chromatography (2% MeOH/CH₂Cl₂) to give 4-amino-3-methyl pyridine as an oil (0.5 g, 1.6 mmol). A solution of the oil (0.2 g, 2 mmol), and (l R)-(-)-10-camphorsulfonic acid (15 mg) in toluene (100 ml) is refluxed with a Dean Stark set up overnight. The mixture is concentrated and the residue is purified by chromatography (2-4% MeOH/CH2C12) to give the title imine as a white foam (0.20 g, 0.54 mmol). Ion spray MS m/z: 367, [M+l]⁺; Η NMR (CDC1₃, 300 MHz) ? 8.20 (d, I H), 8.14 (s. IH), 7.35 (s, 5H), 6.60 (d, IH), 6.18 (dd, IH), 5.15 (s. 2H), 4.97 (d, IH), 430 (s, 2H), 3.78 (t, 2H), 3.50 (bm, 2H), 2.15 (s, 3H).

B. l- 2-(3-Methylpyridin-4-yl-amino)-ethyl]-piperazin-2-one.

4-[2-(3-Methylpyridin-4-ylimino)-ethyl]-3-oxo-piperazine-l -carboxlic acid benzyl ester (0.20 g, 0.54 mmol) is dissolved in anhydrous ethanol (20 mL) and hydrogenated at 50 PSI with 10% Pd/C overnight. After filtration, the filtrate is concentrated. The residue is treated with Pd black in 5% HC0₂H/CH₂C1₂ (10 ml) for 10 minutes. Filtration and concentration gives crude residue, which is purified by chromatography using NH₄OH/MeOH/CH₂Cl₂ ( 1 :5:95) to give the title compound as a clear syrup (0.078 g, 0.33 mmol). 'H NMR (CDC1₃, 300 MHz) ? 8.17 (d, 1 H), 8.03 (s, 1 H). 7.35 (s, 5H), 6.36 (d, IH), 5.30 (b, I H), 3.74 (t, 2H), 3.53 (s, 2H), 3.38 (m, 4H), 3.08 (t, 2H), 2.02 (s, 3H).

EXAMPLE 95. lJ2-(Pyridazin-4-ylamino)-ethyll-piperazin-2-one. l -(2-Aminoethyl)-4-(tert-butyloxycarbonyl)-piperazin-2-one from EXAMPLE 92, Part A ( 1 .0 g, 4.1 mmol) is treated with 3,4,5-trichloropyridazine (0.81 g. 4.1 mmol), triethylamine (0.57 mL, 4.1 mmol), THF (25 mL) and heated to 120°C in a sealed tube for 3 hours. Upon cooling, the solution is diluted with ethyl acetate and washed with aqueous sodium bicarbonate (25 L), water and dried over sodium sulfate. The organic la er is concentrated and chromatographed (5% methanol/methylene chloride) to give a mixture of isomers (0.8 g, 20 mmol). The mixture is dissolved in 0.5 M sodium methoxide in methanol (200 mL), treated with 10% Pd/C (0.5 g) and agitated under 50 PSI of hydrogen for 20 hours. The reaction mixture is filtered; the filtrate is concentrated to a residue which is chromatographed (NH₄OH/H₂0/MeOH/EtOAc, 1 : 1 :2:90) to give crude 4-(tert-butyloxycarbonyl)-l-[2- (pyridazin-4-ylamino)-ethyI]-piperazin-2-one. This material is dissolved in a minimal amount of THF and treated with a saturated solution of HCl in ethyl acetate (50 mL). The solution is stirred at ambient temperature for 2 h and diluted with diethyl ether (50 mL). The precipitated title compound is collected and air dried (OJ g, 1.1 mmol). MS m/z: 367, [M+1 ] ; Η NMR (CD₃OD, 300 MHz) ? 8.8 (d, 1 H), 8.5 (s, IH), 7.4 (d, IH), 4.1 (s, 2H), 3.5-3.8 (m, 8H). EXAMPLE 96. 4-r3-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-propenyll-3-oxo-piperazine- 1 - carboxylic acid tert-butyl ester and 4- 3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-allyll-3-oxo- piperazine-1 -carboxylic acid tert-butyl ester.

A. l-Allyl-4-(tert-butyloxycarbonyl)-piperazin-2-one.

4-(tert-Butyloxycarbonyl)-piperazin-2-one (1.0 g, 5.0 mmol), EXAMPLE 40, is alkylated with allyl bromide (0.48 ml, 5.5 mmol) in THF (20 ml) using the procedure described in Example 92, PartA. The title compound (0.92 g, 3.8 mmol) is obtained as a colorless liquid after chromatographed (50 % ethyl acetate/hexane). El MS m/z 240 (M+); Η NMR (CDC1₃, 300 MHz) ? 5.80-5.68 (m, 1 H), 5.23-5.15 (m, 2H), 4.09 (s, 2H), 4.03 (d. 2H), 3.63 (t, 2H), 3,30 (t, 2H), 1.45 (s, 9H).

B. 4J3-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-propenyl]-3-oxo-piperazine- 1 -carboxylic acid tertbutyl ester and 4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-allyll-3-oxo-piperazine-l-carboxylic acid tert-butyl ester l-Allyl-4-(tert-butylox carbonyl)-piperazin-2-one (0J9 g, 2.0 mmol) is treated with (3-iodo- pyridin-4-yl)-carbamic acid tert-butyl ester (0.64 g, 2.0 mmol), Pd(OAc) (14 mg, 0.06 mmol), P(o-tol)₃ (37 mg, 0.12 mmol), and Et₃N (0.56 mmol) in a seal tube. The mixture is stirred at 100 °C overnight, then diluted with CH₂C1₂ and washed H₂0 (2 X). The CH₂C1₂ layer is concentrated and the residue is chromatographed (5% MeOH/CH₂Cl₂) to give a mixture of two isomers (0J0 g, 0.92 mmol). The mixture is separated into its constituent isomers upon further chromatography (EtOAc) to give 4-[3-(4- tert-butoxycarbonylamino-pyridin-3-yl)-propenyl]-3-oxo-piperazine- 1 -carboxylic acid tert-butyl ester (90 mg, 0.21 mmol, higher R_f v alue) and 4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-allyl]-3-oxo- piperazine-1 -carboxylic acid tert-butyl ester (0.24 g, 0.56 mmol, lower R_f value). For the former: MS m/z 433 (M+1); 'H NMR (CDC1₃. 300 MHz) ? 838 (d, IH), 8.28 (s, IH), 7.93 (d, I H), 7.48 (d, I H), 6.67 (s, IH), 5.10 (m, IH), 4.15 (s, 2H). 3.70 (t, 2H), 3,46 (t, 2H), 3.39 (d, 2H). 1.48 (s, 9H), 1.45 (s, 9H). For the latter: MS m/z 433 (M+1); 'H NMR (CDC1₃, 300 MHz) ? 8.39 (s, IH). 837 (d, I H), 7.98 (d. I H), 6.77 (s, IH), 6.52 (d, I H), 6.07 (m, IH). 4.23 (d, 2H), 4.12 (s, 2H), 3,69 (t, 2H). 3.40 (t, 2H), 1.52 (s, 9H), 1.45 (s, 9H).

EXAMPLE 97. 4-[3-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-propy ll-3-oxo-piperazine-l -carboxylic acid tert-butyl ester

A mixture of the two isomers from EXAMPLE 96, Part B. (0.1 1 g, 0.25 mmol) is dissolved in MeOH (7 ml), treated with with 10%) Pd/C and is stirred under a balloon of hydrogen for 4 hours. Filtration and concentration giv es a white foam (80 mg, 0.18 mmol). El MS m/z 434 (M+); 'H NMR (CDC1₃, 300 MHz) ? 8.33 (d, IH). 8.30 (s, I H), 8.05 (d, IH), 4.08 (s, 2H), 3.64 (t. 2H), 3.50 (t, 2H), 3.35 (t, 2H), 2.58 (t, 2H), 1.90 (m, 2H), 1.51 (s, 9H), 1.48 (s, 9H).

EXAMPLE 98. 4-(Beι-zyloxycarbonyl)-l -(2-pyrrolo[3,2-c1pyridin-l -ylethyl)-piperazin-2-one 4-(Benzyloxycarbonyl)-l-(2-hydroxyethyl)-piperazin-2-one, prepared as described in

EXAMPLE 94, part A. (0.26 g, 0.94 mmol) in methylene chloride (6 mL) is treated with triphenyl phosphine (0.60 g, 2.3 mmol), imidazole (0.16 g, 23 mmol), and iodine (0J7 g, 1.9 mmol) for 0.5 h at 0 °C. The reactin mixture is partitioned between water and methylene chloride; the organic layer is concentrated and the residue is chromatographed (15 % EtOAc/ methylene chloride) to give 4- (benzyloxycarbonyl)-l -(2-iodoethyl)-piperazin-2-one (0.24 g, 0.62 mmol). Pyrrolo[3,2-c]pyridine (0.073 g, g, 0.62 mmol) is dissolved in DMF (3 mL) and treated with 60 % sodium hydride (0.03 g, 0.74 mmol) and all of the 4-(benzyloxycarbonyl)- l -(2-iodoethyl)-piperazin-2-one from the previous step; the reaction mixture is stirred at r.t. for 16 g. The reaction mixture is concentrated to dryness and the residue is partitioned between water and methylene chloride. The organic layer is concentrated and subjected to chromatography (2-5 % MeOH/methylene chloride) to yield the title compound (0.028 g, 0.074 mmol) Ion Spray MS m/z: 379, [M+1]^".

EXAMPLE 99. (±)-l-(3-Amino-4-cyano-benzyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo- piperazine-2-carboxylic acid methyl ester.

A. (±)-l-[3-(Benzhydrylidene-amino)-4-cyano-benzyll-4-(6-chloro-benzo[b1thiophene-2-sulfonyl)-6- oxo-piperazine-2-carboxylic acid methyl ester

A solution containing (±)-l -[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2- carboxylic acid methyl ester (55 mg, 0.12 mmol) in CH₂C1₂ (1 mL) is cooled to 0°C. DIPEA (24 mg, 0.18 mmol) is then added followed by the addition of 6-chloro-benzo[b]thiophene-2-sulfonyl chloride

(32 mg, 0.12 mmol), EXAMPLE 1. The reaction mixture is warmed to ambient temperature. After 16 h, the reaction mixture is absorbed directly onto silica gel and chromatographed (CH₂C1₂ to 2% MeOH/ CH₂C1₂) to provide 60 mg (73%) of the title compound. Η NMR (300 MHz, CDC1J δ 2.77 (dd, J = 12.3, 3.4 Hz, IH). 3.50-3.72 (m. 3H), 3.79 (s, 3H), 4.15 (dd, j = 123, I J Hz, IH). 4.24 (d, J = 16.9 Hz, IH), 5.41 (d, J = 15.3 Hz, lH). 6.50 (s, IH), 6.76 (dd, J = 7.9, 1.4 Hz, IH), 7.1 1-7.86 (m, 15H) ppm; MS (ISP loop): m/z 683 (M+H).

B. (+)-l-(3-Amino-4-cyano-benzyl)-4-(6-chloro-benzo[b1thiophene-2-sulfonyl)-6-oxo-piperazine-2- carboxylic acid methyl ester Concentrated HCl (12M, one drop) is added at 0°C to a mixture containing (±)-l-[3- (benzhydrylidene-amino)-4-cyano-benzyl]-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine- 2-carboxylic acid methyl ester (60 mg, 0.08 mmol) in MeOH (5 mL). Added THF (2 mL) followed by a second drop of 12M HCl and warmed reaction mixture to ambient temperature. The reaction is quenched by pouring the reaction mixture onto a 1 : 1 mixture of CH₂Cl₂/aqueous NaHC0₃ and the layers are separated. The aqueous phase is washed with CH₂C1₂ and then the combined organic phase is washed with brine, dried over anhydrous MgS0₄, filtered and concentrated. The crude residue is chromatographed on silica gel (CH₂C1₂ to 4% MeOH/ CH₂C1₂) to provide 42 mg (93%) of the title compound. Η NMR (300 MHz, CDC1J δ 2.98 (dd, J = 12.5, 3.5 Hz, I H), 3.60 (d, J = 16.8 Hz, IH), 3.69 (d, J = 15.3 Hz, IH), 3.79 (s, 3H), 3.98 (m, I H), 4.21-431 (m, 2H), 4.44 (br s, 2H), 5.36 (d, J = 153 Hz, IH), 6.47 (dd, J = 8.0, 1.4 Hz, IH), 6.54 (s, IH), 7.26 (d, J = 8.0 Hz, I H), 7.45 (dd, J = 8.5, 1.8 Hz, IH), 7.80-7.86 (m, 3H) ppm; MS (ISP loop): m/z 519 (M+H).

EXAMPLE 100. (±)-l-(3-Amino-4-cyano-benzyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo- piperazine-2-carboxylic acid.

Water (5 drops) is added to a solution containing (±)-l-(3-amino-4-cyano-benzyl)-4-(6-chloro- benzo[b]thiophene-2-suifonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (30 mg, 0.05 mmol), EXAMPLE 99, in a 1 : 1 mixture of THF/MeOH (2 mL). At ambient temperature, LiOH monohydrate (7 mg, 1.66 mmol) is then added. After 16 h, the reaction mixture is diluted with water and purified by reverse-phase HPLC [Buffer A: water w/ 0.1 % TFA; Buffer B: CH3CN w/ 0.1 % TFA; Gradient: 0% B to 60% B over 30 min] to provide 10 mg (34%) of the title compound as a white solid. 'H NMR (300 MHz, d₆-DMSO) δ 3.18 (dd, J = 12.1 , 3.5 Hz, I H), 3.61 (d, J = 16.0 Hz, I H), 3.77 (d, J = 16.0 Hz. IH), 3.95 (d, J = 16.0 Hz, IH), 4.06 (d, J = 12.1 Hz, IH), 4.14 (m, IH), 6.40 (d, J = 8.0 Hz, IH), 6.54 (s, IH), 7.21 (d, J = 8.0 Hz, 1 H), 7.57 (dd, J = 8.6, 1.9 Hz, 1 H), 8.06 (d, J = 8.6 Hz, 1 H), 8.18 (s, 1 H), 833 (s, 1 H) ppm; MS (ISP loop): m/z 505 (M+H).

EXAMPLE 101. 4-[4-(6-Chlorobenzo b]thiophene-2-sulfonyl)-2-oxo-piperazine-l- ylmethyllbenzamidine.

To a solution of 4-(2-oxopiperazin-l -ylmethyl)benzamidine bistrifluoroacetate (0.38 g, 0.83mmol). EXAMPLE 66, in CH₂C1₂ (5 mL) is added Et₃N (035 mL, 2.6 mmol) and 6-chloro- benzo[b]thiophene-2-sulfonyl chloride (0.23 g, 0.85 mmol, EXAMPLE 1. After 6 hours, the solution is concentrated. The product is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂O(0.1 % TFA) to 70% CH₃CN/H₂O(0.1% TFA). The appropriate collected fractions are lyophilized to afford the title compound as a white solid (0.37 g, 0.65 mmol). 'H NMR (d⁶-DMSO, 300MHz) δ 9.33 (bs, 2H), 8.96 (bs, 2H), 8.30 (s, 1 H), 8.18 (s. 1 H), 8.04 (d, 1 H), 7.70 (m, 2H), 7.50 (m, 1 H), 7.28 (m, 2H), 4.55 (s, 2H), 3.86 (s, 2H), 3.44 (m, 2H), 3.22 (m, 2H).

The following compounds are prepared from l-(4-Aminoquinazoline-7-ylmethyl)-3-efhyl- piperazine-2-one, Example 77, and the appropriate sulfonyl chloride using the method of Example 101.

EXAMPLE 122. 4-[4-(6-Chloro-l H-benzoimidazol-2-ylmethyl)-2-oxo-piperazin-l -ylmethyl]- benzamidine.

Hydrogen chloride gas is bubbled into an ice-cooled solution of 4-[4-(6-chloro-lH- benzoimidazol-2-ylmethyl)-2-oxo-piperazin-l -ylmethyl]-benzonitrile ( 100 mg, 0.264 mmol), (prepared by deprotecting 4-(4-cyanobenzv l)-3-oxopiperazine- l -carboxylic acid benzyl ester. EXAMPLE 66, Part A, followed by alkylation with 6-chloro-2-chloromethylbenzimidazole) in 15 mL of methanol. The solution contained 3A molecular sieves. The reaction mixture is stored at -30°C. The methanol is removed on the rotovap. Fresh methanol (20 ml) is added folowed by a stream of ammonia gas. The resulting mixture is heated to reflux for three hours. The reaction mixture is filtered at room temperature. The mother liquor is condensed and the resulting residue is purified by reverse phase HPLC (0-50 % ACNJLO). The product is isolated as a white solid with a melting point of 91-95°C . MS C₂₀H₂,ClN₆O m/z: 397, 399. Anal. cald. for C₂₀H,,C1N₆O^»3C₂HF₃O,: C, 42.26: H, 3.27; N, 1 1.37. Found C, 42.20: H, 3.44; N, 1 1.36.

EXAMPLE 123. 4-{4-[3-(5-Chloro-thiophen-2-yl)-(E)-acryloyl]-2-oxopiperazin- l - ylmethyl} benzamidine. To a solution of 4-(2-oxopiperazin-l-ylmethyl)benzamidine bistrifluoroacetate (75 mg, 0.16 mmol), EXAMPLE 66, in 1.5 mL of DMF is added N.N-diisopropylethylamine (0.14 mL, 0.80 mmol). After stirring 10 min at room temperature, 3-(5-chloro-thiophen-2-yl)-(E)-acrylic acid (32 mg, 0.17 mmol), EXAMPLE 25, is added, followed by 2-(lH-benzotriazol-l -yl)-l ,l ,3,3-tetramethyluronium tetrafluoroborate (TBTU) (55 mg. 0.17 mmol). The resulting mixture is stirred at room temperature for 16 h and the solution is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 70% CH3CN/H2O (0.1 % TFA) and the appropriate product fractions are combined and lyopholized to provide the title compound (77 mg, 0.15 mmol) as a white solid. 'H NMR (d6-DMSO. 300 MHz) δ 9.27 (bs, 2H), 9.10 (bs, 2H), 7.77 (d. 2H), 7.65 (d, I H), 7.49 (dd. 2H), 7.39 (m, I H), 7.15 (d. I H), 6.89 (d. I H), 4.65 (s, 2H), 4.45, 4.21 (m, 2H. rotamers). 3.80 (m, 2H), 335 (m, 2H). ESI MS. [M+H]^"=403J05 (Cl pattern). EXAMPLE 124. 3-{4-[3-(5-Chloro-thiophen-2-yl)-(E)-acryloyl1-2-oxopiperazin-l- ylmethyljbenzamidine.

The title compound is prepared as described in EXAMPLE 123 using 3-(5-chloro-thiophen-2- yl)-(E)-acrylic acid (EXAMPLE 25) and 3-(2-oxopiperazin-l-ylmethyi)benzamidine bistrifluoroacetate (prepared from 3-bromomefhyl toluylnitrile as described in EXAMPLE 66). 'H NMR (DMSO-d6, 300 MHz) δ 9.32 (bs, 2H), 9.16 (bs, 2H), 7.65 (m, 5H), 7.39 (m, IH), 7.15 (d, I H), 6.89 (d, IH), 4.64 (s, 2H), 4.44, 4.21 (m, 2H, rotamers), 3.93, 3.79 (m, 2H, rotamers), 3.36 (m, 2H). ESI MS, [M+H]⁺=403J05 (Cl pattern).

EXAMPLE 125. 3J4-(6-Chloro-l H-benzoimidazol-2-ylmethyl)-2-oxo-piperazin-l -ylmethyll- benzamidine.

A white solid (13.0 mg. 13%). C₂₀H_2IClN₆O MS m/z: 397, 399 Anal. cald. for C₂₀H₂₁ClN₆O • 3C₂HF₃0₂: C, 42.26; H, 3.27; N, 1 137. Found C, 43.70; H, 3.71 ; N, 1 1.95.

EXAMPLE 126. l-(2-Aminoquinolin-6-ylmethyl)-4-(5^,-chloro-[2,2^,]bithiophenyl-5-sulfonyl)piperazin- 2-one.

The title compound is prepared as described in Example 101 using l-(2-aminoquinolin-6- ylmethyl)piperazin-2-one, EXAMPLE 67, and 5'-chloro-[2,2']bithiophenyl-5-sulfonyl chloride, EXAMPLE 2. The crude product is triturated in CH₂C1₂ and filtered to provide the title compound as a white solid. 'H NMR (d₆-DMSO, 300 MHz) δ 7.82 (d, 1 H), 7.68 (d, 1 H), 7.42 (m, 3H). 736 (d, 1 H), 7.25 (d, I H), 7.20 (d, I H), 6.70 (d, I H), 6.43 (bs, 2H), 4.53 (s, 2H), 3.78 (s, 2H), 3.31 (m, 4H). MS (ion spray) m/z 519, 521 , (M+H), Cl pattern.

EXAMPLE 127. 6-r4-(6-Chlorobenzo[b1thiophene-2-sulfonyl)-2-oxopiperazin-l -ylmethyn-lH- quinolin-2-one.

The title compound is prepared as described in EXAMPLE 101 , using 6-(2-oxopiperazin-l - ylmethyl)J H-quinolin-2-one, minor product from EXAMPLE 67, Part D, and 6-chlorobenzo[b]thiophene-2-sulfonyl chloride, EXAMPLE 1. The crude product is triturated in CH₂C1₂ and filtered to provide the title compound as a white solid. 'H NMR (d₆-DMSO, 300 MHz) δ 1 1.12 (bs, IH). 8.33 (s, IH), 8.18 (s, IH). 8.07 (d,l H), 7.78 (d,lH), 7.58 (dd, I H), 7.45 (s, lH), 7.30 (dd, IH), 7.18 (d. I H), 6.46 (d, I H), 4.52 (s, 2H), 3.86 (s, 2H), 3.43 (m, 2H), 3.31 (m, 2H). MS (ion spray) m/z 488, 490. (M+H). Cl pattern. The following compounds are prepared using starting materials prepared as described in Examples 67, 68 and 73 and the appropriate carboxylic acid according to the method of Example 123.

The following compounds are prepared from starting materials prepared as described in Example 67 and the appropriate aryl-methyl bromide or allyl-methyl bromide using a K₂C0₃- mediated alkylation reaction.

The following compounds are prepared from starting materials prepared as described in Examples 66, 67, 68 and 73 and the appropriate aryl-methyl bromide or allyl-methyl bromide using a K₂C0₃-mediated alkylation reaction.

EXAMPLE 185. l-(4-Aminoquinazolin-7-ylmethyl)-4-(6-chlorobenzo[b1thiophene-2- sulfonyl)piperazin-2-one.

The title compound is prepared as described in EXAMPLE 101 , substituting l-(4- aminoquinazoline-7-ylmethyl)piperazine-2-one bishydrochloride, EXAMPLE 72, for 4-(2-oxopiperazin- l-ylmethyl)-benzamidine. The product is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1% TFA) to 70% CH₃CN/H₂0 (0.1 % TFA). The appropriate collected fractions are lyopholized to afford the title compound as a white solid. MS (ion spray) m/z 488, 490, (M+H). Η NMR (d₆-DMSO, 300 MHz) δ 9.65 (s, 2H), 8.80 (s, I H), 8.30 (m, 2H), 8.20 (s, I H), 8.05 (d, I H), 7.60 (m, 3H), 4.70 (s, 2H), 3.85 (s. 2H), 3.50-3.20 (m, 4H).

EXAMPLE 186. 4-(4-Amino-quinazolin-7-ylmethyl)-3-oxo-piperazine-l -sulfonic acid 3-chloro- benzylamide. To a solution of ]-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one bishydrochloride,

EXAMPLE 72, (0.1 Og, OJOmmol) is 9 mL of DMF is added 3-chlorobenzyl sulfamyl catechol (0.09g, 0.30mmol), EXAMPLE 4, Et,N (0.08g, 0.75 mmol) and DMAP (0.001 g, 0.12 mmol). The solution is heated to 60°C. After 16 h, the solution is concentrated. The crude product is purified by RP-HPLC eluting with a gradient of 10% CH₃CN/H₂0 (0.1 %TFA) to 100% CH₃CN. The product fractions are lyophilized to give the title compound (0.077g, 0.17 mmol) as the TFA salt. Η NMR (d₆-DMSO, 300 MHz) δ 9.82 (bs, 2H), 8.98 (s. I H), 8.52 (d, IH), 8.32 (d, IH), 7.60 (m, 2H). 7.35 (m, 4H), 4.69 (AB, 2H), 4.1 1 (m, 2H), 3.77 (s, 2H). 3.38 (m, 2H), 3.27 (m, 2H). MS (ion spray) m/z 461 , 463, (M+H), Cl pattern. The following compounds are prepared from the compound of Example 72 and the appropriate sulfonyl choride using the method of Example 101.

The following compounds are prepared from starting materials obtained as described in

Examples 75-88 and the appropriate sulfonyl chloride using the method of Example 101.

The following compounds are prepared from starting materials obtained as described in Examples 72 and 73 and the appropriate sulfonyl chloride according to the method of Example 101 or the appropriate carboxylic acid according to the method of Example 123.

EXAMPLE 213. 4-[2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]- 1 -( 1 H-pyrrolor3,2-c]pyridin-2- ylmethyl)piperazin-2-one.

A. 2-{4-[2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-2-oxopiperazin-l-ylmethyl}pyrrolor3,2- clpyridine-1 -carboxylic acid tert-butyl ester.

To a solution of 2-(2-oxopiperazin-l-ylmethyl)pyrrolo[3.2-c]pyridin-l -carboxylic acid tert-butyl ester (0.71 g, 2.1 mmol), EXAMPLE 69, in CH₃CN (7 mL) is added triethylamine (0.60 mL, 43 mmol) followed by 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride. EXAMPLE 3, (0.57 g. 2.1 mmol). The mixture is stirred overnight, then concentrated to dryness. The residue is diluted with CH₂C1₂ and washed with saturated sodium bicarbonate and brine. The organic layer is dried over MgS0₄, filtered and concentrated in vacuo to give the title compound (1.2 g, 2.1 mmol) as a light yellow solid. The crude material can be used in the subsequent step without further purification. Η NMR (CDC1₃, 300 MHz) δ 8.80 (s, I H), 8.42 (d, I H), 7.88 (d, I H), 7.55 (d, I H), 7.14 (d, I H), 6.98 (d, I H), 6.41 (s, I H),

636 (d, I H). 5.00 (s, 2H), 3.98 (s, 2H), 3.61 (m, 4H), 1.71 (s, 9H). Ion spray MS, [M+H] = 537, 539. Cl pattern.

