ISOXAZOLINE, ISOTHIAZOLINE AND PYRAZOLINE FACTOR Xa INHIBITORS

Abstract: Isoxazolines, isothiazolines and pyrazolines which are inhibitors of Factor Xa, pharmaceutical compositions containing these compounds, and methods of using these compounds as anticoagulant agents for treatment and prevention of thromboembolic disorders. The compounds can be represented by formula (I) where X is O, S or NR<15>.

Description: TITLE Isoxazolme, isothiazoline and pyrazoline Factor Xa Inhibitors FIELD OF THE INVENTION This invention relates to lsoxazolines, isothiazolines and pyrazolmes which are inhibitors of Factor Xa, to pharmaceutical compositions containing these compounds, and to methods of using these compounds as anticoagulant agents for treatment and prevention of thromboembolic disorders. BACKGROUND OF THE INVENTION Stuerzebecher et al., Thrombosis Research, vol. 9, 637-646 (1976) describes comparative studies of a number of benzamidme derivatives as Factor Xa inhibitors. The most active inhibitors were 3-amιdmo-phenylaryl derivatives. Tidwell et al., Thrombosis Research, vol. 19, 339- 349 (1980) describes Factor Xa inhibitory activity of a series of heterocyclic aromatic mono- and di-amidines. Stuerzebecher et al., Thrombosis Research, vol. 17, 545-548 (1980) describes Factor Xa inhibitory activity of a series of a,a' -bis- (4-amιdmobenzyl)cycloalkanones, a,a'-bis- (4-ammobenzylιdene)- and a,a'-bis- (3- ammobenzylidene) cycloalkanones with 5 to 8-membered rings, the corresponding non-cyclic derivatives, and derivatives containing only one amidino group. Hauptmann et al. , Blood Coagulation and Fibnnolvsis, vol. 4, 577-582(1993) and Hauptmann et al. , Thromb. Haemostasis, vol. 63(2), 220-223(1990) report testing of several synthetic compounds as Factor Xa inhibitors: Na-tosylglycyl-3-amιdιnophenylalanme methyl ester; 2,7-bιs(4-amιdιnobenzylιdene) -cycloheptanone- (1) ,- Na-tosyl-4-amιdmophenylalanιne piperidide,- Na- naphthylsulphonylglycyl-4-amιdιnophenylalanme piperidide; 4-methyl-l-N 2 - (methyl-1,2,3,4-tethydro-8- quιnolmesulphonyl-L-argιnyl-2-pιperιdme carbonic acid; and D-phenylalanyl-L-propyl-L-argimne chloromethyl ketone. Nagahara et al., J. Med. Chem. , vol. 37, 1200- 1207(1994) describes several dibasic (amidmoaryl)propanoic acid derivatives as Factor Xa inhibitors. Danchi EPA 0 540 051 Al, published May 5, 1993, discloses aromatic amidme derivatives, including amidino naphthylenes, amidino-mdoles, amι,dmo-benzιmιdazoles, and amidino-benzothiophenes, which have Factor Xa inhibitory activity. DuPont Merck WO 95/14683 and WO 95/14682, published June 1, 1995, disclose isoxazoles and isoxaolines as antagonists of the platelet glycoprotem Ilb/IIIa fibrmogen receptor. The isoxazoles and isoxaolines of WO 95/14683 are represented by the formula: The isoxazolmes of WO 95/14682 are represented by the formula: Copendmg, commonly assigned U.S. Patent Application Serial Number 08/449597, filed May 24, 1995, discloses isoxazolme antagonists of the platelet glycoprotein lib/Ilia fibnnogen receptor having the formula: EP 53095 A and other references disclose various di- anilino-pyrazolme as components of photosensitive systems. EP 438690 and other references disclose various 1- amido-pyrazolines as pesticides, e.g., insecticides, fungicides and acaricides. To date there have been no isoxazolme, isothiazoline or pyrazolme derivatives described as Factor Xa inhibitors. SUMMARY OF THE INVENTION This invention provides novel compounds of Formula including pharmaceutically acceptable salts and prodrug forms thereof, and all stereoisomeric forms thereof and mixtures of such stereoisomeric forms, wherein: U when present (i.e., when u=l) is selected from -CO-NH- (CH 2 ) 0 - -C0- ( CH 2 ) o - -S0 2 -NH-(CH 2 ) o - -S0 2 -(CH 2 ) o - -NHS0 - (CH ) 0 - , provided m ≠ 0 -NHCO- (CH 2 ) 0 -/ provided ≠ 0 -NH-(CH 2 ) 0 -, provided m ≠ 0 -0-(CH 2 ) o -, provided ≠ 0 -S-(CH ) 0 -, provided m ≠ 0 -CH=CH- ( CH 2 ) 0 - Y is selected from R ] is selected from (CH2) P NR 5 R 6 C(NR 14 )NR 5 R 6 NHC(NR 14 )NR 5 R 6 NHC(NR 14 )H CONR 5 R 6 R 2 is selected from H Cι-C 6 alkyl Ci-Cβ alkoxy C0 2 R^ CONHR 5 CONHCH 2 C0 2 R 5 CONH(CH 2 ) q -R 10 R io CO-R 5 COC0 2 R 5 COCONHR 5 SO n R 5 S0 2 NHR 5 NHR 7 CH=CHC0 2 R 5 CH=CHCONHR 5 0-(CH 2 ) n -R 10 SO n -(CH 2 ) n -Rl0 NH- (CH 2 ) n -R 10 U and R 2 taken together provide a spiro compound of formula Ila and lib, or a compound of formula Ilia or Illb: where W = CO, CH 2 , CHOR 5 and r = 1-3 where W = CO, CH 2 , CHOR 5 and t = 0-2 R 3 is selected from (CH 2 ) S NR 5 R 6 C(NR 1 )NR 5 R 6 NHC(NR 14 )NR 5 R 6 NHC(NR 14 )H CONR 5 R 6 V is selected from the following when Z and D are both absent: V is selected from the following when Z and/or D are present : Z when present (i.e., when u = 1) is selected from a single bond, -CO-, -(CH 2 ) C -, -SOn-, -S0 2 NHR 4 , provided D is absent -NH-, -NR 7 -, -0- D when present (i.e., when u = 1) is selected from E is selected from N, NR 5 , 0, S; J is selected from O, NR 7 ; A is selected from CO, CH 2 , SO, S0 2 R 4 is selected from H Ci-Cδ alkyl (CH 2 ) n -phenyl (CH 2 ) n -CONHR 5 (CH 2 ) n -CONHR 5 CH 2 C0 2 R 5 R 5 and R 6 at each appearance are independently H Ci-Cδ alkyl (CH 2 ) n -phenyl R 7 is selected from H Cι-C 6 alkyl S0 2 R 5 COR 5 (CH 2 ) r -R 10 (CH 2 ) n -phenyl R 8 is selected from H Cι-C 6 alkyl halogen N0 2 CF 3 OR 5 R 9 is selected from H C -C 6 alkyl halogen N0 2 NHR 7 S0 2 NHR 11 CF 3 OR 5 C0 2 R 5 CONR 5 R 7 CN (CH 2 ) p NR 5 R 6 C(NR 1 )NR 5 R 6 NHC(NR 14 )NR 5 R 6 NHC(NR 14 )H SO n -R 5 SO n -CF 3 imidazole, pyrazole, 1, 2, 3-triazole, 1, 2, 4-triazole and tetrazole, each optionally substituted with CF 3 , halogen, N0 2 , Cι~C b alkyl, or C 1 -C 5 alkoxy; R 10 is selected from R 11 is selected from H Ci-Cβ alkyl (CH 2 ) n -phenyl COR 5 C0 2 R 5 R 12 is selected from H Cι-C 6 alkyl Ci-Ce alkoxy halogen N0 2 NHR 7 CN CF 3 SONHR 11 R 1 3 is selected from H OH Ci-Cio alkyl Ci-Cio alkoxy nitro halo CF 3 R 14 is selected from H OH Ci-Cio alkyl Ci-Cio alkoxy C0 2 -Cι-Cιo alkyl CO-Ci-Cio alkyl CONH-Ci-Cio alkyl CONH-phenyl C0 2 (CH2) n -phenyl; R 15 is selected from H Cι-C 6 alkyl, Ci-C δ alkoxy C0 2 R 14 CONHR 14 CONHCH 2 C0 2 R 5 CONH(CH 2 ) q -R 10 (CH 2 ) n R lθ CO-R 5 COC0 2 R 5 COCONHR 5 S0 2 NHR 5 at each appearance each of the following are independently: m = 0-2 n = 0-4, except that in -SO n -, n = 0-2; o = 0-2 p = 0-1 q = 0-4 r = 1-2 s = 0-2 t = 0-2 u = 0-1, provided that, when X is NR 15 , Z and D are both absent, then at least one of R 1 and R 3 must be C(NR 14 )NR 5 R 6 NHC(NR 1 )NR5R6 Qr NHC(NR 14 )H. As used in this specification and the claims: the terms "alkyl" and "alkoxy" mean straight or branched chain alkyl and straight or branched chain alkoxy, each optionally substituted with 1 to 3 substituents independently selected from halo, Cι-C 6 straight or branched alkoxy, S(0) n -alkyl where alkyl is Ci-C δ straight or branched alkyl and n is 0-2, morpholmo, Cι-C6 alkylacyloxy, NR 5 R 7 where R 5 and R 7 are as defined in claim 1, CN, N0 2 , and CF ; the term "phenyl" means phenyl optionally substituted with 1 to 3 substituents independently selected from halo, Ci-Cβ straight or branched alkoxy, S(0) n -alkyl where alkyl is Ci-Cβ straight or branched alkyl and n is 0-2, morpholmo, Ci-Cβ alkylacyloxy, NR 5 R 7 where R 5 and R 7 are as defined in claim 1, CN, N0 2 , and CF 3; the terms "halo" and "halogen" mean chloro, fluoro, bromo and lodo. Many compounds of this invention have one or more asymmetric centers or planes. All chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric lsomers of olefins, C=N double bonds, and the like can also be present m the compounds, and all such stable isomers are contemplated m the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by asymmetric synthesis, or synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. Preferred are those compounds of Formula I wherein, independently or concurrently: U is present and is selected from -C0-NH- ( CH 2 ) o- -C0-(CH 2 ) o - -S0 2 -NH- (CH 2 ) 0 - -S0 2 -(CH 2 ) o - -NH- ( CH 2 ) 0 - -0- ( CH 2 ) o - Y is selected from R 1 is selected