BACKGROUND OF THE INVENTION Normal haemeostasis is the result of a complex balance between the processes of clot initiation, formation and clot dissolution. The complex interactions between blood cells, specific plasma proteins and the vascular surface, maintain the fluidity of blood unless injury and blood loss occurs.

Many significant disease states are related to abnormal haemeostasis. For example, local thrombus formation due to the rupture of atherosclerotic plaque is a major cause of acute myocardial infarction and unstable angina. Treatment of an occlusive coronary thrombus by either thrombolytic therapy or percutaneous angioplasty may be accompanied by acute thrombolytic reclosure of the affected vessel.

Furthermore, a high percentage of patients undergoing surgery, particularly in the lower extremities, suffer thrombus formation in the venous vascular system which results in reduced blood flow to the affected area.

There continues to be a need for safe and effective therapeutic anticoagulants to limit or prevent thrombus formation.

Blood coagulation is vital for the containment of bodily fluids upon tissue injury and is an important component of host defense mechanisms. Coagulation or clotting involves the sequential activation of multiple zymogens in a process leading to thrombin generation and the conversion of fibrinogen to an impermeable cross-linked fibrin clot. Thrombin production is the result of a blood coagulation cascade which has been intensively studied and increasingly characterized. See for example, Lawson, J. H., et al.

(1994) J. Biol. Chem. 269: 23357. The coagulation reactions of this cascade involve initiation, amplification and propagation phases. Additionally, the cascade has been divided into extrinsic and intrinsic pathways.

The intrinsic pathway involves factors XII, XI, and IX and leads to the formation of a complex of factor IXa with its cofactor, factor Vllla. This complex converts factor X to Xa. Factor Xa is an enzyme which forms a complex with its cofactor, factor Va, and rapidly converts prothrombin to thrombin. Thrombin converts fibrinogen to fibrin monomers which polymerize to form a clot. The extrinsic pathway involves factor Vlla and tissue factor, which form a complex (TF/factor Vlla), and convert factor X to Xa. As in the intrinsic pathway, factor Xa converts prothrombin to thrombin.

Thrombin (factor IIa), as noted above, occupies a central position in the coagulation cascade by converting fibrinogen to fibrin. Consequently, substantial synthetic efforts have been directed to the development of thrombin inhibitors. See, for example, U. S. 5,656,600; U. S. 5,656,645; U. S. 5,670,479;

U. S. 5,646,165; U. S. 5,658,939; U. S. 5,658,930 and WO 97/30073. Additional compounds which have been prepared as synthetic thrombin inhibitors are N-arylsulfinated phenylalanine amides.

Known inhibitors of factor Xa include bisamidine compounds (Katakura, S. (1993) Biochem.

Biophys. Res. Commun., 197: 965) and compounds based on the structure of arginine (WO 93/15756; WO 94/13693). Phenyl and naphthylsulfonamides have also been shown to be factor Xa inhibitors (WO 96/10022; WO 96/16940; WO 96/40679).

TF/factor VIIa is a serine protease complex that participates in blood coagulation by activating factor X and/or factor IX. Factor VIIa is produced from its precursor, factor VII, which is synthesized in the liver and secreted into the blood where it circulates as a single chain glycopeptide. The cDNA sequence for factor VII has been characterized (Hagen et al., 1986, Proc. Natl. Acad. Sci. U. S. A., 83: 2412-2416).

A variety of natural and synthetic inhibitors of TF/factor VIIa are known and have varying potency and selectivity. Tissue factor pathway inhibitor (TFPI; Broze, 1995, Thromb. Haemostas., 74: 90) and nematode anticoagulant peptide c2 (NAPc2; Stanssens et al., 1996, Proc. Natl. Acad. Sci. U. S. A., 93: 2149) bind factor Xa prior to the formation of a quaternary inhibitory complex with the TF/factor VIIa complex.

Small protein direct inhibitors (Dennis et al, 1994, J. Biol. Chem., 35: 22137) and inactive forms of TF/factor VIIa are also known (Kirchhofer et al, 1995, Arteriosclerosis, Thrombosis and Vascular Biol., 15: 1098; Jang et al, 1995, Circulation, 92: 3041). Additionally, synthetic peptides and soluble forms of mutant TF which retain binding affinity but have reduced cofactor activity have been prepared (Roenning et al, 1996, Thromb.

Res., 82: 73; Kelley et ai, 1997, Blood, 89 : 3219). U. S. 5,679,639 describes polypeptides and antibodies which inhibit serine protease activity. U. S. 5,580,560 describes a mutant factor VIIa which has an improved half-life. U. S 5,504,067 and U. S. 5,504,064 describe a truncated TF for the treatment of bleeding. Kunitz domain-tissue factor fusion proteins have also been shown to be bifunctional anticoagulants (Lee et al, 1997, Biochemistry, 36: 5607-5611). The TF/factor Vlla complex has been indicated as an attractive target for the development of inhibitors based on a dissociation between surgical bleeding and prevention of intravascular thrombosis (Harker et al, 1995, Thromb. Haemostas., 74: 464).

Compounds which block or inhibit enzymes in the coagulation cascade are therapeutically useful in treating or preventing thrombosis in a mammal suspected of having a condition characterized by abnormal thrombosis. For example, with respect to arterial vasculature, abnormal thrombus formation due to deterioration of an established atherosclerotic plaque is a major cause of acute myocardial infarction and unstable angina. Treatment of an occlusive coronary thrombus by thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA) may be accompanied by reclosure of the vessel. In the venous vasculature, many patients undergoing surgery, particularly in the abdominal and lower body regions, experience thrombus formation which reduces blood flow and can lead to a pulmonary embolism.

Disseminated intravascular coagulopathy in both the venous and arterial systems occurs commonly during septic shock, some viral infections, and cancer and may lead to rapid and widespread thrombus formation and organ failure.

PTCA and recanalization are favored procedures for treating occluded vessels. However, arterial thrombosis following these procedures remains a leading cause of failure. Heparin, the most widely used

anticoagulant, has not been shown to be entirely effective in the treatment and prevention of acute arterial thrombosis or rethrombosis.

The synthesis and development of small molecule inhibitors based on the known three-dimensional structure of proteins is a challenge of modem drug development. Many thrombin inhibitors have been designed to have a hirudin-type structure. Stubbs and Bode, Current Opinion in Structural Biology 1994, 4: 823-832. New synthetic thrombin inhibitors, as well as inhibitors of factor Xa and TF/factor Vlla, are reported. See, for example, Annual Reports in Medicinal Chemistry, 1995-1997, Academic Press, San Diego, CA.

U. S. 5,589,173 describes the use of a tissue factor antagonist and a thrombolytic agent to treat myocardial infarction.

U. S. 5,399,487 describes naphthalenesulfonamides which are useful for determining proteolytic enzyme activity or as enzyme inhibitors.

A need continues to exist for compounds which are effective inhibitors of enzymes in the coagulation cascade and which exhibit improved inhibitory activity and/or selectivity towards selected enzymes in the cascade.

SUMMARY OF THE INVENTION Accordingly, one object of the present invention is to provide novel compounds which inhibit factors/enzymes in the coagulation cascade and which are useful to prevent or treat thrombus formation in artertial or venous vessels. These compounds are useful as coagulation factor inhibitors and as anticoagulants in general.

In one embodiment, an object of the invention is to provide inhibitors which inhibit factor Vlla, TF/factor VIIa selectively relative to factor Xa, thrombin or kallikrein. The compounds of this embodiment preferaby inhibit TF/factor VIIa about one order of magnitude (10X), more preferably about two orders of magnitude (lOOX), even more preferably about three orders of magnitude (1000X), better than they inhibit factor Xa, thrombin and/or kallikrein.

In another embodiment, an object of the invention is to provide compounds which specifically inhibit factor Xa relative to the inhibition of factor Vlla, TF/factor Vlla, thrombin or kallikrein. The compounds of this embodiment preferaby inhibit factor Xa about one order of magnitude (10X), more preferably about two orders of magnitude (100X), even more preferably about three orders of magnitude (1000X), better than they inhibit TF/factor Vlla, thrombin and/or kallikrein.

In another embodiment, a specific object of the invention is to provide compounds which inhibit thrombin relative to inhibition of factor Vlla, TF/factor Vlla, Xa, or kallikrein. The compounds of this embodiment preferably inhibit factor thrombin about one order of magnitude (10X), more preferably about two orders of magnitude (100X), even more preferably about three orders of magnitude (1000X), better than they inhibit TF/factor Vlla, factor Xa and/or kallikrein.

A further object of the invention is to provide a method of inhibiting TF/factor Vlla, Xa or thrombin activity by contacting these enzymes with an effective inhibitory amount of the novel inhibitors of the present invention or a composition containing these compounds. A further object is to provide a method of treating a TF/factor Vlla, Xa or thrombin mediated disorder by administering to a mammal in need of such

treatment an effective amount of one of the compounds of the invention or a composition containing the compound. An additional object is to provide a method of preventing thrombosis or treating abnormal thrombosis by administering to a mammal in need of such treatment an effective amount of one of the compounds of the invention or a composition containing the compound and a carrier or excipient.

These and other objects which will become apparent in the course of the following description have been achieved by the compounds of the present invention having the structure shown below: where A and B are independently CH, CR3 or N; X is C=O or (CR4aR4b) m where m = 1 or 2; Y is S (O) n-RI where n = I or 2, S (O) n- NR2R2 where n = I or 2, S (O) n-OR2 where n = 1 or 2, C (O) RI, C (S) RI, C (O)-ORI, C (O)-NR2R2; Nj and N2 are nitrogen atoms; Q and Rl are independently (1) optionally substituted alkyl having 1 to about 10 carbon atoms; (2) optionally substituted aralkyl containing an aryl moiety having 6 to about 10 ring carbon atoms bonded to an alkyl moiety containing 1 to about 10 carbon atoms; (3) optionally substituted heteroaralkyl containing a heteroaryl moiety having 5 to about 10 ring atoms bonded to an alkyl moiety having 1 to about 10 carbon atoms; (4) optionally substituted carbocycloalkyl containing a carbocyclyl moiety having 3 to about 10 ring carbon atoms bonded to an alkyl moiety having 1 to about 10 carbon atoms; (5) optionally substituted heterocycloalkyl containing a heterocyclyl moiety having 3 to about 10 ring atoms bonded to an alkyl moiety having I to about 10 carbon atoms; (6) optionally substituted alkenyl having 2 to about 10 carbon atoms; (7) optionally substituted aralkenyl containing an aryl moiety having 5 to about 10 ring atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms;

(8) optionally substituted heteroaralkenyl containing a heteroaryl moiety having 5 to about 10 ring atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms; (9) optionally substituted carbocycloalkenyl containing a carbocyclyl moiety having 3 to about 10 ring carbon atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms; (10) optionally substituted heterocycloalkenyl containing a heterocyclyl moiety having 3 to about 10 ring atoms bonded to an alkenyl moiety having 2 to about 10 carbon atoms; (11) optionally substituted aryl having 6 to about 10 ring carbon atoms; (12) optionally substituted heteroaryl having 5 to about 10 ring atoms with ring atoms selected from carbon atoms and heteroatoms, where the heteroatoms are nitrogen, oxygen or sulfur; (13) optionally substituted carbocyclyl having 3 to about 10 ring carbon atoms; (14) optionally substituted heterocyclyl having 3 to about 10 ring atoms with ring atoms selected from carbon atoms and heteroatoms, where the heteroatoms are nitrogen, oxygen or sulfur; each R2 is, independently, H, alkyl, substituted alkyl, C (O) R7 or C (NH) R7, or NIR2 and N2R2 are together form the group Nl-CO-N2; R3 is H, CI-C6 alkyl, Cl-C6 alkoxy, halogen or OH; R4a and R5 are, independently, a member selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxyalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted aryl, alkyl-OR7, alkyl-NR7Rg, alkyl-OC (O) R7, alkyl-C (O) OR7, alkyl-C (O) R7, OC (O) R7, C (O) OR7, C (O) R7 and members in which the alkyl, R7 or R8 is substituted with 1-3 F, Cl, Br, 1, OR7, SR7, NR7R8, OC (OR7), C (O) OR7, C (O) R7, C (O) NR7R8, NHC (NH) NH2, P03, unsubstituted or substituted indolyl or unsubstituted or substituted imidazolyl groups; R4b is H, alkyl, or substituted alkyl; each R6 is independently selected from the group selected from H, Cl-C6 alkyl, Cl-C6 alkyl-OR7, Cl-C6 alkyl-N R7R8, Cl-C6 haloalkyl, halo, cyano, OR7, SR7, NR7R8, C (O) OR7, C (O) R7 and OC (O) R7; R7 and R8 are independently H or Cl-C6 alkyl; and acid and base addition salts and prodrugs thereof.

Additionally, the objects of the invention are achieved by compositions containing these compounds and the methods described below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS DEFINITIONS The term"factor Vlla, TF/factor Vlla, factor Xa, thrombin or kallikrein mediated disorder"means a disease or physiological condition involving clotting of the blood and in which inhibition of one or more of these enzymes reduces or eliminates at least one of the physiological symptoms of the disease or condition.

The term"thrombosis"means the development of or formation of a blood clot or thrombus in a blood vessel of a mammal or in a synthetic vessel, such as a plastic or glass tube or vial. A thrombus which has detached from its original site and is found in another site is called a thrombotic embolus.

The term"abnormal thrombosis"means thrombosis occurring in a mammal which is contrary to the good health of the mammal.

The term"alkyl", used alone or as part of another term, means a branched or unbranched, saturated aliphatic hydrocarbon group, having the number of carbon atoms specified, or if no number is specified, having up to and including 12 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2- methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, and the like. The terms"lower alkyl" "Cl-C6 alkyl"and"alkyl of 1 to 6 carbon atoms"are synonymous and used interchangeably. Preferred"Cl- C6 alkyl"groups are methyl, ethyl, I-propyl, isopropyl, I-butyl or sec-butyl.

The terms"substituted alkyl"or"substituted Cn-Cm alkyl"where m and n are integers identifying the range of carbon atoms contained in the alkyl group, denotes the above alkyl groups that are substituted by one, two or three halogen (F, Cl, Br, 1), trifluoromethyl, hydroxy, unsubstituted and substituted Cl-C7 alkoxy, protected hydroxy, amino (including alkyl and dialkyl amino), protected amino, unsubstituted and substituted Cl-C7 acyloxy, unsubstituted and substituted C3-C7 heterocyclyl, unsubstituted and substituted phenoxy, nitro, carboxy, protected carboxy, unsubstituted and substituted carboalkoxy, unsubstituted and substituted acyl, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino, unsubstituted and substituted benzyloxy, unsubstituted and substituted C3-C6 carbocyclyl or Cl-C4 alkoxy groups. The substituted alkyl groups may be substituted once (preferably), twice or three times with the same or with different substituents.

Examples of the above substituted alkyl groups include, but are not limited to; cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, carboxyethyl, trifuoroethyl, trifluoropropyl, carboxypropyl, 2-aminopropyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro (n- butyl), 2-amino (iso-propyl), 2-carbamoyloxyethyl and the like. The alkyl group may also be substituted with a carbocyclo group. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl groups, as well as the corresponding-ethyl,-propyl,-butyl,-pentyl,-hexyl groups, etc.

A preferred group of examples within the above group includes the substituted methyl group, e. g. a methyl

group substituted by the same substituents as the"substituted Cn-Cm alkyl"group. Examples of the substituted methyl group include groups such as hydroxymethyl, protected hydroxymethyl (e. g. tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl, bromomethyl and iodomethyl.

The term"alkoxy"denotes groups having the number of carbon atoms specified such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy and like groups. The term"substituted alkoxy"means these alkoxy groups substituted by the same substituents as the"substituted Cn-Cm alkyl" group, for example, 2,2,2-trifluoroethoxy, 2,2,2-trifluoropropoxy, etc.

The term"acyloxy"denotes herein carboacyloxy groups having the specified number of carbon atoms such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, and the like. The term"substituted acyloxy"means these acyloxy groups substituted by the same substituents as the"substituted Cn-Cm alkyl"group.

The term"alkylcarbonyl","alkanoyl"and"acyl"are used interchangeably herein encompass groups having the specified number of carbon atoms such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.

The terms"carbocyclyl","carbocyclylic"and"carbocyclo"alone and when used as a moiety in a complex group such as a carbocycloalkyl group, refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms. Preferred carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. The terms"substituted carbocyclyl"and"carbocyclo"mean these groups substituted by the same substituents as the"substituted Cn-Cm alkyl"group.

A"carbocycloalkyl"group is a carbocyclo group as defined above covalently bonded to an alkyl group as defined above.

The term"alkenyl"means a branched or unbranched hydrocarbon group having the number of carbon atoms designated containing one or more carbon-carbon double bonds, each double bond being independently cis, trans, or a nongeometric isomer. The term"substituted alkenyl"means these alkenyl groups substituted by the same substituents as the"substituted Cn-Cm alkyl"group.

The term"alkynyl"means a branched or unbranched hydrocarbon group having the number of carbon atoms designated containing one or more carbon-carbon triple bonds. The term"substituted alkynyl"means these alkynyl groups substituted by the same substituents as the"substituted Cn-Cm alkyl" group.

The terms"alkylthio"and"Cl-C12 substituted alkylthio"denote Cj-C alky ! and Cl-Cl2 substituted alkyl groups, respectively, attached to a sulfur which is in turn the point of attachment for the alkylthio or substituted alkylthio group to the group or substituent designated.

The term"aryl"when used alone or as part of another term means a homocyclic aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms. Preferred aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e. g. Lang's Handbook of Chemistry (Dean, J. A., ed) 13th ed. Table 7-2 [1985]).

The term"substituted phenyl"or"substituted aryl"denotes a phenyl group or aryl group substituted with one, two, three, four or five, preferably 1-2,1-3 or 1-4 substituents chosen from halogen (F,

Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (preferably Cl-C6 alkyl), alkoxy (preferably Cl- C6 alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, heterocyclyl, aryl, or other groups specified. One or methyne (CH) and/or methylene (CH2) groups in these substituents may in turn be substituted with a similar group as those denoted above. Examples of the term"substituted phenyl"includes but is not limited to a mono-or di (halo) phenyl group such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5- dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono-or di (hydroxy) phenyl group such as 4- hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3-or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono-or di (lower alkyl) phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4- (iso-propyl) phenyl, 4-ethylphenyl, 3- (n-propyl) phenyl and the like; a mono or di (alkoxy) phenyl group, for example, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3-ethoxy-4-isopropoxyphenyl, 3-ethoxy-s- butoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4- (]-chloromethyl) benzyloxy-phenyl, 3- ethoxyphenyl, 4- (isopropoxy) phenyl, 4- (t-butoxy) phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3-or 4- trifluoromethylphenyl; a mono-or dicarboxyphenyl or (protected carboxy) phenyl group such 4- carboxyphenyl,; a mono-or di (hydroxymethyl) phenyl or (protected hydroxymethyl) phenyl such as 3- (protected hydroxymethyl) phenyl or 3,4-di (hydroxymethyl) phenyl; a mono-or di (aminomethyl) phenyl or (protected aminomethyl) phenyl such as 2- (aminomethyl) phenyl or 2,4- (protected aminomethyl) phenyl; or a mono-or di (N- (methylsulfonylamino)) phenyl such as 3- (N-methylsulfonylamino)) phenyl. Also, the term "substituted phenyl"represents disubstituted phenyl groups where the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2- hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenyl groups where 1,2, or 3 of the substituents are different, for example 3-methoxy-4-benzyloxy-6- methyl sulfonylamino, 3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino.

Preferred substituted phenyl groups include the 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4- methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3- <BR> <BR> <BR> <BR> methoxy-4- (1-chloromethyl) benzyloxy-phenyl, 3-methoxy-4- (l-chloromethyl) benzyloxy-6-methyl sulfonyl aminophenyl groups. Also, the term"substituted phenyl"represents phenyl groups having an aryl, phenyl or heteroaryl group fused thereto. The fused ring may also be substituted with any, preferably 1,2 or 3, of the substituents identified above for"substituted alkyl"groups.

The term"aralkyl"means one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated including but not limited to; benzyl, napthylmethyl, phenethyl, benzhydryl (diphenylmethyl), trityl, and the like. A preferred arylalkyl group is the benzyl group.

The term"substituted aralkyl"denotes an alkyl group, preferably a Cl-C8alkyl group, substituted at any carbon with an aryl group, preferably a C6-C10aryl group, bonded to the alkyl group through any aryl

ring position and substituted on the alkyl portion with one, two or three groups chosen from halogen (F, Cl, Br, 1), hydroxy, protected hydroxy, amino, protected amino, Cl-C7acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, Cl-C6alkylthio, N- (methylsulfonylamino) or Cl-C4alkoxy.

Optionally the aryl group may be substituted with one, two, three, four or five groups chosen from halogen, hydroxy, protected hydroxy, nitro, Cl-C6alkyl, Cl-C6alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, or an N- (methylsulfonylamino) group. As before, when either the Cl-C8 alkyl portion or the aryl portion or both are disubstituted, the substituents can be the same or different. This group may also appear as the substituted aralkyl moiety of a substituted aralkoxy group.

Examples of the term"substituted aralkyl"and this group when it occurs in a"substituted aralkoxy"group include groups such as 2-phenyl-1-chloroethyl, I-phenyl-l-chloromethyl, I-phenyl-l- bromomethyl, 2- (4-methoxyphenyl) ethyl, 2,6-dihydroxy-4-phenyl (n-hexyl), 5-cyano-3-methoxy-2- phenyl (n-pentyl), 3- (2, 6-dimethylphenyl) n-propyl, 4-chloro-3-aminobenzyl, 6- (4-methoxyphenyl)-3- carboxy (n-hexyl), 5- (4-aminomethyl phenyl)-3- (aminomethyl) (n-pentyl), and the like.