B. 4-[2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl1-l-(lH-pyrrolo[3.2-c]pyridin-2-ylmethyl)piperazin-2- one.

Trifluoroacetic acid (2.2 mL, 28.6 mmol) is added dropwise to a slurry of 2-[4-(6- chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazin- 1 -ylmethyl]pyrrolo[3,2-c]pyridine- 1 -carboxylic acid tert-butyl ester (132 g, 2J mmol) in CH₂C1₂ (25 mL) at 0°C. After 1.5 hours, the ice bath is removed and the solution stirred at room temperature for 4 hours. The reaction mixture is diluted with methylene choride and washed with saturated sodium bicarbonate and brine. The organic layer is dried ov er MgS0 . filtered and concentrated in vacuo to give the title compound as the free base. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH,CN/H₂0 (0.1% TFA) to 100% CH₃CN and the appropriate product fractions are lyophilized to provide the title compound (1.29 g, 2.2 mmol) as a white solid. 'H NMR (CDC1₃. 300 MHz) δ 14.90 (bs, 1 H), 12.81 (s, 2H), 9.12 (s, 1 H), 8.41 (d, 1 H), 7.89 (d, I H), 7.60 (d, IH), 7.50 (d. I H), 7.20 (d, I H). 7.12 (d, I H), 6.95 (s, IH), 4.80 (s, 2H), 3.98 (s, 2H), 3.48 (s, 4H). Ion spray MS. [M+H]⁺= 437, 439. Cl pattern.

EXAMPLE 214. 4-(6-Chlorobenzo[b1thiophene-2-sulfonyl)- 1 -( 1 H-pyrrolo[3,2-c]pyridin-2- ylmethyl)piperazin-2-one.

A. 2-[4-(6-Chlorobenzorb1thiophene-2-sulfonyl)-2-oxopiperazin-l -ylmethyllpyrrolo[3,2-clpyridine-l- carboxylic acid tert-butyl ester. Η NMR (CDC1₃, 300 MHz) δ 8.7 (s, 1 H), 8.41 (d, 1 H), 7.9-7.8 (m, 3H), 7.45 (d, 1 H), 7.25 (d,

IH), 6.31 (s, IH), 4.95 (s, 2H). 3.98 (s, 2H), 3.65 (m, 2H), 3.55 (m, 2H). 1.68 (s, 9H). Ion spray MS, [M+H]⁺= 561, 563, Cl pattern.

B. 4-(6-Chlorobenzo[b1thiophene-2-sulfonyl)-l -(l H-pyrrolo[3,2-clpyridin-2-ylmethyl)piperazin-2-one trifluoroacetate.

Η NMR (d6-DMSO. 300 MHz) δ 14.68 (bs, 1 H). 12.6 (s, 1 H). 9.1 (s, 1 H), 836 (d, 1 H), 8.29 (d, IH), 8.17 (s, IH), 8.05 (d, IH). 7.82 (d, I H), 7.56 (m. 2H), 6.83 (s, IH). 4.1 (s, 2H), 3.84 (s, 2H), 3.38 (m, 4H). Ion spray MS, [M+H]^"= 461,463, Cl pattern.

EXAMPLE 215. 4-(6-Chlorobenzo[b]thiophene-2-sulfonyl)- 1 -(5-oxy- 1 H-pyrrolo[3J-c]pyridin-2- ylmethyl)piperazin-2-one.

4-(6-Chlorobenzo[b]thiophene-2-sulfonyl)-l -( l H-pyrrolo[3,2-c]pyridin-2-ylmethyl)piperazin-2- one (0.06 g, 0.13 mmol) is dissolved in anhydrous methylene chloride (20 ml), treated with m- chloroperbenzoic acid (0.03 g. mmol) and stirred at room temperature for 4 hours. The solution is diluted with methylene chloride, washed with NaHC0₃, dried (Na₂S0 ) and concentrated. The residue is purified by flash chromatography (5- 10 % MeOH/CH₂Cl₂) and converted to the TFA salt to provide the title compound (0.015 g, 0.032 mmol). 'H NMR (CDC1₃. 300 MHz) δ 9.14 (bs, I H), 8.95 (d, IH), 7.8- 7.87 (m, 3H), 7.57 (d, IH), 7.48 (dd. IH), 6.87 (s, I H), 4.90 (s, 2H), 3.95 (s. 2H), 3.86 (s, 3H), 3.49 (s, 3H). El MS, [M⁺] = 474, 476, Cl pattern.

EXAMPLE 216. 4-(6-Chlorobenzo[b1thiophene-2-sulfonyl)- 1 -( 1 -methyl- 1 H-pyrrolor3,2-c]pyridin-2- ylmethyl)piperazin-2-one.

4-(6-Chlorobenzo[b]thiophene-2-sulfonyl)- 1 -( 1 H-pyrrolo[3,2-c]pyridin-2-ylmethyl)piperazin-2- one (0.59 g, 1.28 mmol), EXAMPLE 214, is dissolved in anhydrous DMF (30 ml), cooled in an ice bath, treated with 60 % sodium hydride (0.061 g, 1.53 mmol) and stirred at room temperature for 30 minutes. The solution is treated with methyl iodide (83 mL, 133 mmol) and warmed to room temperature over 4 hours. The reaction is quenched with ammonium chloride solution, diluted with ethyl acetate and separated. The organic layer is washed with brine (3x), dried (Na₂S0₄) and concentrated. The residue is purified by flash chromatography (5-10 % MeOH/CH₂Cl₂) to provide the title compound (0.31 g, 0.65 mmol). 'H NMR (CD₃OD, 300 MHz) δ 8.55 (d, IH), 7.99 (dd, IH), 7.82 (m, 3H), 7.49 (dd, IH), 7.43 (d, IH), 6.55 (s, IH), 4.75 (s, 2H), 3.96 (s, 2H), 3.52 (m, 4H), 3.86 (s, 3H), 3.49 (s, 3H). Ion Spray MS, [M+H]⁺=477.

The following compounds are prepared from starting materials obtained as described in

Example 69 and the appropriate sulfonyl chlorides according to the method of Example 101.

EXAMPLE 247. 1 -(4- Amino- 1 H-pyrrolo 3,2-c1pyridin-2-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2- sulfonyl)piperazin-2-one.

A. (2-Chloro-pyridin-4-yl)-carbamic acid tert-butyl ester.

NaHMDS (61.7 mL, 1.OM solution in THF) is rapidly added to a solution of 2-chloro-pyridin- ylamine (4.0 g, 30.9 mmol) amd BOC anhydride (6.74 g, 30.9 mmol) in THF (28 mL) at RT. The reaction mixture is cooled in an ice water bath (0°C) for l h then stirred for 3 hr at RT. The gelatinous mixture is concentrated in vacuo and diluted with ethyl acetate and saturated NH C1 solution. The organic layer is washed with 0.1N HCl, saturated NaHC0₃ and brine. The organic layer is then dried over MgS0₄, filtered and concentrated to dryness. The crude product is chromatographed eluting with 1% MeOH/CH₂Cl₂ to yield the title product (5.57 g, 24.4 mmol) as a yellow solid. Η NMR (CDC1₃, 300 MHz) ? 8.18 (d, IH), 7.48 (d, IH). 7.12 (dd, IH), 1.60 (s, 9H). El MS [M]⁺=228.

B. (2-Chloro-3-iodo-pyridin-4-v l)-carbamic acid tert-butyl ester. tert-Butyllithium (36.3 mL, 1.7M in pentane) is added dropwise to a solution of (2-chloro- pyridin-4-yl)-carbamic acid tert-butyl ester (6.00 g, 26.2 mmol) in THF (46 mL) at -78 °C under Ar. The yellow/orange mixture is stirred for 2 h at -78°C then warmed to -40 °C for 1 h then cooled to -78°C before dropwise addition of I₂ (15.65 g, 61.7 mmol) in THF (49 mL). The reaction mixture is stirred for 1.5 h at -78°C then at - 10°C for 30 minutes. The reaction is quenched with saturated NH₄C1 solution then diluted with CH₂Cl_: and washed with saturated NH C1, saturated sodium thiosulfate, water then brine. The organic layer is dried over MgS0₄, filtered and concentrated to dryness. The crude product is chromatographed eluting with 1 -2% MeOH/CH₂Ci₂ to yield the title product (7.96 g, 22.5 mmol) as a bright yellow solid. 'H NMR (CDC1₃, 300 MHz) 8.14 (d, IH), 8.02 (d, I H), 7.32 (bs, I H), 1.60 (s, 9H). El MS [M]⁺=354. 356, Cl pattern.

C. 4-(4-Chloro-lH-pyrrolo[3J-clpyridin-2-ylmethyl)-3-oxo-piperazine-l-carboxylic acid benzyl ester. Trifluoroacetic acid (10 mL) is added to a solution of 2-(4-benzyloxycarbonyl-2-oxo-piperazin- l-ylmtheyl)-4-chloro-pyrrolo[3.2-c]pyridine-l -carboxylic acid tert-butyl ester (5.66 g, 1 13 mmol, prepared in the same manner as described previously) in CH₂C1₂(10 mL). The solution is stirred overnight then diluted with CH₂Cl₂ and washed with saturated NaHC0₃ and brine. The organic layer is dried over MgS0₄, filtered and concentrated to dryness. The crude product is chromatographed eluting with 1-5% MeOH/CH₂Cl₂ to yield the title product (3.81 g, 9.56 mmol) as a foamy yellow solid.

Η NMR (CDCI₃, 300 MHz) 9.43 (bs, IH), 8.08 (d, IH). 7.38 (s, 5H), 7.18 (d, IH), 6.51 (s, IH), 5.15 (s, 2H), 4.58 (s, 2H), 4.20 (s. 2H). 3.71 (m, 2H), 3.50 (m, 2H). Ion spray [M+H]⁺= 399, 401 , Cl pattern.

D. 4-(l-Benzenesulfonyl-4-chloro-lH-pyrrolo 3,2-clpyridin-2-ylmethyl)-3-oxo-piperazine-l -carboxylic acid benzyl ester.

Powdered NaOH (0.96 g. 23.9 mmol) followed by nBu₄NHS0₄ (032 g, 0.96 mmol) and benzene sulfonyl chloride ( 1.8 mL, 14.1 mmol) is added to a solution of 4-(4-chloro-l H-pyrrolo[3,2-c]pyridin-2- ylmethyl)-3-oxo-piperazine-l -carboxylic acid benzyl ester (3.81 g, 9.56 mmol) in CH₂CI₂(32 mL) at RT. The resulting slurry is stirred for 3.5 h then diluted with CH₂Cl₂ and washed with saturated NaHC0₃ and brine. The organic layer is dried over MgS0 , filtered and concentrated to dryness. The crude product is chromatographed eluting with 1 -5% MeOH/CH₂Cl₂ to yield the title product (5.06 g, 9.38 mmol). Η NMR (CDCI₃, 300 MHz) ? 8.23 (d, I H), 7.97 (d, I H), 7.84 (d, 2H), 7.61 (d, I H). 7.51 (m, 2H), 7.38 (s, 5H), 6.50 (s, I H), 5.18 (s, 2H). 5.03 (s, 2H), 4.29 (s, 2H), 4.29 (s, 2H), 3.80 (m, 2H), 3.51 (m, 2H). Ion spray [M+H]⁺= 539, 541, Cl pattern.

E. l-(l-Benzenesulfonyl-4-chloro-l H-pyrrolo 3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

TMSI (2.1 mL, 19.0 mmol) is added to a solution of 4-(l-benzenesulfonyl-4-chloro-lH- pyrrolo[3,2-c]pyridin-2-ylmethv l)-3-oxo-piperazine-l -carboxylic acid benzyl ester (5.06 g, 9.38 mmol) in CH₃CN (134 mL) at 0°C. The reaction mixture is warmed to RT and stirred for 5 hours. The reaction mixture is concentrated to dryness and the red residue is diluted with MeOH and concentrated to dryness (this is repeated twice). The mixture is diluted with CH₂C1₂ and washed with saturated NaHCO, and brine. The organic layer is dried over MgS0 , filtered and concentrated to dryness. The crude product is chromatographed eluting w ith 1 -5% MeOH/CH₂Cl₂ to yield the title product (0.70 g, 1.14 mmol) and unreacted starting material (3.58 g. 6.64 mmol). 'H NMR (CDC1₃, 300 MHz) ? 8.20 (d, I H), 7.93 (d, I H), 7.85 (d, 2H), 7.60 (d, I H), 7.51 (m, 2H), 6.50 (s, I H), 5.01 (s, 2H), 3.45 (m, 2H), 3.18 (m, 2H). Ion spray [M+H]^"= 405, 407, Cl pattern.

F. 1 -(4- Amino- 1 H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-4-(6-chlorobenzo[b]thiophene-2- sulfonyl)piperazin-2-one.

Anhydrous ammonium acetate (0.56 g, 7.2 mmol), phenol (0J5 g, 4.8 mmol) and 1-(1- benzenesulfonyl-4-chloro-lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2- sulfonyl)-piperazin-2-one (0.31 g, 0J8 mmol, prepared as described previously) are heated to 100°C for 3.5 days. The mixture is cooled to RT then the crude product is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1 % TFA) to 100% CH₃CN then the appropriate product fractions are lyophilized to provide the title compound (1.29 g, 2.2 mmol) as a white solid (22.4 mg, 0.038 mmol). Η NMR (DMSO-d₆, 300 MHz) ? 12.40 (bs, 1 H), 12.00 (bs, 1 H), 8.31 (d, 1 H), 8.20 (s. 1 H), 8.06 (d, 1 H), 8.02 (bs, 2H), 7.57 (dd, IH), 7.48 (m, IH), 6.89 (d, IH), 6.81 (s, I H), 4.60 (s, 2H). 3.81 (s, 2H), 3.40 (m, 4H). LR-FAB MS. [M+H]⁺=476, 478.

EXAMPLE 248. 4-r2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl1-5-(+)-hydroxymethyl-l-( l H- pyrrolo 3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

A. 2-{4-[2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-2-(±)-hydroxymethyl-6-oxo-piperazin-l- ylmethyl}-pyrrolo[3-2-c]pyridine- l -carboxylic acid tert-butyl ester.

Sodium borohydride (0.005 g, 0.13 mmol) is added to a solution of 2-{4-[2-(5-chloro-thiophen- 2-yl)-ethenesulfonyl]-2-(±)-methoxycarbonyl-6-oxo-piperazin-l-ylmethyl}-pyrrolo[3,2-c]pyridine- l - carboxylic acid tert-butyl ester (0.04 g, 0.07 mmol), (prepared from 2-(2-(±)-methoxycarbonyl-6-oxo- piperazin-l-ylmethyl)-pyrrolo[3.2-c]pyridine-l -carboxylic acid tert-butyl ester, EXAMPLE 71 , and 2-(5- chloro-thiophen-2-yl)-ethenesulfonyl chloride, EXAMPLE 3, using the procedure described in

EXAMPLE 214, Part A) in MeOH (3 mL) at RT. The reaction mixture is stirred for 6 h then quenched with water and concentrated in vacuo. The crude product (0.04 g) is taken onto the next step without further purification.

B. 4-[2-(5-Chloro-thiophen-2-\l)-ethenesulfonyll-5-(+)-hydroxymethyl-l -(l H-pyrrolo[3,2-c]pyridin-2- ylmefhyl)-piperazin-2-one.

Trifluoroacetic acid (1.8 mL) is added to a solution of 2-{4-[2-(5-chloro-thiophen-2-yl)- ethenesulfonyl]-2-(±)-hydroxymethyl-6-oxo-piperazin-l -ylmethyl}-pyrrolo[3,2-c]pyridine-l -carboxylic acid tert-butyl ester (0.04 g) in CH₂C1₂ (4.2 mL) at RT. The reaction mixture is stirred for 4 h then 10

concentrated in vacuo. The title compound is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1 % TFA) to 100% CH₃CN and lyophilizing the appropriate product fractions. 'H NMR (DMSO-d₆, 300 MHz) δ 9.10 (s, IH), 8.46 (d, IH), 7.82 (d, 1H),7.50 (d, IH) 7.43 (d, IH), 7.14 (d, IH), 7.01 (d, IH), 6.94 (s, IH), 5.12 (bs, IH), 4.80 (AB, 2H), 3.98 (d, 2H0, 3.90 (m, IH), 3.40-3.50 (m, 4H). APCI MS, [M+H]⁺=467, 469.

The following compounds are prepared from starting materials obtained using the methods of Examples 69, 70 and 71 and the appropriate sulfonyl chorides according to the method of Example 101.

The following enantiomerically pure compounds are obtained by chiral resolution on a

CHIRACEL OD prep column.

EXAMPLE 255. 4-r2-(5-Chloro-thiophen-2-yl)-ethenesulfonyll-6-(R)-hvdroxymethyl-l-dH- pyrrolor3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

A. 6-(R)-(tert-Butyl-dimethyl-silanyloxymethyl)-4-[2-(5-chloro-thiophen-2-yl)-ethenesulfonyl]-l-(lH- pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

Trifluoroacetic acid (0.25 mL) is added to a solution of 2-{2-(R)-(tert-butyl-dimethyl- silanyloxymethyl)-4-[2-(5-chloro-thiophen-2-yI)-ethenesulfonyl]-6-oxo-piperazin-l -ylmethyl}- pyrrolo[3,2-c]pyridine-l -carboxylic acid tert-butyl ester (0.025 g, 0.037 mmol) in CH₂C1₂ (0.5 mL) at room temperature. The reaction mixture is stirred for 2 h then concentrated to dryness. The residue is diluted with CH₂C1₂ and washed with saturated NaHC0₃ and brine. The organic layer is dried over MgS0₄, filtered and concentrated in vacuo. The crude product (0.019 g, 0.033 mmol) is used in the subsequent step without further purification.

B. 4-[^"2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-6-(R)-hydroxymethyl- 1 -( I H-pyrrolo 3,2-c]pyridin-2- ylmethyl)-piperazin-2-one.

Glacial acetic acid (3 mL, 0.046 mmol) and tetrabutylammonium fluoride (92 mL, 0.092 mmol) is added to a solution of 6-(R)-(tert-butyl-dimethyl-silanyloxymethyI)-4-[2-(5-chloro-thiophen-2-yl)- ethenesulfonyl]-l-(l H-pyrrolo[3J-c]pyridin-2-ylmethyl)-piperazin-2-one (0.019 g, 0.033 mmol) in THF (0.5 mL). The resulting solution is stirred for 4 h then concentrated in vacuo. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1 % TFA) to 100% CH₃CN and the appropriate product fractions are lyophilized to provide the title compound (0.009 g, 0.016 mmol) as a white solid. 'H NMR (DMSO-d₆. 300 MHz) ? 14.50 (bs, I H), 12.60 (bs, I H). 9.18 (s, IH), 8.38 (d, IH), 7.89 (d, IH), 7.61 (d, IH), 7.50 (d, IH), 7.21 (d, IH), 7.08 (d, IH), 6.90 (s, IH), 5.03 (s, 2H), 4.63 (d, 2H), 3.70-3.90 (AB, 2H), 3.75 (m, I H), 3.21 (m, 2H). Ion spray MS, [M+H]^"=467, 469, Cl pattern.

The following compounds are prepared from starting materials obtained as described in Examples 69, 70 and 71 and the appropriate sulfonyl chloride according to the method of Example 101.

EXAMPLE 268. 1 -(4-Aminoquinazolin-7-ylmethyl)-4-(6-chlorobenzo[b]thiophene-2- ylmethyl)piperazin-2-one.

To a solution of l-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one bishydrochloride (1.84 g, 5.73 mmol), EXAMPLE 72, in DMF (20 mL) is added 2-bromomethyl-6-chloro-benzo[b]thiophene, EXAMPLE 5, (1.5 g, 5.73 mmol) and K₂C0₃ (4.0 g, 28.7 mmol). The solution is stirred for 16 hours. After this time, the solution is diluted with water. The solution is acidified with trifluoroacetic acid. The product is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1% TFA) to 50% CH₃CN/H₂0 (0.1 % TFA). The appropriate collected fractions are lyopholized to afford the title compound as a white solid. 'H NMR (d⁶-DMSO, 300MHz) δ 9.78 (bs. 3H), 8.82 (s, I H), 834 (d, I H), 8.07 (s, I H). 7.81 (d, IH), 7.63 (d. I H), 7.51 (s, I H), 7.32 (m, 2H), 4.71 (s, 2H), 3.95 (s, 2H), 3.28 (m, 4H), 2.80 (m. 2H).

EXAMPLE 269. 1 -(4-Aminoquinazolin-7-ylmethyl)-4-(6-chloro- 1 H-benzoimidazol-2- ylmethyl)piperazin-2-one.

A mixture of l-(4-aminoquinazolin-7-ylmethyl)piperazin-2-one (50 mg, 0.15 mmol), EXAMPLE 72, 6-chloro-2-chloromethylbenzimidazole (30.5 mg, 0.15 mmol) and potassium carbonate (83 mg, 0.6 mmol) in 2 mL of DMF is stirred at ambient temperature overnight. The mixture is purified on reverse phase HPLC (CH₃CN/H₂0/TFA) to give the trifluoroacetic acid salt of 1 -(4-aminoquinazolin- 7-ylmethyl)-4-(6-chloro- 1 H-benzoimidazol-2-ylmethyl)piperazin-2-one (25 mg) as a solid. 'H NMR (CD₃OD, 300 MHz) δ 8.69 (s, IH). 8.33 (d, IH), 7.79 (s, IH), 1.15-1.69 (m, 3H), 7.57-7.54 (m, IH), 4.86 (s, 2H), 4.22 (s, 2H). 3.31 (m, 4H). 2.99 (m, 2H). MS m/z 422 (M+H). EXAMPLE 270. l -(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzothioazol-2-ylmethyl)-piperazin- 2-one.

To a solution of l-(4-amino-quinazoIin-7-ylmethyl)-piperazin-2-one ( 76 mg, 0.23 mmol), EXAMPLE 72, in 2 mLof DMF is added potassium carbonate (127 mg, 0.92 mmol) followed by 6- chloro-2-chloromethyl-benzothiazole (prepared according to the procedure of B.L.Mylari, Synthesis Comm. 1989, 16, 2921 ) (50 mg, 0.23 mmol). The resulting mixture is stirred overnight at room temperature. The undissolved potassium carbonate is removed by filtration and the mother liquor is purified by reverse phase HPLC (10-100% CH₃CN/H₂0). The desired is product is obtained as a white solid with a melting point of 123-126°C. C₂₁H_l9ClN₆OS MS m/z: 439, 441. Anal. cald. for C_2IH₁₉C1N₆0S - 2C₂HF₃0₂: C, 45.02; H, 3.17 N, 12.60. Found C, 44.15; H, 3.19; N, 1 1.79.

EXAMPLE 271. l-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzooxazol-2-ylmethyl)-piperazin-2- one. The desired product (10.0 mg, 7 %) is isolated as a white solid. C_2lH,₉CIN₆0₂ MS m/z: 423, 425.

EXAMPLE 272. l -(4-Amino-quinazolin-7-ylmethyl)-4-(5-chloro-benzothioazol-2-ylmethyl)-piperazin- 2-one.

The desired product (19.0 mg, 22%) is obtained as a white solid. C₂|H|₉C1N₆0S MS m/z: 438,440. Anal. cald. for C_2iH₁₉ClN₆OS - 2C₂HF₃0₂: C, 45.02; H, 3.17 N, 12.60. Found C, 43.35; H, 3.26; N, 12.65.

EXAMPLE 273. 3-[4-(4-Aminoquinazoline-7-ylmethyl)-3-oxopiperazin-1 -ylmethyl]-7-chloro-lH- quinolin-2-one. The title compound is prepared as described in EXAMPLE 268, substituting 3-bromomethyl-7- chloro- l H-quinoline-2-one, EXAMPLE 8, for 2-bromomethyl-6-chlorobenzo[b]thiophene. The product is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂O(0.1 % TFA) to 50% CH₃CN/H₂O(0.1 %

TFA). The appropriate collected fractions are lyopholized to afford the title compound as a white solid.

'H NMR (d⁶-DMSO, 300MHz) δ 12.18 (bs, l H), 9.75 (m, I H), 8.86 (s, I H), 8.40 (m, I H). 8.1 1 (d, I H), 8.10 (s, IH), 7.78 (m, IH), 7.69 (m, 2H), 7.37 (m, IH), 4.80 (s, 2H), 4.10 (m, 2H), 3.47 (m, 4H), 3.30 (m,

2H). MS (ion spray) m/z 449, (M+H). EXAMPLE 274. 1-(4-Amino-quinazolin-7-ylmethyl)-4-(3-chloro-l H-indol-6-ylmethyl)-piperazin-2- one.

A. 1 -(4-Amino-quinazolin-7-v lmethyl)-4-(3-chloro- 1 -(toluene-4-sulfonyl)- 1 H-indol-6-ylmethyl)- piperazin-2-one.

The title compound is prepared as described in EXAMPLE 268 using 6-bromomefhyl-3-chloro- l-(toluene-4-suIfonyl)-l H-indole. EXAMPLE 16, in place of 2-bromomethyl-6-chloro- benzo[b]thiophene. The crude material 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 combined and lyopholized to give a white solid. Η NMR (DMSO-d₆, 300 MHz) ? 9.75 (bs, 2H), 8.82 (s, IH), 8J0 (d, IH), 7.64 (m. 2H), 7.60 (m, 2H), 7J0 (d, IH), 7.23 (m, IH), 7.19 (m, 2H), 6.99 (d, 2H), 5.09 (s, 2H), 4.78 (s, 2H), 4.10 (m, 2H), 3J0 (m, 4H), 2.49 (s, 3H).

B. l-(4-Amino-quinazolin-7-v lmethyl)-4-(3-chloro- l H-indol-6-ylmethyl)-piperazin-2-one.

To a solution of l-(4-amino-quinazolin-7-ylmethyl)-4-(3-chloro-l-(toluene-4-sulfonyl)-l H- indol-6-ylmethyl)-piperazin-2-one ditrifluoroacetate (31 mg, 0.04 mmol) in 2 L of MeOH is added 0.3 mL of IN NaOH solution. The solution is heated at 100°C for 3 hours. After this time, the solution is diluted with water/acetonitrile and neutralized with trifluoroacetic acid. The crude material is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1 % TFA) to 60% CH₃CN/H₂0 (0.1 % TFA) and the appropriate product fractions are combined and lyopholized to give the title compound (21 mg, 0.03 mmol) as a white solid. 'H NMR (DMSO-d₆, 300 MHz) ? 9.71 (bs, 2H), 8.81 (s, IH), 8J0 (d, I H), 7.63 (m, 3H), 7.53 (d, IH), 7.50 (s. IH), 7.20 (d, I H), 4.78 (s, 2H), 430-3.10 (m, 8H). ESI MS, [M+Hf=421 , 423 (Cl pattern).

EXAMPLE 275. l-(4-Amino-quinazolin-7-ylmethyl)-4- 3-(5-chloro-thiophen-2-yl)-(E)-allyl]-piperazin- 2-one.