from C(NR 14 )NR 5 R 6 NHC(NR 1 )NR 5 R 6 R 2 is selected from H Ci-Cβ alkyl Cι-C 6 alkoxy C0 2 R 5 CONHR 5 CONHCH 2 C0 2 R 5 CONH(CH 2 )q-R 10 R l ° CO-R 5 COC0 2 R 5 COCONHR 5 SO n R 5 S0 2 NHR 5 NHR 7 CH=CHC0 R 5 CH=CHCONHR 5 O- (CH) n -R 10 SO n -(CH) n -Rl° NH- (CH) n -R 10 V is selected from the following when Z and/or D are present: V is selected from the following when Z and D are both absent D when present (i.e., when u = 1) is selected from R 10 is selected from Of the preferred compounds, more preferred are those wherein, independently or concurrently: U is -CO-NH- ( CH 2 ) 0 - Y is selected from R 1 is C (NR 1 ) NR 5 R 6 Z is absent or is present and is selected from -0- and -NR 7 -. Of the more preferred compounds, especially preferred are those having the structures of V and VI: wherein D is selected from V is selected from the following: Specific preferred compounds of this invention include the following and pharmaceutically acceptable salt and prodrug forms thereof: 3- (3-Amιdmophenyl) -5-[ (2-naphthylsulfonyl)ammo]methyl- isoxazolme 3-(3-amιdmophenyl) -5-[ [ (2 '-am osulfonyl- [1,1']- bιphenyl-4-yl)-methyl]aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amιdmophenyl) -5-[ [ (2 '-ammosulfonyl- [1,1']- biphenyl-4-y1)methyl]aminocarbonyl] -5- (ammocarbonylmethyl) isoxazolme 3- (3-amιdmophenyl) -7- (2 ' -ammosulfonyl- [1,1'] -biphenyl- 4-yl)methyl[l-oxa-2,7-dιazaspιro[4,4]non-2-ene-β,8-dιones 3-amιd ophenyl 3- (4-amιdmophenyl) -5- [ (aminocarbonyl)ιsoxazolm-5-yl]aoetamide 4-amιdmophenyl 3- (3-amidinophenyl)-5- [ (carbometoxy) ιsoxazolm-5-yl]acetamιde 3- (3-amιdmophenyl) -5- [ (4- amidinophenyl)aminocarbonyl] isoxazolme 3- (3-amιdmophenyl) -5- [ (4-amidinophenyl)aminocarbonyl]-5- [ (carbomethoxymethyl)ammocarbonylmethyl]isoxazolme 3- (3-amidinophenyl) -5- [ (4-amidinophenyl)aminocarbonyl]-5- (carboxymethyl) isoxazolme 3- (4-amidinophenyl) -5- [ (3-amidinophenyl)aminocarbonyl]-5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl)-5- [ (4- amidmophenyl)methylaminocarbonyl] -5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl) -5- [ (4-benzenesulfonylpιperιdm-l- yl) carbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [ (4-pyrιmιdιn-5-yl)pιperιdιn-l- yl] carbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (4-benzenesulfonylphenyl-l- yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (4-amιdmophenyl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ ( [1, 1 ' ] -bιphenyl-4- yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ ( [1, 1 ' ] -bιphenyl-4- yl) aminocarbonyl] -5- (carboxymethyl) isoxazolme 3- (3-amidinophenyl) -5- t ( [1, 1 ' ] -bιphenyl-4- yl) aminocarbonyl] -5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [([1,1'] -bιphenyl-4- yl)aminocarbonyl] -5- (hydroxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3 ' -n-propyl- [1,1'] -bιphenyl-4-yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -t-butylammosulfonyl- [1,1']- bipheny1-4-y1) aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -t-butylaminosulfonyl- [1,1']- bιphenyl-4-yl) aminocarbonyl] -5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (4 ' -ammo- [1,1']-bιphenyl-4- yl)aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl)-5- [ (2' -tπfluoro ethyl- [1,1']- bιphenyl-4-yl)aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-methyl- [1,1' ] - bιphenyl-4-yl)aminocarbonyl) ]-5- (carbomethoxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-methyl- [1,1']- bιphenyl-4-yl)aminocarbonyl] -5- (carboxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-methyl- [1,1']- bιphenyl-4-yl)aminocarbonyl] -5- (carbomethoxyethylene) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 '-ammosulfonylphenyl-1- yl)pynmιdιn-2-yl]aminocarbonyl] -5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 '-amιnosulfonylphenyl-1- yl)pyrιmιdιn-2-yl]aminocarbonyl]-5- (hydroxyethyl) isoxazolme 3-(3-amidinophenyl) -5- [ [5- (2 '-ammosulfonylphenyl-1- yl)pyrιmιdιn-2-yl]aminocarbonyl]-5- (methoxyethyl) isoxazolme 3- (3-amιdιnophenyl) -5-[ [5- (2 ' -ammosulfonylphenyl-1- yl)pyrlmidm-2-yl]aminocarbonyl] -5-(methyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl- [1,1'] -biphenyl- 4-yl)aminocarbonyl] -5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl- [1,1'] -biphenyl- 4-yl)aminocarbonyl] -5- (carboxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 '-ammosulfonyl- [1,1'] -biphenyl- 4-yl)aminocarbonyl] -5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl) -5- (hydroxyethyl) isoxazolme 3- (3-amidinophenyl)-5- [ (2 ' -ammosulfonyl- [1,1'] -biphenyl- 4-yl)aminocarbonyl] -5- (carbomethoxymethylammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl)-5- [ (2'-ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl] -5- [ (imidazole-4- yl)ethylaminocarbonylmethyl]isoxazolme 3- (3-amidinophenyl) -5- [ (2'-ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl]-5- (methoxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2'-ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl]-5-(methyl)isoxazolme 3-(3-amidinophenyl) -5-[ (2 ' -ammosulfonyl-3-methyl-[1,1']- biphenyl-4-yl)aminocarbonyl] -5- (carbomethoxymethyl)isoxazolme 3-(3-amidinophenyl) -5- [ (2'-ammosulfonyl-3-methyl- [1,1']- biphenyl-4-yl)aminocarbonyl]-5- (carboxymethyl) isoxazolme 3 - ( 3 -amidinophenyl ) - 5- [ ( 2 ' -ammosulfonyl-3 -methyl- [ 1 , 1 ' ] - bιphenyl-4-yl ) aminocarbonyl] -5- ( ammocarbonylmethyl ) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-methyl[1,1']- bipheny1-4-y1)aminocarbonyl] -5- (carbomethoxymethylaminocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-methyl- [1,1']- b phenyl-4-yl)aminocarbonyl]-5- (hydroxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-methyl- [1,1']- b phenyl-4-yl)aminocarbonyl] -5- (methoxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-methyl- [1,1']- bιphenyl-4-yl)aminocarbonyl] -5- (methyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -amιnosulfonyl-3-fluoro- [1,1']- biphenyl-4-yl)aminocarbonyl] -5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -amιnosulfonyl-3-fluoro- [1,1']- biphenyl-4-yl)aminocarbonyl] -5- (carboxymethyl)isoxazolme 3-(3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-fluoro- [1,1']- bipheny1-4-y1)aminocarbonyl] -5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-fluoro- [1,1']- bιphenyl-4-yl)aminocarbonyl] -5- (hydroxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-fluoro- [1,1']- bιphenyl-4-yl)aminocarbonyl]-5- (methoxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -amιnosulfonyl-3-fluoro- [1,1']- bιphenyl-4-yl)aminocarbonyl]-5- (methyl) isoxazolme 3- (3-amidinophenyl) -5- [ [2- (2 '-ammosulfonylphenyl-1- yDpyridm-5-yl]aminocarbonyl] -5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl) -5- [ [2- (2 ' -amιnosulfonylphenyl-1- yl)pyrιdm-5-yl]aminocarbonyl]-5- (carboxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [2- (2 '-ammosulfonylphenyl-1- yl)pyπdm-5-yl]aminocarbonyl]-5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [2- (2'-ammosulfonylphenyl-1- yl)pyridin-5-yl]aminocarbonyl] -5- (hydroxyethyl)isoxazolme 3- (3-amidinophenyl) -5- [ [2- (2 ' -amιnosulfonylphenyl-1- yl)pyrιdm-5-yl]aminocarbonyl]-5- (methoxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [2- (2 '-ammosulfonylphenyl-1- yDpyridm-5-yl]aminocarbonyl]-5- (methyl) isoxazolme 3-(3-amidinophenyl)-5-[ [5- (2 ' -amιnosulfonylphenyl-1- y1) yridin-2-y1]aminocarbonyl]-5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 '-ammosulfonylphenyl-1- yl)pyrιdm-2-yl]aminocarbonyl] -5- (carboxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -amιnosulfonylphenyl-1- yl)pyridin-2-yl]aminocarbonyl]-5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -ammosulfonylphenyl-1- yl)pyrιdm-2-yl]aminocarbonyl] -5- (hydroxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -ammosulfonylphenyl-1- yl) yrιdιn-2-y1]aminocarbonyl] -5- (methoxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -ammosulfonylphenyl-1- yl)pyrιdm-2-yl]aminocarbonyl] -5- (methyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -amιnosulfonylphenyl-1- yl)pyrlmidm-2-yl]aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -ammosulfonylphenyl-1- yl)pyrιmιdm-2-yl] aminocarbonyl] -5- (carboxymethyl) isoxazolme 