The term"carboxy-protecting group"as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6- trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'- dimethoxybenzhydryl, 2,2', 4,4'-tetramethoxybenzhydryl, alkyl such as methyl, ethyl, isopropyl, t-butyl or t- amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4', 4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, beta- (trimethylsilyl) ethyl, beta- (di (n- <BR> <BR> <BR> butyl) methylsilyl) ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl) prop- I-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction (s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject a carboxy-protected molecule to strong nucleophilic bases or reductive conditions employing highly activated metal catalysts such as Raney nickel. (Such harsh removal conditions are also to be avoided when removing amino-protecting groups and hydroxy-protecting groups, discussed below.) Preferred carboxylic acid protecting groups are the allyl and p-nitrobenzyl groups. Similar carboxy-protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to protect a carboxy group substituents. Further examples of these groups are found in E. Haslam,"Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N. Y., 1973, Chapter 5, and T. W. Greene,"Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981, Chapter 5. The term"protected carboxy"refers to a carboxy group substituted with one of the above carboxy-protecting groups.

As used herein the term"amide-protecting group"refers to any group typically used in the peptide art for protecting the peptide nitrogens from undesirable side reactions. Such groups include p- methoxyphenyl, 3,4-dimethoxybenzyl, benzyl, O-nitrobenzyl, di- (p-methoxyphenyl) methyl,

triphenylmethyl, (p-methoxyphenyl) diphenylmethyl, diphenyl-4-pyridylmethyl, m-2-(picolyl)-N'-oxide, 5- dibenzosuberyl, trimethylsilyl, t-butyl dimethylsilyl, and the like. Further descriptions of these protecting groups can be found in"Protective Groups in Organic Synthesis", by Theodora W. Greene, 1981, John Wiley and Sons, New York.

The terms"heterocyclic group","heterocyclic","heterocyclyl", or"heterocyclo"alone and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, or tricyclic saturated or non-aromatically unsaturated ring having the number of atoms designated, generallly from 3 to about 10 ring atoms, where the ring atoms are carbon and 1,2,3 or 4 nitrogen, sulfur or oxygen atoms. Typically, a 5-membered ring has 0 to 2 double bonds and 6-or 7- membered ring has 0 to 3 double bonds and the nitrogen or sulfur heteroatoms may optionally be oxidized, and any nitrogen heteroatom may optionally be quaternized. Examples include pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl, aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl, piperidinyl, and 3,4,5,6- tetrahydropiperidinyl.

A"heterocycloalkyl"or a"heterocycloalkenyl"group is a heterocyclo group as defined above covalently bonded to an alkyl or alkenyl group as defined above.

Unless otherwise specified,"heteroaryl"alone and when used as a moiety in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromatic ring system having the number of atoms designated where at least one ring is a 5-, 6-or 7-membered ring containing from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur, and preferably at least one heteroatom is nitrogen (Lang's Handbook of Chemistry, supra). Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to a benzene ring. Heteroaryls in which nitrogen or oxygen is the heteroatom are preferred.

The following ring systems are examples of the heteroaryl (whether substituted or unsubstituted) groups denoted by the term"heteroaryl": thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo [1,5-b] pyridazinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl.

Heterocyclic 5-membered ring systems containing a sulfur or oxygen atom and one to three nitrogen atoms are also suitable for use in the instant invention. Examples of such preferred groups include thiazolyl, in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, preferably oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. A group of further preferred examples of 5-membered ring systems with 2 to 4 nitrogen atoms include imidazolyl, preferably imidazol-2-yl; triazolyl, preferably 1,3,4-triazol-5-yl; 1,2,3- triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, preferably 1H-tetrazol-5-yl. A preferred group of examples of benzo-fused derivatives are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.

Further suitable specific examples of the above heterocylic ring systems are 6-membered ring systems containing one to three nitrogen atoms. Such examples include pyridyl, such as pyrid-2-yl, pyrid- 3-yl, and pyrid-4-yl; pyrimidyl, preferably pyrimid-2-yl and pyrimid-4-yl; triazinyl, preferably 1,3,4- triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N- oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4- triazin-2-yl groups, are a preferred group.

The substituents for the optionally substituted heterocyclic ring systems, and further examples of the 5-and 6-membered ring systems discussed above can be found in W. Druckheimer et al., U. S. Patent No. 4,278,793.

A particularly preferred group of"heteroaryl"include; 1,3-thiazol-2-yl, 4- (carboxymethyl)-5- methyl-1, 3-thiazol-2-yl, 4- (carboxymethyl)-5-methyl-1, 3-thiazol-2-yl sodium salt, 1,2,4-thiadiazol-5-yl, 3- methyl-1,2,4-thiadiazol-5-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 2-hydroxy-1,3,4-triazol-5-yl, 2- carboxy-4-methyl-1,3,4-triazol-5-yl sodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, <BR> <BR> <BR> <BR> 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2- (hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4- oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-thiadiazol-5-yl, 2- (methylthio)-1,3,4-thiadiazol-5-yl, 2- amino-1,3,4-thiadiazol-5-yl, I H-tetrazol-5-yl, 1-methyl-I H-tetrazol-5-yl, 1-(I-(dimethylamino) eth-2-yl)- I H-tetrazol-5-yl, 1-(carboxymethyl)-I H-tetrazol-5-yl, 1-(carboxymethyl)-I H-tetrazol-5-yl(carboxymethyl)-I H-tetrazol-5-yl, 1-(carboxymethyl)-I H-tetrazol-5-yl sodium salt, 1- (methylsulfonic acid)-I H-tetrazol-5-yl, 1- (methylsulfonic acid)-I H-tetrazol-5-yl sodium salt, 2-methyl-IH- tetrazol-5-yl, 1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3- triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl, 1- <BR> <BR> <BR> <BR> methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as- triazin-3-yl, 1,4,5,6-tetrahydro-4- (formylmethyl)-5, 6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy- astriazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2- methyl-astriazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5- oxo-6-methoxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-2-methyl-as- triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl, tetrazolo [1,5-b] pyridazin-6-yl and 8- aminotetrazolo [l, 5-b]-pyridazin-6-yl.

An alternative group of"heteroaryl"includes; 4- (carboxymethyl)-5-methyl-1, 3-thiazol-2-yl, 4- (carboxymethyl)-5-methyl-1, 3-thiazol-2-yl sodium salt, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, IH- <BR> <BR> <BR> <BR> tetrazol-5-yl, 1-methyl-I H-tetrazol-5-yl, 1- (]- (dimethylamino) eth-2-yl)-1H-tetrazol-5-yl, 1-<BR> <BR> <BR> <BR> <BR> <BR> (carboxymethyl)-I H-tetrazol-5-yl, 1-(carboxymethyl)-I H-tetrazol-5-yl sodium salt, I-(methylsulfonic acid)-lH-tetrazol-5-yl, I-(methylsulfonic acid)-lH-tetrazol-5-yl(methylsulfonic acid)-lH-tetrazol-5-yl sodium salt, 1,2,3-triazol-5-yl, 1,4,5,6- tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4,5,6-tetrahydro-4- (2-formylmethyl)-5, 6-dioxo-as-triazin- 3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2- methyl-as-triazin-3-yl, tetrazolo [1, 5-b] pyridazin-6-yl, and 8-aminotetrazolo [1,5-b] pyridazin-6-yl.

A"heteroaralkyl"or a"heteroaralkenyl"group is a heteroaryl group as defined above covalently bonded to an alkyl group or to an alkenyl group as defined above.

"Pharmaceutically acceptable salts"include both acid and base addition salts."Pharmaceutically acceptable acid addition salt"refers to those salts which retain the biological effectiveness and properties of

the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.

"Pharmaceutically acceptable base addition salts"include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.

The term"prodrug"as used herein means a derivative of a parent drug molecule that enhances pharmaceutically desirable characteristics or properties (e. g. transport, bioavailablity, pharmacodynamics, etc.) and that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active parent drug.

EMBODIMENTS The invention is generally directed to compounds having the structure shown below.

In this structure R,), R5, R6, A, B, N1, N2, Q, X, and Y have the meanings described above. In these meanings, alkyl is preferably unsubstituted or substituted Cl-C6 alkyl; alkenyl is preferably unsubstituted or substituted C2-C6 alkenyl; alkynyl is preferably unsubstituted or substituted C2-C6 alkynyl; aryl is preferably unsubstituted or substituted naphthyl or phenyl, more preferably phenyl; aralkyl is preferably unsubstituted or substituted benzyl. The variable m is preferably 1.

The group Y is preferably S (O) n-ruz where n = 1 or 2 or the group S (O) n- NR2R2 where n = 1 or 2, more preferably S (O) n-Rl In one preferred embodiment, R1, for example when Y is S (O) n-RI, is selected from the group consisting of Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, naphthyl, benzyl and heteroaryl having 5-6 ring atoms selected from carbon atoms and 1-2 heteroatoms, where the heteroatoms are N, S, or O, and R1 optionally substituted with 1-3 substituents selected from the group consisting of halo, nitro, Cl-C6 alkyl, NR7R8, OR7, SR7, Cl-C6 alkyl-C (O) OR7, Cl-C6 alkyl-OC (O) R7, Cl-C6 alkyl-C (O) R7, Cl-C6 alkyl-OR7, Cl-C6 haloalkyl, Cl-C6 alkyl-NR7R8, C (O) OR7, OC (O) R7, C (O) NR7R8, OC (O) NR7R8, NHC (O) R7, and NHC (O) NR7R8, where R7 and R8 independently are H or C l-C6 alkyl. In this embodiment, each of the remaining variables R2, R5, R6, A, B, Q, X, and Y may be independently selected to be any of the groups in the respective definitions described above.

In a second preferred embodiment, Q is phenyl optionally substituted with 1-5, preferably 2-4, more preferably 2-3, substituents selected from the group consisting of halo, nitro, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR7R8, OR7, SR7, Cl-C6 alkyl-C (O) OR7, OCI-C6 alkyl-C (O) OR7, Cl-C6 alkyl-OR7, OC1-C6 alkyl-OR7, C1-C6 alkyl-NR7R8, OC1-C6 alkyl-NR7R8, C1-C6 alkyl-C(O)NR7R8, OC1-C6 alkyl- C (O) NR7Rg, Cl-C6 alkyl-C (O) R7, OCI-C6 alkyl-C (O) R7, Cl-C6 haloalkyl, O-aralkyl (e. g. benzyloxy), () OR7, C (O) NR7R8, OC (O)NR7R8, NHC (O) R7, NHC (O) NR7R8, NR7S (O) nRl, NR7S (O) nR7 S (OR7 S (O) nNR7, where R7 and R8 independently are H or C I-C6 alkyl. In this embodiment, each of the remaining variables R2, R5, R6, A, B, X, and Y (and RI) may be independently selected to have any of the definitions described above. Each alkyl, alkenyl and alkynyl moiety may also be substituted as defined above.

In a third preferred embodiment, Q has the structure

where R9 is H, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 alkoxy, hydroxy, NR7R8, SR7 or OR7, where R7 and R8, independently, are H or unsubstituted or substituted Cl-C6 alkyl; Rlo, Rll and Z2 independently, are each selected from the group consisting of H, halo, nitro, <BR> <BR> <BR> <BR> <BR> cyano, C l-C6 alkyl, C6-C l 0 aryl, NR7R8, OR7, SR7, C I-C6 alkyl-C (O) R7, C l-C6 alkyl-C (O) NR7R8, C l-C6<BR> <BR> <BR> <BR> <BR> <BR> <BR> alkyl-C (O) OR7, Cl-C6 alkyl-OC (O) R7, Cl-C6 alkyl-OR7, OCI-C6 alkyl-C (O) R7, OCI-C6 alkyl-C (O) OR7,<BR> <BR> <BR> <BR> <BR> <BR> <BR> OCI-C6 alkyl-OC (O) R7, O-CI-C6 alkyl-OR7, OCI-C6 alkyl-C (O) NR7Rg, Cl-C6 haloalkyl, OR12, Cl-C6 alkyl-R12, O-CI-C6 alkyl-R12, C (O) OR7, C (O) OR12, C (O) NR7R8, OC (O)NR7R8, NR7C (O) R7, NR7C (O) R12, NR7C (O)-NR7Rg, NR7C (O) OR7, NR7C (O) OR12, NRySn-R,, NRyS (0) n-R7 and NR7S (O) n-R12, where R7 and R8, independently, are H or unsubstituted or substituted Cl-C6 alkyl, R12 is unsubstituted or substituted C6-C10 aryl or heterocycl as defined above and n is 1 or 2; Z1 is H, Cl-C6 alkyl, Cl-C6 alkoxy, halogen or nitro. In this embodiment, each of the remaining variables R2, R5, R6, A, B, X, and Y may be independently selected to have any of the definitions described above. Each alkyl, alkenyl and alkynyl moiety may also be substituted as defined above.

In various aspects of the invention, Z1 and Z2 may be hydrogen; Z1, Z2 and Rl may be hydrogen; or Zl, Rlo and Rl lmay be hydrogen; and the remaining ring substituents are as defined above.

In another embodiment, the substituents at the 4-and 5-positions or at the 5-and 6-positions of the ring when Q is substituted phenyl may be bonded together to form an unsubstituted or substituted carbocyclic or hetercyclic ring. Examples of such compounds are shown below, where the symbol is preferably a 5-membered or a 6-membered carbocyclic or heterocyclic ring which is fused to the phenyl ring in the positions shown below.

Examples of suitable 5-membered or a 6-membered carbocyclic or heterocyclic rings which may be fused to the phenyl ring include the ring systens shown below, where R6 is as defined above.

In another preferred embodiment, Y is S (O) n-Rl where n is 1 or 2, preferably 2. In this embodiment, Rl may be as defined above and each of the remaining variables may be independently selected to have any of the definitions described above.

Compounds in which Q is substituted phenyl and RIO is selected from the group consisting of Cl- C6 alkyl, C I-C6 alkoxy, Cl-C6 aminoalkyl, Cl-C6 haloalkyl, Cl-C6 hydroxyalkyl, phenyl, phenoxy, benzyl, benzyloxy, as well as phenoxy-and benzyloxy-substituted with Cl-C6 alkyl, Cl-C6 alkoxy, halo, Cl-C6 haloalkyl, Cl-C6 hydroxyalkyl, Cl-C6 aminoalkyl, OC (O)-CI-C6 alkyl, C (O) O-CI-C6 alkyl and C (O) OH are also preferred, where each of the remaining variables may be independently selected to have any of the definitions described above.

Also of interest are compounds in which Rl l is NR7CI-C6 alkyl-C (O) NR7R8, NR7S (O) n-R7 or N R7S (O) n-R12, n is 1 or 2 and/or where Z) = Z2 = H and/or where RUZ is OR7, OR12, OC7-C10-aralkyl, OCI-C6 alkyl-OR7 or OCI-C6 alkyl-OR12 where R7 and R12 are unsubstituted or substituted as defined above. Suitable substituted R7 and R12 include these groups substituted as described above, for example, having 1 or 2 Cl-C6 alkoxy, C I-C6 alkoxy-C 1-C6 alkoxy, halo, Cl-C6 haloalkyl, Cl-C6 hydroxyalkyl, C I-C6 aminoalkyl, OC (O)-C I-C6 alkyl, C (O) O-CI-C6 alkyl, Cl-C6 alkyl C (O) OR7, Cl-C6 alkyl OC (O) R7 or C (O) OH. In these compounds, each of the remaining variables may be independently selected to have any of the definitions described above. These compounds are also interesting where, Y is S (O) n- R1 where n is I or 2, that is, disulfonamide comounds.

In another embodiment, A and B are independently CH or CR3, where R3 is H, C 6 alkyl or OH, where the remaining variables may be independently selected to have any of the definitions described above.

In another embodiment, R6 is H or R3 is CH, where the remaining variables may be independently selected to have any of the definitions described above.

In another preferred embodiment, X is a carbonyl group (C=O), where the remaining variables may be independently selected to have any of the definitions described above. In this embodiment, preferably m =1.

Table 1, setting forth examples of some preferred groups at various positions of some compounds of the invention, is shown below. A group of specific compounds is disclosed in this table and is obtained by selecting all unique combinations of substituents, one from each column of the table, for each variable and combining these groups with the structure disclosed above Table 1.

Table I x R9 RIO Z2 RII RI Z3 CH2 OEt OEt H H Me H C=O OMe OH OEt NMeS02Me Et OH CH2CH3 OMe OMe Ph Pr CI CH=CH2 OiPr Ph Naphthyl Bu F CCH OCH2Ph OiPr iPr CH2CCH CH (CH3) Ph OPr NHS02Me iBu H CH (CH2CI) P CH (CH2Cl) Ph NPrS02Me sBu h Pr OCH2CH2CF OCH2CH2CF N (CH2C02H) SO Ph 3 3 2Me OCH2CF3 OCH2CF3 NMeS02CH2CO O-tolyl 2H SCH3 CH (C02H) Ph CH (C02H) Ph NHS02CH2C02 CH2CH2C02 H H SCH2CH3 CH (C02Me) CH (C02Me) P NHCOCH3 CH2CH2CON Ph h H2 NHCH3 Ph Ph NHCOCH2C02H CH2CH2C02 Me NHCH2CH OPh OPh NHS02-p-tolyl 3 thiophene _ NHS02CH2C02 4 _ H chlorophenyl Cl Br NHS02CH2C02 4- Me aminomethylp henyl Br F OCH2C02H 4-aminophenyl F OCH2Ph pyridyl 2- chlorophenyl H NCH2CH3 3-nitrophenyl NHCH2CH3 SCH3 I-naphthyl 2-thiophene 3-thiophene 2-furan 3-furan CH2CH (NH2) CH3 pyridyl 2-naphthyl

METHODS OF MAKING Compounds of the present invention can be prepared by methods employing standard chemical methodologies described and referenced in standard textbooks (e. g. March, J."Advanced Organic Chemistry"McGraw-Hill, New York, 1977; Collman, J. P., Hegedus, L. S., Norton, J. R., Finke, R. G.

"Principles and Applications of Organotransition Metal Chemistry"University Science, Mill Valley, 1987; Larock, R. C."Comprehensive Organic Transformations"Verlag, New York, 1989).

A key intermediate in the synthesis of compounds of the invention has the formula shown below In this formula, A, B, R2, R4a R4b, R5, R6, m and Q have the meanings and preferred meanings described above. This compound can be prepared using several alternative synthetic routes. After preparation, the cyano group may be converted into an amidino group (C (NH) NH2), for example, using known procedures, such as the Pinner reaction. A cyano compound having the formula shown above may be reacted with hydroxyl amine, preferably in an alcohol solvent, followed by reduction with Raney Ni, preferably in an alcohol solvent, or may be reacted first with ethanolic HCl and then with alcoholic ammonia to yield the corresponding amidino compounds. Alternatively, a modified Pinner reaction using pyridine/diethylamine (1/1)/hydrogen sulfide followed by methyl iodide/acetonitrile and then ammonium acetate/ethanol will provide the desired amidino product.

One synthetic route to compounds having the formula shown above is a condensation reaction using appropriately substituted precursors as shown in the scheme below. O OR R5 NHR2 Q NR2 R6 catalyst, ROH R T'A Y"A ! Q-CO-R5 + W-NC R6 2) water/\ (B B, B CN CN This condensation is performed in the presence of a catalyst, preferably a Lewis acid catalyst, and an alkyl alcohol (ROH), preferably a lower alkyl alcohol such as methanol, ethanol, i-propanol, etc., followed by hydrolysis of the intermediate, preferably with an excess of water, generally up to about 10 equivalents of water. Suitable Lewis Acids include BF3 etherate, AIC13, etc. W-NC is an isonitrile in which W may be any suitable hydrocarbon group, generally an alkyl, carbocycloalkyl, or aralkyl group, preferably having no more than about 12 carbon atoms. A particularly preferred isonitrile is benzyl isonitrile. The ester product may be purified by standard techniques, including high pressure liquid chromatography (HPLC), column chromatography, recrystallization, etc.

Reduction of the resulting ester to an alcohol can be accomplished using any known reducing agent ( [H]) which will preferentially reduce an ester before a nitrile. Suitable reducing agents and procedures are well known in the art. See, for example, Modem Synthetic Rections, H. O. House, W. A.

Benjami, Inc., Second Ed., 1972. A useful reducing agent is lithium borohydride. The alcohol may then be converted to an amine using known chemical reactions. Suitable conditions include first reacting the alcohol with hydrogen azide, DEAD, and triphenyl phosphine (PPh3), following by PPh3 and water or first with phthalimide, DEAD and PPh3, followed by hydrazine. These reactions are shown in the scheme below. Alternatively, the ester may be reacted with a reagent having a nucleophilic carbon atom to introduce suitable R4a groups. Such reagents may include an activated methylene carbon, for example a methylene which is adjacent to one or more strong electron withdrawing groups such as nitro (N02), carboalkoxy (COOR4a), etc., Grignard reagents (R4aMgHal, where Hal is a halogen), etc. and then converted to the alcohol and to the amine.

Conversion of the amine functional group to a sulfonamide and the conversion of the nitrile functional group to an amidine may be performed in any desired order. A preferred reaction scheme is shown in the scheme below.

These conversions are accomplished using known chemical reactions, purification and separation procedures. The amine may be converted to a sulfonamide by reaction with an appropriately substituted sulfonyl chloride (CISO2R1) in the presence of a base. The nitrile may be reacted with hydroxyl amine in an alcohol solvent followed by reduction, for example, with Raney nickel and hydrogen, or by reaction with HCI/alcohol and then ammonia/alcohol.