To a solution of l-(4-amino-quinazolin-7-ylmethyl)-piperazin-2-one bishydrochloride (100 mg, 0.31 mmol), EXAMPLE 72, in 3 mL of DMF is added 2-(3-bromo-(E)-propenyl)-5-chloro-thiophene (73 mg, 0.31 mmol), prepared as described in EXAMPLE 17., and K₂C0₃ (0.21 g, 1.54 mmol). The solution is stirred at room temperature for 16 hours. After this time, the solution is diluted with water/acetonitrile and neutralized with trifluoroacetic acid. The crude material is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1 % TFA) to 60% CH₃CN/H₂0 (0.1 % TFA) and the appropriate product fractions are combined and lyopholized to give the title compound (80 mg. 0.12 mmol) as a white solid. 'H NMR (DMSO-d₆, 300 MHz) ? 9.76 (bs, 2H), 8.81 (s, IH), 8J0 (d, I H), 7.70 (s, I H), 7.62 (dd, IH), 7.10 (m, 2H), 6.90 (d, I H), 6.05 (dt, IH), 4.80 (s, 2H), 3.77 (m, 4H), 3.50 (m, 2H), 3.37 (m, 2H). ESI MS, [M+H]⁺=414J16 (Cl pattern). Anal. (C₂₀H₂₀C1N₅OS 2.0TFA 1.1 H₂0) C, H, N.

EXAMPLE 276. l-(4-Amino-quinazolin-7-ylmethyl)-4-r3-(5-chloro-thiophen-2-yl)-but-2-(E)-enyl]- piperazin-2-one ditrifluoroacetate.

Η NMR (DMSO-d₆. 300 MHz) ? 9.70 (bs, 2H), 8.82 (s, I H), 8J0 (d, IH), 7.68 (s, IH), 7.61 (d, I H), 7.10 (m, 2H), 5.88 (t, IH). 4.79 (s, 2H), 3.75 (m, 4H), 3J9 (m, 2H), 3.29 (m. 2H), 2.09 (s, 3H). El MS, [M+H]⁺=427, 429 (Cl pattern).

EXAMPLE 277. l-(4-Amino-quinazolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-2-ιnethyl-(E)-allyfl- piperazin-2-one ditrifluoroacetate.

'H NMR (DMSO-d₆. 300 MHz) ? 9.80 (bs, 2H), 8.85 (s, IH), 8.41 (d, IH), 7.70 (s, IH), 7.68 (d, IH), 7.06 (d, IH), 7.05 (d, I H). 6.70 (bs, I H), 4.80 (s, 2H), 4.30 (bs, 2H), 3.45 (m, 4H), 3.10 (m, 2H), 1.99 (s, 3H). ESI MS, [M+H]^"=428, 430 (Cl pattern).

EXAMPLE 278. l-(4-Amino-qιιinazolin-7-ylmethyl)-4-[3-(4-bromo-furan-2-yl)-(E)-allyl]-piperazin-2- one.

To a solution of l-(4-amino-quinazolin-7-ylmethyl)-piperazin-2-one (50 mg, 0.20 mmol), EXAMPLE 72. in 3 mL of acetonitrile is added 3-(4-bromo-furan-2-yl)-(E)-propenal (43 mg, 0.22 mmol), prepared as described in EXAMPLE 18, 2 drops of HOAc and sodium triacetoxyborohydride (62 mg, 0.29 mmol). The solution is stirred at room temperature for 16 hours. After this time, the solution is diluted with water/acetonitrile. The crude material 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 combined and lyopholized to give the title compound (48 mg, 0.07 mmol) as a white solid. 'H NMR

(DMSO-d₆, 300 MHz) ? 9.75 (bs, 2H), 8.85 (s, I H), 8.60 (d, I H), 7.95 (s, I H), 7.69 (s, IH), 7.62 (d, IH), 6.80 (s, IH), 6.65 (d. IH), 6.19 (dt, IH), 4.80 (s, 2H), 3.70 (m, 4H), 3.50 ( , 2H). 3.28 (m, 2H). ESI MS, [M+H]⁺=441J43 (Br pattern).

EXAMPLE 279. l-(4-Amino-quinazolin-7-ylmethyl)-4-[3-(6-methoxy-pyridin-3-yl)-(E)-allyl]- piperazin-2-one.

Nitrogen (g) is bubbled through a solution of l -(4-amino-quinazolin-7-ylmethyl)-piperazin-2- one (100 mg, 0.39 mmol), EXAMPLE 72, in 2 mL of CH₃CN. After 5 min, acetic acid 3-(6-methoxy- pyridin-3-yl)-(E)-allyl ester (75 mg, 036 mmol, prepared as described in EXAMPLE 19 in 2 mL of CH₃CN, palladium(II) acetate (catalytic amount), triphenylphosphine (catalytic amount), 2 mL of H₂0 and 0.5 mL of triethylamine are added to the solution. The mixture is heated at 80°C for 1 hours. At this time, the mixture is cooled, filtered and concentrated in vacuo. The crude material is purified by RP- HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1 % TFA) to 60% CH₃CN/H₂0 (0.1 % TFA) and the appropriate product fractions are combined and lyopholized to give the title compound (44 mg, 0.07 mmol) as a white solid. Η NMR (DMSO-d₆, 300 MHz) ? 9.86 (s, IH), 9.79 (s, IH), 8.83 (s, IH), 8J0 (d, IH), 8.25 (s, IH), 7.95 (d, IH), 7.75 (s, IH), 7.63 (d, IH), 6.86 (d, IH), 6.82 (d, IH), 6.32 (dt, IH), 4.78 (s, 2H), 3.98 (s, 2H), 3.93 (m, 2H), 3.85 (s, 3H), 3.53 (m, 4H). ESI MS, [M+Hf=405.

EXAMPLE 280. l-(4-Amino-quinazolin-7-ylmethyl)-4-r3-(5-chloro-thiophen-2-yl)-(E)-allvn-4-oxy- piperazin-2-one.

To a solution of l-(4-amino-quinazolin-7-yImethyI)-4-[3-(5-chloro-thiophen-2-yI)-(E)-allyl]- piperazin-2-one ditrifluoroacetate (0.60 g, 0.94 mmol), prepared as described in EXAMPLE 275, in 25 mL of CH₂C1₂ is added m-chloroperoxybenzoic acid (0.30 g, 0.96 mmol, 55% pure grade). The mixture is stirred at room temperature for 3 h and then concentrated in vacuo. The crude material is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1 % TFA) to 60% CH₃CN/H₂0 (0.1% TFA) and the appropriate product fractions are combined and lyopholized to give the title compound (0.5 mg, 0.76 mmol) as a white solid. 'H NMR (DMSO-d₆, 300 MHz) ? 9.68 (bs, 2H), 8.79 (s, IH), 8.39 (d, IH), 7.68 (s, IH), 7.60 (d, IH), 7.17 (d, I H), 7.12 (d, IH), 7.06 (d, I H), 6.17 (dt, I H), 4.84 (s, 2H), 4.53 (m, 2H), 4.50 (AB, 2H), 4.04 (m, 2H), 3.78 (m, I H), 3.60 (m, I H). ESI MS, [M+H]⁺=430J32 (Cl pattern). Anal. (C₂₀H₂₀ClN₅O₂S 2.0TFA 1 JH₂0) C, H, N.

EXAMPLE 281. 1 -(4-Amino-quinazolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-prop-2-ynyll- piperazin-2-one. The title compound is prepared as described in EXAMPLE 275 using 2-(3-bromo-prop- l-ynyl)-

5-chloro-thiophene (prepared as described in EXAMPLE 20) in place of 2-(3-bromo-(E)-propenyl)-5- chloro-thiophene. The crude material is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1% TFA) to 70% CH₃CN/H₂0 (0.1 % TFA) and the appropriate product fractions are combined and lyopholized to give the title compound as a white solid. Η NMR (DMSO-d₆, 300 MHz) ? 9.77 (bs, 2H), 8.83 (s, IH). 8.38 (d, I H), 7.63 (d, I H), 7.58 (s, I H), 7.25 (d, I H), 7.13 (d, I H), 4.74 (s, 2H), 3.74 (s, 2H), 332 (m. 4H), 2.85 (m, 2H). ESI MS, [M+H]⁺=412, 414 (Cl pattern). EXAMPLE 282. l-(4-Amino-quinazolin-7-ylmethyl)-4-r3-(5-chloro-thiophen-2-yl)-propyl]-piperazin- 2-one

The title compound is prepared as described in EXAMPLE 278 using 3-(5-chloro-thiophen-2- yl)-propionaldehyde (EXAMPLE 28, Part A) in place of 3-(4-bromo-furan-2-yl)-(E)-propenal. The crude material is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1% TFA) to 60% CH₃CN/H₂0 (0.1%) TFA) and the appropriate product fractions are combined and lyopholized to give the title compound as a white solid. 'H NMR (DMSO-d₆, 300 MHz) ? 9.77 (bs, 2H), 8.81 (s, I H), 839 (d, IH), 7.71 (s, IH), 7.60 (d, I H), 6.95 (d, IH), 6.77 (d, I H), 4.78 (s, 2H), 3.88 (m, 2H), 3.50 (m, 2H), 3.42 (m, 2H), 3.05 (m, 2H), 2.80 (t, 2H), 1.96 (m, 2H). ESI MS, [M+H]^"=416,418 (Cl pattern).

EXAMPLE 283. l-(4-Amino-quinazolin-7-ylmethyl)-4-prop-2-ynyl-piperazin-2-one. A. l-(4-Amino-quinazolin-7-ylmethyl)-4-prop-2-ynyl-piperazin-2-one.

Propargyl bromide (0.29 g, 1.95 mmol) is added to a solution containing l-(4-amino-quinazolin- 7-ylmethyl)-piperazin-2-one (0.5 g, 1.95 mmol), EXAMPLE 72, and K₂C0₃ (0.40 g, 2.93 mmol) in DMSO (10 mL) at ambient temperature. After 15 min, the reaction mixture is partitioned between aqueous NaHC0₃ ( 100 mL) and CH₂C1₂ ( 100 mL) and the layers are separated. The aqueous phase is subsequently saturated with NaCl and extracted three times with CHC1₃ (50 mL). The combined organic phase is washed with brine, dried over anhydrous Na₂S0 , filtered and concentrated. The residue is purified by flash silica gel chromatography (CH₂C1₂ to 10% MeOH/CH₂Cl₂) to provide 390 mg (68%) of the title compound as a white solid. 'H NMR (300 MHz, CDC1J δ 2.68 (m, I H), 3.13-337 (m, 6H), 4.07 (app q, J = 5.2 Hz, 1 H), 4.63 (s, 2H), 7.28 (dd, J = 8.4, 1.4 Hz, 1 H), 7.42 (s, 1 H), 7.72 (br s, 2H), 8.14 (d, J = 8.4 Hz, I H), 8.34 (s. I H) ppm; MS (ISP loop): m/z 296 (M+H).

EXAMPLE 284. l-(4-Amino-quinazolin-7-ylmethyl)-4-(3-biρhenyl-2-yl-prop-2-ynyl)-piperazin-2-one. A solution containing l -(4-amino-quinazolin-7-ylmethyl)-4-prop-2-ynyl-piperazin-2-one (50 mg, 0.17 mmol), EXAMPLE 283. 2-bromobiphenyl (44 mg, 0.19 mmol), Et₃N (69 mg, 0.68 mmol), (Ph₃P)₄PdCl₂ (6 mg, 0.008 mmol), and Cul (1 mg, 0.005 mmol) in anhydrous DMF (2 mL) is warmed at 80°C for 1 hours. The reaction mixture is cooled to 50 °C and the solvent is removed over 16 h under a stream of nitrogen. The crude residue is purified by flash silica gel chromatography (CH₂C1₂ to 10% MeOH CH₂C1₂) to afford a colorless gum which is triturated with ethyl alcohol to provide 4 mg (5%) of the title compound as a white solid. Η NMR (300 MHz, d₆-DMSO) δ 3.03 (s, 2H), 3.14 (m, 2H), 331 (m. 2H), 3.50 (s, 2H), 7.21-7.55 (m, 1 IH), 7.76 (br s, 2H), 8.18 (d, J = 8.6 Hz, I H), 8.36 (s, IH) ppm; MS (ion spray): m/z 448 (M+H). EXAMPLE 285. l -(4-Amino-quinazolin-7-ylmethyl)-4-(lH-pyrrolo[3J-c]pyridin-2-ylmethyl)- piperazin-2-one.

A. (3-{3-[4-(4-Amino-quinazolin-7-ylmethyl)-3-oxo-piperazin-l-yl]-prop- l -ynyl}-pyridin-4-yl)- carbamic acid tert-butyl ester.

A solution containing l-(4-amino-quinazolin-7-ylmethyl)-4-prop-2-ynyl-piperazin-2-one (100 mg, 034 mmol), EXAMPLE 283. (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester, EXAMPLE 69, Part B, (108 mg, 0.34 mmol), Et.N (140 mg, 136 mmol), (Ph₃P)₄PdCl₂ (12 mg, 0.017 mmol), and Cul (2 mg, 0.01 mmol) in anhydrous DMF (5 mL) is stirred at ambient temperature. After 5 h, the reaction mixture is diluted with EtOAc (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with EtOAc (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH₂C1₂ to 10% MeOH CH₂C1₂) to provide 59 mg (36%) of SC34 as a colorless oil. 'H NMR (300 MHz, CDC1J δ 1.49 (s. 9H), 2.84 (m, 2H), 3.35 (m. 2H), 3.44 (s, 2H), 3.71 (s, 2H), 4.75 (s, 2H), 6.19 (br s, 2H), 7.24 (d, J = 5.5 Hz, I H), 7.41 (d, J = 8.4 Hz, I H), 7.66 (s, I H), 7.79 (d, J = 8.4 Hz, IH), 8.05 (d, J = 5.5 Hz, I H), 8.37 (s, I H), 8.49 (s, I H), 8.58 (s, l H) ppm: MS (ISP loop): m/z 488 (M+H).

B. 2-r4-(4-Amino-quinazolin-7-v lmethyl)-3-oxo-piperazin-l -ylιnethyl]-pyrrolo[3,2-clpyridine- l - carboxylic acid tert-butyl ester. l ,8-Diazabicyclo[5.4.0]undec-7-ene (37 mg, 0.24 mmol) is added to a suspension containing (3- {3-[4-(4-amino-quinazolin-7-ylmethyl)-3-oxo-piperazin- l -yl]-prop- l -ynyl}-pyridin-4-yl)-carbamic acid tert-butyl ester (59 mg, 0.12 mmol) in anhydrous CH₃CN (5 mL) and the mixture is warmed to 50 °C. Dimethylformamide (1 mL) is added to solubilize and the homogeneous solution is maintained for 5 h at 50°C. The reaction mixture is diluted with EtOAc (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with EtOAc (25 mL) and the combined organic phase is washed with brine, dried over anhvdrous Na,S0₄, filtered and concentrated to provide 50 mg of the product as a crude solid which is used directly without further purification. 'H NMR (300 MHz, CDC1 ) δ 1.64 (s, 9H), 2.78 (m, 2H), 3.30 (m, 2H), 3.37 (s, 2H), 3.95 (s, 2H), 4.74 (s, 2H), 6.24 (br s, 2H), 6.63 (s, 1 H), 7.40 (dd, J = 8.5, 1.6 Hz. 1 H), 7.64 (s, 1 H), 7.81 (d, J = 5.8 Hz. 1 H). 7.83 (d, J = 8.5 Hz, 1 H), 7.99 (s, I H), 8.39 (d, J = 5.8 Hz. I H), 8.58 (s, I H), 8.77 (s, I H) ppm. C. l-(4-Amino-quinazolin-7-ylmethyl)-4-(lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

To a solution containing 2-[4-(4-amino-quinazolin-7-ylmethyl)-3-oxo-piperazin-l -ylmethyl]- pyrrolo[3,2-c]pyridine-l -carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) in CH₂C1₂ (5 mL) is added TFA (1 mL) at ambient temperature. After 16 h, the reaction mixture is concentrated to dryness, diluted with water and purified by reverse-phase HPLC [Buffer A: water w/ 0.1% TFA; Buffer B: CH3CN w/ 0.1% TFA; Gradient: 0% B to 45% B over 30 min] to provide 34 mg (73%, two steps) of the title compound as a white, lyophilized solid. Η NMR (300 MHz, CDC1J δ 2.77 (s, 3H), 3.23 (s, 2H), 331 (m, 2H), 3.89 (s, 2H), 4.00 (br s, 3H), 4.71 (s, 2H), 6.94 (s, IH), 7.60 (m, 2H), 7.84 (d, J = 6.5 Hz, IH), 8.36 (m, 2H), 8.81 (s, IH), 9.18 (s, I H), 9.73 (br s, 2H), 12.87 (s, IH) ppm; MS (ion spray): m/z 388 (M+H).

The following compounds are prepared from the compound of Example 72 using the procedures described above.

EXAMPLE 410. l-(4-Aminoquinazolin-7-ylmethyl)-4-f3-(5-chloro-thiophen-2-yI)-(E)- acryloyl]piperazin-2-one.

The title compound is prepared as described in EXAMPLE 123 using l -(4-aminoquinazoline-7- ylmethyl)piperazine-2-one bishydrochloride, EXAMPLE 72, in place of 4-(2-oxopiperazin-l- ylmethyl)benzamidine bistrifluoroacetate. Η NMR (d6-DMSO, 300 MHz) δ 9.77 (bs, 2H), 8.83 (s, 1 H), 8.40 (dd, I H), 7.68 (d, I H), 7.65 (s, IH), 7.58 (d, 2H), 7.15 (d, 2H), 4.80 (s, 2H), 4.33, 4.15 (m, 2H, rotamers), 3.70 (m, 2H), 3.49 (m, 2H). ESI MS, [M+H]⁺=456, 458 (Br pattern).

The following compounds are prepared from the compound of Example 72 using the methods described above.

EXAMPLE 436. 4-(4-Aminoquinazolin-7-ylmethyl)-3-oxopiperazine-l -carboxylic acid 4-chloro- benzylamide.

To a solution of l-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one (25 mg, 0.097 mmol), EXAMPLE 72, in 1 mL of DMF is added 4-chloro-benzyl isocyanate (22 mg, 0.13 mmol, prepared as described in EXAMPLE 37). After stirring 1 h at room temperature, the solution is concentrated. 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 combined and lyopholized to provide the title compound (36 mg, 0.067 mmol) as a white solid. 'H NMR (d6-DMSO, 300 MHz) δ 9.76 (bs, 2H), 8.83 (s, I H), 8.38 (d, IH), 7.64 (d, IH), 7.60 (s, IH), 734 (d, 2H), 7.31 (m, I H), 7.26 (d, 2H), 4.75 (s, 2H), 4.22 (d, 2H), 4.08 (s, 2H), 3.60 (m, 2H), 3.35 (m, 2H). ESI MS, [M+H]⁺=425,427 (Cl pattern).

EXAMPLE 437. 4-(4-Aminoquinazolin-7-ylmethyl)-3-oxopiperazine-l -carboxylic acid (5-chloro- thiophen-2-ylmethyl)amide.

To a solution of (5-chloro-thiophen-2-yl)-acetic acid (0.18 g, 1.04 mmol), prepared as described in EXAMPLE 27 in 6 mL of dry CH₂C1₂ is added Et₃N (0.15 mL g, 1.04 mmol) and diphenylphosphoryl azide (0.24 mL, 1.04 mmol). The mixture is stirred at room temperature for 2.5 h, then heated at 50°C for 2 hours. To the solution is added l-(4-aminoquinazoline-7-ylmethyI)piperazine-2-one (0.10 g, 0J1 mmol), EXAMPLE 72, and Et₃N (0.15 L g, 1.04 mmol) and the mixture is heated at 50°C for 2 h, then stirred at room temperature for 16 hours. The resulting mixture is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂0 (0.1% TFA) to 60% CH₃CN/H₂0 (0.1% TFA) and the appropriate product fractions are combined and lyopholized to provide the title compound (10 mg, 0.02 mmol) as a white solid. Η NMR (d6-DMSO, 300 MHz) δ 9.69 (bs, 2H), 8.80 (s, IH), 8.48 (d, IH), 7.61 (d, IH), 7.60 (s, IH), 7.41 (t, IH), 6.90 (d, IH), 6.80 (d, IH), 4.77 (d, 2H), 430 (d, 2H), 4.10 (s, 2H), 3.61 (m, 2H), 3.38 (m, 2H). ESI MS, [M+H]⁺=431,433 (Cl pattern).

EXAMPLE 438. 4-(4-Aminoquinazolin-7-ylmethyl)-3-oxopiperazine- l -carboxylic acid (5-chloro- thiophen-2-yl)amide. A mixture of 5-chloro-thiophene-2-carbonyl azide (55 mg, 0.29 mmol, prepared as described in

EXAMPLE 38) and l-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one (50 mg, 0.20 mmol), EXAMPLE 72, in 3 mL of dry toluene is heated at 105°C for 1 hours. The resulting mixture is concentrated in vacuo. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1 % TFA) and the appropriate product fractions are combined and lyopholized to provide the title compound (35 mg, 0.02 mmol) as a white solid. 'H NMR (DMSO-d6, 300 MHz) δ 10.04 (s, IH), 9.71 (bs, 2H), 8.81 (s, IH), 8.38 (dd, I H), 7.64 (d, I H), 7.61 (s, IH), 6.77 (d, IH), 6.42 (d, IH). 4.76 (s, 2H), 4.21 (s, 2H), 3.73 (m, 2H), 3.40 (m, 2H). ESI MS, [M+H]⁺=417J19 (Cl pattern).

The following compounds are prepared from the compound of Example 72 using the methods described above.

EXAMPLE 446. 4-(4-Amino-quinazolin-7-ylmethyl)-3-oxo-piperazine-l -carboxylic acid 5-chloro- thiophen-2-ylmethyl ester.

To a solution of 5-chloro-2-thiophene-methanol (0.10 g, 0.67 mmol, prepared by NaBH₄ reduction of 5-chloro-2-thiophene-carboxaldehyde) in 6 mL of CH₂C1₂ is added l J '-carbonyldiimidazole (0J 1 g, 0.67 mmol). The mixture is stirred at room temperature for 3 hours. Then l-(4- aminoquinazoline-7-ylmethyl)piperazine-2-one (0.17 g, 0.67 mmol, EXAMPLE 72) and a catalytic amount of DMAP is added to the solution and the resulting mixture is heated at 35°C for 18 hours. The mixture is dissolved in water/MeOH and the crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate fractions are combined and lyopholized to provide the title compound as a white solid. ESI MS, [M+H]⁺=432,434 (Cl pattern).

The following compounds are prepared from the compound of Example 72 using the methods described above.

EXAMPLE 449. l-(4-Amino-quinazolin-7-ylmethyl)-4-(7-chloro-isoquinolin-3-ylmethyl)-3-(S)-methyl- piperazin-2-one.

To a solution of l-(4-amino-quinazoline-7-yImethyl)-3-methyl-piperazine-2-one, EXAMPLE 80, (0.06g, 0.2mmol) in 2 mL of DMF is added 3-bromomethyl-7-chloroisoquinoline, EXAMPLE 1 1, 0.052g, 0.20mmol), and K₂C0₃ (0.08 g, 0.06 mmol). After 16 h, the reaction mixture is concentrated to dryness. The crude product is purified by RP-HPLC eluting with a gradient of 5%CH₃CN/H₂0 (0.1% TFA) to 50%CH₃CN/H₂O (0.1% TFA). The product fractions are lyophilized to give the title compound as a tristrisfluoroacetic acid salt (0.06g, 0.08 mmol) as a white solid. 'H NMR (d6-DMSO, 300 MHz) δ 9.79 (bs, 2H), 9J0 (s, IH), 8.73 (s, I H), 8.33 (d, I H), 8.25 (s, I H), 8.06 (s, I H), 8.00 (d, I H), 7.79 (d, IH), 7.60 (m. 2H), 4.80 (AB, 2H), 4.72 (AB, 2H), 4.28 (m, I H), 3.54 (m, 4H), 1.96 (d. 3H). MS (ion spray) 447, 449, (Cl pattern). Elemental analysis C₂₈H₂₅ClF₆N₆O₆3CF₃CO₂H0.28H₂O. cal C=4538%, H=3.35%, N=10.58%; found C=45.38, H=335%, N=10.63%.

EXAMPLE 450. 4-(4-Amino-quinazolin-7-ylmethyl)- 4-(3-chloro- 1 H-indol-6-ylmethyl)-3-(S)-methyl- piperazin-2-one.

The title compound is prepared as described in EXAMPLE 274 using l -(4-amino-quinazoIine-7- ylmethyl)-3-methyl-piperazine-2-one, EXAMPLE 80. 'H NMR (DMSO-d6, 300 MHz) ? 9.79 (bs, 2H), 8.82 (s, I H). 8.39 (d, IH), 7.61 (m, 3H), 7.57 (d, I H), 7.52 (d, IH). 7.49 (d, I H), 7.20 (d, I H), 7.10 (d, IH). 4.75 (AB, 2H), 4.57 (m, I H), 4.23 (m, I H), 3.97 (m, I H), 3.50 (m, 3H), 1.65 (d, 3H). ESI MS, [M+Hf= 435.437 (Cl pattern). Anal. (C₂₃H₂₃ClN₆O2.15TFA 0.25H₂O) C, H, N.

The following compounds are prepared from the compound of Example 80 using the methods described above.

EXAMPLE 465 1 -(4-Amino-quinazolin-7-ylmethyl)-4-[3-(4-chloro-thiophen-2-yl)-acryloyll-3-(S)- methyl-piperazin-2-one.

The title compound is prepared as described in EXAMPLE 123, using l-(4-amino-quinazoline-7- ylmethyl)-3-methyl-piperazine-2-one, EXAMPLE 80, and 3-(4-chloro-thiophen-2-yl)-(E)-acrylic acid, EXAMPLE 26. Η NMR (d6-DMSO, 300 MHz) ? 9.74 (bs, 2H), 8.82 (s, IH), 8.40 (d, IH), 7.62 (m, 5H), 7.05 (d, IH), 4.92 (m, IH), 4.80 (m, 2H), 4.73 (m, IH), 4.50 (m, IH), 3.40 (m, 2H), 1.42 (m, 3H). ESI MS, [M+H]⁺= 442, 444 (Cl pattern).

The following compounds are prepared from the compound of Example 80 using the methods described above.

EXAMPLE 478. l-(4-Amino-quinazolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-propyll-3-(S)-ethyl- piperazin-2-one.

The title compound is prepared as described in EXAMPLE 278 using l -(4-aminoquinazoIine-7- ylmethyl)-3-ethyl-piperazine-2-one, EXAMPLE 77 and 3-(5-chloro-thiophen-2-yl)-propionaldehyde, EXAMPLE 28. Η NMR (d6-DMSO + 1 drop TFA, 300 MHz) ? 9.80 (bs, 2H), 8.79 (s, IH), 8.32 (d, IH), 7.58 (m, 2H), 6.88 (d, I H), 6.70 (d, IH), 4.72 (AB, 2H), 4.00 (m, IH), 3.72 (m, IH), 3J8 ( , 2H), 3.23 (m, 3H), 2.72 (m, 2H), 1.96 (m, 4H), 0.98 (m, 3H). MS (ion spray), m/z, (M+H) = 444, 446 (Cl pattern).

The following compounds are prepared from the compound of Example 77 using the methods described above.

EXAMPLE 486. 1 -(4-Amino-quinazolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-acryloyn-3-(S)- ethyl-piperazin-2-one.