3- (3-amιdmophenyl) -5- [5- (2 ' -ammosulfonylphenyl-1- yl)pyπmιdιn-2-yl] aminocarbonyl-5-carbomethoxymethyl- lsoxazoline 3- (3-amidinophenyl) -5- [5- (2 ' -ammosulfonylphenyl-1- yl)pyridm-2-yl]aminocarbonyl-5-carbomethoxymethyl- lsoxazolme 3- (3-amidinophenyl) -5- [2 ' -ammosulfonyl- [1,1'] -biphenyl- 4-y1]aminocarbonyl-5- (tetrazol-1-yl)methyl-lsoxazolme 3- (3-amidinophenyl) -5- [5- (2 ' -amιnosulfonylphenyl-1- yl)pyridιn-2-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl- isoxazolme 3- (3-amidinophenyl) -5- [5- (2 ' -amιnosulfonylphenyl-1- yl)pyrimidm-2-yl]aminocarbonyl-5- (tetrazol-l-yl)methyl- lsoxazolme 3- (3-amidinophenyl) -5- [2 ' -trifluoromethyl- [1,1']- biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl- lsoxazolme 3- (3-amidinophenyl) -5- [5- (2 ' -trifluoromethylphenyl-1- yl)pyπdιn-2-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl- isoxazolme 3- (3-amidinophenyl) -5- [5- (2 ' -trifluoromethylphenyl-1- yl)pyrimidm-2-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl- isoxazolme 3- (3-amidinophenyl) -5- [5- (2 ' - trifluoromethylsulfonylphenyl-l-yl)pyrιdm-2- yl]aminocarbonyl-5- (tetrazol-l-yl)methyl-ιsoxazolme 3- (3-amidinophenyl) -5- [5- (2 ' - trifluoromethylsulfonylphenyl-1-yl)pyrimidm-2- yl]aminocarbonyl-5- (tetrazol-l-yl)methyl-ιsoxazolme 3- (3-amidinophenyl) -5- [2 ' -ammosulfonyl-3-flouro- [1,1']- oιphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl- lsoxazolme 3- (3-amidinophenyl) -5- [2 ' -amιnosulfonyl-3-chloro- [1,1']- bipheny1-4-yl]aminocarbonyl-5- (tetrazol-1-y1)methy1- isoxazolme 3- (3-amidinophenyl) -5- [2 ' -trifluoromethyl-3-flouro- [1,1'] -bιphenyl-4-yl]aminocarbonyl-5- (tetrazol-1- yl)methyl-isoxazolme 3- (3-amidinophenyl) -5- [2 ' -trifluoromethyl-3-chloro- [1,1'] -bιphenyl-4-yl]ammocarbonyl-5- (tetrazol-1- yUmethyl-isoxazolme 3- (3-amidinophenyl)-5- [5- (2 '-ammosulfonylphenyl-1- yl ) pyrιdm-2-yl]ammocarbonyl-5-methoxymethyl-ιsoxazolme 3-(3-amidinophenyl) -5-[2 ' -methylammosulfonyl- [1,1']- bιphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl- lsoxazol e 3- (3-amidinophenyl) -5-[5- (2 '-methylammosulfonylphenyl-1- yl)pyrιdm-2-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl- isoxazolme 3-(3-amidinophenyl) -5- [2'-methylsulfonyl-[1,1'] -biphenyl- 4-yl]aminocarbonyl-5- (tetrazol-1-yl)met yl-isoxazolme 3- (3-amidinophenyl) -5- [2 '-methylsulfonyl-fluoro- [1,1']- bιphenyl-4-yl]ammocarbonyl-5- (tet-razol-1-yl)methyl- isoxazolme 3- (3-amidinophenyl) -5- [2 '-methylsulfonyl-chloro- [1,1']- bιphenyl-4-yl]aminocarbonyl-5- (tetrazol-l-yl)methyl- lsoxazoline 3- (3-amidinophenyl) -5- [2 '-trifluoromethylsulfonyl- [1,1']- bιphenyl-4-yl]aminocarbonyl- - (tetrazol-1-yl) ethyl- isoxazolme 3- (3-amidinophenyl) -5- [2'-ammosulfonyl-[1,1']-biphenyl- 4-yl]aminocarbonyl-5-(lmidazol-1-y1)methyl-isoxazoline 3- (3-amidinophenyl) -5- [2'-trifluoromethylsulfonyl-3- fluoro- [1,1'] -bιphenyl-4-yl]aminocarbonyl-5- (tetrazol-1- yl)methyl-isoxazoline 3- (3-amidinophenyl) -5- [2 '-trifluoromethylsulfonyl-3- chloro- [1,1'] -bιphenyl-4-yl]aminocarbonyl-5- (tetrazol-1- yl)methyl-isoxazolme 3- (3-amidinophenyl) -5- [2 '-ammosulfonyl- [1,1'] -biphenyl- 4-yl]aminocarbonyl-5- dmidazol-1-yl)methyl-isoxazolme 3- (3-amidinophenyl) -4- (2 ' -ammosulfonyl- [1,1' ] -biphenyl- 4-y1)aminocarbonyl-5-methoxymethy1-isoxazolme 3- (3-amidinophenyl) -4- (2 '-ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl-5-trifluoromethyl-isoxazolme 3- ( 3 -amidinophenyl ) -5- ( 2 ' -ammosulfonyl- [ 1 , 1 ' ] -biphenyl- 4-yl ) ammocarbonyl-4-methoxymethyl- ιsoxazolme DETAILED DESCRI PTION OF THE INVENTION Synthesis The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known m the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference. A convenient method for the synthesis of the isoxazolme compounds of this invention utilizes a dipolar cycloaddition of nitrile oxides with appropriate dipolarophiles to prepare the isoxazolme rings present in compounds of Formula I (for reviews of 1,3-dιpolar cycloaddition chemistry, see 1,3-Dipolar Cycloaddition Chemistry (Padwa, ed. ) , Wiley, New York, 1984; Kanemasa and Tsuge, Heterocvcles 1990, 3_Q., 719) . Scheme 1 shows a general synthesis of 3, 5-substιtuted-ιsoxazolmes. An appropriately substituted hydroxylamme is treated with NCS in DMF according to the method of Liu, et al. (J. Orσ. Che . 1980, 4ϋ, 3916). The resulting hydroximinoyl chloride is then dehydrohalogenated n situ using TEA to give a mtrile oxide, which undergoes a 1,3-dipolar cycloaddition to a suitably substituted alkene to afford the isoxazolme. Alternatively, the oxime may be oxidatively chlorinated, dehydrochlormated and the resulting nitrile oxide trapped by a suitable alkene under phase transfer conditions according to the method of Lee (Synthesis 1982, 508). The isoxazolme compounds of the general formula (I) wherein the 4 and 5 positions are substituted can be prepared following the 1,3-dipolar cycloaddition methodology using a suitable 1,2- disubstituted olefm as a dipolarophile. A mixture of regioiso ers is formed and the reg-ioisomers can be separated by column chromatography. An example is shown in Scheme 2. Optically active isoxazolmes can be obtained by chiral HPLC separation of the two enantiomers, or enzymatic resolution on the regioisomeric esters. It can also be obtained by the use of an appropriate chiral auxilliary on the dipolarophile as described by Olsson (J. Orα. Chem. ~ 1, 2468, 1988). The synthetic methods described above may also be used for the synthesis of compounds of this invention where Y is pyridyl or pyrimidyl derivatives m formula (I) . Scheme 1 Scheme 2 Many isoxazolme compounds of this invention can use commercially available substituted alkenes as starting materials. Compounds with R 2 is acid or amide can be prepared from the commercially available alkene-esters or alkene acids. The transformations of the functional groups can be done either at the alkene stage or after the isoxazolme ring is formed. Compounds with R 2 is 0(CH2) n R' H(CH2) n R' S(CH2) n R- where R is R 5 or R 10 , can be prepared from substituted allyl bromide. An example is shown in Scheme 3. The sulfoxides and sulfones can be prepared from oxidation of the thio-compounds (Scheme 3) . Compounds wh R 2 is aromatics and heteroaromatics (R 1 ^) can be prepared from the reaction of the bromide or iodide of the aromatics and hetreoaromatics with allyl of vinyl bromide. The C-linked aromatic and hetreoaromatic compounds can be synthesized using Zinc and Copper organometallics shown by Knochel ( Tet. Lett. 3_1, 4413- 4416, 1990) , or using palladium-catalyzed coupling of an a-stannyl acrylate to aryl iodides or triflates by Levm (Tet. Lett. 34, 6211-6214, 1993) . These reactions are exemplified in Scheme 4. The N-linked heteroaromatic compounds can be prepared by alkylation of the hetroaromatics with allyl bromides. An example is shown in Scheme 5. Compounds with R 2 is COCO2R or COCONHR can be prepared by the method discπbed by Iwanowicz (Bioorα. ' Med. Chem. Lett.. Z, 1607-1612, 1992) . Scheme 3 Targets Targets Targets R = alkyl, phenyl Scheme 4 12 Scheme 5 22 24 CHNOH Bleach pr 11 CN Targets Targets Appropriately substituted crotonate ester can be used as starting material for 4, 5-disubstituted isoxazolmes. The crotonate esters can be obtained from commertial sources or can be obtained from ethyl-4- bromocrotonate by nucleophilic displacement reactions shown in Scheme 6. Trisubstituted olefins as diplolarophiles can be obtained from ethylpropiolate by the cuprate chemistry (Scheme 7) according to the method described by Deslongchamps (Svniett. 660, 1994). Scheme 6 R = H, alkyl 22 Scheme 7 The isothiazoline compounds of this invention of formula (I) can be prepared by cycloaddition reaction of nitrile sulfides with olefins (Howe, J. Orα. Chem. , 43, 3742, 1978) as shown in Scheme 8. The nitrile sulfide is generated by thermolysis of 5-subs«tituted 1,3,4- oxthiazol-2-one. Scheme 8 The pyrazoline compounds of this invention of formula (I) cab be prepared by the method described by Wahoff and Zahran (Synthesis. 