An example of a suitable reaction sequence is shown below.

In this sequence, a = BF3OEt2/EtOH, b = LiBH4/DME, c = phthalimide, DIAD/PPh3/THF, d = H2NNH2/EtOH, e = RISO2Cl, f= H2/Pt/C/EtOH, and g = R7SO2CI/NEt3, NH2OH-HCI/NEt3, H2/Ra- Ni/MeOH.

An analogous related synthetic scheme may be used to prepare the corresponding compounds in which X is a carbonyl as shown below.

Compounds in which m = 2 can be prepared using according to the scheme shown below which provides an alcohol which is homologous to the alcohol shown in the scheme above and which can be converted to an amine (and further elaborated compounds) in an analogous manner. In the scheme below, (a) is a base and (b) is a reducing agent such as LiBH4 R4 COOR NH2/ R4 COOH q (a) Q NH lez N 11 ; / CN B R4 OH Q NH Rs A CN Compounds in which Y is C (O)-RI; C (0)-OR'; C (O)-NR'R2 are prepared as described above using the corresponding acyl halide (preferably an acyl chloride), alkyl haloformate (preferably a chloroformate) or isocyanate as shown in the scheme below: An example of a suitable reaction sequence is shown below. R4 COOR NH2 R4 COOR Rg Base Rg R5 R5 NH C R10 CN C R, o Ro j CN LiBH4 0 Z N R5/Rs O w \ NH DEAD PPh3 NH NH C Riz riz Rto I Ro I 1) NH2NH C (NH) NH 2 CN 2) C) SO :, Rj NEt3 R4 R4 NHS02Rl NHS02RI R 5 R Rs Rs \NH l) H2NOH NH NU t C MeOH/AcOH Rio I Rio CN C (NH) NH 2

The esters resulting from the condensation reactions shown above can also function as intermediates in the synthesis of compounds in which X is a carbonyl group. Conversion of the ester to a carboxylic acid is easily performed by saponification with an alkali-metal hydroxide such as lithium, sodium, or potassium hydroxide. Coupling of a sulfonamide to the acid is accomplished by first activating the carboxylate for coupling using, for example, carbonyl diimidazole or other routine activating agents used in peptide synthesis. The second part of the coupling is done by mixing an alkyl or aryl sulfonamide with a strong base such as DBU or sodium hydride, preferably in an anhydrous solvent, such as a hydrocarbon or ether solvent, e. g. tetrahydrofuran. The nitrile is converted to an amidine by methods already described.

OR OH Ri Rs Rs Ru O Q L. OH R2 R5Q R2 0 R6//A THF/ [JeO R6 i) Activation ! rua R1SOzNHz R5 Base R5 B !! BaseRs CN CN CN H2NOH EtOH 0 O O i! OR-S-R, NH_1°1R Rs O Ru O NR2 Raney Ni Hydrogen Q R6 \ YRs--S Rs R5 R5 B I OH In a more preferred variation of this embodiment, Q is a substituted phenyl having substituents Zlf Z2 and Rg-Rl l as described below.

A further method of preparing intermediate compounds useful in preparing the compounds of the invention is shown below and involves the synthesis of imine compounds from readily available aldehydes and ketones followed by nucleophilic addition of a nucleophilic carbon atom containing reagent, i. e. in general"Nu-."Nu"may be a moiety such as CHR4aNO2, CHR4aCOOR, CH (NO2) (COOR), etc., which are generated using well known Grignard reactions, reactions in which a base is used to remove a proton from the carbon atom adjacent to an electron withdrawing group (CO, COO, NO2), etc.

"Nu"can be converted into a group such as CHR4aNH2 or CHR4aCH2OH or CHR4aNH2CH20H by known reduction reactions as shown below. In these intermediates, an amino group can be further sulfonated or otherwise acylated as described above. An example of a suitable reaction sequence is shown below.

nu2 Ru R5 TSOH toluene Rio ! CN CN N R4 N02 Nô2 R9 Bse 10-R5 Rro 4 3 NU R/ Rlo CN Zn/AcOH ClSo2RINEt3 R4 NHSO2R R4 NHSO2Ri Ru Rg R5 NH 1) H2NOH Rg H,/Ra-Ni NH Rlo Rlo C (NH) NH 2 CN An alternative synthetic procedure can be used to prepare the alcohol intermediates described above. As shown in the scheme below, reaction of an initial styrene derivative with a peracid usually produces a mixture of products containing non-hydrogen R4a and/or R5 substituents as shown below which can be converted without separation to the alcohol by reaction with a cyano-aniline or corresponding cyano- pyridine.

The alcohol can then be used to prepare compounds of the invention as described above.

When the corresponding compounds in which A and B are nitrogen are desired, the aniline or substituted aniline used in the reactions described above is replaced with the corresponding amino-pyridine or substituted amino-pyridine compounds.

Compounds in which the sulfonamide nitrogen bears a substituent can be prepared by conventional alkylation of the nitrogen atom using known reactions, for example, alkylation with dialkyl sulfate, alkyl halide etc, according to known procedures.

In a preferred embodiment, Q is a substituted aryl, and more preferably, a substituted phenyl group and has the structure shown below.

In this structure, Zl, Z2, Rg-Rl are as defined above both generally and in preferred embodiments. Compounds of this embodiment are prepared as described in scheme I above using an appropriately substituted benzaldehyde having structure Q-CHO (R5 is H). These substituted benzaldehydes are readily available from commercial sources or can be easily prepared from known benzaldehydes using well known synthetic chemistry.

In one embodiment, Q is substituted with a nitro group. A preferred position for the nitro group is at R, I (where Zl, Z2, Rg and Rjo are as defined above generally and in preferred embodiments), which nitro group can be further reduced to an amino group using a suitable reducing agent. Generally, the cyano-amine compound or the cyano-sulfonamide compound shown in scheme 3 will be reacted with a reducing agent which will preferentially reduce the nitro group at RI, over the cyano group. Any reducing agent having these properties may be used, for example, hydrogen and a Pt/C catalyst. The aniline resulting from the reduction can then be reacted with a sulfonyl chloride (CISO2W where W is as defined above) to produce a disulfonamide compound.

The preparation of cyclic urea derivatives in which Nl-R2 and N2-R2 together form a urea linkage, i. e. Ni-C (O)-N2, provides additional compounds of the invention and provides an additional method of preparing enentiomerically pure compounds of the invention. The cyclic urea compounds can be used, for example, to prepare dialkoxy bis-sulfonamides and other compounds of the invention as shown in the scheme below.

Alternatively, nitric acid can be replaced by sulfuric acid in the scheme below to give sulfonic acid derivatives which can be further converted to sulfonamides and sulfones by known reactions. 1) H2N H N NO2 I CN LDA R9O THF N 2) Zn, HOAc, HCI Ro/ 3) phosgene CN R9 = alkoxy Ro = alkoxy i) n-BuLi ii) v °q~X} ci CI I i OMe Pi , 1 O=S=O 1) Separation of s . Diastereomers Ru ==o LiOH / R9O OMe Rio N 0 riz CN C !-S-Ri \===/ HNO3 ° CN R I , 1 ors O=S=O 1) HZ/Pt/C R9O I \ N Rl I-S-R R, I-S_R RoJi\/ CL R 7 C N nos S'O ce CN IR1 O=S=O zNH 1) OH R9 'NU 2) H2NOH, TEA, EtOH Rg = alkoxy 0 " Rio=a! koxy 3) H2, RaNi, MeOH, SO 9 Rro = alkoxy NH2 HN

Other compounds of the invention, including heterocyclic compounds, are readily prepared from simple starting materials which can be used in the synthetic schemes described above. For example, beginning with simple nitro and hydroxy substituted aldehydes, condensation as described above provides the corresponding esters which can be converted directly to cyclic urethane or oxazole compounds which can then be further elaborated as already described to provide compounds of the invention. These reactions are shown schematically below for rings fused in the 5-position and 6-position. 0 NH2 N H HN03 I H \ N% + + ruz I OH \ OH/ NO2 CN Un] 02. N BF3-OEt3 \ MeOH \ Steps COzMe CO2Me previously described R9/I NH R9/I NH Final Final'\---- Products 0 2) CICOCI OH HN- N02 con CN \ 1) H2-PUC 2) CICOR/heat Steps CO2Me previously ri described 9\ NH Fanal. Products \o X Nte R CN Compounds in which the ring is fused to the 4-position and the 5-position of the phenyl ring are prepared by analogous methods stating with the appropriately substituted aldehyde as shown below. 0 0 Rye Same as Above 43 H. X HO nez

Other fused heterocyclic compounds are prepared using conventional synthetic chemical reactions and appropriately substituted starting materials which are well known in the art of chemical synthesis to provide additional compounds of the invention. For example, fused furan ring systems can be prepared from the corresponding halo and hydroxy substituted aldehydes as shown below. 0 =, ? Rs(Ph) ZCIZ R9 Ho) DMF Ho I,or Br R Also included in the scope of this invention are prodrugs of the compounds described above.

Suitable prodrugs include known amino-protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the parent compound under physiologic conditions. A preferred class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidino group is substituted with a hydroxy (OH) group, an alkylcarbonyl (-CO- W) group, an alkoxycarbonyl (-CO-OW), an acyloxyalkyl-alkoxycarbonyl (-CO-O-W-O-CO-W) group where W is a monovalent or divalent group and as defined above or a group having the formula-C (O)-O- CP I P2-haloalkyl, where P I and P2 are the same or different and are H, lower alkyl, lower alkoxy, cyano, halo lower alkyl or aryl. Preferably the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the invention. These prodrug compounds are prepared reacting the compounds of the invention described above with an activated acyl compound to bond a nitrogen atom in the compound of the invention to the carbonyl of the activated acyl compound. Suitable activated carbonyl compounds contain a good leaving group bonded to the carbonyl carbon and include acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, in particular acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and defluorophenoxy acyl. The reactions are generally exothermic and are carried out in inert solvents at reduced temperatures such as-78 to about 50C. The reactions are usually also carried out in the presence of an inorganic base such as potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, triethylamine, etc. One manner of preparing prodrugs is described in W098/46576, published 22 October 1998.

Using the synthetic methods described above, the following exemplary compounds of the invention shown in Table 2 below can be prepared (m = 1). For each entry in the table, X may be carbonyl or (CR4aR4b) m where m = I or 2; and the benzamidine ring may bear a halogen, hydroxy or alkyl substituent.

Table 2 NHSO2Ri X NU NH Rio Ril Z2 HN NH2 Compound No. z R R R R 0 oc3 H OCH3 I/ (benzyloxy) 2 oc3 H I//OCH3 3 3 OCH /// 4 4 H ¢ OCH3 ~ H --H 4H) <H3)OCH3 ¢) ~s° H5 OCH3 J H / 6 i i T1 3 t J" OCH 7 7 oc3 H --H / 8 i OCH3 0 H

Compound 21 9,, 10-, 11 No. R R R R o \ No. z R R R I O H 10 \i OCH3 OCH3 Br CH2CI 11 OCH3 \ o H 12 12 -CH(CH3) z OCH3 13 -CH2CH2CH3 OCH3 [f° CHSONH CH3S0z NH 14 NO, A'OCH3 H OCH3 0 H -j I H 14XzNO2 OCH3<° H15 16 a -H oc3 0 H 16 ci i -H OCH3 0 H a 18 17 -CH2CHS OCH3 < H 18 18 OCH nô2 3 H 19 OCH3 0 H Ces 20 19 loch3 S N OCH3 li

Compound2 1 9 10 No. zz CH3, CH3 \ O --H--o OCH3 H CH3 CH3 23 Oc3 H OCHg I/H N02 Nô2 24 CH3 OCH3 H -1 f 25 OCH3 0 H -I-1 I Br 26 24 OCH3 H 25 -H - CH3 27 OCH3 oi 26 N02 28 OCH3 OCH3 0 H OCH3 29 F OC3 H -I F F F F OCH3 II I H --I-I --H i OCH3 0 H --H C02H 32? i OCH3 0 H / 33 -CH2CH2CH3 OCH3 J ! j H --H 34 -CH2CH2CH2CH3 OCH3 /

Compound 2 1 9 10 35 CH3 Cl ruz OCH3 II I H OHci oc3 0 H OH ci OCHg I H Cl OH a 37 CH2Cí -CH2CH2CH3 OCH3 rO u / 38 i -CH2CO2CH2CH3 OCH3 39 oui -CH2CO2H H OCH 40 -H-(CH2) 6CH3 OCH3 C ° H 41 41 -H-CH=CH2 OCH3 < H 42 -CHZ C=CHi -H OCH3 U 43 43 OCH3 H 44 i -H OCH3 0 H / 45 45 46 46 OCHg II I H

Compound 2 1 9 10 No. z R R R R 47 i OCH3 48 0 O OCH3 I H 49 H N \ OCH3 H 50 C3 cl, loch3 51 CN xi H 52 H fez 54 C N LOCH3 54 i i N OCH3 54 i -H OCH3 H N 55 OCH3 OCH3 H 56 H NU y ai --H OCH3 b H 57 N O -H OCH3 II H 58 H N\ O/ -H OCH3 H N 59 OOH -H OOH OCH3 0 H 60 \ -H C OCH2CH3 OCH2CH3 H

Compound 2 1 9 10 11 61 61 I OCH2CH2CH3 2 2 3 62 \ \ oi OCH2CH2CH3 H 63 N (CH 3) 2 i OCH2CH3 I/ H 64 -4-1 OCH2CH3 64 65 OCH2CH3 I \/H 66 s 66 2 2) 4 67 CL3 -H OCH2CH3 0 H 68 68 68 O i ii -H I O \ SN/ OCH2CH3 69 i H ¢) OCH2CH3 OCH3 Br 70 /OCH2CHg 71 -H-CH (CH3) 2 OCH2CH3 ¢)/\ H 72 72 -CHzCHZCH3 OCH2CHg I/ CH3S02---NH

Compound2 19,-, 1011 No. Z R1 R9 R10 R11 73 0 H OCH2CH3 I/H 74 -CHZCHzCH3 OCH CH/CH3CH2- 2 3 02CCH2S°2NH- 75 O -CH2CHZCH3 OCH2CH2CH3 I H02CCH2SO2NH- 76o CCOoCHzCH', i H-CH2CH2CH3 OCHoCWs i" CH3SOzN- 77 --H-CH2CH2CH3 OCH2CH3 0 CH2CO2H 9 CH 3SO2N 78 -H OCH2CH3 I H 79 cl OCH2CH3 I \ H 0 ci 80 --H-CH CH I O 2 3 OCH2CH3 H / 81 OCH2CH3 H NO2 82 OCH2CH3 I H CF3 83 84 S H Nlr 0 i OCHZCH3 \ H Cl3/ 85 CH3 CH3 +/\ O -OCH2CHg i CH3 CH3

Compound 2 No. Z R [9 R 11 uu i -H OCH2CH3 0 H / NO2 87 \/ -CH3 OCH2CH3 I H 88 Br OCH2CH3 Co H Ber Br 89 cl -+)- OCH2CHg I CH3 90 -H N02 OCH2CH3 oi NOH cor 91 ocH3 OCH2CHg 91HX OCH3 OCH2CH3 ¢)/\OHOCH3 92 F F \ -OCH2CH3 F F 93 F F -H OCH2CH3 \ H 94=. -H'-f OCH2CH3) !) ° H CCH 95 HO2C OCH2CH3 \ -H \/I/H 96 96 -CHZCHzCH3 OCHZCH3 I H 97 97 -H CH2CH2CH2CH3 OCH2CH3 U j 98 chai3 OCH2CH3 CH3

Compound No Z R 1 R9 R 1 ° R 11 99 ci --H OCH2CH3 ¢> H U OH ci 100 CH2CI --H-CH2CH2CH3 OCH2CH3 0 H 101 , o, CH2) 6CH3 102 / 102 --H-- OCH2CH3 102HCH =CH 20CH2CH3 1< H103 -CHC-CH --H OCH2CH3 I H 104 -H I"I OCH2CH3 H U 105 --H < OCH2CH3 ~ H 106 O -H OCH2CH3 (H 107 --H OCH2CH3 108 108 ¢ OCH2CH3 ¢)/\ H 107 -H J) j [j OCHCHs j ° H 109 O -H r OCH2CH3 ¢>~ H 110 N -H N OCH2CH3 H --H 0 111 -H OCHCHg j H NoyCH3 OCH2CH3/\ H 0 CH3 112 -H OCH2CH3 ¢ H CON H

Compound 2 1 No. z R R R R 113 i 113 N OCH2CH3 [< H coq" 114 1 i -H OCH2CH3 H 115 115 --H OCH2CH3 1< H / N 116 N -H I N OCH2CHg // , 1 7 O 117 OCH2CH3 H 118 H N, -H OCH2CH3 H 119 119 i -H OCH2CH3 ¢> H s 120 OOH i OOH OCH2CH3 H U 121 \ \ -H OH H 122 122 i -H OH H 123 N (CH 3) 2 --H OH 0 H -H I,, OFi I H 124 OH H 125 125 OH < H H 126 s H 0

1 n 1 1Compound 2 R1 R9 10 11 Nô. 127 128 0 128 O II -H OH 0 H ' 0 H 129 0 -H O OH OCH3 Br 130 130 C, H2CI ? H2C! H W OH ¢)/\ o H 131 i -H-CH (CH3) 2 OH ~o H 132 \ -H--CH2CH2CH3 OH/ CH3SO2-NH- 133 i --H N02 OH I H 134 H OH F OH ¢y~ H 135 Cl OH (\i C Ci 136 --I--CH2CH3 OH 0 H 137 -H 0 OH H N02 138 -H OH 0 H CF3

Compound 2 1 9 R10 R11 No. 39 zizi osr OH ~ H 140 S N II \ O/ -H o OH I/H 141 CH3 CH3/ -H OH H i CH3 CH3 142 -H OH H N0 NO2 143 -H-CH3 OH H 144 ber OH Wo H Br 145 ---H < CH3 OH W H CCH CH3 146 -H vno2 OH \o H Nez 147 H OCH3 OH 0 H OCH3 148 H OH 0 H -H OH H F F 149 F F -H \/ZH OH I \ H

Compound 2 R1 R9 10 R11 Nô. 150 151 H 151 151 H02C OH 0 H 152 152 152 -CH2CH2CH3 OH \ow H H 153 i -H--CH2CH2CH2CH3 OH h H 154 -H CH3 OH 0 H CCH c3/ 155 Cri -H OHo- Cl OH ci 156 2CI H CH2CH2CH3 OH Wo H 157 i -H- (CH2) 6CH3 OH < oz H 158 \ --H-CH=CH2 OH 0 H 159 -CH2-C=CH -H OH H 160 160 i -H OH H / 161 \ -H OH H / 162 H \ -H OH I H

Compound2 1 9 10 Nu 163 --H OH H 164 // 164 \ OH I/H 166 O \ ° To OH I H cl H \ O/ 166 H CH3 CH3 --H OH H con H / O H 168 \ \ OH H N 171 N 172 169 , N oi OH I H 173 H -H i N OH I/H 171 -H N \ i -H OH H N 172 N OH I H 173 H NEZ H OH 0 H 174 H N -" H I/H 175 N H 175 N 176 OCH OH H

Compound 2 No. z R R R R 177 \i \ i -CH3 178 i --CH2CH3 I/ H H"JX CH2CH3 ¢) ~ H179 178 \ \ /--CH2CH3 / 179 N (CH3) 2 180 N (CH3) \Q' -CH2CH3 H H 181 -CH2CH2CH3 182 -CH3 I \/H 183 S H > CH (CH3) 2 < H 184 -CH3 \ H m 185 0 O \i i ii -H O--CH2 (CH2) 3CH3 INi /I H 186 186 --H-CH3 OCH3 Br 187 CH2cl -CH3 \ I H 188 H CH (CH3) 2 CH3 <° H

Compound 2 1 9 10 11 189-H CH2CH2CH3-CH3 < oz CH3SO2 NH- 190 -CH3 I \/H 191 i H (y-F-CH3 h J ° H 192 CL -H 0 H ci 193 \ -H-CH2CH3-CH3 H / 194 -H \-CH3 H NO2 195 -H CH3 0 H CF3 196 -H Br-CH3 0 H 197 H y-CH3 H o 198 CH3 CH3 \ -H--CH3 H i CH3 CH3 CHg CHg 199 H -CH3 I/H NO2 200 / --H-CH3-CH3 H

No Z R1 R9 R10 R11 201 -H -CH3 oi H Br 202 _H 0 cH3-CH3 H CH3 203 zizi N02-CH3 0 H 203 H<NO2-CH3<0 HNOz 204 --H OCH3-CH3 0 H OCH3 205 OCH3 205 -/>-OCH3 C H F F F F C02H I -H-CH3 H 205 0 H -CH3 I H --H C02H 208 -H HO2 X-CH3 < 0 H hou 209 O 209-CH2CH2CH3-CH3 H 210 210 H -H-CH2CH2CH2CH3-CH3 W H 211-- 211 CH3 0 --H-CH3 H C ! c3 ci CL -H--CH3 I \ 0 H OH Cl

Compound 2 1 9 10 R11 Nô.- 213 HZCI -H-CH2CH2CH3-CH3 < O H cr 214 214--H- (CH2) 6CH3-CH3 0 H 215 \ -H-CH=CH2-CH3 < ° H 216 216 -CHz C=CH -H-CHs J H 217 f rTO --H CH3 H 218 218 -H-CH3 H 219 219 220 --H CH3 0 H 220 --H-CH3 0 H 221 N 0 223 H \ rTYO -H-CH3 H / 224 \ i -H 0 CH3 0 H 223 H 225 -H,-CH3 I/H N 224 N// -H N\ I-CH3 I/H 0_ : 225 H nu H H