The title compound is prepared as described in EXAMPLE 123, using l-(4-aminoquinazoline-7- ylmethyl)-3-ethyl-piperazine-2-one, EXAMPLE 77 and 3-(5-chloro-thiophen-2-yl)-(E)-acrylic acid, EXAMPLE 25. Η NMR (d6-DMSO + 1 drop TFA, 300 MHz) ? 9.78 (bs, 2H), 8.79 (s, IH), 8.37 (d, IH). 7.65 (m, 2H), 7.50 (s, IH). 7.41 (m, I H), 7.1 1 (d, I H), 6.98 (d. I H), 4.88 (m, 2H), 4.60 (m, I H), 4.31 (m, l H), 3.52 (m, I H), 3.30 (m, 2H), 1.96 (m, 2H), 0.88 (m, 3H). MS (ion spray), m/z, (M+H) = 456, 458 (Cl pattern). Elemental analysis, cal C₂₂H₂₂C1N₅0₂S-1.5C₂HF₃0₂ %C=47.89, %H=3.78, %N=1 1.17: found %C=47.34, %H=4.00, %N=1 1.12.

The following compounds are prepared from the compound of Example 77 using the methods described above.

EXAMPLE 513. l-(4-Amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thioρhen-2-yloxy)-acetyl1-3-(S)- propyl-piperazin-2-one.

The title compound is prepared as described in EXAMPLE 123, using l-(4-aminoquinazoline-7- ylmethy!)-3-propyI-piperazine-2-one, EXAMPLE 78 and 5-chloro-2-thienyIoxyacetic acid, EXAMPLE 24. Η NMR (d6-DMSO, 300 MHz) ? 9.78 (bs, 2H), 8.81 (s. I H), 8.35 (d, IH), 7.60 (m, 2H), 7.51 (s, I H), 6.69 (m. I H), 6.21 (d, IH), 4.91 (AB, 2H), 4.72 (m, 2H), 3.84 (m, I H), 3.52 (m, 2H), 3.23 (m, I H), 1.80 (m, 2H). 1.24 (m. 2H), 0.82 (m, 3H). MS (ion spray), m/z, 474, 476, (M+H) (Cl pattern). Elemental analysis, cal C₂₂H₂₂C1N₅0₂SC₂HF₃0J .15H₂0 %C=47.31 , %H=4.52, %N=1 1.50; found %C=47.39. %H=4.140. %N=1 1.19.

EXAMPLE 514. 4-[3-(6-Amino-pyridin-3-yl)-acryloyl]-l-(4-amino-quinazolin-7-ylmethyl)-3-(S)- propyl-piperazin-2-one. The title compound is prepared as described in EXAMPLE 123, using l-(4-aminoquinazoline-7- ylmethyl)-3-propyl-piperazine-2-one, EXAMPLE 78 and 3-(6-amino-pyridin-3-yl)-acrylic acid, EXAMPLE 36. 'H NMR (d6-DMSO, 300 MHz) ? 9.73 (bs, 2H), 8.81 (s, I H), 836 (m, 2H), 8.22 (m, 3H), 7.62 (d. IH), 7.52 (m, IH). 739 (m, IH), 7.21 (m, IH), 6.91 (d, IH), 5.00 (m, IH), 4.78 (m, IH), 4.60 (m, 2H). 4.34 (m. I H), 3.30 (m, 2H), 1.87 ( , 2H), 1.24 (m, 2H), 0.90 (m, 3H). MS (ion spray), m/z, 446, 448 (M+H). (Cl pattern).

The following compounds are prepared from the compound of Example 78 using the methods described above.

EXAMPLE 524. H4-Amino-quinazolin-7-ylmethyl)-4J3J5-chloro-thiophen-2-yl)-allvnJJS)- methoxymethyl-piperazin-2-one.

The title compound is prepared as described in EXAMPLE 278 using l -(4-amino-quinazoline-7- ylmethyl)-3-methoxymethy]-piperazine-2-one, EXAMPLE 75 and 2-(3-bromo-(E)-propenyl)-5-chloro- thiophene EXAMPLE 17. 'H NMR (d6-DMS0, 300 MHz) ? 9.74 (bs, 2H), 8.80 (s, I H), 8.38 (d, IH), 7.69 (m, 2H). 7.02 (dd, IH), 6.84 (d, IH), 6.02 (m, I H), 4.76 (AB, 2H), 3.86 (m, 4H), 3.30 (s, 3H), 3.23 (m, 2H), 3.02 (m, 2H). MS (ion spray), m/z, 458, 460, (M+H) (Cl pattern). Elemental analysis, cal C₂₂H₂₄C1N-0₂S2C₂HF₃0₂-1 J5H₂0 %C=43.85, %H=4.09, %N=9.83; found %C=43.92, %H=3.61 , %N=9.63.

The following compounds are prepared from the compound of Example 75 using the methods described above.

EXAMPLE 532. l-(4-Amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-3-(S)- methoxymethyl-piperazin-2-one.

To a solution of 4-(4-aιnino-quinazoline-7-ylmethyl)-2-methoxymethyl-3-oxo-piperazine-l - carboxylic acid benzyl ester. EXAMPLE 75, (0.69g, 2.29mmol) in 9mL of DMF is added N,N- diisopropylethyl amine (0.89g. 6.87mmoi), TBTU (0.76g, 236mmol), and 5-chloro-2-thienyloxyacetic acid, EXAMPLE 24, (OJOg, 2.08mmol). The solution is stirred for 16 hours. After this time the solution is concentrated. The crude material is purified by RP-HPLC eluting with a gradient of 10%CH₃CN/H,O (0.1%TFA) to 80%CH₃CN/H₂O (0.1%TFA). The product fractions are lyophilized to give the product as a white solid (1.0g, 1.57mmol). 'H NMR (d6-DMSO, 300MHz) δ 9.70 (bs, 2H), 8.78 (s, IH), 8.29 (m. I H), 7.55 (m, 2H), 6.72 (m, IH), 6.22 (m, I H), 4.80 (m, 4H),3.78 (m, 4H), 3.59 (m, 3H), 3.3 land 3.2 (s, 3H rotational isomers).MS (ion spray) M+H=476.Elemental Analysis: C21H22CIN504S . JCF3C02H cal: C=45.03%, H=3.68%, N=l 1.04%; found C=44.98%, H=3.71 %, N=1 1.02%. EXAMPLE 533. l-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-1H-benzoimidazole-2-carbonyl)-3- (S)-methoxymefhyl-piperazin-2-one.

To a solution of 4-(4-amino-quinazoline-7-ylmethyl)-2-methoxymethyl-3-oxo-piperazine-l- carboxylic acid benzyl ester. EXAMPLE 75, (20 mg. 0.066 mml) in 1.5 mL of DMF is added TBTU (923J mg, 0.073 mmol), diisopropylethylamine (0.013 ml, 0.073 mmol) and 6-chloro-lH- benzoimidazole-2-carboxylic acid (prepared from literature in Eur.J.med.Chem. 1993, 28, 71) (14.3 mg, 0.073 mmol). The resulting mixture is left to stir at room temperature overnight. The crude mixture is directly purified by reverse phase HPLC (10-70% ACN/H₂0). The product (30.1 mg, 55%) is isolated as a white powder. C₂₃H₂₂C1N₂0₃ MS m/z: 480, 481. Anal. cald. for C₂₃H₂₂C1N₇0₃ • 2C₂HF₃0₂: C, 45.81 ; H, 3.42; N, 13.85. Found C, 45.19; H, 3.59; N, 13.76.

The following compounds are prepared from the compound of Example 75 using the methods described above.

EXAMPLE 582. l -(4-Amino-quinazolin-7-ylmethyl)-4-[(6-chloro-pyridin-3-yloxy)-acetyl]-3-(S)- ethoxymethyl-piperazin-2-one.

The title compound is prepared as described in EXAMPLE 123. using l -(4-aminoquinazoline-7- ylmethyl)-3-ethoxymethyl-piρerazine-2-one, EXAMPLE 79 and. (6-chloro-pyridin-3-yloxy)-acetic acid, prepared similary to the procedure descibed in EXAMPLE 29. Η NMR (d6-DMSO, 300 MHz) ? 9.73 (bs, 2H), 8.81 (s, I H), 837 (m. IH), 8.10 (m, IH), 7.61 (m, 2H), 7.40 (m, 2H), 4.98 (m, 2H), 4.65 (m, 2H), 4.50 (m, IH), 3.91 (m, IH), 3.75 (m, IH), 3.59 (m, 2H), 3.31 (m, 2H), 1.07 (m, 3H). MS (ion spray), m/z, 485, 487 (M+H). (Cl pattern).

The following compounds are prepared from the compound of Example 79 using the methods described above.

The following compounds are prepared from the compounds of Examples 81-85 using the methods described above.

EXAMPLE 609. 1 -(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-naphthalen-2-ylmethyl)-3-(S)- methoxymethyl-6-(S)-methyl-piperazin-2-one.

The title compound is prepared as described in EXAMPLE 268, using l-(4-amino-quinazoline-7- ylmethyI)-3-methoxyrnethyl-6-methyl-piperazine-2-one, EXAMPLE 87, and 2-bromomethyl-6- chloronaphthalene, EXAMPLE 12. Η NMR (CDC1₃, 300 MHz) ? 8.59 (s, IH), 7.79 (d, I H), 7.70-7.12 (m, 3H), 7.68-7.67 (m, 2H), 7.55 (d, IH), 7.39 (d, IH), 4.78 (d, 2H), 3.98 (d, 2H), 3.44 (s, 3H), 3.38 (t, IH), 2.64 (m, 2H), 1.26 (d, 3H). MS (ISP) 490, 492, (M+H), Cl pattern.

The following materials are prepared from starting materials obtained as described in Example

87 using the methods described above.

EXAMPLE 617. l-(4-Amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-3(S)- methoxymethyl-6-methyl-piperazin-2-one.

The title compound is prepared as described in EXAMPLE 123 using l -(4-amino-quinazoline-7- ylmethyl)-3-methoxymethyl-6-methyl-piperazine-2-one. EXAMPLE 87, and 5-chloro-2-thienyloxyacetic acid, EXAMPLE 24. Η NMR (CD₃OD300 MHz) ? 8.68 (s, IH), 8.27 (d, IH), 7.62 (m, 2H), 6.54 (d, IH), 6.18 (m, IH), 7.39 (d, I H). 4.94 (m, 4H), 4.15 (m, 2H), 3.76 (m, 2H), 3.44 (s, 3H), 3.10 (m, 2H), 1.28 (d, 3H).

The following compounds are prepared from compounds obtained as described Examples 75-87 using the methods described above.

EXAMPLE 636. 4-(4-Amino-quinazolin-7-ylmethyl)-2-(S)-methoxymethyl-3-oxo-piperazine-l- carboxylic acid (4-chloro-phenyl)-amide.

The title compound is prepared as described in EXAMPLE 436 using l -(4-amino-quinazoIine-7- ylmethyl)-3-methoxyrnethyI-piperazine-2-one, EXAMPLE 75, and 4-chlorophenyl isocyanate. 'H NMR (DMSO-d6, 300 MHz) ? 9.77 (bs, 2H), 8.81 (s, I H), 8.70 (s, IH), 8.40 (d, IH), 7.64 (d, IH), 7.61 (s, IH), 7.49 (d, 2H). 7.28 (d, 2H), 4.88 (m, I H), 4.80 (AB, 2H), 4.19 (m, I H), 3.96 (m, I H). 3.74-3.42 (m, 4H), 3.28 (s, 3H). ESI MS. [M+H]^"=455,457 (Cl pattern). Anal. (C₂₂H₂₃ClN₆O₃ TFA 1.5H,O) C, H, N. EXAMPLE 637. 4-(4-Amino-quinazolin-7-ylmethyl)-2-(S)-methyl-3-oxo-piperazine-l -carboxylic acid (5-chloro-thiophen-2-yl)-amide.

The title compound is prepared as described in EXAMPLE 438 using l-(4-amino-quinazoline-7- ylmethyl)-3-methyl-piperazine-2-one (EXAMPLE 80) and 5-chloro-thiophene-2-carbonyl azide (EXAMPLE 38). Η NMR (DMSO-d6, 300 MHz) ? 10.01 (s, I H), 9.73 (bs, 2H), 8.83 (s, I H), 8.39 (d, IH), 7.65 (d, IH), 7.58 (s, IH), 6.79 (d, IH), 6.44 (d, IH), 4.85 (d, I H), 4.71 (m, IH), 4.69 (d, IH), 4.17 (d, IH), 3.50 (m, 3H), 1.45 (d, 3H). ESI MS, [M+H]⁺=431 J33 (Cl pattern). Anal. (C₁₉H₁₉ClN₆O,S-TFA-1.9H₂O) C, H, N.

EXAMPLE 638. 4-(4-Amino-quinazolin-7-ylmethyl)-(2S)-methoxymethyl-3-oxo-piperazine-l- carboxylic acid (5-chloro-thiophen-2-yl)-amide.

The title compound is prepared as described in EXAMPLE 439 using l-(4-amino-quinazoline-7- ylmethyl)-3-methoxymethyl-piperazine-2-one (EXAMPLE 75) and 5-chloro-thiophene-2-carbonyl azide

(EXAMPLE 38). 'H NMR (DMSO-d6, 300 MHz) ? 10.00 (s, IH), 9.73 (bs, 2H), 8.82 (s, l H), 8.40 (d, 1 H), 7.65 (d, 1 H), 7.60 (s, 1 H), 6.80 (d, 1 H), 6.42 (d, 1 H), 4.86 (d, 1 H), 4.80 (m, 1 H), 4.70 (d, 1 H), 4.18

(d, IH), 3.96 (dd, I H), 3.60 (m, 4H), 3.30 (s, 3H). ESI MS,

,463 (Cl pattern). Anal.

(C₂₀H₂,ClN₆O₃S TFA 1.1 H₂0) C, H, N.

The following compounds are prepared using the methods described above.

EXAMPLE 663. (3S. 5RS)-l-(4-Amino-quinazolin-7-ylmethyl)-4J6-chloro-benzo[b]thiophen-2- ylmethyl)-3J-dimefhyl-piperazin-2-one.

(3S,5RS)-l-(4-Amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (260 mg, 0.56 mmol), EXAMPLE 88, is dissolved in 5 mL of DMF. Potassium carbonate (193J mg, I J mmol) is added followed by the addition of 2-bromomethyl-6-chloro-benzo[b]thiophene (218 mg, 0.84 mmol), EXAMPLE 5. Reaction is left to stir overnight. The crude mixture is purified by reverse phase HPLC ( 10 -70% ACN/H₂0) to afford the product (27 mg, 6%) as a clear wax with a melting point of 130- 131 °C . C₂₄H₂-,C1N₅0S MS m/z: 466, 468.

EXAMPLE 664. (3S. 5S)-l-(4-Amino-quinazolin-7-ylmethyl)-4-r3J5-chloro-thiophen-2-yl)-allyn-3J- dimethyl-ρiperazin-2-one. and

EXAMPLE 665. (3SJR)-l-(4-Amino-quinazolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-allvn-3J- dimethyl-piperazin-2-one.

(3S,5RS)-l-(4-Amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (60 mg, 0.13 mmol) is dissolved in 1 mL of DMF. Potassium carbonate (53 mg, 0.39 mmol) is added followed by the addition of 3-bromoallyl-5-chloro-thiophene (75 mg. 0.32 mmol). Reaction is left to stir overnight. The two epimers are separated bv reverse phase HPLC (10 -70% ACN) in 43% yield.

The major epimer is assigned as (3S, 5S)-l -(4-Amino-quinazolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2- yl)-allyl]-3,5 -dimeth l-piperazin-2-one trifluoroacetic acid salt (30.8 mg) and is isolated as a yellow solid with a melting point of 69-72 °C . C₂₂H₂₄C1N₅0S MS m/z: 442, 444.

The minor epimer is assigned as (3S, 5R)-l -(4-Amino-quinazolin-7-ylmethyl)-4-[3-(5-chloro-thiophen- 2-yl)-allyl]-3,5-dimethyl-piperazin-2-one trifluoroacetic acid salt (13.1 mg) with a melting point of 67- 70 °C . C₂₂H₂₄C1N,0S MS m z: 442. 444. I H NMR (CD₃OD) δ: 8.67 (s. 1H): 831 (d, IH, j = 8.56 Hz); 7.83 (s, IH); 7.74 (d, 2H, J = 8.56 Hz); 7.14 (d, IH, J = 15.6 Hz): 6.92 (d, IH, J = 3.74 Hz); 6.10-6.03 (m, IH); 5.0-4.74 (m, 2H); 4.25-3.63 (m, 6 H); 1.78 (d, 3H, J = 7.03 Hz); 1.50 (d, 3H, J = 6.47 Hz).

EXAMPLE 666. (3S, 5R)-l-(4-Amino-quinazolin-7-ylmethyl)-4-r2-(5-chloro-thiophen-2-yl)- ethenesulfonyl1-3,5-dimethyl-piperazin-2-one.

(3S,5R)-l-(4-Amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (43 mg, 0.123 mmol), minor epimer fromEXAMPLE 88, Part D, is taken up in methylene chloride to this is added triethylamine (0.034 ml, 0.25 mmol) followed by 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride (40 mg, 0.16 mmol), EXAMPLE 3. The reaction is stirred overnight, and the crude material is purified by preparative thin layer chromatography ( 15 % methanol/CH₂Cl₂). The product ( 1.4 mg, 2.3%) is isolated as a yellow wax. C₂,H₂₂C1N₅0₃S₂ MS m/z: 492, 494. IH NMR (CD₃OD) δ 836 (s, IH); 8.03 (d, IH, J = 7.5 Hz); 7.61 (s, IH); 7.49-7.44 (m, 2H); 7.19 (d, IH, J = 3.83 Hz); 6.98 (d, I H. J = 3.75 Hz); 6.76 (d, 1H, J = 15.1 Hz); 4.86-4.71 (m, 2H); 4.45-439 (m, IH); 4.13-4.09 (m, IH); 3.64-3.7 (m, 2H); 1.63 (d, 3H, J = 7.09 Hz); 1.33 (d, 3H, J = 6.80 Hz).

EXAMPLE 667. (3S, 5S)-l-(4-Amino-quinazolin-7-ylmethyl)-4-[2-(5-chloro-thiophen-2-yl)- ethenesulfonyl]-3,5-dimethyl-piperazin-2-one.

The product (7 mg. 9.4 %) is isolated as a yellow solid with a melting point of 218-221 °C . C₂,H₂₂C1N₅0₃S₂ MS m/z: 492, 494. I H NMR (CD₃OD) δ 8.37 (s, I H): 8.10 (d. IH, J = 8.57 Hz); 7.61- 7.45 (m, 3H); 7.24 (d, I H, J = 3.94 Hz); 6.98 (d, IH, J = 3.85 Hz); 6.71 (d, 1 H, J = 15.1 Hz); 4.76 (s, 2H); 4.32 (m, IH); 3.71 ( . IH); 336 (m, 2H); 1.62 (d, 3H, J = 7.06 Hz); 1.20 (d, 3H, J = 6.63 Hz).

EXAMPLE 668. (3S, 5S)-l-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophen-2- sulfonyl)-3,5-dimethyl-piperazin-2-one. The desired product ( 5.4 mg, 8.5 % ) is isolated as yellow solid with a melting point of 224-226°

C. C₂₃H₂₂C1N₅0₃S₂ MS m/z: 516, 518.

EXAMPLE 669. (3S, 5S)- l-(4-Amino-quinazolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-acryloyll- 3,5-dimethyl-piperazin-2-one. To a solution of (3SJS)-l-(4-amino-quinazolin-7-ylmethyl)-3.5-dimethyl-piperazin-2-one (42 mg, 0.147 mmol). major epimer from EXAMPLE 88, Part D, in 2 mL of DMF is added TBTU (52 mg, 0.162 mmol), triethylamine (0.02 mL, 0.162 mmol) and 3-(5-chloro-thiophen-2-yl)-acrylic acid (28 mg, 0.15 mmol). EXAMPLE 25. After stirring for two hours, the reaction mixture is directly purified by reverse phase HPLC (10-70 % ACN/H₂0). The product (35.5 mg, 36%) is isolated as a yellow solid with a melting point of 1 16-120°C. C₂₂H₂₂C1N₅0₂S: MS m/z: 456, 458. Anal, calcd. for C₂₂H₂₂C1N₅0₂S» C₂HF₃0₂: C, 50.57; H, 4.07; N, 12.29. Found: C, 46.48; H, 3.64; N, 1 1.04.

EXAMPLE 670. (3S, 5R)-4-(4-Amino-quinazolin-7-ylmethyl)-2.6-dimethyl-oxo-piperazine-l- carboxylic acid (4-bromo-phenyl)-amide.

4-Bromo-phenyl isocyanate (20.8 mg, 0.105 mmol) is added to solution of (3S,5R)-l-(4-amino- quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (30 mg, 0.105 mmol), minor epimer from EXAMPLE 88, Part D, in 1 mL of DMF. The reaction is stirred for two hours at room temperature. The product (21.4 mg, 33%) is isolated from reverse phase HPLC (10 -70% ACN/H₂0) as white solid. The melting of the compound is 142-144 °C . C₂₂H₂₃BrN₆0₂ MS m/z: 483, 485. Anal, cald.for C₂₂H₂₃BrN₆0₂ •2C₂HF₃0₂: C, 43.90; H, 3.54; N, 1 1.81. Found: C, 44.52; H, 3.86; N, 12.44.

EXAMPLE 671. (3S, 5S)-4-(4-Amino-quinazolin-7-ylmethyl)-2.6-dimethyl-oxo-piperazine-l -carboxylic acid (4-bromo-phenyl)-amide. The desired product (35 mg, 47%) is isolated as a white solid with a melting point of 142-144°C

. C₂₂H₂₃BrN₆0₂ MS m/z: 483, 485. Anal, cald.for C₂₂H₂₃BrN₆0₂»2C₂HF₃0₂: C, 43.90; H, 3.54; N, 1 1.81.

Found: C, 44.73; H, 3.59; N, 12.38.

EXAMPLE 672. (3S, 5S)-4-(4-Amino-quinazolin-7-ylmethyl)-2.6-dimethyl-oxo-piperazine-l- carboxylic acid (4-chloro-phenyl)-amide. The product (24.7 mg, 50%>) is obtained as a white solid with a melting point of 123-125 °C .

C₂₂H₂₃C1N₆0₂ MS m/z: 439, 441. Anal, cald.for C₂₂H₂₃C1N₆0₂»2C₂HF₃0₂: C, 46.82: H, 3.78; N, 12.60.

Found: C. 47.69; H, 4.33; N, 13.32.

EXAMPLE 673. l-(4-Aminoquinolin-7-ylmethyl)-4-(6-chlorobenzo[b]thiophen-2-sulfonyl)-piperazin- 2-one.

A. l-(4-Chloroquinolin-7-ylmethyl)-4-(6-chlorobenzo[b]thiophen-2-sulfonyl)-piperazin-2-one. l -(4-chloroquinoIin-7-ylmethyl)-3-(S)-methylpiperazin-2-one hydrochloride (0J9 g, I J mmol), EXAMPLE 89, is treated with acetonitrile (20 mL), triethyl amine (1.2 ml, 8.4 mmol) and a solution of 6-chlorobenzo[b]thiophen-2-sulfonyl chloride (0J1 g, 1.54 mmol), EXAMPLE 1 , in acetonitrile (10 mL) at 0°C. After 2 h the solution is poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate and concentrated to yielded the title compound (0J5 g, 0.95 mmol). MS m/z: 506, [M+1 ]^': Η NMR (CD₃OD, 300 MHz) ? 8.8 (d, I H), 8.15 (d, I H), 7.9 (d, 2H), 7.85 (s, IH). 7.4-7.5 (m, 2H). 6.8 (s. IH), 4.8 (s, 2H), 4.0 (s. 2H). 3.4-3.45 (m. 4H). B. l-(4-Azidoquinolin-7-ylmethyl)-4-(6-chlorobenzo[b]thiophen-2-sulfonyl)-piperazin-2-one l-(4-Chloroquinolin-7-ylmethyl)-4-(6-chlorobenzo[b]thiophen-2-sulfonyl)-piperazin-2-one (0.52 g, 1.03 mmol) is dissolved in DMF (15 mL), treated with sodium azide (0.52 g, 8.0 mmol), tetrabutyl ammonium chloride (0.1 g, 0.36 mmol) and heated to 65 °C overnight. The reaction mixture is cooled, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried (sodium sulfate) and concentrated to give the title compound (0.5 g, 1.04 mmol). Η NMR (CD₃OD, 300 MHz) ? 9.0 (d, I H), 8.2 (d, 1H).8.0 (s, IH), 7.9 (d, 2H). 7.8 (dJ H), 7.6 (dJH), 7.5 (dJ H),6.9 (s, IH), 4.85 (s, 2H), 4.0 (s, 2H), 3.5-3.1 (m, 4H).

C. l-(4-Aminoquinolin-7-ylmethyl)-4-(6-chlorobenzo[blthiophen-2-sulfonyl)-piperazin-2-one.

A suspension of l-(4-azidoquinolin-7-ylmethyl)-4-(6-chlorobenzo[b]thiophen-2-sulfonyl)- piperazin-2-one (0.50 g, 1.04 mmol) in 100 mL of acetic acid/methanol (~ 1 : 10) is treated with 10% Pd/C (0.15 g) and stirred under hydrogen for 1.5 hours. The resulting solution is filtered through Celite and the filtrate is evaporated in vacuo. The organic layer is concentrated and the residue is purified by reverse phase HPLC (gradient elution of 30 % of 0.1 % aqueous TFA/acetonitrile to 100 % acetonitrile) and lyopholized to give the title compound (0.39 g, 0.86 mmol). MS (ISP) m/z 487, 489, (M+H), Cl pattern.

The following compounds are prepared from the compound of Example 89 or 91 using the methods described above.

EXAMPLE 683. (S)-lJ4-Aminoquinolin-7-ylmethyl)-4-[3-(5-chlorothiophen-2-yl)-allyn-3- methylpiperazin-2-one.

A. (S)-l-(4-Chloroquinolin-7-ylmethyl)-4-[3-(5-chlorothiophen-2-yl)-allyl]-3-methylpiperazin-2-one.

(S)-l -(4-chloroquinolin-7-ylmethyl)-3-methylpiperazin-2-one hydrochloride (0.25 g, 1.0 mmol), EXAMPLE 91 , is treated with 2-(3-Bromo-(E)-propenyl)-5-chloro-thiophene (0.35 g 1.2 mmol), EXAMPLE 17, and potassium carbonate (0.5 g, 3 mmol). The resulting suspension is sonicated for 10 minutes then stirred vigorously for 16 h at ambient temperature. The reaction mixture is poured into water and extracted with ethyl acetate (2 X 150 mL). The organic layer is washed with water (4 X 200 L), dried over sodium sulfate and concentrated. The residue is chromatographed (3 % methanol/methylene chloride) to give the title compound (0.31 g, 0.73 mmol).