876-879, 1987) . An example of the synthesis is shown m Scheme 9. The hydrozine is coupled with the acyl chloride. The N-acylated hydrozine is reacted with dichlorotriphenylphosphorane and triethylamine. The nitrilimine generated in situ undergoes a 1,3-dipolar cycloaddition reaction with a suitable alkene to give the pyrazoline. The pyrazolines may also be prepared from isoxazolines as shown in Scheme 10. The isoxazoline was reacted with molybdenum hexacarbonyl in the conditions described by Baraldi (Synthesis, 276, 1987) provides the b-hydroxyketone. Dehydration of the b-hydroxyketone with p-toluenesulfonic acid yields the a,b-unsaturated ketone, which was then treated with hydrazine to afford the desired pyrazoline. Scheme 9 Scheme 10 Compounds of this invention where U in formula (I) is CONH may be prepared using substituted acrylates, vinyl acetate, or crotonate as starting materials. The core ring structures can be synthesized as described above and the easter group s then coupled with an appropiate amme using standard conditions for the formation of amide bonds. The nitrile is then converted to the amidme via the lmidate or thioimidate under standard conditions. Some of the compounds are prepared following the procedures described in copendmg commonly- assigned US. Patent application USSN 08/337920. An example of these compounds is shown in Scheme 11. The 3- substιtuted-ιsoxazolιne-5-ylcarboxylιc acids or 3- substιtuted-ιsoxazolme-5-ylacetιc acids can be converted to the corresponding amidines first, followed by protection as the Boc-derivatives or CBZ-derivatives. They were then coupled with appropiate amines as exemplified in Scheme 12. Compounds of this invention where R 1 is NHCH(NR5) ιn formula (I) may be prepared from amme derivatives by reaction of the amme with ethyl formi idate and N,N-dιmethylpyrιdi-ne in refluxmg ethanol. Compounds of this invention where R^ is NHC ( R5) NR5R ιn formula (I) may be prepared from amme derivatives by reaction of the amme with either formamidine sulfonic acid and N,N-dimethylpyridme m refluxmg ethanol (Kim, et al . Tet. Lett . 29, 3183, 1988) , or Bocprotected pyrazole carboxamidine in DMF (Bernatowicz et al . Tet. Lett. 34, 3389, 1993) . Scheme 11 Scheme 12 The sulfone derivatives where U is -Sθ2-(C_-2)o - r © prepared as exemplified by the reactions in Scheme 13. Methyl (triphenylphosphoranylidene) -acetate is reacted with acetyl chloride to give the desired allene. A sulfmic acid, prepared by hydrogen peroxide oxidation of the corresponding thiol, is added into the allene to give the desired alkene (Padwa, J. Qrσ. Chem. 54, 4232, 1989) . This alkene can be used in the previously described cycloaddition reactions. The sulfonamide derviatives where U is -SO2-NH- are prepared as exemplified by the reactions in Scheme 14. V yl sulfonyl chloride is brommated, then reacted with an amme (Barnett, Tet . Lett. , 651, 1968) . Halogen-metal exchange and alkylation with lodoacetate gives the desired substituted vmyl sulfonamide (Stetan, Chem, Ber., 122, 169, 1889) which can be used in the previously described cycloaddition reactions. Scheme 13 Scheme 14 Isoxazolme compounds of the general formula I wherein U is thio, sulfonyl, or sulfonamide can also be prepared by the method outlined in scheme 15. The isoxazolme thioxanthate can be converted to the sulfonylchloride by treatement with chlorine in glacial acetic acid. The sulfonylchloride is then coupled with an appropriate amine to provide the desired sulfonamide. Alternatively the thioxanthate can be hydrolysed with sodium hydroxide in ethanol to the thiol followed by trapmg of the intermediate thiol with an appropriate benzylbromide to afford the thioalkylphenylanalog. Oxidation of the thio-compound with MCPBA or oxone affords the sulfoxide and or sulfone. Scheme 15 4-thιoιsoxazolιne Compounds of this invention where U is alkene, ether, -NHSO2-, ans -NHCO- can be prepared from the same intermediate as shown in Scheme 16. The 5- hydroxymethylisoxazoline is formed by the 1,3-dipolar cycloaddition described above. The alcohol can be oxidized to the corresponding aldehyde aand the converted to the alkene-linked compound by ittig reaction. The alkene-linked compounds can then be reduced to the corresponding alkyl-lmked compounds. The alkyl-lmked compounds can also be prepared using Zinc and Copper organometallics shown by Knochel ( Tet. Lett. 31, 4413- 4416, 1990, see Scheme 4), The 5-hydroxymethyl group can be converted to the azide, and then reduced to the corresponding amine. This amme intermediate is the converted to compounds with -NHSO2-, and -NHCO- using suitable sulfonyl or acyl chloride. The 5- hydroxymethylisoxazolme can be converted to the ether- linked compound by Mitsunobo reaction. The ether and am e linked compounds can also be prepared by displacement of the allyl bromide shown in Scheme 17. Scheme 16 R' = Br, ZD Scheme 17 Compounds of this invention where U is -CO- can be prepared by palladium-catalyzed coupling reactions of organoz c reagents with acid chlorides (Jackson, Svnlett. 819-820, 1995 and Sato, Chem. Lett.. 1135, 1981) or by organimetallics of Zmc and Copper described by Knochel (J. Orπ. Chem. 53. 5791-5793, 1988). Compounds of this invention where Z is absent may be prepared as shown by an example in Scheme 18. 4- Bromoaniline is protected as Boc-derivative and the coupled to 2- (t-butylamιno)sulfonylphenylboronιc acid under Suzuki conditions. 2- (t-Butylammo)sulfonyl- phenylboronic acid is prepared by the method described by Rivero (Bioorσ. Med. Chem. Lett.. 189, 1994). Deprotection with TFA provides the ammobiphenyl compound. The ammobiphenyl is the coupled to the core ring structures first as described above. The Bromoanilme can be linked to the core ring structures first as described above, and then undergoes Suzuki reaction to give the desired product. Scheme 18 Compounds of this invention where -Z- is -SO2- are exemplified by the peperidme derivative shown in Scheme 19. Compounds of this invention where -Z- is -NH-, -0-, and -S- can be prepared by the methods described m Scheme 20. Scheme 19 O O Boc NH PhSO 2 Cl BocN N—S TFA HN N—S CH 2 Cl 2 /Et 3 N M SI "O S2 ^ o Scheme 20 Some of the compounds of this invention may also be prepared as shown in Scheme 21. Itaconic anhydride reacts with appropiate amme to give 3-carboxy-3- butenamide. The benzaldehyde oxime is oxidatively chlorinated and dehydrochlormated. The resulting nitrile oxide then reacted with 3-carboxy-3-butenamide to yield the 3 , 5 , 5-trιsubstιtuted isoxazolme which was then converted to the final benzamidme as described above. Scheme 21 Compounds of this invention where Y is a piperidine derivative in formula (I) may be prepared from piperidine alcohols which are commercially available or prepared by coupling 4-brompyrιdme and appropiate length acetylenic alcohol followed by reduction. The piperidine alcohol is oxidized to the corresponding aldehyde under standard conditions. The aldehyde is converted to the isoxazolme by the same methods described above. An example of such a convertion is shown in Scheme 22 where n = 0-3. Scheme 22 91 22 32 Some of the spiro-compounds of this invention in formula (II) may be prepared as shown m Scheme 23. Itaconyl chloride is reacted with appropiate amme to g ve the a-methylene-succmimide which then undergos 1,3- dipolar cycloaddition to yield the spiro-isoxazoline. Some of the spiro-compounds of this invention in formula (II) may be prepared from ester or acid intermediates. An example of this transformation is shown in Scheme 23. The ester or acid group Scheme 24 can be reduced with L1BH 4 in THF or other reducing agents to give the alcohol. The alcohol is then cyclized using a mesylate intermediate to afford the desired spiro-compound. The alcohol can also be oxidized under Swern oxidation conditions to generate the corresponding aldehyde, which can cyclized to give the spiro-compound. Scheme 23 Scheme 24 ϋ-1 J.Q2 1_ _ As used herein, the term " compound of formula I " or " compounds of this invention" includes pharmaceutically acceptable salts and prodrug forms of the compounds