Compound 2 1 9 10 No. z R R R R 226 \ H -H , i N-Chi3 / f< 1 fTTo -H -CH3 j! J H 228 227 N cl3 H 228 229 N N YO -H NoX CH3 <o H CFi3 I/H 229 N -CH3 I \ H * 230 N N -CH3 I \/H 231 231 N < I/H 232 N -CH3 H O/ 233 OOH --H 0 - 234 234 --H-CH:--CH2 -CH=CHZ I/H 235 i -CH=CH2 236 \ \ 236-H/II-CH=CHZ H 237 (CH3) 2- 0 --H I \ \-CH=CHz H 238 238 -CH=CH2 H

Compound 2 1 9 10 11 239 239 CH=CHCH3 240 s -H-CH=CH2 H 241 N rY'o H oH CH=CH2 ¢ f H 0 242 0 H C CH=CH2 ¢> /II N I ou 243 243 C CH=CH2 OCH3 Br / 244 2cul --H-CH=CH2 0 H 245 CH=CHCH2CH3 t° H 246 246 o H CH2CH2CH3 CH=CH2 lW CH3SO2NH 247 --H N02-CH=CH2 H 248 r' -CH=CHZ\ H 249 249 -H--CH=CHz I \ H 0 250 \ -H--CH2CHg-CH=CH2 I/ H

Compound2 1 9 10 1 No. z R R R R 251 o -H \/-CH=CH2 N02 252 i -H < CH2CH=CH2 ¢ f H CFs 253 CF3 253 -+'Y:--CH2 0 H 254 -CH=CHZi 255 255 CH3 CH3 CH3 CH -H/I H i CH3 CH 256 -CH=CHZ I/H N02 257 -CH2C1-CHZ I/H 258 258 -CH=CHZi H Br 259 H3 \/ -H--. v CH3 CH=CH2 tf H CH3 2 cl3 zizi O -H N02-CH=CH2 H N02 261 OCH3/ -CH=CHZ II H OCH

Compound 2 1 9 10 262 262 --H-CH=CH2 0 H F F 263 -H C02H-CH=CH2 0 H 264 -CH=CHZ I \ O H CCH 265 265 -CH2CH2CH3-CH=CH2 I 266 ou -CH2CH2CH2CH3-CH=CHZ 267 -H \\//CH-CH=CHZ H CH3 H 268 ci 268 C! cl CH=CH2 Wo H Cri 269 H2CI H CH2CH2CH3 CH=CH2 20cl H 270 TO cor 271 271. -H-CH=CHZ-CH=CHz I H 272 i '-CHZ C=CH-CH=CHz 272 H CH2cscH CH=CH2 ¢)/\ H273 -CH=CH2 r H I,

Compound Z 1 R9 R10 R11 274 O -HH,--CH=CHZ H 275 276 i -H-CH=CHZ I \ H 276 276 -H I-CH=CHZ 277 277 N 0 --H-CH=CH2 H 278 0 i -H \ H 279 H --H N 0 -CH=CH2 H N 280 O -H I-CH=CHZ H N H 281 i -H N-CH=CH2 H 282 N O -H I, N-CH=CHZ H lez 283 283 -CH=CHZ I \/H CN 0 N 284 rN fro ¢ N N CH=CH2 ¢> H 285 H -CH=CHZ -H-CH=CH2 H 286 i -CH=CH2 II H

Compound2 1 9 10 1 Nô. 287 < To -H tt-CH=CH2 C H 288 288 COOH ro -H -CH=CHZ I'H 289 -H-CH2C=CH H 290 H X-CH2C-CH H 291 i -H,,-CH2C=CH II H 29 ? N(CH 293 -H 3) 2-CH2C=-CH 0 H 293 -H <-CH2C-CH < H 294 0 -H CH H 295 s z -H-CHZC=CH'I H 296 H \ -H Cz-CH2C-CH < C o H 297 0 298 298 -i 298 fT" -CH2C= CH OCH3 Br 299 2CRI -H X H20CI H

Compound 2 1 R9 R10 R11 No.RR 300 -H-CH (CH3) s-CH2C==CH 301 0 -H-CH2CH2CH3-CH2C=CH j CH3SO :-NH- 302 \ -H N02-CH2C-CH H 303 0 -H /-CHZC°-CH I \ H 304 ci /O -H CH2C=CH H c Cl 305 -H-CHCH3-CH2C=CH t) J H / 306 0 -H CH2C= CH H NO2 307 Qi -H H CF3 308 z -H --Br-CH2C==CH 309 H 0 -H CH H o 310 CH3 CH3 0 -H-CH2C=CH i CH3 CH3 311 0 -H X-CH2C-CH H NO2 312 z -H-CHg-CH2C=CH C\J H

A XCompound2 1 9 10 313 313 H 9 R R R R bu 314 Cl3 0 314 H CH2C CH H CH3 315 --H N02-CH2C CH 0 NO2 316 -H OCH 3-CH 2C-CH 0 H OCH3 317 H _zCH2CCH [<\°HF F -H--CH2C=CH I H F''F F F 318 z -H-<A/)-C02H-CH2C=CH j H 319 -H/-CH2C=CH r H CO2H 320 0 -H-CH2CH2CH3 CH2C CH H 321 \ -H-CH2CH2CH2CH3-CH2C=CH H 322 CH, 0 -CH2C=CH II H CH3 323 ci -H-CH2C=CHi H OH Ci 324 CH2CI -H-CH2CH2CH3 CH2C= CH 0 H

Compound 2 R1 9 10 1 No. ZRRRR 325 326 -CHZC=CH I H 326 326 -H-CH=CH2-CH2C-CH < H 327 327 -CH2 C=CH -H-CH2C-CH W H 328 328 -H H-CHzC=CH I 328 329 \ -H g-CH2C-CH W H 330 z -H-CH2C=CH II H 331 -H ¢ y-CH2C--CH < H 332 N \ ou -H I \-CHZC=CH I/H 333 0-CH2C=CH 0 -H, I/H 334 Nez H -H CH2C= CH H ici N 335 --H I H H H 336 0 -H N-CH2C= CH H 337 i -H g zN-CH2C_CH < H 338 N 0 H -H C \-CHZC=CH/H N N

Compound 2 1 9 No. z R R R R 339 339 -H h.-CH2C==CH j H 340 H NEZ -H O-CH2C--CH W H V l/ 341 NOH -H CY-CH2C-CH C H 342 -H \\/-CH2C=CH H 343 ICOOH gA/\ ow H C> \-CH2C-CH W H 0 344 rr" --H OCH3 OCH3 H 345 H OCH3 OCH3 H \ 346 -H OCH3 OCH3 H 347 W (CH3) -H < OCH3 OCH3 H // 348 -H OCH3 OCH3 H 349 --H OCH3 OCH3 H 350 s -H X OCH3 OCH3 H 351 H N -H f ! T OCH3 OCH3 H /o

Compound 2 1 9 10 11 No. z R R9 RUZ R11 352 o W OCH3 II OCH 353 / 353 --H OCH3 OCH3 Br 354 354 -H OCH3 OCH3 H 355 -H-CH (CH3) 2 OCH3 OCH3 H 356 CH2CH2CH3 -H OCH3 OCH3 CH3SO2-NH- 357 --H N02 OCH3 OCH3 H 358 358 OCH3 OCH3 H 359 Cl OCH3 OCH3 H 360 -H-CH2CH3 OCH3 OCH3 H 361 OCH3 OCH3 H N02 362 OCH3 OCH3 OCH3 H CF3 363 OCH3 OCH3 H 364 s H OCH3 OCH3 H 0

Compound 2 1 9 10 1 nu. 365 CH3 CH CH3 CH3 CHEZ OCH3 H CH3 CH3 C 366 OCH OCH H N02 367 -H-CH3 OCH3 OCH3 H 368 OCH3 OCH3 H Br 369 CH3 ---cH3 OCH3 OCH3 H CH3 370 -H N02 OCH3 OCH3 H 371 N02 H OCH3 OCH3 OCH3 H OCH3 372 F F F OCH3 OCH3 H F F 373 H C02F'OCH3 OCH3 H 374 OCH3 OCH3 H CO2H 375 H-CH2CH2CH3 OCH3 OCH3 H 376 -H-CH2CH2CH2CH3 OCH3 OCH3 H 377 CH3 OCH3 OCH3 OCH3 H CHg

Compound z2 R1 R9 R10 R11 378 cul 378 cul -H OCH3 OCH3 --o H OH Cl 379 -H-CH2CH2CH3 OCH3 OCH3 H 380 -H-ACH2) 6CH3 OCH3 OCH3 H 381 -H-CH=CH2 OCH3 OCH3 H 382 H-CH2-CECH OCH3 OCH3 H 383 H 9 OCH3 OCH3 OCH3 H u 384 OCH3 OCH3 H 385 OCH3 OCH3 H 386 -H OCH3 OCH3 H 387 N OCH3 OCH3 H 388 0 -H OCH3 OCH3 H 389 H H, N OCH3 OCH3 H N 390 -H OCH3 OCH3 H N H 391 -H N OCH3 OCH3 H 392 -H OCH3 OCH3 H

Compound Z 1 R9 10 R11 No. z R R R R 393 N N OCH3 OCH3 H N N 394 NEZ -H ¢N OCH3 OCH3 H 395 NH 395 U -H OCH3 OCH3 H 396 N H t S OCH3 OCH3 H 397 N -H OCH3 OCH3 H 398 COOH -H OCH3 OCH3 H 399 r -H C OCH3 OCH2CH3 H 400 -H OCH3 OCH2CH3 H 401 H -H OCH3 OCH2CH3 402 N(CH3) z -H < OCH3 OCH2CH3 H // 403 OCH3 OCH2CH3 H 404 OCH3 OCH2CH3 H 405 S -H OCH3 OCH2CH3 H 406 H N -H J OCH3 OCH2CH3 H

Compound 2 1 9 10 11 407 0 0 S. i OCH3 OCH2CH3 0 H 408 \i -H OCH3 OCH2CH3 Br 409 --H OCH3 OCH2CH3 H 410 -H-CH (CH3) 2 OCH3 OCH2CH3 H 411 -H-CH2CH2CH3 OCH3 OCH2CH3 CH3S02 NH- 412 -H N02 OCH3 OCH2CH3 H 413 413 -H OCH3 OCH2CH3 H 414 ci -H Q OCH3 OCH2CH3 H ci 415 H-cH2cH3 OCH3 OCH2CH3 H 416 H<OCH3 OCH2CH3 HNO2 OCH H N02 417 -H OCH3 OCH2CH3 H CF3 418 H OCH3 OCH2CH3 H 419 H OCH3 OCH2CH3 H o

Compound 2 1 9 10 1 Nô. 420 CH3 CH3 -H OCH3 OCH2CH3 H i CH3 CH3 421 --H OCH3 OCH2CH3 H NO2 422 N02 -H-CH3 OCH3 OCH2CH3 H 423 -H OCH3 OCH2CH3 H Br 424 CH3 H < CH3 OCH3 OCH2CH3 H CH3 425 -H OCH3 OCH2CH3 H N0 NO2 426 -H OCH3 OCH3 OCH2CH3 H OCH3 427 F F -H OCH3 OCH2CH3 H F F F 428 -H OCH3 OCH2CH3 H 429 -H OCH3 OCH2CH3 H cor 430 -H-CH2CH2CH3 OCH3 OCH2CH3 H

Compound2 1 9 10 nô. 431 H-CH2CH2CH2CH3 OCH3 OCH2CH3 H 432 CH3 OCH2CH3 -H N OCH3 OCHCHs H CH3 433 Cl -H OCH2CH3 OH Cl 434 -H-CH2CH2CH3 OCH3 OCH2CH3 H 435 --(CH2) 6CH3 OCH3(CH2) 6CH3 OCH3 OCH2CH3 H 436 H-CH=CH2 OCH3 OCH2CH3 H 437 -H-CH2-C_CH OCH3 OCH2CH3 H 438 -H X OCH3 OCH2CH3 H 439 H OCH3 OCH2CH3 H 440 r H OCH3 OCH2CH3 H 441 -H OCH3 OCH2CH3 H 442 N ¢ y OCH3 OCH2CH3 H 443 0 -H OCH3 OCH2CH3 H 444 H -H N OCH3 OCH2CH3 H N 445 OCH3 OCH2CH3 H H

Compound 2 R1 Rg rO p11 ni. 446 OCH2CH3 H 4 7 -H g VN OCH3 OCH2CH3 H 448 N OCH3 OCH2CH3 H N 449 N -H t OCH3 OCH2CH3 H 450 450 -H OCH3 OCH2CH3 H 451 v OCH3 OCH2CH3 H S 452 N Y -H t ° OCH3 OCH2CH3 H 453 COOH -H OCH3 OCH2CH3 H 454 -H OCH3 OH H 455 -H OCH3 OH H 456 -H OCH3 OH H 457 N (CH3) 2 -H OCH3 OH H i 458 H OCH3 OH H 459 i -H OCH3 OH H

Compound 2 1 9 10 11 No. z R R R R 460 g -H X OCH3 OH H 461 H N -H N OCH3 OH H 462 o Oh 11 OCH3 0H 463 -H OCH3 OH Br 464 OCH3 OH H 465 -H-CH (CH3) 2 OCH3 OH H 466 H CH2CH2CH3 OCH3 OH CH3SOi--NH- 467 -H OCH3 OH H 468 -H OCH3 OH H 469 c A OH OCH3 H a 470 --H-CH2CH3 OCH3 OH H 471 OH Q02 OCH3 H 472 -H OCH3 OH H CF3 473 -H Br OCH3 OH H 474 H "e H V OCH3 OH H

Compound2 1 9 10 1 No. ZRRRP 475 CHs CHz --H OCH3 OH H CH3CHs 476 OCH3 OH H 477 OCH3 OH H 478 OH /OH H<OCH3 Hci 479-CH2CH3 OCH3 OH H OCH3 OH H 480 'No, OCH3 OH H 481 --H OCH3 OH H CF3 482 OCH3 OH H 483 H w OCH3 OH H 484 CHzCH3 -H OCH3 OH H 485'" -H OCH3 OH H N02 486 H-CH3 OCH3 OH H 487 -H OCH3 OH H Br 488 -H OCH3 OH H 489 -H OCH3 OH H N02

Compound 2 1 R9 R10 R11 No. 490 -HocOCH, OCH3 OH H OCH3 491 F F -H F OCH3 OH H F F 492 /'cozr, OCHg OH H 493 -H OCH3 OH H CO: H 494 494 -H-cH2cH2cH3 OCH3 OH H 495 -CH-CI+zCFi2CH3 OCH3 OH H 496 /=\ CH3 -H C H 3 OCH3 OH H 497 cl ci --H OH OH ci OH 498 -H-cH2cH2cH3 OCH3 OH H 499 -H- (CHeCHg OCH3 OH H 500 -H-cH=cH2 OCH3 OH H 501 -H-cH2-c-cH OCH3 OH H 502 -H "J OCH3 OH H 503 -H HA. OCH3 OH H 504 -H OCH3 OH H

Compound 2 R1 R9 R10 R11 No. z R R R R 505 -H OCH3 OH H 506 -H tNy OCH3 OH H 507 0 OCH3 OH H 508 H -H OCH3 OH H N 509/ \ -H OCH3 OH H N H H OCH3 OH H 511 NEZ OCH3 OH H 512 Nez -H OCH3 OH H N 513 -H OCH3 OH H 514 H OCH3 OH H J 515 N -H OCH3 OH OH 516 H N -H OCH3 OH H N 517 COOH -H OH H 518 OCH3 OH CHgCH2S02NH- --H

Compound Z 1 9 10 11 519 OH OCH3 OH CH3 (CH2) 2S02N- H W OCH3 520 -H C OCH3 OH CH3 (CH2) 3SO2Ne- 521 H OCH3 OH (CH3) 3CS02NH- '' 522 H C OCH3 OH (CH3) 2CHSO2NH- 523 523 OCH OH A t! ) --sOsNH- 524 -HCOCH3 OHLso2NH-524 H OCH3 OCH3 CH3CH2SO2NH- 525 -H!J OCH3 OCH3 ( (CHSCNH- 526 oc3 OCH3 CH3 (CH2) 3SO2Ni1- 527 OCH3 OCH3 (CH3) 3CS02NH- 528 rY -H OCH3 OCH3 (CH3) 2CHS02NH- 529 T A H OCH3 530 r -H C OCH3 OCH2CH3 CH3CH2SO2NH- 531 -H O OCH3 OCH2CH3 CH3 (CH2) 2SO2NH- 532 -H OCH3 OCH2CH3 CH3 (CH2) 3So2Nl4 533 -H OCH3 OCH2CH3 (CH3) 3CS02NH- 534 --H OCH3 OCH2CH3 (CH3) 2CHS02NH- 535 -H J OCH3 OCH2CH3/-\-so :. NH- 536 COOH -H ( :) x OCH3 OH CH3CH2SO2NH-

Compound 2 1 9 10 11 No. 537 COOH H ¢ OCH3 OH CH3 (CH2) 2SO2N (J- 538 COOH H CJ OCH3 OH CH3 (CH2) 3SO2Nii 539 COOH H C'\ OCH3 OH (CH3) 3CS02NH- i 540 COOH -H Ci OCH3 OH (CH3) 2CHSO2 u 541 COOH A H < OCH3 OH/\ so2NH 542 -H-CH2CH2CH3-OCH2CH3-OCH2CH3-OCH2C02H 543 -H-CH2CH2CH3-OCH2CH3-OCH2Ph-OCH2CO2H 544 -H-OCH2CH3-OCH2CH3-OCH2CO2H 545 -H-OCH2CH3-OCH2Ph-OCH2CO2H 546 -H-OCH2CH3-OCH2Ph-OCH2CO2H 547 -H-OCH2CH3-OCH2CH3-OCH2CO2H 548 -H-n-Butyl-OCH2CH3-OCH2CH3-OCH2CO2H 549 -H-isopropyl-OCH2CH3-OCH2CH3-OCH2C02H 550 -H-isobutyl-OCHzCH3-OCHzCH3-OCH2CO2H 551 -H-sec-butyl-OCH2CH3-OCH2CH3-OCH2CO2H 552 -H-CH2CH2CI-OCH2CH3-OCH2CH3-OCH2CO2H 553 -H-CH2CH2CH2Ci-OCH2CH3-OCH2CH3-OCH2CO2H 554 -H-CH2CH2CH3-OCH2CH3-OCH2CH3 CH2CO2H -NS02CH3 555 -H-CH2CH2CH3-OCH2CH3-OCH2Ph CH2CO2Et -S02CH3

Compound 2 R1 R9 10 11 No.RRR 556 -H-/)-OCH2CH3-OCH2CH3 CHCOsH -NS02CH3 557 CHZCOZEt -H-OCH2CH3-OCH2Ph CH2CO2Et -NS02CH3 558 558-H OCH2CH3-OCH2Ph CH2CO2H -NS02CH3 559 -H OCH2CH3-OCH2CH3 CH2CO2H -NS02CH3 560 -H-n-Butyl-OCH2CH3-OCH2CH3 CH2CO2H -NS02CH3 561 -H-isopropyl-OCH2CH3-OCH2CH3 CH2CO2H -NS02CH3 562 -H-isobutyl-OCH2CH3-OCH2CH3 CH2CO2H -NS02CH3 563 -H-sec-butyl-OCH2CH3-OCH2CH3 CH2CO2H -NSO2CH3 564 564-H-CH2CH2Cf-OCH2CH3-OCH2CH3 CH2CO2H NS02CH3 565 -H-CH2CH2 CH2C1-OCH2CH3-OCH2CH3 CH2C02H -NS02CH3 566 -H-CH2CH2CH3-OCH2CH3-OCH (CH3) 2-NHS02CH3 567 -H-OCH2CH3-OCH (CH3) 2-NHS02CH3 / 568-H-OCH2CH3-OCH (CH3) 2-NHS02CH3 569 -H-n-Butyl-OCH2CH3-OCH (CH3) 2-NHS02CH3 570 -H-isopropyl-OCH2CH3-OCH (CH3) 2-NHS02CH3 571 -H-isobutyl-OCH2CH3-OCH (CH3) 2-NHS02CH3 572 -H-sec-butyl-OCH2CH3-OCH (CH3) 2-NHS02CH3 573-H -CH2CH2CI-OCH2CH3-OCH (CH3) 2-NHS02CH3

Compound 2 R1 R9 R10 R11 Nu 574 -H-CH2CH2CH2CI-OCH2CH3-OCH (CH3) 2-NHS02CHg 575-OCH CH -H-CH2CH2CH3 OCs-OCH (CH3) Et-NHS02CH3 576 576-H-isobutyl-OCH2CH3-OCH (CH3) Et-NHS02CH3 577 -H-sec-butyl-OCH2CH3-OCH (CH3) Et-NHS02CHg 578 0, 0 -H-CH2CH2CH3-OCH2CH3-OCH2CH3 'J 579 00 579 CH2CH2CH3 OCH2CH3 OCH2Ph 0/sto -rC 580 00 -OCH2CH3-OCH2CH3- 581 00 -OCH2CH3-pCH2Ph- 582 00 -OCH2CH3-OCH2Ph 583.4so° -OCH2CH3-OCH2CH3 O o 584-H-n-Butyl-OCH2CH3-OCH2CH3 jS -No 585 ou 585-H-isobutyl-OCH2CH3-OCH2CH3 N\ 00 0 0 -H-sec-butyl-OCH2CH3-OCH2CH3 js -nez 587° -H-CH2CH2C1-OCH2CH3-OCH2CH3 js o o 5 8 -H-CHZCHZCHZCI-OCHzCH3-OCH2CH3 js -nu 589 589-H-CH2CH2CH3-OCH2CH3-OCH2CH3-NHSO2CH2CO2Et 590 _H-CH2CH2CH3-OCH2CH3--OCH2Ph-NHSO2CH2CO2Et