B. (S)-l-(4-Aminoquinolin-7-ylmethyl)-4-[3-(5-chlorothiophen-2-yl)-allyl]-3-methylpiperazin-2-one. (S)-l-(4-Chloroquinolin-7-ylmethyl)-4-[3-(5-chlorothiophen-2-yl)-allyl]-3-methylpiperazin-2- one (035 g, 0.82 mmol) is treated with phenol (2 g) and ammonium acetate (0.7 g, 9.1 mmol) and heated to 120 °C in a sealed vessel for 1 hour. Upon cooling, the solution is partitioned between 2 N NaOH and ethyl acetate. The organic layer is separated and washed with fresh 2 N NaOH (3 X 100 mL) and water. The organic layer is concentrated and the residue is purified by reverse phase HPLC to give the title compound as a white solid (0.15 g, 0.35 mmol). MS (ISP) m/z 427, 429, (M+H), Cl pattern. The following compounds are prepared from starting materials prepared as described in Examples 61-64, 89 or 91 using the methods described above.

EXAMPLE 703. (S)-l -(4-Aminoquinolin-7-ylmethyl)-4-[3J4-bromothiophen-2-yl)acryloyl]-3-methyl- piperazin-2-one.

A. (S)-1 -(4-Chloroquinolin-7-ylmethyl)-4-[3-(4-bromothiophen-2-yl)acryloyl]-3-methyl piperazin-2- one.

(S)- l-(4-chloroquinolin-7-ylmethyl)-3-methylpiperazin-2-one hydrochloride (035 g, I J mmol), EXAMPLE 91 Js treated with DMF (20 mL), 3J4-bromothiophen-2-yl)-(E)-acrylic acid (0.32 g, 1.4 mmol), prepared according to EXAMPLE 26, using 4-bromothiophene-2-carboxaldehyde, triethyl amine (0.21 ml, I J mmol) and 2-(lH-benzotriazol-l-yl)l ,l ,3,3-tertamethyluronium tetrafluoroborate (0J5 g, 1.4 mmol) and heated to 50 °C for 5 minutes. The reaction mixture is stirred at ambient temperature for 16 h then partitioned between ethyl acetate and water. The organic layer is concentrated and the residue is chromatographed (5% methanol/methylene chloride) to give crude title compound (0.5 g , 0.9 mmol). MS m/z: [M+H]⁺ = 504. Η NMR (CDC1₃, 300 MHz) ??8.9 (d, I H), 8.2-83(m, 2H), 8.0 (s, I H), 7.7-7.8 (m, IH), 7.4 (s, IH), 7.3-7.4 (m, IH), 6.7-6.8 (m, IH), 6.6 (d, IH), 5.1-5.2 (m, IH), 4.6-4.7 (m, 2H), 3.4- 3.6 (m, 2H). 3.0-33 (m, 2H). 1.5 (d, 3H).

B. (S)-l-(4-Aminoquinolin-7-ylmethyl)-4-[3-(4-bromothiophen-2-yl)acryloyl]-3-methyl-piperazin-2- one. (S)- 1 -(4-Chloroquinolin-7-ylmethyl)-4-[3-(4-bromothiophen-2-yl)acryloyl]-3-methyl piperazin-

2-one (0.50 g, 0.9 mmol) is treated with phenol (~ 2 g) and ammonium acetate (0.5 g, 6J mmol) and heated to 120 °C in a sealed vessel for 1 hour. Upon cooling, the solution is partitioned between 2 N NaOH and ethyl acetate. The organic layer is separated and washed with fresh 2 N NaOH (3 X 100 mL) and water. The organic layer is concentrated and the residue is purified by reverse phase HPLC (gradient elution of 10 % of 0.1 % aqueous TFA/acetonitrile to 100 % acetonitrile) to give the title compound (0.22 g, 0.56 mmol). MS m/z: [M+H]⁺ = 485, 487, Cl pattern. Η NMR (CD₃OD, 300 MHz) ? 8.2-8.4 (m, 2H), 7.7-7.8 (m, 2H), 7.6 (d, IH), 7.5 (s, IH), 7.3 (s, IH), 6.9-7.0 (m, IH), 6.7 (d, IH), 5.0-5.1 (m, IH), 4.9 (q, 2H), 4.3-4.4 (m. IH), 3.5-3.7 (m, 2H), 3.3-3.4 (m, 2H), 1.5 (d, 3H).

The following compounds are prepared from starting materials prepared as described in Examples 75-87 using the methods described above.

EXAMPLE 718. l-(4-Aminocinnolin-7-ylmethyl)-4- 2-(5-chlorothiophen-2-yl)-ethenesulfonyll- piperazin-2-one.

A. l-(4-Chlorocinnolin-7-ylmethyl)-4-[2-(5-chlorothiophen-2-yl)-ethenesulfonyl]-piperazin-2-one l-(4-chlorocinnolin-7-ylmethyl)-piperazin-2-one hydrochloride (0.14 g, 0J mmol), EXAMPLE 90, is treated with acetonitrile (20 mL), triethylamine (2 mL, 14 mmol) and 2-(5-chlorothiophen-2- yl)ethene-sulfonyl chloride (0.097 g, 0J mmol), EXAMPLE 3, at 0°C. The solution is warmed to ambient temperature over 1.5 h and diluted with ethyl acetate. The solution is washed with 10 % sodium bicarbonate solution and water, dried (sodium sulfate) and concentrated to yield the title compound (0.17 g, 0.35 mmol). MS m/z: [M+H]^' = 483; Η NMR (CDC1₃, 300 MHz) ??9.4 (s, IH), 8.4 (s, IH), 8.3 (d, IH) 7.85 (d, IH), 7.7 (d, IH). 7.1 (d, IH), 6.95 ( d, I H), 6.35 (d, I H), 4.9 (s, 2H), 4.0 (s, 2H), 3.4-3.5 (m, 4H).

B. l-(4-Aminocinnolin-7-ylmethyl)-4-r2-(5-chlorothiophen-2-yl)-ethenesulfonyπ-piperazin-2-one l-(4-Chlorocinnolin-7-ylmethyl)-4-[2-(5-chlorothiophen-2-yl)-ethenesulfonyl]-piperazin-2-one (0.06 g, 0.12 mmol) is treated with phenol (0.20 g) and ammonium acetate (0.2 g, 2.6 mmol) and heated to 120 °C for 45 minutes. The reaction mixture is cooled, diluted with ethyl acetate and washed with 1 N NaOH (3 X 100 mL) and water. The organic layer is concentrated and the residue is purified by reverse phase HPLC (20 % aqueous TFA (0.1 %)/acetonitrile to 100 % acetonitrile). Fractions containing the desired product are lyophilized to obtain the title compound (0.02 g, 0.043 mmol). MS m/z: [M+H]" = 464; Η NMR (CD₃OD. 300 MHz) ??8.6 (s, 1 H), 8.4 (d, 1 H), 7.75 (d, 1 H), 7.65 (d, 1 H), 7.35 (d, 1 H), 7.1 (dJ H), 6.8 (d, IH). 4.9 (s. 2H), 4.05 (s, 2H). 3.6 (m. 4H). EXAMPLE 719. 4J6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl)- 1 -[2Jpyridin-4-ylamino)-ethyl]- piperazin-2-one. l-[2-(Pyridin-4-ylamino)-ethyl]-piperazin-2-one (0.20 mmol), EXAMPLE 90, is dissolved in MeCN (5 mL) and treated with 4-methylmorphorline (0.055 ml, 0.50 mmol). 6-Chloro-thieno[2,3- b]pyridine-2-sulfonyl chloride (54 mg, 0.20 mmol) in MeCN (2 mL) is added dropwise. The reaction mixture is stirred at r.t. for 1.5 h, then subjected to HPLC purification, to give the title compound as white solid (0.021 g, 0.037 mmol). MS m/z 452, 454 (M+1); Η NMR (CD₃OD, 300 MHz) ? 8.37 (d, IH), 8.30 (b, IH), 8.12 (d, IH), 8.02 (s, IH), 7.97 (d, IH), 7.57 (d. IH), 6.98 (d, IH), 6.88 (d, 2H), 3.73 (s, 2H), 3.60-3.48 (m, 8H).

EXAMPLE 720. 4-(6-Chloro-benzo[b1thiophene-2-sulfonyl)-l-[2Jmethyl-pyridin-4-yl-amino)-ethyl]- piperazin-2-one.

A portion (-50%) of the crude l-[2-{(Methyl)-(pyridin-4-yl)-amino}-ethyl]-piperazin-2-one,

EXAMPLE 93 is reacted with 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (54 mg, 0.20 mmol), EXAMPLE 1. using same procedure as described in EXAMPLE 719. The residue obtained after HPLC purification is subjected to silica gel chromatography using NH₄OH/MeOH/CH₂Cl₂ ( 1 :4:95) as eluant to give title compound (30 mg, 0.064 mmol) as a white solid. MS m/z 465, 457 (M+1 ); 'H NMR (CDC1₃,

300 MHz) ? 8.15 (d, 2H), 7.88 (s, I H), 7.85 (d, IH), 7.79 (s, I H), 7.47 (d, I H), 6.47 (d. 2H), 3.80 (s, 2H),

3.50 (m, 4H), 3.43 (d, 2H), 3.30 (d, 2H), 2.98 (s, 3H).

EXAMPLE 721. 4-[2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl1- 1 J2J3-methyl-pyridin-4-ylamino)- ethyl]-piperazin-2-one. l -[2-(3-Methylpyridin-4-yl-amino)-ethyl]-piperazin-2-one (38 mg, 0.16 mmol), EXAMPLE 94, is reacted with 2-(5-chloro-thiophen-2-yI)-ethenesuIfonyl chloride (40 mg, 0.16 mmol), EXAMPLE 3, using the same procedure as described in EXAMPLE 719. Reverse phase HPLC purification gives the title compound (29 mg, 0.052 mmol) as a white solid. MS m/z 441 , 443 (M+H); 'H NMR (CD₃OD, 300

MHz) ? 8.08 (d, IH), 7.98 (s. I H), 7.56 (d, IH), 7.30 (d, IH), 7.02 (s, I H), 7.00 (d. IH), 6.78 (d, IH),

3.87 (s, 2H). 3.70-3.50 (m, 8H), 2.15 (s, 3H). The following compounds are prepared from starting materials obtained as described in Examples 92-97 using the methods described above.

EXAMPLE 736. 4J6-Chloro-benzo[b1thiophene-2-sulfonyl)-l -[2-(pyridazin-4-yl-amino)-ethyl]- piperazin-2-one. l-[2-(Pyridazin-4-ylamino)-ethyl]-piperazin-2-one hydrochloride (0.5 g, 1.7 mmol), EXAMPLE 95, is reacted with 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (0J0 g, 1.5 mmol), EXAMPLE 1 , using essentially the same procedure as described in EXAMPLE 719. Reverse phase HPLC purification gives the title compound (034 g, 0.75 mmol) as a white solid. MS m/z (M+H= 452); Η NMR (CD₃OD, 300 MHz) δ 8.6 (d, IH), 8.4 (d. IH), 8.05 (s, IH), 8.05 (s, IH), 7.9 (d, IH), 7.5 (d, IH), 7.2 (d, IH), 3.8 (s,2H), 3.4-3.7 (m, 8H).

EXAMPLE 737. l -[3-(4-Amino-pyridin-3-yl)-propenyl]-4-[2-(5-chloro-thiophen-2-yl)-ethenesιιlfonyfl- piperazin-2-one.

4-[3-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-propenyl]-3-oxo-piperazine-l -carboxylic acid tert-butyl ester from EXAMPLE 96, Part B (45 mg, 0.10 mmol) is dissolved in 20% TFA/ CH,C1₂ and stirred at r.t. for 2 hours. The solution is concentrated to residue. The residue is dissolved in MeCN (2.5 ml) and treated with 4-methylmorphorline (0.027 ml, 0.25 mmol). 2-(5-Chloro-thiophen-2-yl)- ethenesulfonyl chloride (24 mg. 0.10 mmol), EXAMPLE 3, in MeCN (1 mL) is then added dropwise. The reaction mixture is stirred at r.t. for 1 h, then subjected to reverse phase HPLC purification, to give the title compound as white solid (0.040 g, 0.037 mmol). MS m/z 439. 441 (M+H); JI NMR (CD₃OD, 300 MHz) δ 8.20 (br, IH), 8.10 (s, I H), 8.08 (d, IH), 7.60 (d, IH), 7.53 (d. I H), 7.35 (d, I H), 7.21 (d, IH), 7.07 (dJH), 6.82 (d, IH). 5.27 (m, IH), 3.88 (s, 2H), 3.60-3.50 (m, 4H), 3.30 (d, 2H). The following compounds are prepared from starting materials obtained as described in Examples 92-97 using the methods described above.

EXAMPLE 743. 4-r2-(5-Chlorothiophen-2-yl)-ethenesulfonyn- l -(2-pyrrolo[3.2-c1pyridin-l-ylethyl)- piperazin-2-one.

4-(Benzyloxycarbonyl)-l-(2-pyrrolo[3,2-c]pyridin- l-yIethyl)-piperazin-2-one (0.028 g, 0.074 mmol), EXAMPLE 98, is treated with 4 % HC0₂H/MeOH (5 mL) and a catalytic amount of Pd black for 5 minutes. The reaction mixture is filtered washed with methanol and the filtrate is concentrated to a residue. The residue is treated with acetonitrile (3 mL) excess N-methylmorpholine (0.04 mL) and 2-(5- chlorothiophen-2-yl)ethene-sulfonyl chloride (0.018 g, 0.074 mmol), EXAMPLE 3, and processed as usual (EXAMPLE 719). Further chromatographic purification (NR,OH/MeOH/CH₂Cl₂: 1/4/95) yields the title compound: MS m/z 451 , 453 (M+H); Η NMR (CDC1₃, 300 MHz) δ 8.93 (bs, IH), 8.24 (bs, I H), 7.41 (d, lH), 7.23 (d, IH). 7.14 (m, 2H), 6.94 (d, lH), 6.68 (d. lH), 6.18 (d, IH). 4.43 (t, 2H), 3.67 (t, 2H), 2.88 (t, 2H), 2.66 (t. 2H).

EXAMPLE 744. 4-Prop-2-vnyl-I-( lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

A. 2-(2-Oxo-4-prop-2-ynv l-piperazin-l-ylmethyl)-pyrrolo[3,2-c]pyridine- l -carboxylic acid tert-butyl ester. A solution containing 2-(2-oxo-piperazin-l-ylmethyl)-pyrrolo[3,2-c]pyridine-l -carboxylic acid tert-butyl ester (4.3 g, 13.0 mmol), EXAMPLE 69, in CH₃CN (250 mL) is cooled to 0°C. Potassium carbonate (1.98 g, 14.3 mmol) is added to the reaction mixture followed by propargyl bromide ( 1.55g, 13.0 mmol). The mixture is slowly warmed to ambient temperature and maintained until complete consumption of starting material is observed by TLC (approx. 8 h). The mixture is concentrated to dryness and then partitioned between aqueous NaHC0₃ (200 mL) and CH₂C1₂ (200 mL) and the layers are separated. The aqueous phase is extracted twice with CH₂C1₂ (100 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH₂C1₂ to 5% Me0H/CH₂Cl₂) to provide 3.38 g (70%) of the title compound as a pale yellow solid. Η NMR (300 MHz, CDC1J δ 1.69 (s, 9H), 2.34 (t, J = 2.4 Hz, I H), 2.89 (m, 2H), 3.42 (s, 2H), 3.45 (d, J = 2.4 Hz, 2H), 3.52 (m, 2H), 4.95 (d, J = 1.4 Hz, 2H), 6.42 (br s, I H), 7.88 (dd, J = 5.8, 0.8 Hz, I H), 8.41 (d, J = 5.8 Hz, I H), 8.78 (d, J = 0.8 Hz, IH) ppm; MS (El): m/z 368 (M+).

B. 4-Prop-2-ynyl-l-(lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

To a solution containing 2-(2-oxo-4-prop-2-ynyl-piperazin-l -ylmethyl)-pyrrolo[3,2-c]pyridine- 1 -carboxylic acid tert-butyl ester (13 g, 3.53 mmol) in CH₂C1₂ (100 mL) is added TFA (20 mL) at 0 °C. After 6 h, the reaction mixture is concentrated to dryness and then partitioned between aqueous NaHC0₃ (500 mL) and CH₂C1₂ (200 mL) and the layers are separated. The aqueous phase is extracted four times with CH₂C1₂ (100 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0 , filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH₂C1₂ to 10% MeOH/CH₂Cl₂) to provide 616 mg (65%) of the title compound as a pale yellow solid. 'H NMR (300 MHz, CDC1₃) δ 2.27 (app t, J = 2.4 Hz, IH), 2.76 (m, 2H), 3.33 (s, 2H), 3.83 (d, J = 2.4 Hz, 2H), 3.45 (m, 2H), 4.57 (s, 2H), 6.47 (s, IH), 7.23 (d, J = 5.7 Hz, IH), 8.28 (d, J = 5.7 Hz, IH), 8.85 (d, J = 0.9 Hz, 1 H), 9.34 (br s, 1 H) ppm; MS (El): m/z 268 (M+).

EXAMPLE 745. lJ-Bis-(lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

A. 2-{4- 3-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-prop-2-ynyπ-2-oxo-piperazin-l-ylmethyl}- pyrrolo[3J-c]pyridine- l -carboxylic acid tert-butyl ester.

A solution containing 2-(2-oxo-4-prop-2-ynyl-piperazin- 1 -ylmethyl)-pyrrolo[3,2-c]pyridine- 1 - carboxylic acid tert-butyl ester ( 100 mg, 0.27 mmol), EXAMPLE 743, (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (87 mg, 0.27 mmol), EXAMPLE 69, Part B, Et₃N ( 1 10 mg, 1.08 mmol), (Ph₃P)₄PdC!_: (10 mg, 0.013 mmol), and Cul ( 1 mg, 0.008 mmol) in anhydrous DMF (5 mL) is stirred at ambient temperature. After 5 h, the reaction mixture is diluted with EtOAc (50 L) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with EtOAc (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH₂C1₂ to 10% MeOH CH₂C1₂) to provide 77 mg (51%) of SC41 as a coloriess oil. 'H NMR (300 MHz, CDC1₃, -2: 1 mixture of rotamers) major rotamer: δ 1.53 (s, 9H). 1.69 (s, 9H), 2.98 (m, 2H), 3.49 (s, 2H), 3.56 (m, 2H), 3.78 (s, 2H), 4.98 (s, 2H), 6.43 (s, IH), 7.89 (m, IH), 8.09 (m, 2H), 8.34 (m, IH), 8.41 (m, IH), 8.75 (m, IH) ppm; MS (ISP loop): m/z 561 (M+H).

B. 2-[4-(l-tert-Butoxycarbonyl-l H-pyrrolo[3,2-c1pyridin-2-ylmethyl)-2-oxo-piperazin-l-ylmethyl]- pyrrolo[3,2-c]pyridine-l -carboxylic acid tert-butyl ester. l ,8-Diazabicyclo[5J.0]undec-7-ene (42 mg, 0.27 mmol) is added to a suspension containing 2- {4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-prop-2-ynyl]-2-oxo-piperazin-l-ylmethyl}-pyrrolo[3,2- c]pyridine-l -carboxylic acid tert-butyl ester (SC41 , 77 mg, 0.14 mmol) in anhydrous CH₃CN (10 mL) and the mixture is warmed to 50 °C. After 4 h, the reaction mixture is concentrated to dryness and the residue is partitioned between CH₂C1₂ (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with CH₂C1₂ (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0 , filtered and concentrated to provide 85 mg of the title compound as a crude solid which is used directly without further purification. 'H NMR (300 MHz, CDC1₃) δ 1.68 (s, 9H), 1.70 (s. 9H), 2.91 (m, 2H), 3.41 (s, 2H), 3.49 (m, 2H), 4.26 (s, 2H), 4.95 (d, j = 1.1 Hz, 2H), 6.39 (d, J = 0.7 Hz. IH), 6.68 (d, j = 0.7 Hz, IH), 7.86 (m, IH), 8.41 (m, IH), 8.76 (br s, IH), 8.82 (br s, IH) ppm; MS (El): m/z 561 (M+H).

C. l J-Bis-(l H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one. To a solution containing 2-[4-(l-tert-Butoxycarbonyl-l H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2- oxo-piperazinJ-ylmethyl]-pyrrolo[3,2-c]pyridineJ -carboxylic acid tert-butyl ester (85 mg, 0.14mmol) in CH₂C1₂ (5 mL) is added TFA (1 mL) at 0°C and the solution is allowed to slowly warm to ambient temperature. After 16 h, the reaction mixture is concentrated to dryness, diluted with water and purified by reverse-phase HPLC [Buffer A: water w/ 0.1% TFA; Buffer B: CH3CN w/ 0.1 % TFA; Gradient: 0% B to 45% B over 30 min] to provide 35 mg (36%, two steps) of SC43 as a pale yellow, lyophilized solid. Η NMR (300 MHz, d₆-DMSO) δ 2.80 (m, 2H), 3.25 (s, 2H), 3.37 (m, 2H), 3.93 (s, 2H), 4.76 (s, 2H), 6.88 (s, I H). 6.94 (s, I H), 7.85 (d, J = 6.6 Hz, I H), 7.89 (d, j = 6.6 Hz, I H), 8.37 (d, j = 6.7 Hz, I H), 8.38 (d. J = 6.7 Hz, I H), 9.17 (s, I H), 9.19 (s, I H), 12.80 (s, I H), 12.96 (s, I H), 14.91 (br s, 2H) ppm; MS (ion spray): m/z 361 (M+H). C₂₃H₂₅ClN OS MS m/z: 441 ,443. The following compounds are prepared from starting materials obtained as described in Examples 69-71 using the methods described above.

The following compounds are prepared from 3-(S)-methoxymethyl-l-(lH-pyrrolo[3,2-c]pyridin- 2-ylmethyl)-piperazin-2-one using the procedures described above.

EXAMPLE 768. 4-(6-Chloro-benzo[b]thiophene-2-carbonyl)- l -(l H-pyrrolo[3J-c]pyridin-2- ylmefhyl)piperazin-2-one.

A. 2-[4-(6-Chloro-benzo[b1thiophene-2-carbonyl)-2-oxopiperazin-l -ylmethyl]-(pyrrolo[3,2-c1pyridiι--l- carboxylic acid tert-butyl ester. The title compound is prepared as described in EXAMPLE 123 using 6-chloro- benzo[b]thiophene-2-carboxylic acid, EXAMPLE 1 and 2-(2-oxopiperazin-l-ylmethyl)-pyrrolo[3,2- c]pyridin- l -carboxylic acid tert-butyl ester EXAMPLE 69. The mixture is stirred overnight, then concentrated to dryness. The residue is diluted with CH₂C1₂ and washed with saturated sodium bicarbonate and brine. The organic layer is dried over MgS0₄, filtered and concentrated in vacuo to give the title compound as a solid. The crude material can be used in the subsequent step without further purification.

B. 4-(6-Chloro-benzo[b1thiophene-2-carbonyl)-l-(lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)piperazin-2- one.

Trifluoroacetic acid (0.5 mL) is added dropwise to a solution of 2-[4-(6-chloro- benzo[b]thiophene-2-carbonyl)-2-oxopiperazin-l-ylmethyl]-(pyrrolo[3,2-c]pyridin-l -carboxylic acid tert-butyl ester (0.14 g, 0.27 mmol) in 6 mL CH₂C1₂ at 0°C. After 1 h, the ice bath is removed and the solution stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo. The crude residue is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN and the appropriate product fractions are combined and lyophilized to provide the title compound (0.07 g, 0.13 mmol) as a white solid. ESI MS, [M+H]^~=425, 427 (Cl pattern).

The following compounds are prepared using starting materials obtained as described in Example 69 using the methods described above.

EXAMPLE 784. (±)-l-(4-Amino-quinazolin-7-ylmethyl)-4-(5-chloro-l H-indol-2-ylmethyl)-6-oxo- piperazine-2-carboxylic acid methyl ester.

A. (±)-4- 3-(Benzhydrylidene-amino)-4-cyano-benzyl]-5-oxo-piperazine-1 ,3-dicarboxylic acid 1-allyl ester 3-methyl ester.

To a solution containing (S)-5-oxo-piperazine-l ,3-dicarboxylic acid 1-allyl ester 3-methyl ester (0J3 g, 1.77 mmol), EXAMPLE 56, and 2-(benzhydrylidene-amino)-4-bromomethyl-benzonitrile (0.66 g. 1.11 mmol), EXAMPLE 13Jn anhydrous DMF (5 mL) at 0°C is added 60% NaH (78 mg, 1.95 mmol). After 30 min, the reaction mixture is warmed to ambient temperature and maintained for 6 hours. The reaction mixture is carefully quenched with water and then diluted with water and diethyl ether. The layers are separated and the organic phase is washed twice with water, brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is chromatographed on silica gel (2: 1 hexane/ethyl acetate to 1 :1 hexane/ethyl acetate) to provide 0.37 g (39%) of the title compound as a glassy solid.

Η NMR (300 MHz, CDC1J δ 3.01 -3.22 (m, 2H), 3.58 (m, 2H), 3.73 (s, 3H), 3.86-3.92 (m, IH), 4.42- 4.58 (m, 4H), 5.25 (m, 2H), 5.93 (m, IH), 6.57 (br s, IH), 6.85 (d, J = 8.2 Hz, 1 H), 7.17-7.51 ( , 9H), 7.76 (m, 2H) ppm; MS (ion spray): m/z 537 (M+H).

B. (±)-l-[3-(Benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2-carboxylic acid methyl ester.

Tetrakis(triphenylphosphine)palladium(0) (237 mg, 0.2 mmol) is added to a solution containing (+)-4-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-5-oxo-piperazine-13-dicarboxylic acid 1-allyl ester 3-methyl ester ( 1.10 g, 2.05 mmol) and morpholine (894 mg, 10.2 mmol) in CH₂C1₂ (30 mL). After ~5 min, the reaction mixture is absorbed onto silica gel and chromatographed (CH₂C1₂ to 10% MeOH/ CH₂C1₂) to provide 900 mg (97%) of the title compound as a viscous yellow oil. Η NMR (300 MHz, CDClJ δ 1.83 (br s, IH), 2.95 (dd, J = 13.5, 4.3 Hz, I H), 3.27 (br d, J = 13.5 Hz, I H), 3.46-3.72 (m, 4H), 3.73 (s, 3H), 5.40 (d, J = 15.3 Hz, IH), 6.57 (br s, I H), 6.83 (dd, J = 8.0, 1.2 Hz, I H), 7.17-7.50 (m, 9H), 1.15-1.11 (m, 2H) ppm; MS (ion spray): m/z 453 (M+H).

C. (±)-2-{4-[3-(Benzhydrylidene-amino)-4-cyano-benzyl]-3-methoxycarbonyl-5-oxo-piperazin-l- ylmethyl}-5-chloro-indole-l -carboxylic acid tert-butyl ester.