of formula I . "Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to Formula I in vi vo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula I are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vi vo, to the parent compounds. Prodrugs include compounds of Formula I wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I, and the like. The pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formula I formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propiomc, succmic, glycolic, stearic, lactic, malic, tartaπc, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybβnzoιc, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, lsethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometπc amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents. The pharmaceutically acceptable salts of the acids of Formula I with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amme, e.g., dibenzylethylenediamme, tπmethylamine, piperidine, pyrrolidme, benzyla me and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like. As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference. The compounds of this invention and their preparations can be understood further by the following examples which do not constitute a limitation of the invention. In these examples, unLess otherwise indicated, all temperatures are in degrees centigrade and parts and percentages are by weight. Example 1 3-amidinophenyl-5- (4-amidinophenyl)aminocarbonyl-5- carbomethoxymethvl-isoxazolme, Bistrifluoroacetic Acid Salt Part A. Preparation of 3-cyanobenzaldehyde oxime 3-Cyanobenzaldehyde (25.0 g, 0.19 mol) and hydroxyamine hydrochloride (16.6 g, 0.24 mol) were added together with 100 mL of pyridine and 100 mL of ethanol. The mixture was stirred at room temperature under N 2 for 12h. The mixture was concentrated to half of its volume and 200 mL of water was added. A white precipitate formed. It was filtered and dried to afford 25.9 g of the oxime (93%) . ϊ HN R (DMSO) : d 7.61 (t, 1H) ; 7.85 (d, 1H ) ; 7 . 96 ( d, 1H ) ; 8 . 00 ( s , 1H ) ; 8 . 21 ( s , 1H ) ; 11 . 61 ( s , 1H ) . Part B. Preparation of 3- (3-cyanophenyl)-5-carbomethoxy methyl-ιsoxazolm-5-ylcarboxylιc acid 3-cyanobenzaldehyde oxime (26.9 g, 0.18 mol) and ltacomc acid monomethyl ester (31.8 g, 0.22 mol) were added together with 600 mL of THF. To the above mixture was added bleach ( 467 mL of 0.67M aqueous solution) dropwise at room temperature. The reaction mixture was then stirred at RT under N 2 for 12h. The THF was removed vacuo. The aqueous mixture was diluted with aqueous NaOH and then extracted with ethyl acetate. After residual organic solvents were removed from the aqueous mixture, it was acidified with aqueous HCl. A white precipitate formed and it was filtered and dried to give 39.4 g of the desired product (74%). T -HNMR (DMSO): d 3.12 (m, 2H) ; 3.63 (s, 3H) ; 3.66 (d, 1H) ; 3.95 (d, 1H);7.68 (t, 1H) ; 7.85 (d, 1H) ; 7.95 (d, 1H) ; 8.04 (d, 1H) ; 8.12 (s, 1H) . Part C. Preparation of 3- (3-cyanophenyl) -5- (4- cyanophenyl)aminocarbonyl-5-carbomethoxymethyl- isoxazolme 3- (3-Cyano henyl)-5-carbomethoxy methyl-isoxazolm-5- ylcarboxylic acid (1.00 g, 3.47 mmol) , 4-cyanoaniline (0.41 g, 3.47 mmol), and (2-(lH-benzotπazol-1-yl)- 1, 1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (1.11 g, 3.47 mmol) were added together with DMF (25 mL) and tnethylamme (2 mL) . The mixture was stirred at room temperature under N 2 for 48 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic solution was washed with brme, dried over MgS0 4 and concentrated. It was then purified by chromatography (silica gel, 30-50% EtOAc m hexane) to give 0.33 g of the desired product (24%) . MS 406, (M+NH 4 ) + - T HNMR (CDC1 3 ) : d 3.06 (d, IH) ; 3.32 (d, IH) ; 3.69 (s, 3H); 3.78 (q, 2H) , 7.51-7.62 (m, 3H) ; 7.71 (d, 2H); 7. 70 (s, IH) , 7.85 (d, IH) ; 7.92 (s, IH) ; 8.81 (s, IH) . Part D. Preparation of 3-amidinophenyl-5- (4- amid ophenyl) -ammocarbonyl-5-carbomethoxymethyl- isoxazolme, Bistπfluoroacetic Acid Salt 3- (3-Cyanophenyl) -5- (4-cyanophenyl)aminocarbonyl-5- carbomethoxymethyl-isoxazolme (0.63 g, 1.62 mmol) was dissolved m 10 mL of anhydrous methanol and 30 mL of CHC1 . The mixture was cooled in an ice-bath and HC1 gas was bubbled-in until the solution was saturated. The reaction mixture was sealed and placed at 0°C for 12 h. The reaction mixture was concentrated to dryness, and dried under vacuum. The resulting solid was dissolved in 20 mL of anhydrous methanol and ammonium acetate (0.77 g, 10 mmol) was added. The reaction mixture was sealed and stirred at RT for 12 h. The mixture was concentrated and precipitated with ether. The precipitate was filtered and purified by HPLC (C18 reversed phased) eluted with 0.5% TFA in H 2 0/CH 3 CN to give 0.20 g of the bisbenzamidine TFA salt (20%) . MS 423.2, (M+H) + ; 212.1, (M+2H) 2+ . i H R (DMSO-d 6 ) : d 3.20 (m, 2H) ; 3.58 (s, 3H) ; 3.70-4.02 (m, 2H) ; 7.65-8.09 (m, 8H) ; 9.04 (s, 2H) ; 9.18 (s, 2H) , 9.30 (s, IH) ; 9.40 (s, 2H) ; 10.49 (s, IH) . Example 2 3- n-Amidmophenvl) -5- r (2-naphthvlsulfonvl)ammolmethyl- lsoxazolme Trifluoroacetic Acid Salt Part A. Preparation of 3- (3-cyanophenyl) -5-hydroxymethyl- lsoxazolme 3-Cyanobenzaldehyde oxime (27.57 g, 0.189 mol) and allyl alcohol (21.95 g, 0.378 mol) were added together with 1000 mL of THF. The reaction mixture was cooled to 0°C. To the above mixture was added bleach (480 mL of 0.67M aqueous solution) dropwise. The reaction mixture was allowed to slowly warm to RT under N 2 for 12h. The THF was removed in vacuo. The aqueous mixture was extracted with ethyl acetate. The combined organic extracts were triturated with diethyl ether. A white precipitate formed and it was filtered and dried to give 20.78 g of the desired product (54%). : HNMR (DMSO-d 6 ) : d 3.16-3.56 (m, 5H) , 4.74 (m, IH) , 4.98 (t, 3H) , 7.62 (t, IH) , 7.86 (dd, IH) , 7.98 (m, IH) . Part B. Preparation of 3- (3-cyanophenyl) -5- (4- methylphenylsulfonyloxy)methylisoxazolme 3- (3-Cyanophenyl)-5-hydroxymethylιsoxazolme (1.0 g, 4.95 mmol) and p-toluenesulfonyl chloride (0.95 g, 4.98 mmol) were dissolved in 5 mL of pyridine and stirred at RT under N 2 for 12 h. After diluting with saturated aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate. The combined organic extracted were back-extracted with water, dried with MgS0 4 , and then the solvent was removed m vacuo to give 1.53 g (87%) of the desired compound as a white solid. "HNMR (DMSO-d 6 ) : d 3.15 (dd, IH) , 3.51 (dd, IH) , 4.14 (m, 2H) , 4.97 ( , IH) , 7.36 (m, IH) , 7.44 (d, IH) , 7.63 (t, IH) , 7.75 (m, 2H) , 7.95 (m, 2H) , 8.55 (d, IH) . Part C. Preparation of 3- (3-cyanophenyl) -5-azιdomethyl- lsoxazolme 3- (3-Cyanophenyl) -5- (4- methylphenylsulfonyloxy)methylisoxazolme (1.00 g, 2.81 mmol) and sodium azide (0.55 g, 8.42 mmol) are dissolved 10 mL of DMSO and stirred at RT under N 2 for 72 h. After diluting with water, the mixture was extracted with ethyl acetate, dried with MgS0 4 , and then the solvent was removed m vacuo to give 0.64 g (100%) of the desired compound as a white solid. HNMR (CDC1 3 ) : d 3.24 (dd, IH) , 3.46 (m, 2H) , 3.61 (dd, IH) , 5.00 (m, IH) , 7.56 (t, IH) , 7.67 (d, IH) , 7.95 (m, 2H) . Part D. Preparation of 3- (3-cyanophenyl) -5-amιnomethyl- lsoxazolme 3- (3-Cyanophenyl) -5-azιdomethylιsoxazolme (0.64 g, 2.81 mmol) and 10% palladium on carbon (0.10 g) are added to 50 mL of ethanol and stirred at RT under H 2 for 4 h. The reaction mixture was filtered through celite and then the solvent was removed m vacuo to give 0.57 g (100%) of the desired compound as a white solid. X HNMR (CDC1 3 ) : d 2.90 (m, IH) , 3.06 (m, IH) , 3.18 (dd, IH) , 3.36 (dd, IH) , 4.88 (m, IH) , 7.32 (t, IH) , 7.48 fd, IH) , 7.95 (m, 2H) . Part E. Preparation of 3- (3-cyanophenyl) -5- [ (2- naphthylsulfonyl)amino]methylisoxazolme 3- (3-Cyanophenyl)-5-ammomethylιsoxazolme (0.56 g, 2.81 mmol) was dissolved in 20 mL of DMF and 2- naphthanenesulfonyl chloride (0.68 g, 3.00 mmol) and pyridine (0.48 mL, 6.2 mmol) were added. The reaction mixture was allowed to stir at RT under N 2 for 12h. After diluting with saturated aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate, dried with MgS0 4 , and then the solvent was removed in. vacuo . The crude product mixture was chromatographed on silica gel eluted with ethyl acetate/hexane (1:3) to give 0.30 g (27%) of the desired compound as a white solid. X HNMR (DMSO-d 6 ) : d 3.03 (m, 2H) , 3.22 (dd, IH) , 3.49 (dd, IH) , 4.81 (m, IH), 7.65 (m, 3H) , 7.83-8.08 ( , 5H) , 8.12 (m, 3H) . Part F. Preparation of 3- (3-amidinophenyl) -5- [ (2- naphthylsulfonyl)amino]methylisoxazolme Trifluoroacetic 3- (3-Cyanophenyl) -5- [ (2- naphthylsulfonyl)amino]methylisoxazolme (0.30g, 0.77 mmol) was dissolved m 50 mL of MeOH. The reaction mixture was cooled m an ice/salt bath (-5°C) , and HC1 gas was bubbled-m for 2h. The mixture was sealed, allowed to warm to RT, and stirred for 12h. The solvent was removed m vacuo and the resulting solid was dried and used m the next step. The lmidate formed above was added with ammonium carbonate (0.73 g, 7.6 mmol) to 50 mL of methanol. The mixture was sealed and stirred at RT for 12h. The crude benzamidine was purified by HPLC fC18 reverse phase) eluted with 0.5% TFA in H 2 0/CH 3 CN to give 0.03 g of the benzamidine TFA salt (9.5%). MS 409.3, (M+H) \ X HNMR (DMSO-d 6 ) : d 3.03 (t, 2H) , 3.22-3.58 (m, 2H) , 4.82 (m, IH) , 7.67-7.73 (m, 3H) , 7.85 (m, 2H) , 7.95 (d, IH) , 8.06 ( , 2H), 8.11-8.18 (m, 3H) , 9.27 (s, IH) , 9.43 (s, IH) . Example 3 4-amιdmophenyl f3- (3-amidinophenyl)-5-Carbomethoxy- ιsoxazolm-5-vllacetamιde, Bistrifluoroacetic Acid Salt Part A. Preparation of N-4-cyanophenyl 3-carboxy-3- butenamide Itaconic anhydride (0.56 g, 5.0 mmol) and 4- cyanoanilme (0.71 g, 6.0 mmol) were added together with 25 mL of CHC1 . The mixture was stirred at RT under N 2 for 1/2 h. It was then refluxed for 12 h. The mixture was cooled and the solid formed was filtered and dried (1.06 g, 92%). MS 248, (M+NH 4 ) + . Part B. Preparation of 4-cyanophenyl [3- (3-cyanophenyl) - 5-carboxy-ιsoxazolιn-5-yl]acetamide N-4-cyanophenyl 3-carboxy-3-butenamide (1.06 g, 4.6 mmol) and 3-cyanobenzaldehyde oxime (0.67 g, 4.6 mmol) were dissolved in 50 mL THF. Bleach (12 mL of 0.67M solution) was added dropwise at RT under N 2 . The mixture was stirred at RT for 12 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. It was then washed with 0.1N HCl and brme, dried over MgS0 and concentrated to a solid. The solid was washed with CH 2 Cl 2 to give 0.81 g off-solid (47%). MS 392, (M+NH 4 ) + . Part C. Preparation of 4-amιdmop enyl [3- (3- amidmophenyl) -5-Carbometoxy-isoxazolin-5-yl]acetamide, Bistπfluoroacetic Acid Salt 4-cyanophenyl [3- (3-cyanophenyl) -5-carboxy- ιsoxazolm-5-yl]acetamide (0.30 g, 0.80 mmol) was dissolved in 20 mL of CHCI3 and 10 mL of MeOH. It was cooled in an ice-bath and HCl gas was bubbled-in until the solution was saturated. It was sealed and stirred at RT for 12 h. The solvents were removed in vacuo and the resulting solid was then dried under vacuum. The solid was dissolved in 20 mL of MeOH and ammonium acetate ( 0.37 g) was added. The reaction mixture was sealed and stirred at RT for 12 h. It was concentrated and then precipitated with ether, the solid was filtered and then purified by HPLC (C18 reversed phased) eluted with 0.5% TFA H 2 O/CH 3 CN to give 84 mg of the bisbenzamidme TFA salt (16%). MS 423.2, (M+H) + . i HNMR (DMSO-d 6 ) : d 3.72 (S, 3H) ; 3.60-4.09 (m, 4H) ; 7.70-8.10 (m, 8H) ; 8.90 (br.S, IH) ; 8.95 (br.s, IH) , 9.20 (d, 2H) ; 9.40 (s, IH) ; 10.68 (s, IH) . Example 4 3 - ( 3 -amidinophenyl ) - 5- \ 2 ' -ammosul fonyl- f l , 1 ' 1 -biohenyl- 4 -vl l aminocarbonyl- 5-carbomethoxy methyl- isoxazolme , Tπ fluoroacet c Acid Salt Part A. Preparation of 2- (t- butylamino ) sul fonylphenylboronic acid To a solution of 34.0 g (0.16 mol) of benzene-N- (t- butylsulfonamide m 500 mL of THF under N 2 was added 160 mL (0.36 mol) of 2.25M n-butyllith um in hexane over 35 mm, keeping the temperature between 0°-2°C. The reaction mixture was allowed to warm to room temperature over 1.5h, during which time a th_,ck precipitate formed. Tπisopropylborate (46 mL, 0.20 mol) was added, keeping the temperature below 35°C. After lh, the reaction mixture was cooled, IN HCl (260 mL) was added, and the mixture was stirred for 30 mm. After diluted with 520 mL of water, the mixture was extracted with 3x400 mL of ether. The combined organic extracts were extracted with 3x250 mL of IN NaOH. The aqueous extracts were acidified to pH 1 with 6N HCl, and then extracted with 3x250 mL of ether. The ether extracts were washed with 250 mL of brme, dried over MgSθ 4 , and the solvents were removed m vacuo to yield 45 g of a thick oil. After addition of Toluene (45 mL) , the mixture was agitated for lh on the rotary evaporator. A small quantity of solid formed, which was used to induce partial solidification of the remaining crude product. Addition toluene (150 mL) was added, and the mixture was reduced to 1/2 volume m vacuo, keeping the temperature from 0°-10°C. The resulting precipitate was collected and washed with hexane, then dried under vacuum to give 24.6 g (60%) of the title compound as white crystals, m.p. 118°-119°C. 1HNMR (CDC1 3 ) : d 1 . 18 ( s , 9H ) ; 5 . 13 ( s , IH ) ; 6 . 29 ( br s , 2H) ; 7 . 53 (m, 2H ) ; 7 . 82 ( d , IH ) ; 8 . 00 ( d, IH ) . Part B. Preparation of 2' -t-butylammosulfonyl-4-nιtro- [1,1' ] -biphenyl A mixture of 4.4 g (0.020 mol) of l-bromo-4- mtrobenzene and 5.14 g (0.020 mol) of 2-(t- butylammo)sulfonylphenylboronic acid , 1.16 g of tetrakis(triphenylphosphme) palladιum(O) (0.001 mol), 0.32 g of tetrabutylammonium bromide (0.001 mol), and 20 mL of 2M aqueous sodium carbonate were refluxed with 180 mL of benzene under N 2 for 5.5h. After cooling the mixture was diluted with methylene chloride and water. the two phases were separated and organic phase was washed with water and brine, dried over MgSθ 4 and concentrated. The resulting solid was recrystallized from EtOAc/hexane to afford 3.25 g of the desired biphenyl. (49%) . HNMR (CDCI3): d l.07(s, 9H) ; 3.60 (br s, 2H) ; 7.29 (d, IH) ; 7.59 (m, 2H) ; 7.69 (d, 2H) ; 8.20 (d, 2H) ; 8.30 (d, 2H) . Part C. Preparation of l-Bromo-4-t- butoxycarbony1ammobenzene To a mixture of NaH (4.13, 0.14 mol) THF was added 4-bromoanιlιne. The resulting mixture was refluxed under N 2 for lh. It was then cooled and di-t-butyl dicarbonate (33 g, 0.15 mol) was added. After stirred for l/2h, more NaH (4.13 g, 0.14 mol) was added and the reaction mixture was refluxed under N overnight. The reaction mixture was cooled and carefully quenched with water. The mixture was extracted with ether. The combined organic solution was washed with saturated aqueous NH 4 CI and saturated aqueous NaHC0 3 , dried over MgSθ 4 , and concentrated. It was then purified by chromatography on silica gel eluted with hexane to yield 27.2 g of the desired product (80%) . iHNMR (CDCI3) : d 1.52 (s, 9H) ; 6.48 (br s, IH) ; 7.27 (d, 2H) ; 7.40 (d, 2H) . Part D. Preparation of 2 ' -t-butylammosulfonyl-4-ammo- [1,1' ] -biphenyl Method A: A suspension of 3.00 g (0.009 mol) of 2'-t- butylammosulfonyl-4-nιtro- [1, 1 '] -biphenyl and 0,30 g of 10% Pd/C in 90 mL of methanol was stirred at room temperature under H 2 (gas) d at ) for l/2h. The solubility of the starting material was very poor in methanol, so 60 mL of ethyl acetate was added and the mixture was stirred for 4h. The reaction mixture was filtered through celite and the f_J. rate was concentrated. The crude product was recrystallized from benzene/hexane to give 2.32 g (85%) of the aniline. !HNMR (CDCI3) : d 0.99 (s, 9H) ; 3.72 (br s, 1H);3.83 (br s, 2H); 6.76 (d, IH) ; 7.27 (d, IH) ,- 7.33 (d, 2H) ; 7.43 (t, IH); 7.53 (t, IH) ; 8.14 (d, IH) . MS m/e 305 (M+H) + . Method B: A mixture of 12.8 g (0.047 mol) of l-Bromo-4-t- butoxycarbonylaminobenzene and 12.3 g (0.048 mol) of 2- (t-butylammo) sulfonylphenylboronic acid , 3.0 g of tetrakis (triphenylphosphme) palladιum(O) (0.0026 mol), 0.80 g of tetrabutylammonium bromide (0.0024 mol), and 13.8 g (0.10 mol, in 30 ml of water) potassium carbonate were refluxed with 300 mL of toluene under N 2 for 6h. The toluene was removed in vacuo and the residue