Compound2 R R10 R11 No. z R 591 -H-OCH2CH3-OCH2CH3-NHSO2CH2CO2H 592 -H-OCH2CH3--OCH2Ph-NHSO2CH2CO2Et 593 -H-OCH2CH3-OCH2Ph-NHS02CH2CO2H 594 -OCH CH -H-OCH2CH3H2CH3-NHSO2CH2CO2Et 595 -H-n-Butyl-OCH2CH3-OCHzCH3-NHSO2CH2CO2Et 596 596-H-propyl-OCH2CH3-OCH2CH3-NHS02CH2CO2H 597 -H-isobutyl-OCH2CH3-OCH2CH3-NHSO2CH2CO2Et 598 -H-sec-butyl-OCH2CH3-OCH2CH3-NHSO2CH2CO2Et 599 -H-CH2CH2C1-OCH2CH3-OCH2CH3-NHSO2CH2CO2Et 600 -H-CH2CH2CH2CI-OCH2CHg-OCH2CH3-NHSO2CH2CO2Et 601 601-H-CH2CH2CH3-OCH2CH3-OCH2CH3-N CH3SO2CH3 602 -H-CH2CH2CH3-OCH2CH3-OCH2Ph-N CH3S02CHg 603 -H \/-OCH2CH3-OCH2CH3-N CH3SO2CH3 604 -H < OCH2CH3 OCH2Ph-N CH3SO2CH3 605 -H-OCH2CH3-OCH2Ph-N CH3SO2CH3 606 _H-OCHZCH3-OCHZCH3-N CH3S02CHg 607 607-H-n-Butyl-OCH2CH3-OCH2CH3-N CH3SO2CH3 608 608-H-isopropyl-OCH2CH3-OCH2CH3-N CH3SO2CH3 609 609-H-isobutyl-OCH2CH3-OCH2CH3-N CH3SO2CH3 610 -H-sec-butyl-OCH2CH3-OCH2CH3-N CH3SO2CH3

Compound 2 1 9 10 11 Nu. 611 -H-CH2CH2C-OCHZCH3-OCH2CH3-N CHgS02CH3 612 -H-CH2CH2CH2CI-OCH2CH3-OCH2CH3-N CH3SO2CH3 613 -H-CH2CH2CH3-OCH2CH3-OCH2CH3-NHS02i-Pr 614 -H-CH2CH2CH3-OCH2CH3-OCH2Ph-NHS02i-Pr 615 -H-OCH2CH3-OCH2CH3-NHS02i-Pr 616 -H-OCH2CH3-OCH2Ph-NHS02i-Pr 617 -H \ I-OCH2CH3--OCH2Ph-NHS02i-Pr 618 -H-OCH2CH3-OCH2CH3-NHS02i-Pr 619 -H-n-Butyl-OCH2CH3-OCH2CH3-NHS02i-Pr 620 -H-isopropyl-OCH2CH3-OCH2CH3-NHS02i-Pr 621 -H-isobutyl-OCH2CH3-OCH2CH3-NHS02i-Pr 622 -H-sec-butyl-OCH2CH3-OCH2CH3-NHS02i-Pr 623 -H-CH2CH2CI-OCH2CH3-OCH2CH3-NHS02i-Pr 624 -H-CH2CH2CH2Ci-OCH2CH3-OCH2CH3-NHS02i-Pr 625 -H-CH2CH2CH3-OCH2CH3-OCH2CH3-NHS02Ph 626 -H-CH2CH2CH3-OCH2CH3-OCH2Ph-NHS02Ph 627 -H \/-OCH2CH3-OCH2CH3-NHS02Ph 628 -H \/-OCH2CH3-OCH2Ph-NHSO2Ph 629 -H \ I-OCHZCH3--pCH2Ph-NHS02Ph

Compound 2 1 9 10 11 Nô. 630 -H 4 OCH2CH3 OCH2CH3-NHSO2Ph 631 -H-n-Butyl-OCH2CH3-OCHzCH3-NHS02Ph 632 -H-isopropyl-OCH2CH3-OCH2CH3-NHS02Ph 633 633-H-isobutyl-OCH2CH3-OCH2CH3-NHS02Ph 634 -H-sec-butyl-OCH2CH3-OCH2CH3-NHS02Ph 635 635-H-CH2CH2CI-OCH2CH3-OCH2CH3-NHS02Ph 636 636-H-CH2CH2CH2CI-OCH2CH3-OCH2CH3-NHS02Ph 637zon -H-CHZCHZCH3-OCH2CH3-OCHzCH3-Nrso z 0 CH3 638.. _H-CHZCHzCH3-OCN2CH3-OCHZPh -NHSO--) -0 CH3 639 M 639 N+, -OCH2CH3-OCH2CH3-Nrso z CH CHg 640 -OCH2CH3-OCH2Ph CHg S 641 N -OCHZCH3-OCHzPh N°z\ CH3 CH3 642 -OCHzCH3-OCHZCH3-Nrsoz 643 643 643 -H-n-Butyl-OCHzCH3-OCHZCH3-Nsoz /o CH3 644 -H-isopropyl-OCH2CH3-OCH2CH3-Nso2 \-'o CH3 645 Nw -H-isobutyl-OCH2CH3-OCH2CH3-N-so2 po CH3 646 -H-sec-butyl-OCHZCH3-OCHZCH3-Ni so z zozo CHj

9 R10 R11Compound Z2 R1 Rg R R11 Nô. 647 -H-CH2CHZCl-OCHZCH3-OCH2CH3-Nrso2 zozo CH3 cl3 648-H-CH2CH2CH3-OCH2CH3-OCH2CH3-NHSO \ N 649 LJ 649 649-H CH2CH2CH3 OCH2CH3 OCH2Ph NHSO2tN z 650 -H \0/2CH3-OCH2CH3 651 -OCH2CH3-OCHzPh-NHSOzN 652 -OCH2CH3-OCH2Ph-NHSOz N z 653 -OCH2CH3-OCH2CH3-NHSOZN 654 -H-n-Butyl-OCH2CH3-OCH2CH3 -NHS02-'N 655 655 -H-isopropyl-OCH2CH3-OCH2CH3-NHSOp 656 656-H-isobutyl OCH2CH3 OCH2CH3 NHSO2<N 657 657 -H-sec-butyl-OCH2CH3-OCH2CH3-NHSO 658 658-H-CH2CH2C1-OCHZCH3-OCH2CH3 -NHSOp, N 659 659 -H-CH2CH CH2CI-OCH2CH3-OCH2CH3 660 660 660-H-CH2cH2cH3-OCH2CH3-OCH2CH3-OCHMeCO2H 661 -H-CH2CH2CH3-OCH2CH3-OCH2Ph-OCHMeCO2H 662 -H \/-OCH2CH3-OCH2CH3-OCHMeC02H 663 -H-OCH2CH3-OCH2Ph-OCHMeCO2H

Compound 2 1 9 10 11 Nu 664 -H-OCH2CH3-pCH2Ph-OCHMeCO2H 665 s -H-OCH2CH3-OCH2CH3-OCHMeCO2H 666 -H-n-Butyl-OCH2CH3-OCH2CH3-OCHMeCO2H 667 -H-isopropyl-OCH2CH3-OCH2CH3-OCHMeCO2H 668 -H-isobutyl-OCH2CH3-OCH2CH3-OCHMeCO2H 669 -H-sec-butyl-OCH2CH3-OCH2CH3-OCHMeCO2H 670 -H-CH2CH2CI-OCH2CH3-OCH2CH3-OCHMeCO2H 671 -H-CH2CH2 CH2CI-OCH2CH3-OCH2CH3-OCHMeCO2H 672 -H-CH2CH2CH3-OCH2CH3-OCH2CH3-NHS02CH3 673 -H \/-OCHzCH3-OCH2CH3-NHS02CH3 674 -H/-OCHZCH3CHZPh-NHS02CHg 675 675 -H 4 OCH2CH3 OCH2Ph-NHSO2CH3 676 -H-OCH2CH3-OCH2CH3-NHS02CH3 677 -H-propyl-OCH2CH3-OH-NHS02CHg 678 -H-isopropyl-OCH2CH3-OCH2CH3-NHS02CH3 679 -H-tsobutyl-OCH2CH3-OCH2CH3-NHS02CHg 680 -H-sec-butyl-OCH2CH3-OCH2CH3-NHSO2CHg 681 -H-CH2CH2CI-OCH2CH3-OCH2CH3-NHS02CH3 682 -H-CH2CH2 CH2CI-OCH2CH3-OCH2CH3-NHS02CH3

Compound z p p9 0. 10 nil No. 683-OCH2CH3-CH2CH2CH3-OCH2CH3-H-H 684-OCH2CH3-CH2CH3-OCH2CH3-H-H 685-OCH2CH3-CH2CH2CH2CH3-OCH2CH3-H-H 686-OCH2CH3 <-OCH2CH3-H-H 687-OCH2CH3 C-OCH2CH3-H-H 688-OCH (CH3) 2-CH2CH2CH3-OCH2CH3-H-H 689-OCH (CH3) 2-CH2CH3-OCH2CH3-H-H 690-OCH (CH3) 2-CH2CH2CH2CH3-OCH2CH3-H-H 691-OCH (CH3) 2 < H / S 692-OCH (CH3) 2-OCH2CH3-H-H 693 N \y-OCHzCHs-H-H 694-CH2CH2CH3-OCH2CH3-H-H H2 Ho 695-H C X NH2-OCH2CH3-OCH2CH3-N-S- H2 CH3 6 696-H C X NH2-OCH2CH3-OCH2CH3-\N-Os _ H2 CH3 6 H 0 C02H H n CH 697-H H CHs-OCH2CH3-OCH2CH3-N-S | C3 0 H, 0 698-HC\/NHz-OCHZCH3-OCH2CH3 CH3 6

Compound z2 R R9 Rio R" No. S 699-H OCH2CH3-OCH2CH3-H O_j N-s °% s 700-H CH2CH2CH3-OCH2CH3-OCH2CH3 N OS/O 701-H-CH2CH3-OCHzCH3-OCH2CH3 O 6 702-H-CHzCH2CH2CH3-OCH2CH3-OCHZCH3 N--j"0 6 703-H 0 o 704-H 2CH3-OCH2CH3 N-_ 6 705-H-CH2CH2CONHz-OCH2CH3-OCH2CH3-N- 6 706-H-CH2CHzCH20H-OCHzCHs-OCHzCHs-N 6 707-H H 2CH3-OCH2CH3 N-s- H O 708-H-H-OCH2CH3-OCHzCH3-N- 6 709-H-OCH2CH3-OCH2CH3-N-,, HO / 710-H _N/t3-OCH2CH3-OCH2CH3 NS H O 711 _H-HCOzH-OCHzCH3-OCHZCH3 N-l' 712-H-N'\-OCH2CH3-OCHZCH3 "6 713-H N-OCH2CH3-OCH2CH3 N'°S 6 s- -N-OCH-OCH-H 0 o 715-H N-OCH2CH3-OCH2CH3 NS 6

Compound z2 R1 R9 No. CH2NH2 H 0 716-H <-OCH2CH3-OCH2CH3 N-S- 6 717-H 4 NH2-OCH2CH3-OCH2CH3-N-S- 6 NH2 OCH2CH3-OCH2CH3-N-11 O NHz 719-H-H-OCH2CH3-OCH2CH3 N S 6 H p COZH -OCH2CH3-OCH2CH3-N H O /-OCHZCH3-OCHZCH3-N O2H 721-H H H COOH H 0 CCH 722-H H-OCH2CH3-NH o JCO2H H 6 COOH 723-H-HCOzH-OCHZCH3-OCHZCH3 N 6 ! Q COH 724-H-N-\-OCHzCH3-OCHZCH3-NSJ H 6 CCH 725-H-N-OCH2CH3-OCHzCH3- ö H 0 CO2H 726-H \-OCH2CH3-OCH2CH3 N Õ 6 COOH -OCHzCH3-OCH2CH3 6 /CH2NH2 H O CO2H 728-H <-OCH2CH3-OCH2CH3 N-S X 6 CCH 729-H 0 C02H 729-H NH2 6 COzH 730-H CH3-OCH2CH3-H 0 C02H - 6

The compounds of the invention contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses described above may employ racemates, diastereomers or enantiomers as starting materials or as intermediates.

Diastereomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated using the same techniques or others known in the art. Each of the asymmetric carbon atoms may be in the R or S configuration and both of these configurations are within the scope of the invention.

UTILITY It has been discovered that the compounds of the invention when made and selected as disclosed herein are inhibitors of serine protease enzymes, for example, factor VIIa, TF/factor VIIa, factor Xa, kallikrein and/or thrombin. These compounds are capable of inhibiting the catalytic activity of these enzymes and as such function to inhibit the coagulation cascade and prevent or limit coagulation and/or the formation of thrombi or emboli in blood vessels and/or increase the time of coagulation of blood. The compounds of the present invention, therefore, inhibit the ability of TF/factor VIIa to convert factor X to factor Xa, inhibit the ability of factor Xa to convert prothrombin to thrombin (factor IIa); and/or the ability of thrombin to convert fibrinogen to fibrin monomers.

The selectivity of the compounds of the invention as inhibitors of these enzymes can be determined using Ki values as described in the examples below. Representative selectivities are shown in the tables below. RI X R9 RIO Z2 RII Ki (TFVIIa) uM Ph C=O OEt OiPr H H 0.003 Pr CH2 OEt OCH2Ph H NHS02Me 0.004 Ph C=O OEt OEt H H 0.005 Ph C=O OEt H OEt H 0. 007 RI x R9 RIO Z2 RII Ki (IIa) uM Ph CH2 OMe OCH (CH2Cl) Ph H H 0.001 2-thiophene CH2 OMe OCH2Ph H H 0. 016 Ph C=O OEt OiPr H H 0. 113 Pr CH2 OMe OCH (CH2Cl) Ph Ho0. 001 RI x R9 RIO Z2 RII Ki (Kallikrein) uM Pr CH2 OEt OiBu H NHS02Pr 0.001 Pr CH2 OEt OiPr H NHS02Me 0. 001 Et C=O OEt OiPr H H 0.011 PhC=O OEt OEt H H 0.002

R1 X R9 R10 Z2 R11 Ki(Xa) uM Et C=O OEt OiPr H H 0.565 Bu C=O OEt OiPr H H 0.624 Ph C=O OEt OiPr H H 0.898 Pr CH2 OMe OCH (CH2Cl) Ph H H 0. 140 The anti-coagulant activity of the compounds of the invention can be tested using assays.

Prothrombin time (PT) and activated partial thromboplastin time (APTT) clotting time assays can be performed in pooled normal plasmas (human or various animal species) following addition of increasing concentrations of inhibitors to the plasma. Clotting times are determined using an ACL 300 Automated Coagulation Analyzer (Coulter Corp., Miami, FL) and commercially available reagents as follows.

PT assay: Aqueous solutions of inhibitor at various concentrations are added to pooled normal plasma in a ratio of 1 part inhibitor to 9 parts plasma. These mixtures are then added to the analyzer's sample cups. Innovin (Dade International Inc., Miami, FL), a mixture of human relipidated tissue factor and Ca++ ions is added to the reagent cup. Precise volumes of sample and Innovin are automatically transferred to cells of an acrylic rotor that is pre-equilibrated to 37C. Following a 2 minute incubation period, coagulation is initiated when the two components are mixed together by centrifugation. Coagulation is monitored optically and clotting time is reported in seconds. In agreement with Janson et al. (Janson, T. L., et al., 1984, Haemostasis 14: 440-444) relipidated human tissue factor is a potent initiator of coagulation in all species tested. In this system, the clotting time of control plasmas (plasma plus inhibitor diluent) is typically 8 to 10 seconds. A curve is fit to the clotting time versus inhibitor concentration data and the concentration at which the PT is doubled compared to control plasma is determined for each inhibitor.

APTT assay: Inhibitor and plasma are mixed together and transferred to the ACL 300 sample cups as described above. Actin FSX and CaC12 (Dade International Inc., Miami, FL), are added to reagent cups I and 2 respectively. Precise volumes of sample and activator (Actin Fus@) are automatically transferred to cells of a pre-equilibrated rotor (37C) and mixed by centrifugation. Following a 2 minute activation period, coagulation is initiated by the addition of CaC12. Coagulation is monitored and data calculated as described in the PT method. APTT of plasma controls is typically 12 to 32 seconds, depending on the species of plasma used in the assay.

Representative PT and APTT assay results are shown in Table 3 below.

Table 3 Compound No. 2 x PT (pM) 2 x APTT (M) 7 14 8 13 16 57 33 5. 5 72 30 60 589 22 40 596 8 140 628 125 90 672 34 78

The compounds of the invention are useful as diagnostic reagents in vitro for inhibiting clotting in blood drawing tubes. The use of stoppered test tubes having a vacuum therein as a means to draw blood is well known. Kasten, B. L.,"Specimen Collection", Laboratory Test Handbook, 2nd Ed., Lexi-Comp Inc., Cleveland, PP 16-17, Eds. Jacobs, D. S. et al, 1990. Such vacuum tubes may be free of clot-inhibiting additives, in which case, they are useful for the isolation of mammalian serum from the blood. They may also contain clot-inhibiting additives, such as heparin salts, citrate salts or oxalate salts, in which case they are useful for the isolation of mammalian plasma from the blood. The compounds of the invention may be incorporated into blood collection tubes and function to inhibit TF/factor Vlla, factor Xa, thrombin and/or kallikrein and to prevent clotting of the mammalian blood drawn into the tubes.

When used in blood collection tubes, the compounds of the invention may be used alone, as mixtures or in combination with other clotting inhibiting compounds known in this art. The amount of the compound of the invention should be an amount sufficient to prevent or inhibit the formation of a clot when blood is drawn into the tube. These compounds may be introduced into the tubes in the same manner as known clot-inhibiting compounds such as heparin salts. Liquids are usually lyophilized using known methods. Typically, the tubes will contain about 2 to about 10 ml of mammalian blood and the compounds are added in an amount sufficient to prevent coagulation of this amount of blood. A suitable concentration is about 10-1000 nM.

These compounds also inhibit the formation of emboli and thrombi in the circulatory system in mammals and therefore are useful in vivo. Thromboembolic disorders have been shown to be directly related to the susceptibility of the mammal to formation of emboli and thrombi. For example, the formation of a thrombus in a veinous vessel results in thrombophlebitis, which is typically treated with rest and the administration of anticoagulants. Other conditions which can be treated with the anticoagulant compounds of the invention include, thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangiitis, and thromboarteritis.

Mammals exposed to medical procedures such as angioplasty and thrombolytic therapy are particularly susceptible to thrombus formation. The compounds of the present invention can be used to inhibit thrombus formation following angioplasty. They may also be used in combination with antithrombolytic agents such as tissue plasminogen activator and its derivatives (US patents 4,752,603;

4,766,075; 4,777,043; EP 199 574; EP 238 304; EP 228 862; EP 297 860; PCT W089/04368; PCT W089/00197), streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial reocclusion following thrombolytic therapy. When used in combination with the above thrombolytic agents, the compounds of the present invention may be administered prior to, simultaneously with, or subsequent to the antithrombolytic agent.

Mammals exposed to renal dialysis, blood oxygenation, cardiac catheterization and similar medical procedures as well as mammals fitted with certain prosthetic devices are also susceptible to thromboembolic disorders. Physiologic conditions, with or without known cause may also lead to thromboembolic disorders.

Thus, the compounds described herein may be useful in treating thromboembolic disorders in mammals. The compounds described herein may also be used as adjuncts to anticoagulant therapy, for example in combination with aspirin, heparin or warfarin and other anticoagulant agents. The various coagulation disorders described above are treated with the compounds of the invention in such a fashion as to prevent bleeding as a result of the disorder. The application of the compounds described herein for these and related disorders will be apparent to those skilled in the art.

Compounds of this invention are also useful as intermediates generally, or as precursors of coagulation serine protease inhibitors and thus in addition to treating cardiovascular disease, these compounds may be usefully employed in metastatic disease, or for any disease where inhibition of coagulation is indicated.

Typically, the inhibitors used in the method of this invention is formulated by mixing it at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i. e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment.

The inhibitory compound for use herein is preferably sterile. The compound ordinarily will be stored as a solid composition, although lyophilized formulations or aqueous solutions are acceptable.

The composition of the invention will be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The"therapeutically effective amount"of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the coagulation factor mediated disorder. Such amount is preferably below the amount that is toxic to the host or renders the host significantly more susceptible to bleeding.

As a general proposition, the initial pharmaceutically effective amount of the inhibitor administered parenterally per dose will be in the range of about 0.01-100 mg/kg, preferably about 0.1 to 20

mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.

The compound of the invention is administered by any suitable means, including oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, if desired for local immunosuppressive treatment, intralesional administration (including perfusing or otherwise contacting the graft with the inhibitor before transplantation). Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. All patent and literature citations are herein incorporated by reference in their entirety.

EXAMPLES The compounds of the invention can be prepared generally by the reaction scheme shown below.