To a mixture of (+)-l-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2- carboxylic acid methyl ester (630 mg, 139 mmol) and ₂C0₃ (380 mg. 2.78 mmol) in anhydrous CH₃CN (5 mL) at 0 °C is added 2-bromomethyl-5-chloro-indole-l -carboxylic acid tert-butyl ester (720 mg, 2.09 mmol), EXAMPLE 21. in CH₃CN (4 mL). The reaction mixture is allowed to warm to ambient temperature then maintained for 16 hours. The reaction mixture is diluted with diethyl ether/water and the layers are separated. The organic phase is washed twice with water, brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is chromatographed on silica (CH₂C1₂ to 2% MeOH/ CH₂C1₂) to provide 550 mg (55%) of the title compound which is used directly in the next reaction without further characterization.

D. (±)-2-r4-(3-Amino-4-cyano-benzyl)-3-methoxycarbonyl-5-oxo-piperazin-l-ylmethyll-5-chloro- indole-1 -carboxylic acid tert-butyl ester. Partially-purified (±)-2-{4-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-3-methoxycarbonyl-5- oxo-piperazin-l -ylmethyl}-5-chloro-indole-l -carboxylic acid tert-butyl ester (550 mg, 0.76 mmol) is suspended in reagent grade MeOH (20 mL). To the heterogeneous mixture is added 12M HCl (5 drops) and the reaction mixture is maintained at ambient temperature until homogeneous (-30 min). The reaction mixture is partitioned between diethyl ether and water containing excess NaHC0₃ (500 mL). The layers are separated and the organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is chromatographed on silica gel (CH₂C1₂ to 2% MeOH/ CH₂C1₂) to provide 400 mg (94%) of the title compound which is used directly in the next reaction. MS (ISP loop): 532 (M+H).

E. (±)-2-[4-(4-Amino-quinazolin-7-ylmethyl)-3-methoxycarbonyl-5-oxo-piperazin-l-ylmethyl]-5- chloro-indole-1 -carboxylic acid tert-butyl ester.

A solution containing (±)-2-[4-(3-amino-4-cyano-benzyl)-3-methoxycarbonyl-5-oxo-piperazin- l-ylmethyl]-5-chloro-indo!e-l -carboxylic acid tert-butyl ester (100 mg, 0.18 mmol), 1 ,3,5-triazine (146 mg, 1.81 mmol), and glacial HOAc (99 mg, 1.81 mmol) in absolute EtOH (10 mL) is maintained at reflux for 16 hours. A second portion of 1,3,5-triazine (146 mg, 1.81 mmol) and glacial HOAc (99 mg, 1.81 mmol) is added and the reaction mixture is maintained at reflux for an additional 16 hours. The reaction mixture is concentrated in vacuo and the crude product is diluted with water/CH₃CN and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH₃CN w/0.1% TFA; Gradient: 0%B to 60%B over 30 min] to provide 26 mg (20%) of the title compound as a white solid which is used directly in the next reaction without further characterization.

F. (+)- 1 -(4-Amino-quinazolin-7-ylmethyl)-4-(5-chloro- 1 H-indol-2-ylmethyl)-6-oxo-piperazine-2- carboxylic acid methyl ester. To a solution containing (±)-2-[4-(4-amino-quinazolin-7-ylmethyl)-3-methoxycarbonyl-5-oxo- piperazin-l-ylmethyl]-5-chloro-indole-l -carboxylic acid tert-butyl ester (26 mg. 0.03 mmol) in CH₂C1₂ (4 mL) is added trifluoroacetic acid (l mL) at ambient temperature. After 4 h, the reaction mixture is concentrated in vacuo and then dissolved in water/CH₃CN and purified by reverse-phase HPLC [Buffer A: water w/0.1 % TFA; Buffer B: CH₃CN w/0.1% TFA; Gradient: 0%B to 60%B over 30 min] to provide 10 mg (47%) of the title compound as a white solid. 'H NMR (300 MHz, d₆-DMSO) δ 2.62 (m, IH), 3.05-3.51 (m, 4H), 3.59 (s, 3H). 3.81 (d, J = 14.0 Hz, l H), 4.26 (m, I H), 4.69 (ABq, Δ_AB = 310 Hz, J_AB = 16.4 Hz, 2H). 6.26 (s, IH), 7.02 (dd, J = 8.6, 2.0 Hz, I H), 731 (d, J = 8.6 Hz, I H). 7.49 (d, J = 2.0 Hz, IH), 7.52 (s. I H), 7.61 (d, J = 8.7 Hz, IH), 8.30 (d, J = 8.6 Hz, I H), 8.47 (s, I H). 8.77 (s, IH), 9.69 (br s, 2H), 1 1.17 (s. 1 H) ppm; MS (ion spray): m/z 479 (M+H). EXAMPLE 785. (±)-l J4-Amino-quinazolin-7-ylmethyl)-4-(5-chloro- lH-indol-2-ylmethyl)-6-oxo- piperazine-2-carboxylic acid.

A. (±)-l -(3-Amino-4-cyano-benzyl)-4-(5-chloro-l H-indol-2-ylmethyl)-6-oxo-piperazine-2-carboxyIic acid.

LiOH monohydrate (380 mg, 9.06 mmol) is added at ambient temperature to a solution containing (±)-2-[4-(3-amino-4-cyano-benzyl)-3-methoxycarbonyl-5-oxo-piperazin-l-ylmethyl]-5- chloro-indole-1 -carboxylic acid tert-butyl ester (1.0 g, 1.81 mmol), EXAMPLE 784, Part EJn 1 : 1 : 1 THF/MeOH/water (30 mL). After 16 h, HOAc (0.5 mL) is added and the reaction mixture is concentrated in vacuo. The residue is dissolved in CH₃CN/water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH₃CN w/0.1 % TFA: Gradient: 0%B to 60%B over 30 min] to provide 378 mg (48%) of the title compound as a white solid. Η NMR (300 MHz, d₆-DMSO) δ 3.03 (m, lH), 3.48 (m, IH), 3.51 (ABq, Δ_AB = 69.2 Hz, J_AB = 16.4 Hz, 2H), 3.78 (d, J = 15.9 Hz, 1H), 4.05- 4.09 (m, 2H), 5.04 (d, J = 15.9 Hz, IH), 6.41 (m, 2H), 6.58 (s, I H), 7.04 (dd, J = 8.6, 2.0 Hz, IH), 7.25 (d, J = 8.0 Hz, IH), 7.35 (d, J = 8.6 Hz, IH), 7.51, d, J = 2.0 Hz, IH) ppm; MS (ISP loop): m/z 438 (M+H).

B. (+)- 1 -(4-Amino-quinazolin-7-ylmethyl)-4-(5-chloro- 1 H-indol-2-ylmethyl)-6-oxo-piperazine-2- carboxylic acid

A solution containing (±)-l-(3-amino-4-cyano-benzyl)-4-(5-chloro-l H-indol-2-ylmethyl)-6-oxo- piperazine-2-carboxylic acid (200 mg, 0.30 mmol), 1 ,3,5-triazine (244 mg, 3.00 mmol). and glacial HOAc (180 mg, 3.00 mmol) in absolute EtOH (20 mL) is maintained at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and the solid is collected on a Buchner funnel and washed with EtOH followed by diethyl ether. Oven-drying in vacuo provided 13 mg (76%) of the title compound as an off-white solid. Η NMR (300 MHz, d₆-DMSO) δ 2.63 (m, I H), 3.06 (d, J = 16.4 Hz, IH), 3.24-3.42 (m. 4H), 3.68 (ABq, Δ_AB = 34.5 Hz, J_AB = 14.1 Hz, 2H), 3.96 (m, IH). 4.63 (ABq, Δ_AB = 400 Hz, J_AB = 15.8 Hz, 2H), 6.27 (s, IH), 6.99 (dd, J = 8.6, 2.0 Hz, I H), 7.29 (d. J = 8.5 Hz, 2H), 7.40 (s, IH), 7.46 (s, 1 H). 7.69 (br s, 2H), 8.10 (d. J = 8.5 Hz, 1 H), 8.32 (s, 1 H), 1 1 .20 (s, 1 H) ppm; MS (ion spray): m/z 465 (M+H). EXAMPLE 786. (±)- 1 -(4-Amino-quinazolin-7-ylmethyl)-4-(5-chloro- 1 H-indol-2-ylmethyl)-6-oxo- piperazine-2-carboxylic acid methylamide

To a solution containing (±)-l-(4-amino-quinazolin-7-ylmethyl)-4-(5-chloro-l H-indol-2- ylmethyl)-6-oxo-piperazine-2-carboxylic acid (25 mg, 0.03 mmol), EXAMPLE 785, and N-methylmorpholine (36 mg, 0.36 mmol) in anhydrous DMF (1 L) is added methylamine hydrochloride (10 mg, 0.14 mmol) followed by HATU (40 mg, 0.10 mmol) at ambient temperature. After 3 h, the solvent is removed under high vacuum and the residue is dissolved in CH₃CN/water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA: Buffer B: CH₃CN w/0.1% TFA; Gradient: 0%B to 60%B over 30 min] to provide 22 mg (88%>) of the title compound as a white solid. 'H NMR (300 MHz, d₆-DMSO) δ 2.57 (d, J = 4.4 Hz, 3H), 2.70 (m, I H), 3.0 (m, I H), 3.66 (d, J = 14.2 Hz, IH), 3.77 (d, J = 14.2 Hz. lH), 3.85 (m, IH), 4.03 (d. J = 16.3 Hz, IH), 5.18 (d, J = 16.3 Hz, IH), 6.28 (s, 1 H), 7.02 (dd, J = 8.5. 2.0 Hz, 1 H), 7.31 (d, J = 8.5 Hz. 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.51 (s, IH), 7.58 (d, J = 8.6 Hz, IH). 7.97 (m, IH), 8.31 (d, J = 8.6 Hz, l H), 8.79 (s, I H), 9.72 (br s, 2H), 1 1.18 (s, IH) ppm; MS (ISP loop): m/z 478 (M+H).

Table 1 : Amide Analogs Derived From C-6 Carboxylic Acid.

The following compounds are prepared using the procedures described above.

EXAMPLE 799. (±)- l-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6- oxo-piperazine-2-carboxylic acid methyl ester.

A solution containing (±)-l-(3-amino-4-cyano-benzyl)-4-(6-chloro-benzo[b]thiophene-2- sulfonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (42 mg, 0.08 mmol), EXAMPLE 99, 1 ,3,5- triazine (40 mg, 0J8 mmol). and glacial HOAc (30 mg, 0J8 mmol) in absolute EtOH (1 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated and then dissolved in water/CH₃CN and purified by reverse-phase HPLC [Buffer A: water w/ 0.1 % TFA; Buffer B: CH3CN w/ 0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 17 mg (32%) of the title compound as a white solid.

'H NMR (300 MHz, d₆-DMSO) δ 3J7 (m, IH), 3.67 (s, 3H), 3.71 (d, J = 16.1 Hz, lH), 4.00 (d, J = 16.5 Hz, IH), 4.05 (m, IH), 4.52 (m, IH), 4.72 (ABq, Δ_AB = 248 Hz, J_AB = 16.5 Hz, 2H), 7.57 (m, 2H), 8.05 (d. J = 8.6 Hz, IH), 8.20 (s, IH), 8.23 (d, j = 8.5 Hz, IH), 8.35 (d, j = 1.9 Hz, IH), 8.49 (s, IH), 8.72 (s, IH), 9.57 (br s, 2H) ppm; MS (ion spray): m/z 546 (M+H).

EXAMPLE 800. (±)-l-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6- oxo-piperazine-2-carboxylic acid. Water (1 mL) is added to a solution containing (±)-l-(4-amino-quinazolin-7-ylmethyl)-4-(6- chloro-benzo[b]thiophene-2-suIfonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (20 mg, 0.03 mmol), EXAMPLE 799, in a 1 :1 mixture of THF/MeOH (2 mL). At ambient temperature, LiOH monohydrate (15 mg, 0.35 mmol) is then added. After 16 h, the reaction mixture is diluted with water and purified by reverse-phase HPLC [Buffer A: water w/ 0.1 % TFA; Buffer B: CH3CN w/ 0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 12 mg (63%) of the title compound as a white solid. 'H NMR (300 MHz, d₆-DMSO) δ 3.69 (d, j = 16.0 Hz, I H), 3.97 (d, j = 16.0 Hz. IH), 4.08 (d, J = 1 1.7 Hz, IH), 4.18 (d, J =16.2 Hz, IH), 431 (d, J = 2.7 Hz, I H), 5.20 (d, j =16.2 Hz. IH), 7.47 (d, j = 8.7 Hz, 1 H). 7.52 (s, 1 H), 7.58 (dd, J = 8.6, 1.9 Hz, 1 H), 8.06 (d, j = 8.7 Hz, 1 H), 8.16 (d. j = 8.6 Hz, 1 H), 8.19 (s. IH), 8.34 (d, J = 1.9 Hz, IH), 8.54 (s, IH), 8.77 (br s, I H) ppm; MS (ion spray): m/z 532 (M+H).

EXAMPLE 801. (±)-l-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6- oxo-piperazine-2-carboxylic acid amide

To a mixture containing (+)-l-(4-amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene- 2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid (45 mg, 0.08 mmol), EXAMPLE 800, N- methylmorpholine (18 mg, 0.18 mmol), and HATU (35 mg, 0.09 mmol) in anhydrous DMF (1 mL) is added NH₃ (7N in MeOH, 2 drops, approx. 0.5 mmol). The heterogeneous mixture is stirred 16 h at ambient temprature and then concentrated to dryness. The residue is dissolved in water and purified by reverse-phase HPLC [Buffer A: water w/ 0.1% TFA; Buffer B: CH3CN w/ 0.1 % TFA; Gradient: 0% B to 60% B over 30 min] to provide 25 mg (46%) of the title compound as a white solid. 'H NMR (300 MHz, d₆-DMSO) δ 3.63 (d, j = 16.0 Hz, I H), 4.01 (m, 4H), 5.17 (d, j = 16.6 Hz. I H), 7.58 (m. 3H), 8.08 (d. J = 8.6 Hz, IH), 8.17 (s, IH), 8.26 (d, J = 8.6 Hz, IH), 8.34 (d, J = 1.9 Hz. IH). 8.74 (s, IH). 9.63 (br s, 2H) ppm; MS (ISP loop): m/z 531 (M+H). The following compounds are prepared using the procedures described above.

EXAMPLE 808. (+)- 1 -(4-Amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo- piperazine-2-carboxylic acid methyl ester.

A. (±)-l -[3-(Benzhydrylidene-amino)-4-cyano-benzyl]-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo- piperazine-2-carboxylic acid methyl ester.

To a solution containing (±)-l-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2- carboxylic acid methyl ester (1.17 g, 2.6 mmol), EXAMPLE 784, Part B, 5-chlorothiophen-2-yloxyacetic acid (0.5 g, 2.6 mmol), EXAMPLE 24,and N-methylmorpholine (0.58 g, 5.72 mmol) in anhydrous DMF (10 mL) is added HATU (1.09 g. 2.86 mmol) at ambient temperature. After 1.5 h, the reaction mixture is diluted with CH₂C1₂ (100 mL) and aqueous NaHC0₃ (100 mL) and the layers are separated. The aqueous phase is washed four times with CH₂C1₂ (100 mL) and the combined organic phase is washed once with brine, dried over anhydrous Na₂S0 , filtered and concentrated. The crude amide is purified by flash silica gel chromatography (hexane/EtOAc, 4: 1 to 1 :2) to afford 1.5 g of the title compound which is used directly in the next reaction. Η NMR (300 MHz, CDC1₃, -2: 1 mixture of rotomers) major rotomer: δ 3.55 (d, J = 15.2 Hz, IH), 3.60 (m, I H), 3.69 (m, 5H), 4.37 (d, J = 17.7 Hz, IH), 4.62 (m, 2H), 4.79 (d, J = 13.3 Hz, IH), 5.35 (d, J = 15.2 Hz, IH), 6.05 (d, J = 3.9 Hz, IH), 6.52 (m. 2H), 6.84 (d, J = 8.1 Hz, IH), 7.18-7.49 (m, HH), 7.76 (m, IH) ppm; MS (ISP loop): m/z 627 (M+H).

B. (+)- 1 -(3-Amino-4-cyano-benzyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2- carboxylic acid methyl ester.

Concentrated HCl (12M, 0.5 mL) is added at 0 °C to a solution containing (±)-l-[3- (benzhydrylidene-amino)-4-cyano-benzyl]-4-[(5-chloro-thiophen-2-yIoxy)-acetyl]-6-oxo-piperazine-2- carboxylic acid methyl ester ( 1.5 g, 2.39 mmol) in 4: 1 MeOH/THF (25 mL). After 1.5 h, the reaction mixture is concentrated to dryness and then partitioned between a 1 : 1 mixture of EtOAc/aqueous NaHC0₃ (200 mL) and the layers are separated. The aqueous phase is extracted with EtOAc and then the combined organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is chromatographed on silica gel (hexane/EtOAc, 4: 1 to 1 :2) to provide 934 mg (84%, two steps) of the title compound. Η NMR (300 MPiz, CDC1₃, -2: 1 mixture of rotomers) selected peaks: δ 3.16 (app. dd, J 14.0, 3.8 Hz, IH), 3.68 (s, 3H), 3.96 (app. dd, J = 3.8, 2.0 Hz, I H), 4.17 (d, J = 17.7 Hz, I H), 4.45 (br s, 2H), 4.62 (m, 2H), 4.87 (d, J = 14.1 Hz. I H), 5.21 (d, J = 15.1 Hz, IH), 6.07 (m, I H), 6.51 (d, J = 3.8 Hz, IH), 6.57 (d, J = 7.9 Hz, IH), 6.62 (br s, I H), 7.35 (d, J = 7.9 Hz, IH) ppm; MS (ISP loop): m/z 463 (M+H).

C. (±)- l-(4-Amino-quinazolin-7-ylmethyl)-4- (5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2- carboxylic acid methyl ester.

A solution containing (±)-l-(3-amino-4-cyano-benzyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6- oxo-piperazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol), 13,5-triazine (207 mg, 2.55 mmol), and glacial HOAc (157 mg, 2.55 mmol) in absolute EtOH (5 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated to dryness and then purified by reverse-phase HPLC [Buffer A: water w/ 0.1 % TFA; Buffer B: CH3CN w/ 0.1 % TFA; Gradient: 0% B to 60% B over 30 min] to provide 50 mg (32%) of the title compound as a white solid. Η NMR (300 MHz, d₆-DMSO) δ 3.34- 3.89 (m, 2H), 3.60 (s, 3H), 4.14-4.54 (m, 3H), 4.64 (br d, J = 14.4 Hz, IH), 4.78-5.1 1 (m, 3H), 6.19 (d, J = 4.1 Hz, I H), 6.73 (d, J = 4.1 Hz, IH), 7.64 (s, I H), 7.65 (d, J = 9.0 Hz, I H). 8.34 (d, J = 9.0 Hz, IH), 8.79 (s, I H), 9.71 (br s, 2H) ppm: MS (ion spray): m/z 490 (M+H). EXAMPLE 809. (±)-l -(4-Amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyll-6-oxo- piperazine-2-carboxylic acid methylamide.

Water (1 mL) is added to a solution containing (±)-l-(4-amino-quinazolin-7-ylmethyl)-4-[(5- chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (20 mg, 0.03 mmol), EXAMPLE 808, in a 1 : 1 mixture of THF/MeOH (2 mL). At ambient temperature, LiOH monohydrate (3 mg, 0.07 mmol) is then added. After 16 h, the reaction mixture is diluted with water and purified by reverse-phase HPLC [Buffer A: water w/ 0.1% TFA; Buffer B: CH3CN w/ 0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 25 mg (>100 %>) of the associated acid as a white solid after lyophilization which is used directly in the next reaction. To a mixture containing (+/-)- l-(4-amino- quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid (12 mg, 0.02 mmol), N-methylmorpholine (19 mg, 0.19 mmol), and HATU (22 mg, 0.05 mmol) in anhydrous DMF (1 mL) is added MeNH₂ hydrochloride (5 mg, 0.19 mmol). The reaction mixture is stirred 1 h at ambient temperature and then concentrated to dryness. The residue is dissolved in water and purified by reverse-phase HPLC [Buffer A: water w/ 0.1% TFA: Buffer B: CH3CN w/ 0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 7 mg (58%) of the title compound as a white solid. 'H NMR (300 MHz, d₆-DMSO) mixture of rotamers: δ 2.51 (m, 3H), 4.07-4.54 (m, 6H), 4.87 (m, 2H), 5.10 (m, IH), 6.18 (m, IH), 6.74 (m, IH), 7.62 (m, 2H), 8.06 (br s, IH), 8.32 (br d, J = 8.8 Hz, I H), 8.78 (s, IH), 9.61 (br s, 2H) ppm; MS (ISP loop): 489 (M+H).

The following compound is prepared using the procedures described above.

EXAMPLE 81 1. (+/-)-! -(4-Amino-quinazolin-7-ylmethyl)-4-r(5-chloro-thiophen-2-yloxy)-acetyl]-6- oxo-piperazine-2-carboxylic acid. Water (0.5 L) is added to a solution containing (±)-l-(3-amino-4-cyano-benzyl)-4-[(5-chloro- thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (35 mg, 0.08 mmol), EXAMPLE 808, Part B, in a 1 : 1 mixture of THF/MeOH (1 mL). At ambient temperature, LiOH monohydrate (4 g. 0.10 mmol) is then added. After 16 h, an additional portion of LiOH monohydrate (4 mg, 0.10 mmol) is added and the reaction mixture is stirred for another 2 h then diluted with water and purified by reverse-phase HPLC [Buffer A: water w/ 0.1 % TFA; Buffer B: CH3CN w/ 0.1 % TFA; Gradient: 0% B to 60% B over 30 min] to provide 40 mg (95%) of the associated acid as a white solid after lyophilization which is used directly in the next reaction. MS (ISP loop): m/z 449 (M+H).

A solution containing (+/-)- 1 -(3-amino-4-cyano-benzyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyI]- 6-oxo-piperazine-2-carboxylic acid (20 mg, 0.03 mmol), 1,3,5-triazine (28 mg. 0.34 mmol), and glacial HOAc (20 mg, 034 mmol) in absolute EtOH (6 L) is maintained at reflux for 16 hours. The reaction mixture is concentrated to dryness and then purified by reverse-phase HPLC [Buffer A: water w/ 0.1% TFA; Buffer B: CH3CN w/ 0.1 % TFA; Gradient: 0% B to 60% B over 30 min] to provide 15 mg (75%) of the title compound as a white solid. 'H NMR (300 MHz, d₆-DMSO) δ 3.75-4.38 (m, 5H), 4.67 (d, J = 14.8 Hz, IH), 4.79 (d, J = 15.3 Hz, lH), 4.95 (m, I H), 5.09 (br d, J = 16.0 Hz, IH), 6.18 (m, IH), 6.71 (m, IH), 7.64 (m, 2H), 8.31 (d, J = 8.5 Hz, IH), 8.75 (s, IH), 9.64 (br s, 2H) ppm; MS (ISP loop): m/z 476 (M+H).

EXAMPLE 812. 4-Prop-2-ynyl- 1 -( 1 H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

A. 2-(2-Oxo-4-prop-2-ynyl-piperazin-l-ylmethyl)-pyrrolo[3,2-c]pyridine-l -carboxylic acid tert-butyl ester.

A solution containing 2-(2-oxo-piperazin-l -ylmethyl)-pyrroIo[3,2-c]pyridine- l -carboxylic acid tert-butyl ester (4.3 g, 13.0 mmol), EXAMPLE 69, in CH₃CN (250 mL) is cooled to 0°C. Potassium carbonate (1.98 g, 14.3 mmol) is added to the reaction mixture followed by propargyl bromide (1.55g, 13.0 mmol). The mixture is slowly warmed to ambient temperature and maintained until complete consumption of starting material is observed by TLC (approx. 8 h). The mixture is concentrated to dryness and then partitioned between aqueous NaHC0₃ (200 mL) and CH₂C1₂ (200 mL) and the layers are separated. The aqueous phase is extracted twice with CH₂C1₂ (100 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH₂C1₂ to 5% MeOH/CH₂Cl₂) to provide 3.38 g (70%) of the title compound as a pale yellow solid. Η NMR (300 MHz, CDC1J δ 1.69 (s, 9H), 234 (t, J = 2.4 Hz, IH), 2.89 (m, 2H), 3.42 (s, 2H), 3.45 (d, J = 2.4 Hz, 2H), 3.52 (m, 2H), 4.95 (d, J = 1.4 Hz, 2H), 6.42 (br s, IH), 7.88 (dd, J = 5.8. 0.8 Hz, IH), 8.41 (d, J = 5.8 Hz, IH), 8.78 (d, J = 0.8 Hz, IH) ppm; MS (El): m/z 368 (M+).

B. 4-Prop-2-ynyl-l -(lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

To a solution containing 2-(2-oxo-4-prop-2-ynyl-piperazin-l -ylmethyl)-pyrrolo[3,2-c]pyridine- 1 -carboxylic acid tert-butyl ester (1.3 g, 3.53 mmol) in CH₂C1₂ (100 mL) is added TFA (20 mL) at 0 °C. After 6 h. the reaction mixture is concentrated to dryness and then partitioned between aqueous NaHC0₃ (500 mL) and CH₂C1₂ (200 mL) and the layers are separated. The aqueous phase is extracted four times with CH₂C1₂ (100 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH₂C1₂ to 10% MeOH/CH₂Cl₂) to provide 616 mg (65%) of the title compound as a pale yellow solid. 'H NMR (300 MHz, CDC1₃) δ 2.27 (app t, J = 2.4 Hz, IH), 2.76 (m, 2H), 3.33 (s, 2H), 3.83 (d, J = 2.4 Hz, 2H), 3.45 ( , 2H), 4.57 (s, 2H), 6.47 (s, IH), 7.23 (d, J = 5.7 Hz, IH), 8.28 (d, J = 5.7 Hz, IH), 8.85 (d, J = 0.9 Hz, IH), 9.34 (br s, IH) ppm; MS (El): m/z 268 (M+).

EXAMPLE 813. l J-Bis-(l H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

A. 2-{4-[3-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-prop-2-ynyl]-2-oxo-piperazin-l -ylmethyl}- pyrrolo[3,2-c]pyridine-l -carboxylic acid tert-butyl ester.

A solution containing 2-(2-oxo-4-prop-2-ynyl-piperazin-l-ylmethyl)-pyrrolo[3,2-c]pyridine-l- carboxylic acid tert-butyl ester (100 mg, 0.27 mmol), EXAMPLE 812, (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (87 mg, 0.27 mmol), EXAMPLE 69, Part B, Et₃N ( 1 10 mg, 1.08 mmol), (Ph₃P)₄PdCl₂ (10 mg, 0.013 mmol), and Cul (1 mg, 0.008 mmol) in anhydrous DMF (5 mL) is stirred at ambient temperature. After 5 h, the reaction mixture is diluted with EtOAc (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with EtOAc (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH₂C1₂ to 10% MeOH CH₂C1₂) to provide 77 mg (51%) of SC41 as a colorless oil. Η NMR (300 MHz, CDC1₃, -2: 1 mixture of rotamers) major rotamer: δ 1.53 (s, 9H), 1.69 (s, 9H), 2.98 (m, 2H), 3.49 (s, 2H), 3.56 (m, 2H), 3.78 (s, 2H), 4.98 (s, 2H), 6.43 (s, IH), 7.89 (m, IH), 8.09 (m, 2H), 8.34 (m, IH), 8.41 (m, IH), 8.75 (m, IH) ppm; MS (ISP loop): m/z 561 (M+H).