was dissolved in methylene chloride and water. The two phases were separated and organic phase was washed with water and brme, dried over MgS0 and concentrated, the crude product was purified by chromatography on silica gel eluted with EtOAc/hexane (1:3) to afford 12.66 g of the desired biphenyl. (67%) . The protected ammobiphenyl compound (2.80 g, 6.9 mmol) was stirred with 10 mL of triflouroacetic acid and 20 mL of methylene chloride at room temperature for 2h. The solvents were removed m vacuo. The residue was dissolved in methylene chloride and precipitated with hexane to give 1.20 g of the desired product as the TFA salt. i HNMR (DMSO-de) : d 1.01 (ε, 9H) ; 6.80 (s, IH) ; 7.20-7.68 (m, 8H);8.03 (d, IH) . Part E. Preparation of 3- (3-cyanophenyl)-5-N- [2 '-t- butylammosulfonyl- [1,1']-biphenyl-4-yl]amιnocarbonyl-5- carbomethoxy methyl-isoxazolme 3- (3-cyanophenyl)-5-carbomethoχy methyl-ιsoxazolιn-5- ylcarboxylic acid (0.50 g, 1.73 mmol) was refluxed with 10 mL of acetonitrile and 0.76 mL (10.4 mmol) of thionyl chloride for lh under N 2 . The solvent was removed m vacuo. Residual thionyl chloride was removed by adding toluene and then evaporating to dryness. The resulting solid was dissolved in 20 mL of THF and 2'-t- butylammosulfonyl-4-ammo- [1,1'] -biphenyl, TFA salt (0.60 g, 1.40 mmol) was added followed by triethylam e (1.5 mL, 10.4 mmol) . The reaction mixture was stirred at RT and the reaction was completed in less than 30 mm. The mixture was diluted with ethyl acetate and the solution was washed with water and br e. It was dried over MgSθ 4 and concentrated. The crude product mixture was chromatographed on silica gel eluted with methylene chloride/ethyl acetate (9:1) to give 0.57 g of the desired product (71%). MS 575.2, (M+H) + . i H MR (CDC1 3 ): d 0.95 (s, 9H) ; 3.03 (d, IH) ; 3.27 (d, 1H);3.60 (d, IH) ; 3.66 (s, 3H); 3.78 (d, IH) ; 7.19 (d, IH) ; 7.39-7.71 (m, 8H); 7.83 (d, IH) ; 7.92 (s, IH) ; 8.09 (d, IH) ; 8.68 (s, IH) . Part F . Preparation of 3 - ( 3 -cyanophenyl ) - 5 -N- [ 2 ' - ammosulfonyl - [ 1 , 1 ' ] -bιphenyl-4-yl ] ammocarbonyl - 5 - carbomethoxy methyl-isoxazolme 3- (3-Cyanophenyl) -5-N- [2 '-t-butylammosulfonyl- [1,1'] -bιphenyl-4-yl]aminocarbonyl-5-carbomethoxy methyl¬ isoxazolme (1.12 g, 1.95 mmol) was refluxed with 25 ml of trifluoroacetic acid under N 2 for l/2h. The TFA was removed m vacuo, the residue was dissolved in methylene chloride and then precipitated with ether to give 1.0 g of white solid (99%). MS 519.2, (M+H) + . i HNMR (CDCI 3 ): d 3.14 (d, IH); 3.40 (d, IH) ; 3.76 (s, 3H) ,- 3.85 (dd, 2H) ; 4.40 (br s, 2H) ; 7.35 (d, IH) ; 7.48-7.80 (m, 8H) ; 7.83 (d, IH) ; 8.01 (s, IH) ; 8.18 (d, IH) ; 8.82 (s, IH) . Part G. Preparation of 3- (3-amidinophenyl) -5-N- [2 ' - ammosulfonyl- [1,1'] -biphenyl-4-yl]aminocarbonyl-5- carbomethoxy methyl-isoxazolme, Trifluoroacetic Acid Salt 3- (3-Cyanophenyl) -5-N- [2 ' -ammosulfonyl- [1, 1' ]- biphenyl-4-yl]aminocarbonyl-5-carbomethoxy methyl¬ isoxazolme (1.2 g, 1.93 mmol) was dissolved in 90 mL of CHCI 3 and 20 mL of MeOH. The reaction mixture was cooled in an ice-bath, and HCl gas was bubbled-in for 30 mm until the solution was saturated. The mixture was sealed and placed at 0°C for 12h. The solvents were removed in vacuo and the resulting solid was dried and used in the next step. The lmidate formed above was added with 0.92 g (12.0 mmol) of ammonium acetate and 30 mL of methanol. The mixture was sealed and stirred at RT for 12h. The crude benzamidine was purified by HPLC (C18 reversed phased) eluted with 0.5% TFA in H 2 0/CH 3 CN to give o.47 g of the benzamidine TFA salt (37%). MS 536.4, (M+H) + . i HNMR (DMSO-de) : d 3.20 ( , 2H) ; 3.48 (s, 3H) ; 3.70-4.01 (m, 2H); 7.20-7.32 (m, 4H) ; 7.52 (m, 2H) ; 7.72 (d, 2H) ; 7.88 (d, IH); 7.98 (d, IH) ; 8.05 (d, IH) ; 8.07 (s, IH) ; 9.24 (S, 2H) ; 9.40 (s, 2H); 10.05 (s, IH) . Example 5 and Example 6 3- (3-amidinophenyl) -5- [ [ (2 '-ammosulfonyl- [1,1']- bιphenyl-4-yl)-methyl]aminocarbonyl]-5- (carbomethoxymethyl) isoxazolme, trifluoroacetic acid salt (Ex.5) 3- (3-amidinophenyl) -7- (2 '-ammosulfonyl- [1,1'] -biphenyl- 4-yl)methyl [l-oxa-2,7-dιazaspιro[4,4]non-2-ene-6,8- diones,trifluoroacetic acid salt (Ex.6) Part A. Preparation of 2 ' -t-butylammosulfonyl-4- am omethyl- [1,1'] -biphenyl 2 '-t-butylamιnosulfonyl-4-methyl- [1,1']-biphenyl (prepared by the same method described in Part B of Exaple 1) (1.57 g, 5.18 mmol) was refluxed with N- bromosuccmamide (0.92 g, 5.18 mmol) and AIBN (0.10 g) in 50 mL of CCI 4 for 2h. The mixture was cooled and the precipitae was flltered-off. The filtrate was concentrated to an off-white solid. The resulting solid was dissovled in 20 mL of DMF and sodium azide (0.67 g, 10.3 mmol) was added, the mixture was heated to 100 °C for 6 h under N 2 . The reaction mixture was cooled and pourted into water. It was extracted with EtOAc. The combined organic solution was washed with br e and dried over MgSθ 4 . It was the concentrated to a white solid, this solid was the added together with 0.2 g of Pd(OH) , 0.5 mL of concentrated HCl, and 100 mL of MeOH. The mixture was placed under balloon H 2 for 5 h. The resulting mixture was filtered through celite and washed with MeOH. The filtrate was concentrated and precipitated with Et 2 0 to give 1.32 g of white solid (72 %) . MS (DCI) 336 (M+NH 4 ) + , 319 (M+H) +. Part B. Preparation of 3- (3-cyanophenyl) -5-N- [2 ' -t- butylam osulfonyl- [1,1'] -bιphenyl-4- methyl] aminocarbonyl-5-carbomethoxy methyl-isoxazolme This compound was prepared by the same method described m Part G of Example 4 using 2'-t- butylammosulfonyl-4-ammomethyl- [1, 1 '] -biphenyl and 3- (3-cyanophenyl) -5-carbomethoxy methyl-ιsoxazolm-5- ylcarboxylic acid as the starting materials. MS (DCI) 606 (M+NH 4 ) + . Part C. Preparation of 3- (3-amidinophenyl) -5- [ [ (2 ' - ammosulfonyl- [1,1'] -bιphenyl-4-yl.) - methyl]aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme, trifluoroacetic acid salt (EX 5) and 3- (3- amidinophenyl) -7- (2 ' -ammosulfonyl- [1,1'] -bιphenyl-4- yl)methyl [l-oxa-2, 7-dιazaspιro[4,4]non-2-ene-6, 8- diones, trifluoroacetic acid salt (EX 6) . 3- (3-cyanophenyl) -5-N- [2 ' -t-butylaminosulfonyl- [1,1']- bipheny1-4-methy1]aminocarbonyl-5-carbomethoxy methy1- isoxazolme was subjected to the Pmner - amidine reaction protocol described in Part D of Example 1. The crude product mixture was purified by HPLC (C18 reversed phased) eluted with 0.5 % TFA H 2 O and CH 3 CN to give Compounds Ex 5 and Ex 6 as the TFA salts. Ex 5: MS (ESI) 518.4, (M+H) + . Ex 6 : MS (ESI) 550.4, (M+H) + . Example 7 3- (3-amidinophenyl) -5- [ (4-benzenesulfonylphenyl-l- yl)aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme, trifluoroacetic acid salt Part A: Preparation of 4-amιnodιphenylsulphone To a suspension of 4-nιtrodιphenylsulphone (1.00 g, 3.80 mmol) and Pd-C ( 61.6 mg, 5%) in MeOH (50 mL) was added 3N aqueous HCl (1.30 mL, 3.90 mmol) . The mixture was placed under H2 at 50 psi for 4h. It was filtered through celite and washed with MeOH. The filtrate was concentrated and preticipated with ether to give 0.79 g of pale orange solid (77%) . MS 234.1, (M+H)+. T-HNMR (DMSO-d 5 ) : d 6.61 (d, 2H) ; 6.85 (br. s, 2H) ; 7.55 (m, 5H) , 7.81 (d, 2H) . Part B: Preparation of 3- (3-cyanophenyl) -5- [ (4- benzenesulfonylpheny1-1-y1)aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme This compound was prepared by the method described in Part C of Example 1 using 3- (3-cyanophenyl) -5- carbomethoxy methyl-ιsoxazolιn-5-ylcarboxylιc acid and 4- ammodiphenylsulphone as starting materails. MS 504.2, (M+H) + . ! H MR (CDCI3) : d 3.02-3.34 (m, 2H) , 3.69 (s, 3H); 3.78 (m, 2H) , 7.48 (t, 3H) ; 7.52 (t, IH) , 7.75 (d, 3H); 7.90 (m, 6H) ; 8.78 (br.s, IH) . Part B: Preparation of 3- (3-amidinophenyl) -5- [ (4- benzenesulfonylphenyl-1-yl)aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme, trifluoroacetic acid This compound was prepared as described in Part D of Example 1. MS 521.2, (M+H) + . Example 8 3 - ( 3 -amιdmophenvl ) -5- ( 2 ' -ammosulfonyl- f 1 . 