Compounds other than the specific product shown are prepared as described above using corresponding starting materials. For example, additional compounds can be prepared by using different starting styrene compounds, which are readily prepared from commercially available starting compounds and standard reactions which are well known in this art. 0 OH H I I Ny 1) MCPBA 0 CN S Ç T F S B CH H2NNH2 Q//2) LiClO a THF PPh3 H2NNH, Con COOH CON COOH L qui R top R CI--SI I 1) H NOH-NEf3 I \ 0 NH NH NE 2) H DC D- t Hui0 v w \ w Con Example1 4-benzyloxy-3-methoxy-styrene (lOg, 42 mmoles) was dissolved in dichloromethane (400 ml).

Solid potassium bicarbonate (I Ig, 110 mmoles) was added and the reaction cooled to zero degrees Celsius.

Meta-chloroperbenzoic acid (12g, ca. 42 mmoles) was added and the reaction allowed to warm to room temperature and stirred for 16 hours. The reaction was monitored by thin-layer chromatography. An additional amount of meta-chloroperbenzoic acid (4g) was added and the reaction stirred for an additional 4 hours to completely consume starting material. The reaction was poured into a separtory funnel and washed first with water, then with sodium bicarbonate and finally with NaOH. The organic layer was separated and dried over anhydrous sodium sulfate. The solution was filtered and the solvent removed in vacuo to yield approximately 11 g of crude product.

The crude product was then dissolved in acetonitrile (60 ml) and lithium perchlorate (8.5 g, 80 mmoles) added. The suspension was stirred for five minutes at which time the reaction became homogeneous. 4-amino-benzonitrile (9.5 g, 80 mmoles) was added and the reaction heated to 60 degrees C for 12 hours. Thin layer chromatography showed the presence of a new product at lower Rf. The solvent was removed in vacuo and the residue taken up in ethyl acetate, washed with water an dried over anhydrous sodium sulfate. The crude product was then submitted to flash chromatography (hexanes: ethyl acetate 1: 1) to yield 6 grams of 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2-hydroxy-ethylamino]-benzoni trile A.

IHNMR (CDC13): 7.3-7.45, (m, 7H), 6.8 (m, 3 H), 6.5 (d, 2H), 5.18 (s, 2H), 4.42 (m, IH), 3.95 (dd, IH), 3.85 (s, 3H), 3.8 (dd, IH).

4- [I- (4-Benzyloxy-3-methoxy-phenyl)-2-hydroxy-ethylamino]-benzoni trile A (470 mg, 1.25 mmoles), phthalimide (1.47 g, 10 mmoles), and triphenylphosphine (787mg, 3 mmoles) were added to 40 ml of tetrahydrofuran. The mixture was stirred for 10 minutes and then cooled to zero degrees Celsius.

Diisopropylazodiacarboxylate (DIAD, 0.6 ml, 3 mmoles) was then added slowly. The reaction was allowed to stir 1 hour. TLC indicated new product. The solvent was removed in vacuo and the residue taken up in 50 ml of ethyl acetate. The solution was washed three times with 2N sodium hydroxide and twice with water.

The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue submitted to flash chromatography (hexanes: ethyl acetate, 1: 1) to yield 478 mg of product 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl)-ethylamino]- benzonitrile B (76% yield). IHNMR (CDC13): 7.85 (m, 2H,), 7.75 (m, 2H), 7.23-7.45 (m, 9H), 6.9 (m, 3H), 6.42 (d, 2H), 5.45 (d, 1 H), 5.15 (s, 2H), 4.62 (m, 1 H), 4.0 (m, 2H), 3.83 (s, 3H).

4- [I- (4-Benzyloxy-3-methoxy-phenyl)-2- (1, 3-dioxo- 1, 3-dihydro-isoindol-2-yl)-ethylamino]- benzonitrile B was then dissolved in ethanol (60 ml) and hydrazine hydrate (2 g) was added. The solution was heated to 60-70 degrees C for 1.5 hours. TLC showed reaction was complete. The suspension was filtered to remove by-product and the ethanol removed in vacuo. The residue was submitted to flash chromatography on silica gel (ethyl acetate: 2N NH3 in methanol, 9: 1) to yield 372 mg of 4- [2-Amino-1- (4- benzyloxy-3-methoxy-phenyl)-ethylamino]-benzonitrile D (100%).. IHNMR (CDCl3): 7.3-7.45 (m, 7H), 6. 32 (m, 3H), 6.5 (d, 2H), 5.52 (d, 1H), 4.3 (q, IH), 3.83 (s, 3H), 3.08 (m, 2H), 1.95 (s, 2H).

4- [2-Amino-1- (4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzonitrile D (300 mg, 0.8 mmoles) was dissolved in ethanol (3 mi) and hydroxylamine-hydrochloride (350 mg, 5 mmoles) and triethylamine (Iml, 5.7 mmoles) were added. The reaction was heated to 65-70 degrees C for 2 hours. The residue was taken up in ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and replaced with 4 ml methanol with 0.5 mi acetic acid.

Raney nickel (ca. 300 ul suspension in sodium hydroxide, Aldrich) was added and the reaction placed under a hydrogen atmosphere. The reaction was stirred vigorously for 3 hours, the catalyst filtered off and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel (ethyl acetate: acetone: methanol: ammonia, 2: 1: 1: 0.05) to yield 160 mgs of 4- [2-Amino-I- (4-benzyloxy-3-methoxy- phenyl)-ethylamino]-benzamidine E. MS (M+H) = 391. 0 iR NHZ NH O nu NH ClS02R0 NH Net3 d f H20 C f Hop0 H NH2 H NH2 HNNH, k HN-NH,

4- [2-Amino-1- (4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzamidine E (20 mg, 0.03 mmoles) was dissolved in acetonitrile (2 ml) containing triethylamine (17 ul, 0.12 mmoles) and water (0.3 ml). To this was added the desired sulfonyl chloride having a formula CISO2R (0.03 mmoles) and the reaction stirred for 4 hours. The solvent was removed in vacuo and the compounds purified by reverse-phase preparative HPLC (gradient acetonitrile/water with 0. 1 % trifluoroacetic acid) to yield the final product upon lyophilization.

Examples 2a-2dd Using an analogous procedure, other compounds of the invention were prepared, including: a) 4- [Benzenesulfonylamino-1- (4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzamidine: MS (M+H) = 531, b) N-t4- [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethylsulfamoyl]-phenyll- acetamide: MS (M+H) = 588, c) 4- [I- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-nitro-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 576, d) 4- [I- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-fluoro-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 549, e) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-fluoro-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 565, f) 4-1- (4-Benzyloxy-3-methoxy-phenyl)-2- (3-nitro-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 576, g) 4- [I- (4-Benzyloxy-3-methoxy-phenyl)-2- (2, 5-dichloro-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 599, h) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (2-bromo-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 609, 611, i) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-bromo-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 609, j) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-isopropyl-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 573,

k)4- [I- (4-Benzyloxy-3-methoxy-phenyl)-2-phenylmethanesulfonylamino- ethylamino]-benzamidine: MS (M+H) = 545, <BR> <BR> I) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carboxy-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 575, m) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (3-carboxy-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 575, n) 4- [I- (4-Benzyloxy-3-methoxy-phenyl)-2- (2, 4-dinitro-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 621, <BR> <BR> o) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (2,3,5,6-tetramethyl-benzenesulfonylamino)-ethylamino]- benzamidine: MS (M+H) = 587, p) 4- [I- (4-Benzyloxy-3-methoxy-phenyl)-2- (3, 5-dichloro-2-hydroxy-benzenesulfonylamino)-ethylamino]- benzamidine: MS (M+H) = 615, q) 4- [I- (4-Benzyloxy-3-methoxy-phenyl)-2- (3, 4-dimethoxy-benzenesulfonylamino)-ethylamino]- benzamidine: MS (M+H) = 591, r) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (thiophene-2-sulfonylamino)-ethylamino]-benzamidine: MS(M+H) = 537, s) N- {5- [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethylsulfamoyl]-4-methyl- thiazol-2-yl}-acetamide: MS (M+H) = 595, t) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (naphthalene-2-sulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 581, u) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (naphthalene-1-sulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 581, v) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (2-phenyl-ethenesulfonylamino)-ethylamino]-benzamidine: MS (M+H) = 557, <BR> <BR> w) 4- [I- (4-Benzyloxy-3-methoxy-phenyl)-2- (3-trifluoromethyl-benzenesulfonylamino)-ethylamino]- benzamidine: MS (M+H) = 599,

x) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- (2,3,4,5,6-pentafluoro-benzenesulfonylamino)-ethylamino]- benzamidine: MS (M+H) = 521, <BR> <BR> y) 4-[l-(4-Benzyloxy-3-methoxy-phenyl)-2-methanesulfonylamino-e thylamino]-benzamidine: MS (M+H) =469, <BR> <BR> z) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2-ethanesulfonylamino-ethylam ino]-benzamidine: MS (M+H) =483, aa) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2-propanesulfonylamino-ethyla mino]-benzamidine: MS (M+H) =497, bb) 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2-butanesu lfonylamino-ethylamino]-benzamidine: MS (M+H) =511, cc) [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethylsulfamoyl]-acetic acid ethyl ester MS (M+H) = 541, dd) [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethylsulfamoyl]-acetic acid.

Example 3 4- [1- (4-Benzyloxy-3-methoxy-phenyl)-2- ( 1, 3-dioxo-1, 3-dihydro-isoindol-2-yl)-ethylamino]- benzonitrile B (1.8g) was dissolved in a mixture of ethanol (50 ml), acetic acid (3ml), methanol (5ml), and ethyl acetate (5 ml). This solution was added to a Parr flask containing 10% Pd/C (500mg) and hydrogenated at 35 psi for 16 hours. The catalyst was removed by filtration through Celite and the solvent removed in vacuo to provide Ig of the product 4- [2- (1, 3-Dioxo-1, 3-dihydro-isoindol-2-yl)-1- (4-hydroxy-3- methoxy-phenyl)-ethylamino]-benzonitrile (68%).

4-[2-(1, 3-Dioxo-1, 3-dihydro-isoindol-2-yl)-1-(4-hydroxy-3-methoxy-phenyl)-ethy lamino]- benzonitrile (Ig, 2.43 mmoles) was dissolved in tetrahydrofuran (30ml) and triphenylphosphine (1.27 g, 4.84 mmoles), (S)-2-chloro-1-phenyl-ethanol (1.13 g, 7.26 mmoles) added. The reaction was cooled to 0 °C and diethylazodicarboxylate (0.842 g, 4.8 mmoles) added. The reaction temperature was allowed to come to room temperature and the reaction stirred for 2.5 hours. The solvent was removed in vacuo and the residue taken up in ethyl acetate, washed with 0.5 N sodium hydroxide several times, washed once with brine and dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes) to yield 1.1 g of 4- [I- [4- (2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitri le, (82%).

4- [1- [4- (2-Chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2- ( 1, 3-dioxo-1, 3-dihydro-isoindol-2-yl)- ethylamino]-benzonitrile (0.5 g) was dissolved in ethanol (40 ml) and hydrazine hydrate (0.14 g) added. The reaction was heated at 65 OC for 2 hours. The solvent was removed and replaced with ethyl acetate. The solution was washed twice with water and once with brine. The solution was dried over anhydrous sodium sulfate and the solvent removed in vacuo to yield 318 mg of desired amine 4- {2-Amino-1- [4- (2-chloro-1- phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-benzonitrile, (83%).

4- {2-Amino-I- [4- (2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-ben zonitrile, (O. lg, 0.237 mmoles) was dissolved in dichloromethane (6ml) and triethylamine (34 ul, 0.3 mmoles) added.

Phenyl sulfonylchloride (46 ul, 0.26 mmoles) was added and the reaction stirred for 90 minutes. The reaction was diluted with dichloromethane and washed once with sat. sodium bicarbonate and once with water. The solution was dried over sodium sulfate and the solvent removed in vacuo. The product was purified by silica gel to yield 100 mg of desired product N- [2- [4- (2-chloro-1-phenyl-ethoxy)-3-methoxy- phenyl]-2- (4-cyano-phenylamino)-ethyl]-benzenesulfonamide.

N- [2- [4- (2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2- (4-cyano-phenylamino)-ethyl]- benzenesulfonamide (100 mg 0.18 mmoles) was dissolved in ethanol (3ml) and hydroxylamine- hydrochloride (62 mg, 0.89 mmoles) added. To this was added triethylamine (90 mg, 0.89 mmoles) and later potassium carbonate (62 mg). The reaction was heated to 80 °C for 48 hours. The reaction was cooled and the solvent removed in vacuo. The residue was taken up in ethyl acetate and washed twice with water and once with brine. The solution was dried over sodium sulfate and the solvent removed. The crude intermediate was dissolved in methanol (4 ml) and a few drops of acetic acid added. Approximately 50-100 mg of Raney nickel suspended in sodium hydroxide (Aldrich) was added and the reaction placed under an atmosphere of hydrogen. The suspension was stirred vigorously for 8 hours, the catalyst filtered off and the solvent removed in vacuo. The crude product was purified by reverse-phase chromatography to yield 4-{2- benzenesulfonylamino-l- [4- (2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-ben zamidine (32 mg). MS (M+H) = 579.

Example 4 4- {2-propanesulfonylamino-1- [4- (2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}- benzamidine was prepared similarly to Example 2, except propanesulfonyl chloride was substitued for benzenesulfonyl chloride in the reaction with 4- {2-amino-1- [4- (2-chloro-1-phenyl-ethoxy)-3-methoxy- phenyl]-ethylamino}-benzonitrile. MS (M+H) = 545.

Example 5

4-Benzyloxy-5-methoxy-2-nitrobenzaldehyde (12.2 g 42 mmoles) and 4-aminobenzonitrile (5 g, 42 mmoles) were dissolved in methanol (165 ml) and stirred for two hours and then heated to 60°C for 30 minutes. The reaction was allowed to cool to room temperature and benzyl isonitrile (5 g. 42 mmoles) added. The reaction was cooled to 0°C and boron trifluoroetherate (16 ml, 126 mmoles) added dropwise over five minutes. The reaction was stirred at 0°C for 20 minutes and then allowed to come to room temperature and then stirred at ambient temperature for two hours. Water (4ml) was added and the mixture stirred at room temperature overnight. A yellow precipitate was evident the next morning and the solid filtered off. The solid was washed with methanol and air dried to yield 8 grams of the desired product. The solvent from the filtrate was removed in vacuo and replaced with ethyl acetate. The solution was washed with water and saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and the solvent removed. The crude material was submitted to flash chromatography (hexanes: ethyl acetate, 1: 1) to yield an additional 7 g of the desired product (4-Benzyloxy-5-methoxy-2-nitro-phenyl)- (4-cyano-phenylamino)-acetic acid methyl ester.

IHNMR (CDC13): 7.68 (s, IH), 7.4 (m, 7H), 7.0 (s, IH), 6.61 (d, 2H), 6.2 (s, IH), 5.2 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H).

(4-Benzyloxy-5-methoxy-2-nitro-phenyl)- (4-cyano-phenylamino)-acetic acid methyl ester (4.5 g, 10 mmole) was dissolved in dimethoxyethane and lithium borohydride (0.210 g, 10 mmole) added. The reaction was heated to reflux for three hours and cooled to room temperature. The reaction was quenched with water containing acetic acid and diluted with ethyl acetate. After transferring to a separatory funnel, the organic layer was washed with water several times. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed. The crude material was then submitted to flash chromatography to yield 3.1 g of 4- [I- (4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-hydroxy-ethylamino] -benzonitrile (74%). IHNMR (CDC13): 7.77 (s, lH), 7.3-7.5 (m, 7H), 7.15 (s, IH), 6.42 (d, 2H), 5.4 (bs, IH), 5.18 (dd AB syst., 2H), 4.15 (dd, 1H), 3.83 (s, 3H), 3.79-3.86 (dd, IH).

4- [1- (4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-hydroxy-ethylamino] -benzonitrile (3.1 g, 7.4 mmoles) was dissolved in tetrahydrofuran (120 ml) and triphenylphosphine (5.9 g, 22 mmoles) and phthalimide (5.4 g, 37 mmoles) added. The reaction was cooled to 0 C and diisopropylazadicarboxylate (DIAD, 4.6 g) added dropwise. The reaction was allowed to come to room temperature and stirred overnight. The solvent was removed in vacuo and replaced with ethyl acetate. The solution was washed with I N NaOH several times and dried over anhydrous sodium sulfate. Flash chromatography (hexanes: ethyl acetate, 1: 1) provided the desired material with some DIAD still present. The solid was washed several times with ethanol to yield 3.2 g of the desired phthalimide 4- [1- (4-Benzyloxy-5-methoxy-2- nitro-phenyl)-2- (1, 3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile (3.2g,). IHNMR (CDC13): 7.83 (m, 2H), 7.75 (m, 2H), 7. 37 (m, 7H), 6.91 (s, IH), 6.41 (d, 2H), 6.17 (d, IH), 5.65 (m, IH), 5.18 (s, 2H), 4.27 (m, 2H), 3.61 (s, 3H).

4- [1- (4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2- ( 1, 3-dioxo-1, 3-dihydro-isoindol-2-yl)- ethylamino]-benzonitrile (2.7g, 5 mmoles) was dissolved in ethanol (100 ml) and hydrazine hydrate (0.65 ml, 20 mmoles) added. The reaction was heated to 60 °C for 3 hours then at room temperature for 48 hours.

The solids that precipitated were filtered off and the residue submitted to flash chromatography to yield 4- [2- Amino-I- (4-benzyloxy-5-methoxy-2-nitro-phenyl)-ethylamino]-benzonitr ile (1.5 g). IHNMR (CDC13): 7.75 (s, lH), 7.3-7.5 (m, 7H), 7.05 (s, lH), 6.45 (d, 2H), 5.80 (bs, IH), 5. 32 (m, IH), 5.19 (s, 2H), 3.81 (s, 3H), 3.25 (dd, IH), 3.0 (dd, IH), 1.65 (bs, 2H).

4- [2-Amino-l- (4-benzyloxy-5-methoxy-2-nitro-phenyl)-ethylamino]-benzonitr ile (0.227 g, 0.66 mmoles) was dissolved in dichloromethane (4 ml) and triethylamine (0.14 ml, 1 mmoles). The reaction was cooled to OC and 1-propanesulfonyl chloride (0.085 mi, 0.75 mmoles). The reaction was stirred for 20 minutes and the product purified by flash chromatography (hexanes: ethyl acetate 1: 1) to yield 260 mg of desired product-propane-l-sulfonic acid [2- (4-benzyloxy-5-methoxy-2-nitro-phenyl)-2- (4-cyano- phenylamino)-ethyl]-amide. I HNMR (CDC13): 7.77 (s, IH), 7.3-7.5 (m, 7H), 7.12 (s, IH), 6.41 (d, 2H), 6.0 (d, IH), 5.3 (m, I H), 5.17 (dd, A-B, 2H), 4.75 (t, IH), 3.85 (s, 3H), 3.65 (m, IH), 3.5 (m, IH), 3.04 (m, 2H), 1.83 (m, 2H), 1.05 (t, 3H).

Propane-1-sulfonic acid [2- (4-benzyloxy-5-methoxy-2-nitro-phenyl)-2- (4-cyano-phenylamino)- ethyl]-amide (0.250 g) was dissolved in ethanol (10 ml) and added to Pt/C (5%). The reaction was placed under a hydrogen atmosphere and stirred vigorously for 3 hours. The catalyst was filtered off and the product chromatographed (hexanes: ethyl acetate 1: 2) to yield 133 mg of Propane-1-sulfonic acid [2- (2- amino-4-benzyloxy-5-methoxy-phenyl)-2- (4-cyano-phenylamino)-ethyl]-amide. IHNMR (CDC13): 7.3- 7.45 (m, 7H), 6.71 (s, IH), 6.52 (d, 2H), 6.3 (s, IH), 5. 33 (2, IH), 5.08 (s, 2H), 5.0 (t, IH), 4.42 (q, IH), 3.75 (s, 3H), 3.70 (bs, 2H), 3.45 (t, 2H), 2.97 (m, 2H), 1.80 (m, 2H), 1.03 (t, 3H).

Propane-I-sulfonic acid [2- (2-amino-4-benzyloxy-5-methoxy-phenyl)-2- (4-cyano-phenylamino)- ethyl]-amide (133 mg, 0.27 mmoles) was dissolved in dichloromethane and triethylamine added (0.05 ml, 0.35 mmoles). The reaction was cooled and methanesulfonyl chloride (0.023 ml, 0.3 mmoles) added dropwise. The reaction was stirred for two hours and the product purified by flash chromatography (hexanes: ethyl acetate, 1: 1). The product was then taken-up in ethanol and hydroxylamine hydrochloride (35 mg, 0.5 mmoles) added. Sodium ethoxide (48 mg, 0.7 mmoles was added and the reaction heated for 48 hours. The ethanol was removed and water (4 ml) added. The solid was filtered off and washed with water.

The crude product was then taken up in 4 ml of methanol with 0.5 ml acetic acid. Raney Nickel (ca. 50 mg as a suspension in sodium hydroxide, Aldrich) was added and the reaction placed under a hydrogen atmosphere. The reaction was stirred vigorously for 3 hours and the catalyst filtered off. The crude product was submitted to reverse-phase preparative chromatography to yield the final product 4- [1- (4-Benzyloxy-2- methanesulfonylamino-5-methoxy-phenyl)-2-(propane-1-sulfonyl amino)-ethylamino]-benzamidine(propane-1-sulfonylamino)-ethy lamino]-benzamidine (12 mg): MS (M+H) =590.