B. 2-[4-(l -tert-Butoxycarbonyl-lH-pyrrolo[3,2-clpyridin-2-ylmethyl)-2-oxo-piperazin-1 -ylmethyπ- pyrrolo 3,2-c]pyridine-l -carboxylic acid tert-butyl ester. l,8-Diazabicyclo[5.4.0]undec-7-ene (42 mg, 0.27 mmol) is added to a suspension containing 2- {4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-prop-2-ynyI]-2-oxo-piperazin-l-ylmethyl}-pyrrolo[3,2- c]pyridine-l -carboxylic acid tert-butyl ester (SC41 , 77 mg, 0.14 mmol) in anhydrous CH₃CN (10 mL) and the mixture is warmed to 50 °C. After 4 h, the reaction mixture is concentrated to dryness and the residue is partitioned between CH₂C1₂ (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with CH₂C1₂ (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated to provide 85 mg of SC42 as a crude solid which is used directly without further purification. 'H NMR (300 MHz, CDC1J δ 1.68 (s, 9H), 1.70 (s, 9H), 2.91 ( , 2H), 3.41 (s, 2H). 3.49 (m, 2H), 4.26 (s, 2H), 4.95 (d, J = 1.1 Hz, 2H), 6.39 (d, J = 0.7 Hz, IH), 6.68 (d, J = 0.7 Hz, IH). 7.86 ( , IH), 8.41 (m, IH), 8.76 (br s, IH), 8.82 (br s, IH) ppm; MS (El): m/z 561 (M+H).

C. lJ-Bis-(lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one.

To a solution containing 2-[4-(l-tert-Butoxycarbonyl-lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2- oxo-piperazin-l-ylmethyl]-pyrrolo[3,2-c]pyridine-l -carboxylic acid tert-butyl ester (85 mg, 0.14mmol) in CH₂C1₂ (5 mL) is added TFA (1 L) at 0 °C and the solution is allowed to slowly warm to ambient temperature. After 16 h, the reaction mixture is concentrated to dryness, diluted with water and purified by reverse-phase HPLC [Buffer A: water w/ 0.1% TFA; Buffer B: CH3CN w/ 0.1% TFA; Gradient: 0%

B to 45% B over 30 min] to provide 35 mg (36%, two steps) of SC43 as a pale yellow, lyophilized solid.

'H NMR (300 MHz, d₆-DMSO) δ 2.80 (m, 2H), 3.25 (s, 2H), 3.37 (m, 2H), 3.93 (s, 2H), 4.76 (s, 2H), 6.88 (s, I H), 6.94 (s, IH), 7.85 (d, J = 6.6 Hz, I H), 7.89 (d, J = 6.6 Hz, I H), 837 (d, J = 6.1 Hz, IH), 8.38

(d, J = 6.7 Hz, IH), 9.17 (s, IH). 9.19 (s, IH), 12.80 (s, IH), 12.96 (s, IH), 14.91 (br s, 2H) ppm; MS (ion spray): m/z 361 (M+H). C₂₃H₂₅ClN₄OS MS m/z: 441 ,443.

EXAMPLE 814. 2-Amino-4-[4-(6-chloro- 1 H-benzoimidazol-2-ylmethyI)-2-oxo-piperidin- 1 -ylmethyl]- benzonitrile.

A. { l-[3-benzhydrylidene-amino)-4-cyano-benzyl]-2-oxo-piperidin-4-yl}-acetic acid ethyl ester:

Sodium hydride (140 mg, 3.51 mmol) is added to a cooled solution of (2-oxo-piperidin-4-yl)- acetic acid ethyl ester (500 mg. 2.70 mmol) in 10 mL of THF. After stirring for forty five minutes, 2- (benzhydrylidene-amino)-4-bromomethyl-benzonitrile (1.43 g, 3.82 mmol), EXAMPLE 13, is added, and the reaction is left to stir ov ernight. THF is removed, and the residue is taken up in 250 mL of ethyl acetate. Excess sodium hydride is quenched with 5 mL of water, and normal aqueous work-up followed.

The crude product is chromatographed on silica gel (50% EtOAc/Hexane) to give{ l -[3-benzhydrylidene- amino)-4-cyano-benzyl]-2-oxo-piperidin-4-yl}-acetic acid ethyl ester (732 mg, 57%)as a light yellow solid. C₃₀H₂₉N₃O₃ MS m/z: 480. 482. Anal cald. for C₃₀H₂₉N₃O₃: C,75.13; H, 6.09; N, 8.76. Found C,

73.01 ; H, 6.02; N, 8.46. B. { l-[3-benzhydrylidene-amino)-4-cyano-benzyl]-2-oxo-piperidin-4-yl}-acetic acid

To a solution of { l-[3-benzhydrylidene-amino)-4-cyano-benzyl]-2-oxo-piperidin-4-yl}-acetic acid ethyl ester (732 mg, 1.53 mmol) in 5 mL of THF is added IN sodium hydroxide (1.53 ml, 1.53 mmol). After stirring for four hours, the THF is removed and EtOAc (500 mL) is added. The reaction mixture is acidified to a pH of 6 and normal aqueous work-up followed. The desired carboxylic acid (571 mg, 83% yield) is isolated as a white solid.

C. N-(2-amino-5-chloro-phenyl)-2-{ l -[3-(benzhydrylidene-amino)-4-cyano-benyl]-2-oxo-piperidin-4- yl}-acetamide

To a slurry of the { l-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-2-oxo-piperidin-4-yl}-acetic acid (190 mg, 0J22 mmol) in THF (5 mL) and methylene chloride (3 mL) is added triethylamine (0.09 ml, 0.633 mmol). The solution is cooled to 0 °C , and IM isopropyl chloroformate in toluene (0J22 mL, 0J22 mmol) is added. The homogenous mixture is allowed to warm to room temperature, and 4-chloro- 1 ,2-phenylene-diamine (150 mg, 1.06 mmol) is added. The reaction is stirred at room temperature overnight. The volatile solvents are removed, and the resulting residue is chromatographed (Si0₂, 5%MeOH/EtOAc) to give N-(2-amino-5-chloro-phenyl)-2-{ l-[3-(benzhydrylidene-amino)-4-cyano- benyl]-2-oxo-piperidin-4-yl}-acetamide (200 mg, 82% yield). C₃₄H₃₀ClN₅O₂ MS m/z: 576, 578.

D. 2-(Benzhydrylidene-amino)-4-[4-(6-cloro-lH-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-l- ylmethylj-benzonitrile

The acetamide (200 mg. 0.35 mmol) is dissolved in 2 mL of acetic acid and refluxed for three hours. The acetic acid is removed, and the residue taken up in ethyl acetate and washed with saturated sodium bicarbonate. Concentration of the solvent afforded 2-(benzhydrylidene-amino)-4-[4-(6-cloro- lH-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-l-ylmethyl}-benzonitrile (200 mg, 100% yield) which is used without further purification. C₃₄H₂₈C1N₅0₅ MS m/z:+ 558, 560.

E. 2-Amino-4-[4-(6-chloro-l H-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-l -ylmethyl1-benzonitrile hydrochloric acid salt The above benzonitrile (220 mg, 0.36 mmol) is dissolved in 5 ml of methanol. Hydrochloric acid is bubbled into the ice-cooled methanol solution followed by three drops of water. After stirring at room temperature for one hour, the MeOH is removed. The resulting white solid is titurated with EtOAc. After drying under high vacuum, 2-amino-4-[4-(6-chloro-lH-benzoimidazol-2-ylmethyl)-2-oxo- piperidin-l-ylmethyl]-benzonitrile hydrochloric acid salt (145.6 mg, 87% yield) is obtained as a white solid. C₂₁H₂₀ClN₅O: MS m/z: 394,396.

EXAMPLE 815. 4-r4-(6-Chloro-lH-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-l-ylmethyll- benzamidine

Hydrochloric acid is bubbled into an ice cooled solution of 4-[4-(6-chloro-lH-benzoimidazol-2- ylmethyl)-2-oxo-piperidin-l-ylmethyl]-benzonitrile (127 mg, 0.336 mmol) in 10 mL of methanol. The solution also contained 3A molecular sieves. The reaction is stored at -30 for forty-eight hours. The methanol is condensed on the rotovap. Fresh methanol (15 mL) is added followed by a stream of ammonia gas. The reaction is heated to reflux for two and half hours. The reaction mixture is filtered at room temperature. Methanol is removed from the mother liquor. The resulting residue is purified by reverse phase HPLC (0-50 % ACN/H₂0). The product is isolated as a white solid with a melting point of 105-110 °C . C₂,H₂₂C1N₅0 MS m/z: 396,398. Anal. cald. for C₂,H₂₂C1N₅0 • 2C₂HF₃0₂: C, 48.13; H, 3.88; NJ 1.22. Found: C, 45.05; H, 3.52; N, 9.89.

EXAMPLE 816. 1 -(4-Amino-quinazolin-7-ylmethly)-4-(6-chloro- 1 H-benzoimidazol-2-ylmethyl)- piperidin-2-one.

To a solution of 2-Amino-4-[4-(6-chloro-lH-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-l- ylmethyl]-benzonitrile hydrochloric acid salt (143 mg, 0.308 mmol), EXAMPLE 814, Part E, in 2 mL of ethanol is added triethylamine (0.05 mL, 0.366 mmol), glacial acetic acid (0.02mL, 0.366 mmol) and triazine (15 mg, 0.183 mmol). The resulting mixture is refluxed overnight. The volatile solvents are removed on the rotovap, and the residue is purified by reverse phase HPLC (0 - 50% Acetonitrile/H₂0). The desired product (1 10 mg, 55% yield) is isolated as a white powder with a melting point of 128-132 °C . C₂₂H₂,C1N₆0 MS m/z: 421, 423. Anal, calcd. for C₂₂H_2IC1N₆0: C, 48.12; H, 3.57; N, 12.95. Found: C, 45.79; H, 3.68; N, 1 1.94. H NMR (CD₃OD) δ: 8.67 (s, 1H); 831 (d, IH, J = 4.0 Hz); 7.83-7.55 (m, 5H): 4.93-4.73 (m, 2H); 3.48-3.42 (m, 2H); 331-3.21 (m, 2H); 2.71-2.58 (m, 2H); 2.43-2.33 (m, IH); 2.07- 2.01 (m, IH); 1.82 - 1.69 (m, IH).

EXAMPLE 817. 4-(6-Chloro- 1 H-benzoimidazol-2-ylmethyl)- 1 -(2J-diamino-quinazolin-7-ylmefhyl)- piperidin-2-one

2-Amino-4-[4-(6-chloro- 1 H-benzoimidazol-2-ylmethyl)-2-oxo-piperidin- 1 -ylmethyl]- benzonitrile hydrochloric acid salt (70 mg, 0.15 mmol), EXAMPLE 814, Part E, pyridine (1.0 mL) and freshly made chloroformamide hydrochloride (150 mg, 133 mmol) are placed in a sealed tube and heated to 200 °C . The resulting mixture is heated for twenty four hours. The crude reaction mixture is directly purified by reverse phase HPLC (0-50% ACN/H₂0). The product (53 mg, 45% yield) is isolated as a tanish solid. C₂₂H₂₂C1N₇0 MS m/z: 436,438. Anal, calcd. for C₂₂H₂₂C1N₇0: C, 43.23; H, 3.24; N, 12.60. Found: C, 43.16; H, 3.44; N, 13.40.

EXAMPLE 818. l-(4-Amino-2-methyl-quinazolin-7-ylmethly)-4-(6-chloro-l H-benzoimidazol-2- ylmethyl)-piperidin-2-one.

A stream of hydrogen chloride gas is bubbled intermittently through an ice-cold mixture of 2- amino-4-[4-(6-chloro-lH-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-l-ylmethyl]-benzonitrile hydrochloric acid salt (57 mg. 0.123 mmol), EXAMPLE 814, Part E, and acetonitrile (0.03 mL, 0.93 mmol) in 1.5 mL of dioxane for six hours. The dioxane is removed; the residue is purified by reverse phase HPLC (0-40 % ACN/H₂0). The desired product (9.5 mg, 12% yield) is isolated as a clear wax. C₂₃H₂₃C1N₆0 MS m/z : 435, 437.

The following compounds are prepared using the methods described above.

EXAMPLE 823. 2J4J6-Chlorobenzo[blthiophene-2-sulfonyl)-2-oxopiperazinJ-yll-NJ2J3H- imidazol-4-yl)-ethyl]acetamide.

A. 4-tert-Butoxycarbonylmethyl-3-oxo-piperazine-l -carboxylic acid benzyl ester.

To a solution of 3-oxopiperazine-l -carboxylic acid benzyl ester (4.68g, 20mmol) in 20 mL of DMF at ) 0°C is added sodium hydride (60%, 880 mg, 22 mmol). The suspension is stirred at ambient temperature for one t-butyl bromoacetate (4.68 g, 24 mmol) is added. The resulting mixture is stirred at ambient temperature overnight. After dilution with ethyl acetate (200 mL), the mixture is washed with brine (3 x 50 mL). The crude residue obtained from concentration of the organic phase is chromatographied on silica gel (30% ethyl acetate/Hexane) to give 5.57 g (80%) of 4-tert- butoxycarbonyImethyl-3-oxopiperazine-l -carboxylic acid benzyl ester as a white solid.

B. (2-Oxo-piperazin-l-yl)acetic acid tert-butyl ester.

4-tert-Butoxycarbonylmethyl-3-oxopiperazine-l -carboxylic acid benzyl ester (2.0g, 5.75 mmol ) is dissolved in 20 mL of methanol and 2 mL of acetic acid. Palladium (5%) on carbon (100 mg) is added, and the reaction mixture is stirred in an atmosphere of hydrogen overnight. The mixture is filtered and concentrated. Ethyl acetate is added, and the mixture is neutralized to pH 7 using IN NaOH. The organic layer is concentrated to give (2-oxo-piperazin- 1 -yl)acetic acid tert-butyl ester ( 1.22g).

C. [4-(6-Chlorobenzo[blthiophene-2-sulfonyI)-2-oxopiperazine-l -yl]acetic acid tert-butyl ester.

To a solution of (2-oxo-piperazin- l-yl)acetic acid tert-butyl ester (1.22 g, 5.7 mmol) in 10 ml of methylene chloride is added triethylamine ( 1.2 mL, 8.55 mmol) and 6-chlorobenzothiophenesulfonyl chloride (1.52 g, 5.7 mmol). The reaction mixture is stirred overnight at ambient temperature. Flash column chromatography (50 % ethyl acetate / hexane) affords 2.3 g (92%) of [4-(6- chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazine-l-yl]acetic acid tert-butyl ester.

D. [4-(6-Chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazine- 1 -yl]-acetic acid. [4-(6-Chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazine- 1 -yl]acetic acid tert-butyl ester (500 mg, 1.13 mmol) is dissolved in 1 mL of trifluoroacetic acid and 3 mL of CH2CI2. The solvents are azeotropically removed with toluene. [4-(6-chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazine-l- yl]acetic acid (438 mg) is isolated as a white solidΛ

E. 2-[4-(6-Chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazin- 1 -yll-N-[2-(3H-imidazol-4-yl)- ethyllacetamide.

To a slurry of [4-(6-chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazine-l-yl]acetic acid (47 mg, 0.12 mmol ) in 2 mL of tetrahydrofuran is added E-3N (0.025 mL, 0.18 mmol). The mixture is cooled to 0°C, and IM solution of isopropyl chloroformate in toluene (0.12 mL, 0.12mmol) is added. The mixture is stirred for fifteen minutes and histamine (13.3 mg, 0.12 mmol) is added. The mixture is stirred overnight at room temperature. Reverse phase HPLC (AcCN/H₂0/TFA) affords 2-[4-(6- Chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazin- l -yl]-N-[2-(3H-imidazol-4-yl)-ethyl]acetamide trifluoroacetic acid salt (17 mg. 25%) as a solid, mp 77-82°C; MS m/z 482 (M+H). The followin compounds are prepared from the appropriate starting materials using the method of EXAMPLE 823.

836 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]- 496, 498 N-[2-(3-methyl-3H-imidazol-4-yl)-ethyI]-acetamide

837 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]- 493, 495 N-(2-pyridin-2-yl-ethyl)-acetamide

838 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]- 493, 495 N-(2-pyridin-3-yl-ethyl)-acetamide

839 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]- 482, 484 N-(2-imidazol- 1 -yl-ethyl)-acetamide

840 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]- 495, 497 N- [2-( 1 -methyl- 1 H-pyrrol-2-yl)-ethyl]-acetam ide

841 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]- 496, 498 N-[2-(5-methyl-l H-imidazol-4-yl)-ethyl]-acetamide

842 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]- 510, 512 N-(4-dimethylamino-[l ,3,5]triazin-2-yl)-acetamide

843 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]- 479, 481 N-methyl-N-pyridin-4-yl-acetamide

844 N-[2-(2-Amino-pyridin-4-yl)-ethyl]-2-[4-(6-chloro- 508, 510 benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]-acetamide

845 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin- l -yl]- 513, 515 N-[2-(4-methyl-thiazol-5-yl)-ethyl]-acetamide

846 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l -yl]- 499, 501 N-(2-thiazol-4-yl-ethyl)-acetamide

847 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]- 487, 489 N-(3-guanidino-propyl)-acetamide trifluoroacetic acid salt

848 N-(3-Amino-propyl)-2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)- 445, 447 2-oxo-piperazin- 1 -v l]-acetamide

849 2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l -yl]- 514, 516 N-[2-(2-mercapto-l H-imidazol-4-yl)-ethyl]-acetamide

EXAMPLE 853. 4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-l-[3-(3H-imidazol-4-yl)-propyll-piperazin- 2-one.

A. 3-Oxo-4-[3-(3-trityl-3H-imidazol-4-yl)-allyl-piperazine-l -carboxylic acid benzyl ester. 3-Oxo-piperazin-l -carboxylic acid benzyl ester (702 mg, 3.0 mmol) is dissolved in dimethylformamide (10 mL) and cooled to 0°C . Sodium hydride (60%, 148 mg, 3.1 mmol) is added, followed by the addition of 5-(3-chIoro-propenyl)- l-trityl-lH-imidazoIe (473 mg, 1.2 mmol). The resulting mixture is left to stir at room temperature overnight. Most of the dimethylformamide is removed on the high vacuum. The reaction mixture is diluted with ethyl acetate (250 mL) and quenched with water. The two layers are separated and ethyl acetate (2x 100 mL) is used to extract and dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (50% EtOAc/hexane) to give 3-oxo-4-[3-(3-trityl-3H-imidazol-4-yl)-alIyl-piperazine-l -carboxylic acid benzyl ester (360 mg) as the desired product.

B. 4-[3-(3-tert-Butoxycarbonyl-3H-iιrιidazol-4-yl)-allyl]-3-oxo-piperazine- l -carboxylic acid benzyl ester.

3-Oxo-4-[3-(3-trityl-3H-imidazol-4-yl)-allyl-piperazine-l -carboxylic acid benzyl ester (360 mg, 0.62 mmol) is stirred vigorouslv in a 30% solution of trifluoroacetic acid and methylene chloride (10 mL). After stirring for three hours, the trityl group is removed. The volatile solvents are removed in vacuo, and the crude product is taken-up in methylene chloride (10 mL). Pyridine (0.5 ml) and Di-tert- butyl dicarbonate (176 mg. 0.81 mmol) is added to the solution, and the resulting mixture is left to stir overnight. The reaction mixture is condensed and purified by flash column (Si0₂, 20% EtOAc/Hexane) to give 4-[3-(3-tert-butoxycarbonyl-3H-imidazol-4-yl)-allyl]-3-oxo-piperazine-l -carboxylic acid benzyl ester (100 mg). C. 5-{3-[4-(6-Chloro-benzo[blthiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]-propyl}-imidazol-l- carboxylic acid tert-butyl ester.

Palladium on carbon (10 %>, 15 mg) is added to a solution of 4-[3-(3-tert-butoxycarbonyl-3H- imidazol-4-yl)-allyl]-3-oxo-piperazine-l -carboxylic acid benzyl ester (50 mg, 0.1 14 mmol) in 5 mL of methanol. The reaction mixture is left to stir in an atmosphere of hydrogen overnight. The palladium is filtered off, and the volatile solvents are removed on the rotovap. The crude product (50 mg, 0.1 14 mmol) is redissolved in methylene chloride (5 mL). Triethylamine (0.06 ml, 0J3 mmol) 6-chloro- benzo[b]thiophene-2-sulfonyI chloride (39 mg, 0.15 mmol) is added, and the resulting mixture is stirred overnight. The crude product is directly purified by flash column (Si0₂, 30% EtOAc/Hexane) to afford 5- {3-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]-propyl}-imidazol-l -carboxylic acid tert-butyl ester (30 mg).

D. 4-(6-Chloro-benzo[b1thiophene-2-sulfonyl)-l-[3-(3H-imidazol-4-yl)-propyl]-piperazin-2-one:

5-{3-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-l-yl]-propyI}-imidazol-l- carboxylic acid tert-butyl ester (30 mg, 0.055 mmol) is stirred vigorously in a 30 % solution of trifluoroacetic acid and methylene chloride (2 mL). The reaction is complete after stirring for three hours. The volatile solvents are removed on the rotovap, and the gummy solid is titurated with ether several times to afford 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)- l -[3-(3H-imidazol-4-yl)-propyl]- piperazin-2-one trifluoroacetic acid salt (30 mg) as a yellow solid. Cι₈H|₉ClN 0₃S₂ (m/z)+: 439, 441. Anal cald. for C₁₈H_I9C1N₄0₃S₂ - C₂HF₃0₂ : C, 43.44; H, 3.65; N, 10.13. Found C, 42.03; H, 3.55; N, 8.26.

The following compounds are prepared using the methods described above.

EXAMPLE 860. 4-r(5-Chloro-thiophen-2-yloxy)-acetyn-3-(S)-methoxymethyl-l-[4-(6-methoxy- pyridin-3-yl)-benzyl]-piperazin-2-one.

A. 3-Methoxymethyl-4-[4-(6-methoxy-pyridin-3-yl)-benzyll-3-oxo-piperazine- 1 -carboxylic acid benzyl ester.

The title compound is prepared by the method in EXAMPLE 66. Part A, substituting 5-(4- bromomethyl-phenyl)-2-methoxy-pyridine for 4-bromomethyl tolynitrile and 2-methoxymethyl- 3oxopiperazin-l -carboxylic acid benzyl ester for 3-oxopiperazin- l -carboxylic acid benzyl ester. MS (ISP) m/z 476, (M+H).

4-[(5-Chloro-thiophen-2-yloxy )-acetyl]-3-(S)-methoxymethyl-l-[4-(6-methoxy-pyridin-3-yl)-benzyl]- piperazin-2-one

The title compound is prepared by deprotecting 3-methoxymethyl-4-[4-(6-methoxy-pyridin-3- yl)-benzyl]-3-oxo-piperazine-l -carboxylic acid benzyl ester as described in EXAMPLE 75, Part C. The crude amine is then coupled as described in EXAMPLE 123 with 3-(5-chloro-fhiophen-2-yl)-(E)-acrylic acid, EXAMPLE 25. MS (ISP) m/z 516, 518, (M+H). Cl pattern.

The following compounds are prepared according to the method of Example 860.

EXAMPLE 874. 1 -(3-Amino- 1 H-indazol-6-ylmethyl)-4-(6-chloro-benzo[b]thiophen-2-ylmethyl)- piperazin-2-one.

A. 2-Amino-4-(2-oxo-piperazin-l -ylmethyl)-benzonitrile.

To a solution of 4-(3-Amino-4-cyano-benzyl)-3-oxo-piperazine-l -carboxylic acid benzyl ester hydrochloride (4.0 g. l O.Ommol) in CH₃OH (45 ml) and CH₂C1₂ (10 ml) is added 10% Pd on carbon (0.6 g). The mixture is stirred under an atmosphere of H₂ for 2 hours then is filtered through a pad of celite. The filtrate is concentrated and the residue purified by column chromatography eluting with 10% 7M NH₃ in CHjOH / CH₂C1_; to yield the title compound ( 1.62 g, 7.0 mmol). Η NMR (DMSOJOOMHz) ? 734 (d, I H). 6.64 (s, I H). 6.46 (d. I H), 6.04 (bs, 2H), 4.40 (s, 2H), 3.28 (s, 2H), 3.14 (m, 2H), 2.87 (m, 2H), 2.77 (bs. I H). MS (ion spray): m/z 231 (M+H)^'. B. 2-Amino-4-[4-(6-chloro-benzo[blthiophen-2-ylmethyl)-2-oxo-piperazin-l-ylmethyl1-benzonitrile.

To a cooled solution (0° C) of 2-Amino-4-(2-oxo-piperazin-l-ylmethyl)-benzonitrile (0.345 g, 1.5 mmol) in DMF (2 ml) is added finely powdered anhydrous K₂C0₃ (0.31 1 g, 2.25 mmol) and allowed to stir for 20 minutes. To this mixture is added a solution of 2-bromomethyl-benzo[b]thiophene (0.392 g, 1.5 mmol) in DMF (3 ml), the cold bath removed and allowed to stir for 2 hours. The reaction mixture is concentrated under high vacuum and the residue purified by column chromatography eluting with 55% EtOAc/ 5% CH₃OH/ hexane to yield the title compound (0.477 g, 1.16 mmol) as a white solid. 'H NMR (DMSOJOOMHz) ? 8.06 (d, IH), 7.78 (d, IH), 7.37 (m, 3H), 6.64 (s, I H), 6.44 (d, IH), 6.09 (bs, 2H), 4.42 (s, 2H). 3.88 (s, 2H), 3.21 (m, 4H), 2.72 (m, 2H). MS (ion spray): m/z 41 1, 413 (M+H)⁺, Cl pattern.

C. I-(3-Amino-lH-indazol-6-ylmethyl)-4-(6-chloro-benzo[b]thiophen-2-ylmethyl)-piperazin-2-one.

To a cooled solution (0° C) of 2-Amino-4-[4-(6-chloro-benzo[b]thiophen-2-ylmethyl)-2-oxo- piperazin-l-v lmethyl]-benzonitrile (0.365 g, 0.89 mmol) in concentrated HCl (2.1 ml) is added dropwise a solution of sodium nitrite (0.068 g, 0.98 mmol) in H₂0 (0.2 ml). The reaction mixture is added to a cooled solution (0° C) of tin (II) chloride dihydrate (1.61 g, 7.12 mmol) in concentrated HCl (0.62 ml) and H₂0 (3 ml). The precipitate is collected by vacuum filtration and dried under high vacuum. The crude solid is purified by column chromatography eluting with 10%> 7M NH₃ in CH₃OH / CH₂C1₂ to yield the title compound (0.144 g, 0.34 mmol) as a yellow solid. 'H NMR (DMSO,300MHz) ? 1 1.35 (bs, IH). 8.05 (d. IH), 7.78 (d, IH). 7.64 (d, IH), 7.37 (m, 2H), 7.08 (s, I H), 6.78 (d, I H), 5.75 (s, I H), 5.40 (bs. IH), 4.58 (s, 2H), 3.88 (s, 2H), 3.20 (m, 4H), 2.70 (bt, 2H). MS (ion spray): m/z 426 (M+H)⁺. Anal, cald. for C_2IH₂₀N₅OSCl;(H₂O)₀₂₅: C, 58.6; H, 4.8; N, 163. Found C, 58.6; H, 4.7; N, 15.9. M.P = 246- 248°C.

EXAMPLE 875. l-(3-Amino-l H-indazol-6-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)]-piperazin-2-one. A. 2-Amino-4-{4-[3-(5-chloro-thiophen-2-yl)-allyl]-2-oxo-piperazin-l-ylmethyl)-benzonitrile.

Using essentially the same procedure as in EXAMPLE 874, Part B using 2-(3-bromo-propenyl)- 5-chloro-thiophene is obtained the title compound. MS (El): m/z 386, 388 (M , Cl pattern.

B. l-(3-Amino-lH-indazol-6-ylιnethyl)-4-[3-(5-chloro-thiophen-2-yl)l-piperazin-2-one. Using essentially the same procedure as in EXAMPLE 874, Part C there is obtained the title compound. 'H NMR (DMSO, 300MHz) ? 1 132 (bs, 1 H), 7.62 (d, 1 H), 7.06 (s, 1 H), 7.02 (d, 1 H), 6.96 (d, IH), 6.78 fd. I H), 6.67 (d, I H), 5.96 (m, IH), 5.32 (bs, 2H), 4.57 (s, 2H), 3.19 (bt, 2H), 3.12 (m, 4H), 2.64 (bt, 2H). MS (El): m/z 401. 403 (M⁺), Cl pattern. Anal. cald. for C₁₉H₂₀C1N₅OS: C. 56.8; H, 5.0; N, 17J. Found C. 56.6; H. 4.8; N, 17.2. M.P.= 167- 169°C EXAMPLE 876. 1 -(3-Amino-lH-indazol-6-ylmethyl)-4-(6-chloro-benzo[blthiophene-2-sulfonyl)- piperazin-2-one.

A. 2-Amino-4- 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperzin-1-ylmethyl]-benzonitrile. Using essentially the same procedure as in EXAMPLE 874, Part B except using 6-chloro- benzo[b]thiophene-2-sulfonyl chloride, EXAMPLE 1 , is obtained the title compound. MS (ion spray): m/z 461, 463 (M+H)⁺, Cl pattern.

B. l-(3-Amino-lH-indazol-6-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-2-one. Using essentially the same procedure as in EXAMPLE 874, Part C there is obtained the title compound. 'H NMR (DMSO. 300MHz) ? 1 1.29 (s, IH), 835 (s. I H), 8.18 (s, IH), 8.08 (d, IH), 7.58 (m. 2H), 7.05 (s, IH), 6.70 (d, IH), 5.30 (bs, 2H), 4.56 (s, 2H), 3.84 (s, 2H), 3.40 (m, 2H), 330 (m, 2H). MS (ion spray): m/z 476, 478 (M+H)⁺, Cl pattern. Anal. cald. for C₂₀H₁₈ClN₅O₃S₂: C, 50.5; H, 3.8; N, 14.7. Found C, 50.3; H, 3.6; N, 14.5. M.P.=274-276°C.

The following compounds are prepared using the procedures described above.

Inhibition of Factor Xa

The compounds described herein inhibit blood coagulation by virtue of their ability to inhibit the penultimate enzyme in the coagulation cascade, controlling the activity of Factor Xa. Both the activity of free Factor Xa and Factor Xa assembled in the prothrombinase complex (Factor Xa. Factor Va, calcium and phospholipid) are inhibited by compounds of formula 1. The inhibition of the Factor Xa activity is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III. Effective inhibition of the Factor Xa activity is achieved by administering the compounds either by oral administration, continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the activity of Factor Xa induced formation of thrombin from prothrombin.

Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally 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, intermittent claudication and bypass grafting of the coronary (CABG) or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long- term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular 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 resulting in the formation of life-threatening thrombin throughout the microvasculature of several organ systems. The indications discussed above include some, but not all, of the possible clinical situations where anticoagulant therapy is warranted. Those experienced in this field are well aware of the circumstances requiring either acute or chronic prophylactic anticoagulant therapy.

Accumulated experimental evidence has also reflected that prothrombin activation is only one of the biological activities of Factor Xa. EPR-1 (effector cell protease receptor- 1 , recognizing Factor Xa), is believed to mediate several of the vascular wall interactions by Factor Xa. It has been shown to be expressed on human umbilical v ein endothelial cells, rat smooth muscle cells and platelets(CR McKenzie, et al., Arterioscler Thromb Vase Biol 16 1285-91 (1996); also F Bono, et al., J Cell Physiol 172 36-43 (1997), AC Nicholson, et al., J Biol Chem 27J 28407-13 (1996)J.M. Herbert, et al, j Clin Invest 101 993- 1000 ( 1998)). This protease-receptor interaction could mediate not only prothrombinase- catalyzed thrombin generation, but also diverse cellular functions such as cell proliferation, release of PDGF and DNA syntheses. The mitogenic effect of Factor Xa has been reported to be dependent on Factor Xa enzymatic activity (F Bono, et al, J Cell Physiol 112 36-43 (1997), J.M. Herbert, et al, J Clin Invest 1PJ 993- 1000 (1998)). TAP for example inhibited the mitogenesis of human and rat cultured vascular smooth muscle cells (F Bono, et al, J Cell Physiol 172 36-43 (1997)). In a study of the rabbit carotid artery air-drying injury model, increased EPR-1 expression is detected after vascular injury. Animals treated with the specific Factor Xa inhibitor, DX-9065a, exhibited less neointimal proliferation. The important regulatory role of Factor Xa in the coagulation process coupled with its mitogenic effects points to Factor Xa's involvement in the formation of thrombin at the luminal surface of the vessel wall and contribution to the atherothrombotic process and abnormal proliferation of vascular cells resulting in restenosis or angiogenesis. These compounds may be used alone or in combination with other diagnostic, anticoagulant, antiplatelet or fϊbrinolytic agents. For example adjunctive administration of inhibitors of the activity of Factor Xa with standard heparin, low molecular weight heparin, direct thrombin inhibitors (i.e. hirudin), aspirin, fibrinogen receptor antagonists, streptokinase, urokinase and/or tissue plasminogen activator may result in greater antifhrombotic or thrombolytic efficacy or efficiency. The compounds described herein may be administered to treat thrombotic complications in a variety of animals such as primates including humans. Inhibition of factor Xa is useful not only in the anticoagulant therapy of individuals having thrombotic conditions but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus, any inhibitor of Factor Xa activity can be added to or contacted with any medium containing or suspected of containing Factor Xa and in which it is desired that blood coagulation be inhibited.

In addition to their use in anticoagulant therapy, Factor Xa inhibitors may find utility in the treatment or prevention of other diseases in which the generation of thrombin has been implicated as playing a physiologic role. For example, thrombin has been proposed to contribute to the morbidity and mortality of such chronic and degenerative diseases as arthritis, cancer, atherosclerosis and Alzheimer's disease by virtue of its ability to regulate many different cell types through specific cleavage and activation of a cell surface thrombin receptor, mitogenic effects, diverse cellular functions such as cell proliferation, for example, abnormal proliferation of vascular cells resulting in restenosis or angiogenesis. release of PDGF and DNA syntheses. Inhibition of Factor Xa will effectively block thrombin generation and therefore neutralize any physiologic effects of thrombin on various cell types. According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, a physiological condition which can be ameliorated bv the administration of an inhibitor of the Factor Xa activity, for example conditions as hereinbefore described, which comprises the administration to the patient of a therapeutically effective amount of compound of formula I or a composition containing a compound of formula I. "Effective amount" is meant to describe an amount of compound of the present invention effective in inhibiting the activity of Factor Xa and thus producing the desired therapeutic effect.

The present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of formula I in association with a pharmaceutically acceptable carrier or coating.

In practice compounds of the present invention may generally be administered parenterally, intravenously, subcutaneously intramuscularly, colonically, nasally, intraperitoneal ly, rectally or orally. The products according to the invention may be presented in forms permitting administration by the most suitable route and the invention also relates to pharmaceutical compositions containing at least one product according to the invention which are suitable for use in human or veterinary medicine. These compositions may be prepared according to the customary 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 may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations.

The choice of 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 mode of administration and the provisions to be observed 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 may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the 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. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation or microfiltration.

Suitable compositions containing the compounds of the invention may be prepared by conventional means. For example, compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier 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.

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. In the adult, the doses are generally from about 0.01 to about 100, preferably about 0.01 to about 10, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.01 to about 50, preferably 0.01 to 10, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.

The products according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day. Compounds within the scope of the present invention exhibit marked pharmacological activities according to tests described in the literature which tests results are believed to correlate to pharmacological activity in humans and other mammals. The following pharmacological test results are typical characteristics of compounds of the present invention. Enzyme Assays:

The ability of the compounds in 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 which resulted in a 50% loss in enzyme activity (IC50) using purified enzymes.

All enzyme assays are carried out at room temperature in 96-well microtiter plates using a final enzyme concentration of 1 nM. The concentrations of factor Xa and thrombin are determined by active site titration and the concentrations of all other enzymes are based on the protein concentration supplied by the manufacturer. Compounds according to the invention are dissolved in DMSO, diluted with their respective buffers and assayed at a maximal final DMSO concentration of 1.25%. Compound dilutions are added to wells containing buffer and enzyme and pre-equilibrated for between 5 and 30 minutes. The enzyme reactions are initiated by the addition of substrate and the color developed from the hydrolysis of the peptide-p-nitroanilide substrates is monitored continuously for 5 minutes at 405 nm on a Vmax microplate reader (Molecular Devices). Under these conditions, less than 10% of the substrate is utilized in all assays. The initial velocities measured are used to calculate the amount of inhibitor which resulted in a 50% reduction of the control velocity (IC50). The apparent Ki values are then determined according to the Cheng-Prusoff equation (IC50 = Ki [1+[S]/Km]) assuming competitive inhibition kinetics.

An additional in vitro assay may be used to evaluate the potency of compounds according to the invention in normal human plasma. The activated partial thromboplastin time is a plasma-based clotting assay that relies on the in situ generation of factor Xa, its assembly into the prothrombinase complex and the subsequent generation of thrombin and fibrin which ultimately yields the formation of a clot as the assay endpoint. This assay is currently used clinically to monitor the ex vivo effects of the commonly used anticoagulant drug heparin as well as direct acting antithrombin agents undergoing clinical evaluation. Therefore, activity in this in vitro assay is considered as a surrogate marker for in vivo anticoagulant activity.

Human Plasma Based Clotting Assay:

Activated partial thromboplastin clotting times are determined in duplicate on a MLA Electra 800 instrument. A volume of 100 ml of citrated normal human pooled plasma (George King

Biomedical) is added to a cuvette containing 100 ml of a compound according to the invention in Tris/NaCI buffer (pH 7.5) and placed in the instrument. Following a 3 minute warming period the instrument automatically adds 100 ml of activated cephaloplastin reagent (Actin, Dade) followed by 100 ml of 0.035 M CaCl2 to initiate the clotting reaction. Clot formation is determined spectrophotometrically and measured in seconds. Compound potency is quantitated as the concentration required to double a control clotting time measured with human plasma in the absence of the compound according to the invention.

A compound according to the invention may also be evaluated for their in vivo antithrombotic efficacy in two well established animal experimental models of acute vascular thrombosis. A rabbit model of jugular vein thrombosis and a rat model of carotid artery thrombosis are used to demonstrate the antithrombotic activity of these compounds in distinct animal model paradigms of human venous thrombosis and arterial thrombosis, respectively.

Experimental Plazma Protein Binding Assay

Compounds are dissolved into DMSO to prepare a 10 mM stock. Serial dilutions of compounds are made in a buffer containing 0.05M Tris, 0.15M NaCl, 0.1% PEG-8000, PH 7.5. Human FXa and the substrate, Spectrozyme FXa, are prepared in the aforementioned buffer containing human Albumin and fibrinogen at 3.45 mg/ml and 2.3 mg/ml, respectively. The FXa assay is carried out at room temperature in the 96-well microtiter plates with a final enzyme concentration and substrate concentration of InM and 200 μM. respectively. Compound dilutions are added to the wells containing buffer and FXa and preincubated for 30 minutes. The enzyme reactions are initiated by the addition of substrate, Spectrozyme FXa, and the color developed from the release of p-nitroanilide from each chromogenic substrate is monitored continuously for 5 minutes at 405 nm on a Thermomax microtiter plate reader(Molecular Devices, Sunnyvale, CA.). In the final reaction mixture, the concentration of albumin and fibeinogen is 3mg/ml and 2 mg/ml, respectively. Under the experimental conditions, less than 10% of the substrate is consumed in all assays. The initial velocities measured are used to determine the amount of inhibitor required to diminish 50% of the control velocity and defined as IC₅₀ of the inhibitor. Assuming the kinetic mechanisms are competitive inhibition, the apparent Ki values are then calculated according to the Cheng-Prusoff equation , Ki = IC₅₀/(1 + [S]/Km)

Experimental In Vivo Rabbit Venous Thrombosis Model:

This is a well characterized model of fibrin rich venous thrombosis that is validated in the literature and shown to be 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. Hoist, 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 of utilizing this model is to evaluate the ability of compounds to prevent the formation of venous thrombi (clots) in vivo generated at a site of injury and partial stasis in the jugular vein.

Male and female New Zealand white rabbits weighing 1.5-2 kg are anesthetized with 35 mg/kg of ketamine and 5 mg/kg xylazine in a volume of 1 ml/kg (i.m.). The right jugular vein is cannulated for infusion of anesthetic (ketamine/xylazine 17/2.5 mg/kg/hr at a rate of approximately 0.5 ml/hr) and administration of test substances. The right carotid artery is cannulated for recording arterial blood pressure and collecting blood samples. Body temperature is maintained at 39°C with a GAYMAR T- PUMP. The left external jugular vein is isolated and all side branches along an exposed 2-3 cm of vessel are tied off. The internal jugular vein is cannulated, just above the bifurcation of the common jugular, and the tip of the cannula is advanced just proximal to the common jugular vein. A 1 cm segment of the vein is isolated with non-traumatic vascular clamps and a relative stenosis is formed by tying a ligature around the vein with an 18G needle just below the distal most clamp. This creates a region of reduced flow and partial stasis at the injury site. The isolated segment is gently rinsed with saline 2-3 times via the cannula in the internal jugular. Thereafter the isolated segment is filled with 0.5 ml of 0.5%> polyoxyethylene ether (W-1 ) for 5 minutes. W-1 is a detergent which disrupts the endothelial cell lining of the segment, thus providing a thrombogenic surface for initiating clot formation. After 5 minutes the W-1 is withdrawn from the segment, and the segment is again gently rinsed with saline 2-3 times. The vascular clamps are then removed, restoring blood flow through this portion of the vessel. Clot formation is allowed to form and grow for 30 minutes after which the vein is cut just below the stenotic ligature and inspected for blood flow (the absence of blood flow is recorded as complete occlusion). The entire isolated segment of vein is then ligated and the formed clot is removed and weighed (wet weight). The effect of test agents on final clot weights is used as the primary end point. Animals are maintained for an additional thirty minutes to obtain a final pharmacodynamic measure of anticoagulation. Drug administration is initiated 15 minutes prior to vascular injury with W-1 and continued through the period of clot formation and maturation. Three blood samples (3 ml ea.) are obtained for evaluation of hemostatic parameters: one just prior to administration of W-1 ; a second 30 minutes after removal of the vascular clamps and a third at the termination of the experiment. Antithrombotic efficacy is expressed as a reduction in the final clot weight in preparations treated with a compound according to the invention relative to vehicle treated control animals.

Experimental In Vivo Rat Arterial Thrombosis Model:

The antithrombotic efficacy of factor Xa inhibitors against platelet-rich arterial thrombosis may be evaluated using a well characterized rat carotid artery FeCl2-induced thrombosis model (Superior Activity of a Thromboxane Receptor Antagonist as Compared with Aspirin in Rat Models of Arterial and Venous Thrombosis, W.A. Schumacher, CL. Heran, T.E. Steinbacher, S. Youssef and M.L. Ogletree. 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 a variety of agents including heparin and the direct acting thrombin inhibitors.

Sprague Dawley rats weighing 375-450 g are 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 aseptic surgery. Electrocardiogram electrodes are connected and lead II is monitored throughout the experiment. The right femoral vein and artery are cannulated with PE-50 tubing for administration of a compound according to the invention and for obtaining blood samples and monitoring blood pressure, respectively. A midline incision is made in the ventral surface of the neck. The trachea is exposed and intubated with PE-240 tubing to ensure airway patency. The right carotid artery is isolated and two 4-0 silk sutures are placed around the vessel to facilitate instrumentation. An electromagnetic flow probe (0.95-1.0 mm lumen) is placed around the vessel to measure blood flow. Distal to the probe a 4x4 mm strip of parafilm is placed under the vessel to isolate it from the surrounding muscle bed. After baseline flow measurements are made, a 2x5 mm strip of filter paper previously saturated in 35% FeCh is placed on top of the vessel downstream from the probe for ten minutes and then removed. The FeCl2 is thought to diffuse into the underlying segment of artery and cause deendothelialization resulting in acute thrombus formation. Following application of the FeCl2- soaked filter paper, blood pressure, carotid artery blood flow and heart rate are monitored for an observation period of 60 minutes. Following occlusion of the vessel (defined as the attainment of zero blood flow), or 60 minutes after filter paper application if patency is maintained, the artery is ligated proximal and distal to the area of injury and the vessel is excised. The thrombus is removed and weighed immediately and recorded as the primary end point of the study.

Following surgical instrumentation a control blood sample (Bl) is drawn. All blood samples are collected from the arterial catheter and mixed with sodium citrate to prevent clotting. After each blood sample, the catheter is flushed with 0.5 ml of 0.9% saline. A compound according to the invention is administered intravenously (i.v .) starting 5 minutes prior to FeCl2 application. The time between FeCl2 application and the time at which carotid blood flow reached zero is recorded as time to occlusion (TTO). For vessels that did not occlude within 60 minutes, TTO is assigned a value of 60 minutes. Five minutes after application of FeCh. a second blood sample is drawn (B2). After 10 minutes of FeCl2 exposure, the filter paper is remov ed from the vessel and the animal is monitored for the remainder of the experiment. Upon reaching zero blood flow blood a third blood sample is drawn (B3) and the clot is removed and weighed. Template bleeding time measurements are performed on the forelimb toe pads at the same time that blood samples are obtained. Coagulation profiles consisting of activated partial thromboplastin time (APTT) and prothrombin time (PT) are performed on all blood samples. In some instances a compound according to the invention may be administered orally. Rats are restrained manually using standard techniques and compounds are administered by intragastric gavage using a 18 gauge curved dosing needle (volume of 5 ml/kg). Fifteen minutes after intragastric dosing, the animal is anesthetized and instrumented as described previously. Experiments are then performed according to the protocol described above.

Experimental Canine intravenous and intragastric dosing experiments.

Beagle dogs (9-13 kg) of either sex are used to evaluate the pharmacodynamic effect of compounds of this invention after intravenous and intragastric dosing. Blood samples for these experiments are obtained via venipuncture of the cephalic vein. After discarding the first 0.5 ml of blood drawn, the control sample of 4.5 ml of blood is drawn into chilled plastic syringes containing 0.5 ml of trisodium citrate. After drug administration, 0.9 ml of blood is obtained at each time point (after discarding the first 0.5 ml of blood) by drawing the sample directly into chilled plastic syringes containing 0.1 ml trisodium citrate.

For the intravenous experiments, compounds are administered in the cephalic vein in the forelimb contralateral to that used for blood sampling. Compounds are dissolved in saline (0.5 ml/kg body weight) and administered as an i.v. bolus. Post-dosing blood samples are obtained at specific time points after dosing.

For the intragastric experiments, Compounds (in 0.5% methyl cellulose and 1 % polysorbate-80, 1 ml/kg dosing volume) are administered via an intragastric feeding tube. A pre-dosing control blood sample is obtained as above and post-dosing samples are obtained at specific time points after dosing.

Coagulation times. Platelet-poor plasma is used for determination of activated partial thromboplastin time (APTT) and prothrombin time (PT), which are measured using a Microsample

® Coagulation Analyzer (MCA210. Bio Data Corp, Horsham, PA) and Dade reagents (Thromboplastin-C

® Plus and Actin FS Activated PTT reagent, Baxter Diagnostics, Inc., Deerfield, IL). Ex vivo inhibition of Factor Xa. Factor-Xa inhibitory activity is analyzed by chromogenic methods using reagents (bovine factor Xa and spectrozyme Xa) supplied by American Diagnostica

(Greenwich, CT). The rate of change of optical density (Vmax, 405 nm) is measured using a

SPECTRAmax microtiter plate spectrophotometer and Softmax Pro software (Molecular Devices Corp, Sunnyvale, CA). Inhibition of Xa activity is determined as follows: percent inhibition of Xa activity = 1- (Vmax of sample with inhibitor/Nmax of the pre-drug control sample) X 100.

One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects of the invention and obtain the ends and advantages mentioned, as well as those inherent therein. The compounds, compositions and methods described herein are presented as representative of the preferred embodiments, or intended to be exemplary and not intended as limitations on the scope of the present invention.

Claims

We Claim 1.

wherein

R' is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkoxy, aminoalkyl, -CH₂OZ, or - CH(CH₃)OZ;

R² is hydrogen, optionally substituted alkyl, aryl, aralkyl, heteroaryl, or heteroarylalky; R³ is hydrogen or methyl, X is N or O;

Z is lower alkyl, or alkoxycarbonylalkyl;

Cy, is an optionally substituted six-membered aryl group, or optionally substituted heteroaryl; and

Cy₂ is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclenyl, optionally substituted fused arylcycloalkyl, optionally substituted fused arylcycloalkenyl, fused arylheterocyclyl, optionally substituted fused arylheterocyclenyl, optionally substituted fused heteroarylcycloalkyl, optionally substituted fused heteroarylcycloalkenyl, optionally substituted fused heteroarylheterocyclyl or optionally substituted fused heteroarylhetercyclenyl; or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable prodrug thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.

2. A compound according to claim 1 wherein Cy₂ contains at least one nitrogen atom and when Cy₂ is optionally substituted aryl. optionally substituted cycloalkyl. optionally substituted cycloalkenyl, optionally substituted fused phenylcycloalkyl or optionally substituted fused phenylcycloalkenyl, then said nitrogen atom is a basic nitrogen atom.

A compound according to claim 2 wherein Cy₂ is an azaheteroaryl.

4. A compound according to claim 3 wherein Cy₂ is optionally substituted benzamidines, optionally substituted thiopheneamidines, optionally substituted aminoquinazolines, optionally substituted aminoisoquinolines, optionally substituted aminoquinolines, optionally substituted azaindoles, optionally substituted aminopyridines, optionally substituted isoquinoline, optionally substituted quinazoline, optionally substituted thienopyrimidine, optionally substituted pyridothiophenes.

5. A compound according to claim 4 wherein Cy₂ is 4-aminoquinazolin-7yl.

6. A compound according to claim 1 wherein R' is hydrogen, lower alkyl, aralkyl, -CH₂OZ, or -

CH(CH₃)OZ.

7. A compound according to claim 1 wherein R² is hydrogen, or lower alkyl.

8. A compound according to claim 1 wherein R³ is hydrogen.

9. A compound according to claim 1 wherein X is O.

10. A compound according to claim 1 wherein Cy, is optionally substituted phenyl, or optionally substituted heteroaryl.

1 1 . A compound according to claim 10 wherein Cy, is substituted with one or more groups selected from halo, lower-alkoxyl, CF₃S-. carboxyalkyl, carbamylalkyl, alkoxycarbonylalkyl, and alkyl.

12. A compound according to claim 1 1 wherein Cy, is chlorophenyl, chlorothienyl, chloropyridinyl, chloropyrimidinyl, chloro-thiazinyl, amino-pyridine. amino-pyrimidine, amino-pyridazine, amino- pyrimidine, aminothiazole, or amino-thiophene.

13. A compound according to claim 1 wherein Cy₂ is 4-aminoquinazolin-7yl; R' is alkyl, -CH₂OCH₃, -CH₂OCH₂CH₃, or aralkyl; and

R² is hydrogen or lower alkyl.

14. A compound according to claim 1 wherein Cy₂ is 4-aminoquinazolin-7yl; R¹ is alkyl, -CH₂OCH₃, -CH OCH₂CH₃, or aralkyl; R² is hydrogen or lower alkyl; and

Cy, is optionally substituted aryl or optionally substituted heteroaryl.

15. A compound according to claim 1 which is selected from the groups consisting of

209

; or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable prodrug thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.

16. A compound according to claim 1 which is

; or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable prodrug thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.

17. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.

18. A method of inhibiting Factor Xa comprising contacting a Factor Xa inhibitory amount of a compound according to claim 1 with a composition containing Factor Xa.

19. A method of inhibiting the formation of thrombin comprising contacting Factor Xa inhibitory amount of a compound according to claim 1 with a composition containing Factor Xa.

20. A method for treating a patient suffering from a physiological condition capable of being modulated by inhibiting activity of Factor Xa comprising administering to said patient a pharmaceutically effective amount of the compound according to claim 1.

21. The method according to claim 20 wherein the physiological condition is venous vasculature, arterial vasculature, abnormal thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy, percutaneous transluminal coronary angioplasty, transient ischemic attacks, stroke, intermittent claudication or bypass grafting of the coronary or peripheral arteries, vessel luminal narrowing, restenosis post coronary or venous angioplasty, maintenance of vascular access patency in long-term hemodialysis patients, pathologic thrombus formation occurring in the veins of the lower extremities following abdominal, knee and hip surgery, a risk of pulmonary thromboembolism, or disseminated systemic intravascular coagulopathy occurring in vascular systems during septic shock, certain viral infections or cancer.

22. The method according to claim 20 wherein the physiological condition is abnormal thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy, transient ischemic attacks, intermittent claudication or bypass grafting of the coronary or peripheral arteries, restenosis post coronary or venous angioplasty, pathologic thrombus formation occurring in the veins of the lower extremities following abdominal, knee and hip surgery or a risk of pulmonary thromboembolism.

23. The method according to claim 20 wherein the physiological condition is stroke, vessel luminal narrowing, maintenance of vascular access patency in long-term hemodialysis patients, or disseminated systemic intravascular coagulopathy occurring in vascular systems during septic shock, certain viral infections or cancer.

24. The method according to claim 20 wherein the administration is oral.

25. A compound as described and shown in the examples.