Example 6a-6g Using a procedure analogous to Example 5, the following compounds were prepared: a) 4-[2-Benzenesulfonylamino-1-(2-benzenesulfonylamino-4-benzyl oxy-5-methoxy-phenyl)-ethylamino]- benzamidine. The procedure was the same as above except phenyl sulfonyl chloride was used instead of propanesulfonyl chloride and methane sulfonyl chloride. MS: (M+H) = 686. b) 4-[2-Benzenesulfonylamino-1-(2-benzenesulfonylamino-4-benzyl oxy-5-ethoxy-phenyl)-ethylamino]- benzamidine. The procedure was the same as above except starting with 3-ethoxy, 4-benzyloxy, 6-nitro- benzaldehyde. MS: (M+H) = 700. c) 4- [1- (4-Benzyloxy-5-ethoxy-2-methanesulfonylamino-phenyl)-2- (propane-1-sulfonylamino)-ethylamino]- benzamidine. The procedure was the same as above except starting with 3-ethoxy, 4-benzyloxy, 6-nitro- benzaldehyde. MS (M+H) = 604. d) 4- []- (4, 5-Diethoxy-2-methanesulfonylamino-phenyl)-2- (propane-I-sulfonylamino)-ethylamino]- benzamidine. The procedure was the same except starting with 3,4-diethoxy, 6-nitrobenzaldehyde. MS (M+H) = 542. e) {5-Benzyloxy-2- [1- (4-carbamimidoyl-phenylamino)-2- (propane-1-sulfonylamino)-ethyl]-4-methoxy- phenylsulfamoyl}-acetic acid ethyl ester. The procedure was the same except using chlorosulfonyl-acetic acid ethyl ester instead of methanesulfonyl chloride. MS: (M+H) = 676. <BR> <BR> f) {5-Benzyloxy-2- [1- (4-carbamimidoyl-phenylamino)-2- (propane-1-sulfonylamino)-ethyl]-4-methoxy- phenylsulfamoyl}-acetic acid. {5-Benzyloxy-2- [1- (4-carbamimidoyl-phenylamino)-2- (propane-I- sulfonylamino)-ethyl]-4-methoxy-phenylsulfamoyl}-acetic acid ethyl ester (10 mg) was dissolved in water (2

ml) and tetrahydrofuran (2moi) and LiOH added (3 mg). Allowed to stir overnight. Product purified by reverse-phase preparative HPLC. 3 mg MS (M+H) = 648. g) 4- [l-(3, 4-Dimethoxy-2-methanesulfonylam inophenyl)-2-(propane-1-sulfonylam ino)-ethylamino]- benzamidine. This compound was prepared with a similar procedure as described above except 2-bromo- 3,4-dimethoxybenzaldehyde was used instead of 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde. MS (M+H) = 499.

Examples7a-7g The compounds 7a-7g were generally prepared as follows. Compound E (20 mg, 0.03 mmoles) was dissolved in acetonitrile (2 ml) containing triethylamine (17 ul, 0.12 mmoles) and water (0.3 ml). To this was added the respective acyl chloride, alkyl chloroformate, or isocyanate (0.03 mmoles) and the reaction stirred for 4 hours. The solvent was removed in vacuo and the compounds purified by reverse-phase preparative HPLC (acetonitrile/water with 0. I % trifluoroacetic acid) to yield the final product upon lyophilization.

7a: N- [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethyl]-2,2,2-trifluoro- acetamide, MS (M+H) = 487.

7b: N- [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethyl]- acetamide, MS (M+H) = 433.

7c: N- [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethyl]- butyramide, MS (M+H)= 461.

7d: N- [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethyl]- 2-chloro-acetamide, MS (M+H) = 467.

7e: [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethyl]-carbonic acid methyl ester, MS (M+H) = 449.

7f : [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethyl]-carbonic acid isobutyl ester, MS (M+H) = 491.

7g: [2- (4-Benzyloxy-3-methoxy-phenyl)-2- (4-carbamimidoyl-phenylamino)-ethyl]-carbonic acid 2,2,2- trichloro-ethyl ester, MS (M+H) = 565 Example 8

The methyl ester of the acid shown above (920 mg 2.85 mmoles) was suspended in 3/1 THF/water (40 ml) and cooled to 0 °C. The solution was treated with 1 N LiOH (7.1 ml, 7.1 mmoles) and allowed to stir overnight. The reaction was acidified with trifluoroacetic acid until pH = 4.0 was obtained. The solvent was removed in vacuo and the crude material purified by flash chromatography (ethyl acetate with 0.5% acetic acid) to yield Ig of carboxylic acid.

Carbonyl diimidazole (131 mg, 0.8 mmoles) was dissolved in anhydrous THF (1.6 ml) and the carboxylic acid prepared above (251 mg, 0.8 mmoles) added dropwise as a solution in THF (1.6 ml). The reaction was allowed to stir at room temperature for 30 minutes, refluxed for 30 minutes and then cooled to room temperature again. n-Propylsulfonamide (100 mg) was added and stirred for 10 minutes. DBU (123 mg) was added as a solution in THF (1.6 ml). The reaction was worked up by acidification and extraction into ethyl acetate. The solvent was removed and the crude product purified by flash chromatography (Si02, ethyl acetate) to yield 195 mg of the acyl sulfonamide shown above.

The nitrile prepared above (90 mg, 0.2 mmoles) was dissolved in ethanol (2.5 ml).

Diisopropylethylamine (202 mg, 1.56 mmoles) was added followed by hyroxylamine hydrochloride (83 mg, 1.2 mmoles). The reaction was heated to 70 °C for 21 hours. The reaction was cooled and the solvent removed in vacuo. The residue was taken up in 30% acetonitrile/water (4 ml) and purified by preparative reverse-phase chromatography (water/acetonitrile 0.1% TFA gradient) to yield 14 mg of the hydroxyamidine shown above.

The hydroxyamidine product was then taken up in ethanol (2 mi) and acetic acid (8 drops). Raney Ni (ca. 100 mg) was added and the reaction stirred vigorously under a hydrogen atmosphere for 2 hours 45 minutes. The product was filtered through Celite and the Celite rinsed first with 30% acetonitrile/water containing 0.1% TFA and then with acetonitrile. The solvent was removed in vacuo and the crude product purified by preparative reverse-phase chromatography (water/acetonitrile 0.1% TFA gradient) to yield the desired product (6 mg). M+H = 435.

Example 9. Synthesis of enantiomerically pure 6-alkylsulfonylamino sulfonamides.

3-Ethoxy-4-hydroxybenzaldehyde (40 g) was added to dimethylformamide (600 mL) followed by potassium carbonate (40 g, 1.2 Equiv.). Ethyl iodide (28.87 mL, 1.5 Equiv.) was added and the solution was heated to 60 °C for six hours. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The solution was diluted with ethyl acetate (500 mL), and washed with water, brine, dried with magnesium sulfate, and evaporated to yield the crude product 3,4-ethoxybenzaldehyde (49 g, 104 %). The 3,4-ethoxybenzaldehyde (45 g) was dissolved in ethanol (300 mL), and the solution was cooled to 0 °C. In a separate flask, potassium hydroxide (19.5 g, 1.5 Equiv.) was added to ethanol (300 mL) followed by nitromethane (26 g, 1.5 Equiv.) and the solution was stirred at room temperature for ten minutes and cooled to 0 °C. This solution was added to the 3,4-ethoxybenzaldehyde and stirred for 20 minutes and poured onto concentrated hydrochloric acid (200 mL) at 0 °C. The ethanol was removed under reduced pressure, and the solution was diluted with water (300 mL) and the reaction mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate and the solvent removed to yield crude product. The crude product was purified by recrystallization with ethyl acetate (47 g, 87 %). MS (M + H) = 238.

The l-nitro-2- (3,4-diethoxyphenyl) ethylene (16.64 g) and 4-aminobenzonitrile (9.12 g, 1.1 Equiv.) were added to tetrahydrofuran (350 mL), and cooled to 0 °C. Lithium diisopropylamide (47.8 mL, 1.02 Equiv.) was added slowly until a persistent purple color was formed. Zinc (50 g) was added in one portion, followed by acetic acid (35 mL). The solution was warmed to room temperature and stirred for 2 hours followed by the addition of acetic acid (35 mL) and zinc (10 g). After an additional 2 hours, acetic acid (25mL) was added and the reaction mixture was stirred for one hour. Concentrated hydrochloric acid (15 mL) was added and the solution was stirred an additional hour. The solution was filtered through a pad of celite and water (250 mL) was added. The solution was concentrated to 300 mL under reduced pressure and added to citric acid (0.5 M, 500 mL) and ethyl acetate/hexane (500 mL). The citric acid layer was collected and ammonium hydroxide was added until the solution became basic. This solution was extracted with ethyl acetate (3 x 200 mL), and the combined organics were dried with magnesium sulfate, and evaporated under reduced pressure to yield the crude product. The crude product was diluted with dichloromethane (350 mL) and cooled to 0 °C. Phosgene (40.88 mL of a 20% solution in toluene, I. I Equiv.) was added followed by Hunigs base (24.46 mL, 2 Equiv.). The solution was stirred for ten minutes and water (200 mL) was added.

The dichloromethane was collected, dried with magnesium sulfate, and purified by flash chromatography on silica gel (80% ethyl acetate/20% hexane) to yield the product as a white solid (9.76 g, 40%). MS (M + H) =352.

The 4- [5- (3, 4-diethoxyphenyl)-2-oxo-imidazolidin-1-yl-benzonitrile (2.10 g) was added to tetrahydrofuran (200 mL) and cooled to-78 °C. n-Butyllithium (3.74 mL, I Equiv.) was added dropwise, and the solution stirred for ten minutes. (S)- (+)-2- (6-methoxy-2-naphthyl) propionyl chloride (1.49 g, 1 Equiv.)

was added in one portion as a solid and the reaction was stirred for one hour. The reaction mixture was warmed to room temperature, and evaporated under reduced pressure to 50 mL. The solution was diluted with ethyl acetate (300 mL), and washed with citric acid (0.5M), water, brine, and dried with magnesium sulfate. The solution was evaporated under reduced pressure and purified by flash chromatography on silica gel (50% ethyl acetate/50% hexane) to yield the product 4- {5- (3, 4-diethoxyphenyl)-3- [2- (6- methoxynaphthalen-2-yl)-propionyl]-2-oxo-imidazolidin-1-yl}- benzonitrile as one diastereomer (1.20g, 71%). This product was added to methanol (200 mL) followed by lithium hydroxide (1 mL of a 10% aqueous solution) and stirred for fifteen minutes. Acetic acid (10 drops was added, the methanol was removed under reduced pressure and the product was purified by flash chromatography on silica gel (80% <BR> <BR> <BR> ethyl acetate/20% hexane) to yield the product (0.71 g, 95%) as a white solid. [a] Na-55.0 (c 2.20, acetone).

MS (M + H) = 352.

The (R)- (-)-4- [5- (3, 4-diethoxyphenyl)-2-oxo-imidazolidin-1-yl-benzonitrile (0.710 g) was added to tetrahydrofuran (20 mL) and cooled to-78 °C. n-Butyllithium (1.27 mL of a 1.6 M solution in hexane, I Equiv.) was added dropwise and the solution was stirred for ten minutes. I-Propylsulfonylchloride (0.275 mL, 1.2 Equiv.) was added and the solution was stirred for fifteen minutes and warmed to room temperature.

Acetic acid (10 drops) was added, the solvent removed under reduced pressure, and the product was purified by flash chromatography on silica gel (50% ethyl acetate/50% hexane) to yield the product (0.740 g, 80%).

This material (0. 300 g) was diluted with dichloroethane (10 mL) and cooled to 0 °C. Nitric acid (0.137 mL, 5 Equiv.) was added dropwise and the solution was stirred for one hour. The solution was diluted with dichloroethane (100 mL), and washed with water, saturated sodium bicarbonate, dried with magnesium sulfate, and the solvent was evaporated under reduced pressure. This material was diluted with methanol (50 mL), and acetic acid (I mL), and platinum (0.050 g, 5% on carbon) was added. The solution was hydrogenated for one hour, filtered through a pad of celite, and the solvent was evaporated under reduced pressure. This material was dissolved in dichloromethane (5 mL), and Hunigs base (0.177 mL, 1.5 Equiv.) and chlorosulfonylacetic acid ethyl ester (0.189 g, 1.5 Equiv.) was added and the solution was stirred for two hours. The solution was purified by direct flash chromatography on silica gel (50% ethyl acetate/50% hexane) to yield the product (0.160 g) (R)- {2- [3- (4-cyanophenyl)-2-oxo-1- (propane-1-sulfonyl)- imidazolidin-4-yl]-4,5-diethoxyphenylsulfamoyl}-acetic acid ethyl ester. MS (M + H) = 624.

(R)- {2- [3- (4-cyanophenyl)-2-oxo-1- (propane-1-sulfonyl)-imidazolidin-4-yl]-4,5- diethoxyphenylsulfamoyl}-acetic acid ethyl ester (0.160 g) was diluted with ethanol (5 mL) followed by lithium hydroxide (1 mL of a 10% aqueous solution, 10 Equiv.) and the solution was stirred for forty eight hours. The solution was purified by direct flash chromatography on silica gel (20% methanol/80% dichloromethane) to yield the product. This product was diluted with ethanol (I mL) and hydroxylamine (0.035 g, 10 Equiv.) and Hunigs base (0.088 mL, 10 Equiv.) was added and the solution was heated to 60 °C for six hours. The reaction mixture was cooled to room temperature and stirred for twelve hours. Ethanol (3 mL) and acetic acid (0.5 mL), and Raney nickel (0.025g) was added and the solution was hydrogenated for one hour. The reaction mixture was filtered through a pad of celite and the solvent was removed under reduced pressure. The product was purified by reverse-phase preparative chromatography to yield {2- [I- (4- carbamimidoylphenylamino)-2- (propane-1-sulfonylamino)-ethyl]-4, 5-diethoxyphenylsulfamoyl} acetic acid (52mg). [a] Na-42.1 (c 1. O 1, methanol) MS (M + H) = 587.

Example 10. 6-alkoxysubstituted sulfonamides.

Aminoacetonitrile (14.25 g, 92.5 mmoles) was dissolved in 1,2-dichloroethane (150 ml) and the reaction was placed under N2. Triethylamine (32.76 g, 324 mmoles) was added and the reaction was cooled to zero degrees Celsius. A solution of propane-1-sulfonyl chloride (13.19 g, 92.5 mmoles) in 1,2- dichloroethane (20 ml) was added dropwise and the reaction was allowed to warm to room temperature and was stirred for 16 hours. Thin-layer chromatography showed the presence of a new product with a higher Rf.

The solvent was removed in vacuo and the crude product was submitted to flash chromatography (methylene chloride: ethyl acetate, 9: 1) to yield 10.56 g of propane-1-sulfonic acid cyanomethyl-amide. HNMR (CDC13): 5.40 (s, IH), 4.11 (s, 2H), 3.15 (m, 2H), 1.89 (q, 2H), 1.10 (t, 3H).

3-Ethoxy-4-hydroxy-benzaldehyde (Aldrich, 100 g, 0.602 mole) was dissolved in N, N- dimethylformamide (1 L). The reaction was placed under N2. Solid potassium carbonate (103 g, 0.662 moles) was added and the reaction was stirred 10 minutes. Iodoethane (175 g, 1.26 moles) was added and the reaction was stirred for 16 hours at room temperature. The reaction was monitored by thin-layer chromatography which indicated complete consumption of the phenol to give a new product. The reaction was filtered to remove the potassium carbonate and solvent removed in vacuo. The residue was dissolved in methylene chloride and filtered. Silica gel (200 g) was added and the dichloromethane removed in vacuo.

The crude product absorbed on silica gel was submitted to flash chromatography (hexane, 100%, 2L, then ethyl acetate: hexane, 1: 3,2L, then ethyl acetate: hexane, 1: 1) to yield 109.36 g of 3,4-diethoxy-benzaldehyde HNMR (CDC13): 9.83 (s, 1H), 7.41 (m, 2H), 6.96 (d, 1H), 4.17 (m, 4H), 1.50 (t, 3H) 1.47 (t, 3H).

3,4-Diethoxy-benzaldehyde (31.45 g, 0.162 moles) was dissolved in methylene chloride (500 ml).

3-Chloroperbenzoic acid was added and the reaction was heated to reflux for 4 hours. Thin-layer chromatography showed consumption of the aldehyde. The reaction was cooled to room temperature, diluted with methylene chloride and quenched with saturated aqueous potassium carbonate. The layers were separated and the aqueous solution extracted with methylene chloride. The methylene chloride extracts were combined, washed with water, brine, and dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to yield a crude oil.

The crude oil was dissolved in methanol (300 ml) and a solution of 10% aqueous KOH (60 ml) was added. The reaction was stirred at room temperature for 16 hours. Thin-layer chromatography showed consumption of the intermediate which had formed. The methanol was removed in vacuo and the aqueous solution was acidified with 1.2 N HCI. The solution was extracted with ethyl acetate. The ethyl acetate extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. The residue was submitted to flash chromatography (hexane: ethyl acetate, 3: 1) to yield 22.08 g of 3, 4-diethoxy-phenol.'HNMR (CDCl3): 6.56 (d, 1H), 6.25 (d, 1H), 6.10 (dd, 1H), 3.82 (m, 4H), 1.22 (t, 3H), 1.20 (t, 3H).

Nitrobenzene (100 ml) was cooled to zero degrees Celsius and saturated with HCl gas. To this solution was added of 3, 4-diethoxy-phenol (11.64 g, 64 mmoles), propane-I-sulfonic acid cyanomethyl- amide (10.36 g, 64 mmoles) and zinc chloride (17.45 g, 128 mmoles). The reaction was stirred for 1 hour at zero degrees Celsius and then allowed to warm to room temperature. Stirring was continued for 2 hours.

Thin-layer chromatography showed consumption of 3,4-diethoxy-phenol. Water (100 ml) was added cautiously and the reaction was heated to 100 degrees Celsius for I hour. The reaction was cooled, and extracted with methylene chloride. The extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was submitted to flash chromatography (2.5-5% ethyl acetate in methylene chloride). The purified product was triturated with ether, filtered and air dried to yield 17.3 g of propane-I-sulfonic acid [2- (4,5-diethoxy-2-hydroxy-phenyl)-2-oxo-ethyl]-amide.

'HNMR (CDCI3): 11.86 (s, IH), 6.93 (s, IH), 6.46 (s, IH), 5.26 (t, I H), 4.55 (d, 2H), 4.14 (q, 2H), 4.03 (q, 2H), 3.05 (m, 2H), 1.90 (m, 2H), 1.45 (m, 6H), 1.07 (t, 3H).

Propane-1-sulfonic acid [2- (4,5-diethoxy-2-hydroxy-phenyl)-2-oxo-ethyl]-amide (200 mg, 0.579 mmoles) was dissolved in tetrahydrofuran (5 ml), placed under N2, and cooled to zero degrees Celsius.

Borane: THF complex (1.74 ml, 1.0 M in THF, 1.74 mmoles) was added dropwise. The reaction was stirred 15 minutes and the allowed to warm to room temperature over 2 hours. Thin-layer chromatography showed consumption of starting material and formation of a new product with a lower Rf. The reaction was quenched in 1.2 N aqueous HCI (2.5 ml), diluted with water and extracted with ethyl acetate. The extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo to yield 190 mg of a crude oil.

The crude oil was dissolved in acetonitrile (5 ml). 4-Aminobenzonitrile (194 mg, 1.64 mmoles) and lithium perchlorate (233 mg, 2.19 mmoles) were added. The reaction was heated to 90 degrees Celsius for 3.5 hours then stirred at room temperature for 18 hours. Thin-layer chromatography showed the presence of

a new product with a higher Rf. versus the product from the reduction. The reaction was quenched in water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo. The residue was submitted to flash chromatography (ethyl acetate: methylene chloride, 1: 9) to yield 134 mg of propane-1-sulfonic acid [2- (4- cyano-phenylamino)-2- (4, 5-diethoxy-2-hydroxy-phenyl)-ethyl]-amide.'HNMR (CDCI,): 7.34 (d, 2H), 6.71 (s, IH), 6.61 (d, 2H), 6.41 (s, IH), 5.58 (d, IH), 4.79 (m, lH), 4.57 (m, IH), 3.99 (m, 4H), 3.48 (t, 2H), 3.00 (m, 2H), 1.80 (q, 2H), 1.41 (t, 3H), 1. 34 (t, 3H), 1.03 (t, 3H).

Propane-I-sulfonic acid [2- (4-cyano-phenylamino)-2- (4, 5-diethoxy-2-hydroxy-phenyl)-ethyl]- amide (100 mg, 0.223 mmoles) was dissolved in dimethylformamide (1.5 ml) and treated with solid potassim bicarbonate (22 mg, 0.223 mmoles) followed by ethyl bromoacetate (0. 37 ml, 0.223 mmoles). The reaction was stirred under N2 for 67 hours. Thin-layer chromatography showed presence of a new product with a <BR> <BR> <BR> higher Rf. The reaction was quenched in water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The residue was submitted to flash chromatography (ethyl acetate: methylene chloride 1: 9) to yield 78 mg of {2- [I- (4-cyano-phenylamino)-2- (propane-1-sulfonylamino)-ethyl]-4, 5-diethoxy-phenoxy}-acetic acid ethyl ester.'HNMR (CHC13): 7. 35 (d, 2H), 6.81 (s, 1H), 6.57 (d, 2H), 6.43 (s, 1H), 4.81 (t, 1H), 4.68 (ABq, 2H), 4.56 (t, IH), 4.26 (q, 2H), 4.05 (q, 2H), 3.95 (m, 2H), 3.54 (t, 2H), 2.98 (m, 2H) 1.80 (m, 2H) 1.42 (t, 3H), 1. 32 (t, 6H), 1.02 (t, 3H). MS (M + H): 534.

{2- [1- (cyano-phenylamino)-2- (propane-1-sulfonylamino)-ethyl]-4, 5-diethoxy-phenoxy}-acetic acid ethyl ester (76 mg, 0.142 mmoles) was dissolved in tetrahydrofuran (3 ml). Water (I ml) was added and the reaction was cooled to zero degrees Celsius. Aqueous LiOH (1.0 M, 0.42 ml, 0.42 mmol) was added to the reaction. After stirring for 5 minutes, the reaction was allowed to warm to room temperature and was stirred for 16 hours at room temperature. The disappearance of the ester was monitored by analytical high pressure liquid chromatography. Additional LiOH (1.0 M. 0.14 ml) was added. The reaction was stirred another 8 hours at room temperature. Consumption of the ester was not complete so freshly prepared LiOH (1.0 M, 0.14 ml), was added and the reaction stirred 24 hours. More LiOH (1.0 M, 0.28 ml) was added and after 67 hours, analytical RP HPLC showed consumption of the ester (total 1.0 M LiOH =0.98 mL, 6.9 equiv.). The reaction was acidified with acetic acid and the THF was allowed to evaporate under a stream of N,. The solution was clarified by addition of acetonitrile and then purified by preparative reverse-phase HPLC (gradient acetonitrile/water with 0.1% trifluoroacetic acid) to yield after lyophilization 44 mg of the mono- TFA salt of {2- [1- (cyano-phenylamino)-2- (propane-I-sulfonylamino)-ethyl]-4, 5-diethoxy-phenoxy}-acetic acid.'NMR (CD30D): 7.15 (d, 2H), 6.70 (s, 1H), 6.48 (d, 2H), 6.45 (s, 1H), 4.76 (t, 1H), 4.60 (s, 2H), 3.85 (q, 2H), 3.73 (m, 2H), 3.43 (dd, IH), 3.26 (dd, IH partially obscured by the CH30H solvent peak), 2.76 (m, 2H), 1.52 (m, 2H), 1.18 (t, 3H), 1.07 (t, 3H), 0.77 (t, 3H). MS (M + H): 506.

{2- [1- (cyano-phenylamino)-2- (propane-1-sulfonylamino)-ethyl]-4, 5-diethoxy-phenoxy}-acetic acid, mono-TFA salt form (44 mg, 0.071 mmoles) was dissolved in ethanol (I ml) and treated with diisopropylethylamine (0.89 ml, 0.515 mmoles) and solid hydroxylamine hydrochloride (25 mg, 0. 355 mmoles). The reaction was placed under N2 and heated to 60 degrees Celsius for 3 hours. Analytical high pressure liquid chromatography analysis after 3 hours revealed the reaction had not gone to completion. The reaction mixture was cooled to room temperature and stirred at room temperature for 16 hours and the progress of the conversion assessed by HPLC. The reaction mixture was heated at 60 degrees Celsius for 8 hours, stirred at room temperature for 16 hours, heated at 70 degrees for 8 hours and stirred at room temperature for 16 hours. HPLC showed consumption of starting material. The reaction was acidified with acetic acid, Raney nickel added and the reaction was hydrogenated at approximately 1 atm under a balloon of hydrogen for 3 hours. Analytical HPLC showed consumption of the hydroxy amidine intermediate. The Raney nickel catalyst was filtered and the solvent was removed in vacuo. The residue purified by preparative reverse-phase HPLC (gradient acetonitrile/water with 0.1% trifluoroacetic acid) to yield after lyophilization

5.6 mg of {2- [1- (carbamimidoyl-phenylamino)-2- (propane-1-sulfonylamino)-ethyl]-4, 5-diethoxy-phenoxy}- acetic acid, bis-TFA salt form. MS (M + H): 523.

Example 11.6-alkylsulfonyl-alkyl-amino substituted acylsulfonamide synthesis 4,5 diethoxy-2-nitrobenzaldehyde (55.5 g 206 mmoles) and 4-aminobenzonitrile (23 g, 195 mmoles) were dissolved in methanol (700 ml) and stirred at 60°C for 2 hours. The reaction was allowed to cool to 0 °C and tosylmethylisonitrile (45 g. 230 mmoles) added. Boron trifluoroetherate (78 ml, 620 mmoles) was added dropwise over 10 minutes. The reaction was stirred at 0°C for 30 minutes, allowed to come to room temperature and then stirred at ambient temperature for 1.5 hours. Water (18 ml) was added and the mixture stirred at room temperature overnight. The following day the methanol was removed in vacuo and the residue taken up in ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the ethyl acetate removed in vacuo.

The crude material was submitted to flash chromatography (hexanes: ethyl acetate, 2: 1 then 1: 1) to yield 46 g of the desired product (4-ethoxy-5-ethoxy-2-nitro-phenyl)- (4-cyano-phenylamino)-acetic acid methyl ester.

(4-ethoxy-5-ethoxy-2-nitro-phenyl)- (4-cyano-phenylamino)-acetic acid methyl ester (I Ig, 27.5 mmole) was dissolved in ethyl acetate (300m) and added to a flask containing 5% Pt/C (3 g) under a nitrogen atmosphere. The nitrogen was removed and replaced by hydrogen (balloon) and the reaction stirred vigorously for 6 hours. The catalyst was filtered off and the solvent removed in vacuo. The residue was taken up in dichloromethane (ca. 300 ml) and pyridine (5.6 ml, 70 mmole) added. The reaction was cooled to 0 °C and methanesulfonyl chloride (2.5 ml, 33 mmole) added dropwise. The reaction was stirred overnight. The solution was washed with water and the solvent removed in vacuo. The crude product was

chromatographed on silica using flash chromatography (Hexane: ethyl acetate 1: 1) to yield 5 g of desired material- (4-cyano-phenylamino)- [4, 5-diethoxy-2- (methanesulfonylamino)-phenyi]-acetic acid methyl ester.

The product from about (4-cyano-phenylamino)-4, 5-diethoxy-2-methanesulfonylamino-phenyl)-acetic acid methyl ester (5 g, 10.7 mmoles) was dissolved in dry DMF (100 ml) and cesium carbonate (7.25 g, 22 mmoles) and iodomethane (1 ml, 16 mmoles) added. The reaction was stirred at room temperature for 3 hours and the solvent removed in vacuo. The residue was taken up in ethyl acetate, acidified with IN hydrochloric acid and the organic layer washed once with water. The material was dried over anhydrous sodium sulfate and the solvent removed in vacuo. The residue was flash chromatographed (hexane: ethyl acetate, 1: 1) to yield 2.6 g of desired material- (4-cyano-phenylamino)- [4, 5-diethoxy-2- (methanesulfonyl- methyl-amino)-phenyl]-acetic acid methyl ester.

The (4-cyano-phenylamino)-4,5-diethoxy-2-methanesulfonyl-methyl- amino-phenyl)-acetic acid methyl ester obtained above (2.6 g, 5 mmole) was dissolved in methanol. 1 N LiOH was added (25 ml) and the reaction stirred at room temperature for 5 hours. The methanol was removed in vacuo and the reaction was acidified with 1 N hydrochloric acid. The product was extracted into ethyl acetate and washed with water. Flash chromatography (Ethyl acetate with 5% acetic acid) yielded 1.9 g the desired acid- (4-cyano- phenylamino)- [4, 5-diethoxy-2- (methanesulfonyl-methyl-amino)-phenyl]-acetic acid.

The (4-cyano-phenylamino)-4,5-diethoxy-2-methanesulfonyl-methyl- amino-phenyl)-acetic acid obtained above (350 mg, 0.75 mmole) was combined with carbonyl diimidazole (610 mg, 3.77 mmole) in dry THF (6 ml). The reaction was heated at 60 °C for I hour and cooled to room temperature. To this solution was added phenylsulfonamide (650 mg, 4.14 mmole) and DBU (5 mmole) as a solution in 5 ml THF. The reaction was stirred for 3 hours and the THF removed in vacuo. The residue was taken up in ethyl acetate and acidified with I N hydrochloric acid. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography (Hexanes: ethyl acetate 1: 1 then ethyl acetate with 5% acetic acid) to yield 302 mg of desired product-N- { (4-cyano-phenylamino)- [4, 5-diethoxy-2- (methanesulfonyl-methyl-amino)-phenyl]- acetyl} benzenesulfonamide.

The N- { (4-cyano-phenylamino)- [4, 5-diethoxy-2- (methanesulfonyl-methyl-amino)-phenyl]- acetyl} benzenesulfonamide obtained above (126 mg, 0.21 mmole) was dissolved in ethanol (1.8 ml) and heated to 60 °C. Diisopropylethylamine (DIPEA-260 ul, 1.5 mmole) was added followed by hydroxylamine-hydrochloride (74 mg, 1.04 mmole). The reaction was stirred at 60 °C under a nitrogen atmosphere for 6 hours. The reaction was then allowed to cool to room temperature. The solution was diluted with methanol (5 ml) and acetic acid (2 ml) and Raney Nickel 2800 (ca. 50 mg) added as a suspension. The reaction was then stirred vigorously under a hydrogen atmosphere for 1 hour. The catalyst was filtered off and the solvent removed. The crude product was purified by preparative reverse-phase HPLC using a water-acetonitrile (0.1% TFA) gradient to yield 40 mg of desired 4-{2-benzenesulfonylamino- 1- [4, 5-diethoxy-2- (methanesulfonyl-methyl-amino)-phenyl]-2-oxo-ethylamino} benzamidine as its trifluoroacetic acid salt. MS: (M+H) = 604.

Example 12.

4-isopropoxy-5-ethoxy-benzaldehyde (10.6 g 50 mmoles) and 4-aminobenzonitrile (5.9 g, 50 mmoles) were dissolved in methanol (150 ml) and stirred at 60°C for 1.6 hours. The reaction was allowed to cool to 0 °C and tosylmethylisonitrile (9.75 g. 50 mmoles) added. Boron trifluoroetherate (19 ml, 150 mmoles) was added dropwise over 10 minutes. The reaction was stirred at 0°C for 30 minutes, allowed to come to room temperature and then stirred at ambient temperature for 1.5 hours. Water (4.5 ml) was added and the mixture stirred at room temperature 2 days. The methanol was removed in vacuo and the residue taken up in ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the ethyl acetate removed in vacuo. The crude material was submitted to flash chromatography (hexanes: ethyl acetate, 1: 1) to yield 12.5 g of the desired product (4- isopropoxy-5-ethoxy-phenyl)- (4-cyano-phenylamino)-acetic acid methyl ester.

The product from above, (4-isopropoxy-5-ethoxy-phenyl)- (4-cyano-phenylamino)-acetic acid methyl ester, (6 g, 16.3 mmole) was treated with I N LiOH (ca. 50 ml) in THF (ca. 150 ml). The reaction was stirred at room temperature for 6 hours and acidified with 1 N hydrochloric acid. The THF was removed in vacuo and the product extracted into ethyl acetate. The crude material was purified by reverse phase chromatography (ethyl acetate 3% acetic acid) to yield 4.85 g of desired acid- (4-isopropoxy-5-ethoxy- phenyl)- (4-cyano-phenylamino)-acetic acid.

The (4-isopropoxy-5-ethoxy-phenyl)- (4-cyano-phenylamino)-acetic acid obtained above (200 mg, 0.57 mmole) was combined with carbonyl diimidazole (200 mg, 1.2 mmole) in dry THF (4 ml). The reaction was allowed to stir at room temperature for 1 hour. To this solution was added the corresponding alkyl or arylsulfonamide (2.2 mmole) and DBU (2.2 mmole) as a solution in 3 ml THF. The reaction was stirred overnight and the THF removed in vacuo. The residue was taken up in ethyl acetate and acidified with acetic acid. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography (Hexanes: ethyl acetate 1: 2) to yield desired product-N- { (4-cyano-phenylamino)- [4 isopropoxyl, 5-ethoxy-phenyl]-acetyl} (alkyl or aryl) sulfonamide.

The N-1 (4-cyano-phenylamino)- [4 isopropoxyl-5-ethoxy-phenyl]-acetyll (alkyl or aryl) sulfonamide obtained above (ca. 0.24 mmole) was dissolved in ethanol (1-3 ml) and heated to 60 °C.

Diisopropylethylamine (DIPEA-260 ul, 1.5 mmole, 6 eq.) was added followed by hydroxylamine- hydrochloride (84 mg, 1.25 mmole, 5 eq.). The reaction was stirred at 60 °C under a nitrogen atmosphere for ca. 6 hours. The reaction was then allowed to cool to room temperature. The solution was diluted with methanol (5 ml) and acetic acid (2 ml) and Raney Nickel 2800 (ca. 50 mg) added as a suspension. The reaction was then stirred vigorously under a hydrogen atmosphere for 1-6 hours. The catalyst was filtered off and the solvent removed. The crude products were purified by preparative reverse-phase HPLC using a water-acetonitrile (0.1% TFA) gradient or by flash chromatography (ethyl acetate: acetone: water: acetic acid, 6: 2: 1: 1) to yield the desired 4- {2- (alkyl or aryl) sulfonylamino-1- [4-isopropoxy, 5-ethoxy)-phenyl]-2-oxo- ethylamino} benzamidine as its trifluoroacetic acid or acetic acid salt.

Using an analogous procedure, the following compounds having different Rl groups were prepared:

R = ethyl: 4- {2-ethylsulfonylamino-I- [4-isopropoxy, 5-ethoxy)-phenyl]-2-oxo-ethylamino} benzamidine: MS (M+H) = 463.

Rl = n-propyl: 4- {2-propylsulfonylamino-I- [4-isopropoxy, 5-ethoxy)-phenyl]-2-oxo- ethylamino} benzamidine: MS (M+H) = 477.

Rl = n-butyl: 4- {2-butylsulfonylamino-1- [4-isopropoxy, 5-ethoxy)-phenyl]-2-oxo-ethylamino} benzamidine: MS (M+H) = 491.

R = CH2CH2CO2Me: 3- [ (4-carbamimidoyl-phenylamino)- (3-ethoxy-4-isopropoxy-phenyl)- acetylsufamoyl]-propionic acid methyl ester: MS (M+H) = 521.

RI = phenyl: 4- {2-benzenesulfonylamino-1- [4-isopropoxy, 5-ethoxy)-phenyl]-2-oxo- ethylamino} benzamidine: MS (M+H) = 511.

Example 13. Acylsulfonamide with substitution on the aminobenzamidine ring 2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF (200 ml). Potassium carbonate (11 g. 80 mmole) and benzyl bromide (9 ml, 75 mmole) were added. The reaction was stirred at room temperature overnight. The DMF was removed in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated, washed with I N NaOH, then with water, and dried over sodium sulfate. The crude product (5 g) was dissolved in ethyl acetate (75 ml) and added to a flask containing 5% Pt/C (500 mg). The reaction was placed under a hydrogen atmosphere (balloon) and stirred vigorously for several hours until the reaction was done (TLC). The catalyst was filtered off and the solvent removed. The product was purified by flash chromatography to yield 4.12 g of 4-amino, 2-benzyloxybenzonitrile.

4,5-diethoxy-benzaldehyde (3.6 g, 17.8 mmole) and 4-amino-2-benzyloxybenzonitrile (3.7 g, 17.8 mmole) were dissolved in methanol (40 ml) and stirred for 2 hours. Tosylmethylisonitrile (3.48 g. 17.8 mmoles) was added. The reaction was cooled to 0 °C and boron trifluoroetherate (6.7 ml, 54 mmoles) was added dropwise. The reaction was stirred at 0°C for 30 minutes, allowed to come to room temperature and then stirred at ambient temperature for 3.5 hours. Water (1.6 ml) was added and the mixture stirred at room temperature 2 days. The methanol was removed in vacuo and the residue taken up in ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the ethyl acetate removed in vacuo. The crude material was submitted to flash chromatography (hexanes: ethyl acetate, 4: 1) to yield 4.2 g of the desired product (3-benzyloxy-4-cyano- phenylamino)-3,4-ethoxy-phenyl-)-acetic acid methyl ester.

The product from above was treated with LiOH (1.96 g) in water (50ml) methanol ( 00m), and THF (50 ml). The reaction was stirred at room temperature for 3 hours and acidified with acetic acid. The solvent was removed in vacuo and the product extracted into ethyl acetate. The crude material was purified by reverse phase chromatography (ethyl acetate 3% acetic acid) to yield 5 g of desired acid-product (3- benzyloxy-4-cyano-phenylamino)-3, 4-ethoxy-phenyl-)-acetic acid.

(3-benzyloxy-4-cyano-phenylamino)-3, 4-ethoxy-phenyl-)-acetic acid (750 mg, 1.68 mmoles) was dissolved in dry THF (3 ml) and carbonyl diimidizole (CDI-545 mg, 3. 36 mmoles) was added. The reaction was heated to 40 degrees for I hour then cooled to room temperature. To this was added a solution of benzenesulfonamide (1.05 g, 6.7 mmoles), DBU (1.02 g 6.72 mmoles) in THF (3ml). The reaction was stirred overnight and then 1 N hydrochloric acid was added. The THF was removed in vacuo and the product purified by flash chromatography (ethyl acetate 2% acetic acid) to yield the desired product. This material (215 mg) was dissolved in ethanol (5 ml) containing acetic acid (I drop) and added to 5% Pd/C (100 mg). The reaction was placed under a hydrogen atmosphere and stirred vigorously until the reaction was complete. The catalyst was filtered off and than solvent removed in vacuo. The crude product was purified by flash chromatography to yield 150 mg of desired product-N- [ (3-hydroxy-4-cyano-phenylamino)- (3,4- diethoxy-phenyl-acetyl] benzenesulfonamide.

The N- [ (3-hydroxy-4-cyano-phenylamino)- (3, 4-diethoxy-phenyl-acetyl] benzenesulfonamide obtained above (75 mg, 0.15 mmoles) was dissolved in ethanol (2 ml ml) and heated to 60 °C.

Diisopropylethylamine (DIPEA-185 ul, I mmole) was added followed by hydroxylamine-hydrochloride (53 mg, 0.75 mmole). The reaction was stirred at 60 °C under a nitrogen atmosphere for ca. 6 hours. The reaction was then allowed to cool to room temperature overnight. The solution was diluted with acetic acid (1 ml) and methanol (1 ml). Raney Nickel 2800 (ca. 50 mg) was added as a suspension. The reaction was then stirred vigorously under a hydrogen atmosphere for 0.5 hours. The catalyst was filtered off and the solvent removed. The crude products were purified by preparative reverse-phase HPLC using a water-acetonitrile (0.1% TFA) gradient to yield the desired amidine product-4- [2-benzenesulfonylamino-l- (3,4 diethoxy- phenyl)-2-oxo-ethylamino]-2-hydroxybenzamidine. MS (M+H) = 513.

Using an analogous procedure, the corresponding halogen containing compounds can be made from 2-chloro-4-nitro-benzonitrile and 2-bromo-4-nitro-benzonitrile.

Example 14. Tissue Factor/Factor VIIa Antagonist Assay This procedure can be used to determine the constant of inhibition (Ki) for a sample compound of the invention.

Materials: Assay Buffer: 100 mM Hepes pH 7.8,140 mM NaCI, 0.1 % PEG-8000,0.02 % Tween-80,5 mM CaC12 Coagulation Factor: recombinant human factor VIIa (NB #25942-16) Cofactor: soluble Tissue Factor (1-219) Substrate: Chromozym-tPA (Boehringer Mannheim, Cat. #1093 037) Reconstitute at 20 mM in H20. Dilute to 4 mM in assay buffer with CaC12 prior to use.

Samples: Dilute samples to 3 % DMSO in assay buffer (lacking CaC12).

Procedure: 1. Prepare a solution of 2 llg/mL (90 nM) tissue factor and 1.5 pg/mL (30 nM) factor VIIa in assay buffer with CaCl2.

2. Incubate for 15 minutes at room temperature.

3. Add 50 1L sample to each well.

4. Add 50 liL tissue factor/factor VIIa solution to each well.

5. Incubate for 15 minutes at room temperature with gentle agitation.

6. Add 50 gL substrate to each well.

7. Agitate plate for 20-25 sec.

8. Monitor absorbance at 405 nM every 10 sec for a total of 5 minutes at room temperature.

9. Calculate Vmax over 10 points.

Example 15. Factor Xa. Thrombin, and Plasma Kallikrein Assays These procedures can be used to determine the constant of inhibition (Ki) for a sample compound of the invention.

Materials: Assay Buffer: 100 mM Hepes pH 7.8,140 mM NaCI, 0. 1 % PEG-8000,0.02 % Tween-80 Coagulation human Factor Xa, Thrombin, or Plasma Kallikrein (Hematologic Technologies) Factor: Dilute to 0.45tlg/mL (9.8 nM) in assay buffer.

Substrate: S-2222, S2366 or S2302- (See below-Chromogenix Inc,) Reconstitute at 5 mM in H20. Dilute to 1.5 mM in assay buffer prior to use.

Samples: Dilute samples to 3 % DMSO in assay buffer.

Procedure: 1. Add 50 gL sample to each well.

2. Add 50 liL appropriately diluted coagulation factor to each well.

3. Incubate for 5 minutes at room temperature with gentle agitation.

4. Add 50 1L appropriately diluted substrate to each well.

5. Agitate plate for 20-25 sec.

6. Monitor absorbance at 405 nM every 10 sec for a total of 5 minutes at room temperature.

7. Calculate Vmax over 10 points.

Assay-Enzyme, Substrate and Final Concentrations Assay TF/FVIIaFXaThrombin PlasmaKallikrein Coag Factor Final 10 nM FVIIa 3.3 nM 8.2 nM 1.5 nM concentration 30 nM TF Substrate Chromozyme S-2222 S-2366 S-2302 tPA Final Conc. of Substrate 1. 33 mM 0. 5 mM 0 3 mM 0. mM