1 ' 1 -binhenvl - 4-vl ) aminocarbonyl - 5- ( tet azol-1 -vl ) methvl-isoxazolme , Tri f l uoroacetic Acid Salt Part A. Preparation of 3- (3-cyanophenyl) - -Carbomethoxy- 5- (tetrazol-1-yl)methyl-isoxazolme 1H-Tetrazole(0.89 g, 14.0 mmol) and K 2 CO 3 were added together with 50 mL of DMF. Methyl 2- (bromomethyl) acrylate (2.5 g, 14.0 mmol) was added. The mixture was stirred at room temperature under 2 for 12h. The mixture was poured into water and extracted with EtOAc. The combined organic solution was washed with brine, dried over MgSθ 4 , and then concentrated to give 1.63 g of methyl 2- (tetrazolemethyl)acrylate. This crude product mixtre was added together with 3- cyanobenzaldehyde oxime prepared as described in Example 1 (1.42 g, 9.69 mmol) and THF (50 mL) . To the above mixture was added dropwise bleach (25 mL of 0.67M solution) . The resulting mixture was stirred at room temperature under N 2 for 3h. The THF was removed. The mixture was diluted with water and extracted with EtOAc. The combined organic solution was washed with brine, dried over MgS0 4 , and concentrated. It was purified by chromatography (silica gel, 5-15% EtOAc in CH 2 C1 2 ) to give 1.61 g of the desired product and 0.50 g of the regioisomer 3- (3-cyanophenyl) -5-Carbomethoxy-5- (tetrazol- 2-yl)methyl-isoxazoline. l UNMR (DMΞO-d 6 ) : δ3.78 (s, 3H) ; 3.80-4.10 (q, 2H) ; 5.09-5.20 (q, 2H) ; 7.68 (t, IH) ; 7.98 (d, IH) ; 8.07 (s, IH) ; 9.45 (s, IH) . MS(ES + ) 313.1 (M+H) + . Part B. Preparation of 3- (3-cyanophenyl) -5-Carboxylιc acιd-5- (tetrazol-l-yl)methyl-ιsoxazolιne 3- (3-Cyanophenyl) -5-Carbomethoxy-5- (tetrazol-1-yl- methyl) -isoxazolme (1.60 g, 5.12 mmol) was added together with 75 mL of THF. LiOH ( 12 mL of 0.5 M aqueous solution) was added. The mixture was stirred at room temperature under N 2 for lh. The THF was removed. The mixture was diluted with water and acidified with concentrated HCl. It was extracted with EtOAc. The combined organic solution was washed with brme, dried over MgSθ4, and concentrated to a white solid (1.54 g) . T HNMR (DMSO-d 6 ): 53.70-4.02 (q, 2H) ; 5.02-5.18 (q, 2H) ; 7.67 (t, IH); 7.97 (d, IH) ; 8.04 (s, IH) ; 9.42 (s, IH) . MS(ES + ) 299 (M+H) + . Part C. Preparation of 3- (3-cyanophenyl) -5- [2 '-t- Butylammosulfonyl- [1,1' ]-biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl-isoxazolme 3- (3-Cyanophenyl) -5-Carboxylιc acιd-5- (tetrazol-1- yl)methyl-isoxazolme (0.55 g, 1.84 mmol) was refluxed with CH 3 CN (20 mL) and SOCl 2 (1.34 mL, 18.4 mmol) under N 2 for lh. The solvent was remove^!. Residual SOCl 2 was removed by dissolving in toluene and then removing the solvent to dryness. The resulting solid was dissolved in CH 2 CI 2 (20 mL) . 2 '-t-Butylaminosulfonyl-4-cLnu.no- [1,1' ] - biphenyl prepared as described in Example 4 (0.28 g, 0.92 mmol) was added followed by Et 3 N (1.5 mL, 18.4 mmol). The mixture was stirred at room temperature under N 2 for 1/2 h. It was diluted with CH 2 C1 2 and washed with water and brme. It was dried over MgSθ 4 and concentrated. The desired product was the purified by chromatography (silica gel, 20% EtOAc in CH 2 CI 2 ) to give 0.59 g off- white solid. i HNMR (DMSO-d 6 ) : 61.01 (s, 9H) ; 3.90-4.10 (q, 2H) ; 5.08-5.16 (q, 2H) ; 6.70 (s, IH) , 7.24-7.38 (m, 3H), 7.50-7.77(m, 5H) , 7.98-8,03 (m, 3H) ; 8.12 (s, IH) ; 9.42 (s, IH) . MS(ES + ) 585.2 (M+H) + . Part D. Preparation of 3- (3-amidinophenyl)-5- [2'- ammosulfonyl- [1,1']-bιphenyl-4-yl]amιnocarbonyl-5- (tetrazol-l-yl)methyl-ιsoxazolιne, Trifluoroacetic Acid Salt 3- (3-Cyanophenyl) -5- [2 ' -t-Butylaminosulfonyl- [1,1']- bipheny1-4-y1]aminocarbonyl-5- (tetrazol-1-y1)methyl- isoxazolme (0.41 g, 0.70 mmol) was dissolved in anhydrous CHCI 3 (20 mL) and anhydrous CH 3 OH (5 mL) . HCl gas was bubbled-in until the solution was saturated (about 15 mm) . The reaction mixture was sealed and placed in a refrigerator for 12 h. The solvents were removed. The resulting solid was dried under vacuum. The lmidate formed above was dissolved in 20 mL of anhydrous CH 3 OH. Ammonium acetate (0.55 g, 7.0 mmol) was added. The mixture was sealed and stirred at room temperature for 12 h. The solvent was removed. The solid was dissolved in CH 3 CN/H 2 0/TFA, and purifed by reversed phase HPLC (Ciβ reversed phase column, 0.5% TFA in H 2 O/CH 3 CN) to give the desired TFA salt (0.15 g) . *HNMR (DMSO-d 6 ) : 53.89-4.16 (q, 2H) ; 5.13-5.31 (q, 2H) ; 7.22-7.48 (m, 5H) , 7.52-7.78(m, 5H) , 7.91 (d, IH) ; 8.00- 8,08 (m, 3H); 9.12 (s, 2H) ; 9.41 (s, 2H) ; 9.43 (s, IH) . MS(ES + ) 546.3 (M+H) + . Example 9 3- ( -amidinophenyl) -5- (2 ' -ammosulfonyl- f1.1 ' 1 -binhenyl- 4-vl )oxvmethvl-5-ethoxvmethvl-isoxazolme. Trifluoroacetic Acid Salt Part A. Preparation of 3- (3-cyanophenyl) -5-ethoxymethyl- 5- (4-bromophenoxy)methyl-isoxazolme Sodium hydride (0.74 g of 60% oil dispersion, 18.4 mmol) was washed with Petrolium ether and then suspended m 50 mL of THF. To it was added 4-bromophenol (2.89 g, 16.7 mmol) . The mixture was stirred at room temperature for 15 mm, and methyl 2- (bromomethyl) acrylate (2.99 g, 16.7 mmol) was added. The mixture was stirred at room temperature under N 2 for 12 h. The reaction was quenched with ethanol and the solvents were removed. The resulting material was dissovled m EtOAc and washed with water and brine. It was dried over MgS04 and concentrated to 3.93 g of methyl 2- [ (4-bromophenoxy)methyl]acrylate. Methyl 2- [ (4-bromophenoxy) ethyl] acrylate (2.01 g, 7.4 mmol) was dissolved in 50 mL of THF. The mixture was cooled at -78°C under N 2 and DIDAL-H (12.3 mL, 18.5 mmol) was added. The mixture was stirred for 1 h at -78°C and 1 h at -20°C, and then quenched carefully with ethanol and the solvents were removed. The resulting material was dissovled in EtOAc and washed with water and brme. It was dried over gS04 and concentrated. Column chromatography on silica gel (4:1 hexane/EtOAc) gave 0.21 g of corresponding alcohol. Sodium hydride (0.11 g of 60% oil dispersion, 4.4 mmol) was washed with Petrolium etjier and then suspended in 30 L of THF. The mixture was stirred at room temperature for 15 min, and ethyl iodide (0.62 g, 4.0 mmol) was added. The mixture was refluxed under N 2 for 12 h. The reaction was quenched with ethanol and the solvents were removed. The resulting material was dissovled in EtOAc and washed with water and brine. It was dried over MgSθ4, concentrated, chromatographed on silica gel (4:1 hexane/EtOAc) to give 0.38 g of 2-[ (4- bromophenoxy)methyl] -2- (ethoxymethyl) alkene. 2- [ (4-Bromophenoxy)methyl] -2- (ethoxymethyl) alkene (0.38 g, 1.4 mmol) and 3-cyanobenzaldehyde oxime prepared as described in Example 1 (0.21 g, 1.4 mmol) were dissolved in THF (10 mL) . Clorox bleach (3.6 mL of o.67M) was added dropwise. The mixture was stirred at room temperature under N 2 for 12 h. It was diluted with EtOAc and washed with brme. The organic mixture was dried over MgS04, concentrated, and recrystalized from EtOAc/hexane to give 0.48 g of 3- (3-cyanophenyl) -5- ethoxymethyl-5- (4-bromophenoxy)methyl-isoxazolme. Part B. Preparation of 3- (3-cyanophenyl) -5- [2 '-t- Butylammosulfonyl- [1,1'] -bιphenyl-4-yl]oxymethyl-5- ethoxymethyl-isoxazolme 3- (3-Cyanophenyl)-5-ethoxymethyl-5- (4- bromophenoxy)methyl-isoxazolme ( 0.48 g, 1.15 mmol), 2- (t-butylammosulfonylphenyl boronic acid prepared as described in Example 4 (0.38 g, 1.49 mmol), tetrabutyl ammonium bromide (0.062 g, 0.054 mmol), sodium carbonate (0.36 g, 3.4 mmol), water (3.0 mL) , and benzene (50 mL) were added. Nitrogen gas was bubbled through the mixture for 5 mm and tetrakis(triphenylphosphme)palladium was added. The mixture was refluxed under N for 12 h. The solvents were removed. The resulting material was dissovled in EtOAc and washed with water and brine. It was dried over MgSθ 4 , concentrated., chromatographed on silica gel (3:1 hexane/EtOAc) to give 0.18 g of the desired product. ^NMR (CDCI3): δ l.00 (s, 9H) ; 1.21(t, 3H) ; 3.43 (m, 2H) ; 3.73-3.80 (m, 5H) ; 4.20 (m, 2H) ; 7.00 (d, 2H) ; 7.27 (d, IH) ; 7.42 (d, 2H) ; 7.46-7.58 (m, 3H) ; 7.71 (d, IH); 7.98 (m, 2H) ; 8.15 (d, IH) . Part C. Preparation of 3- (3-amidinophenyl) -5- [2 '- ammosulfonyl- [1,1'] -bιphenyl-4-yl]oxymethyl-5- ethoxymethyl-isoxazolme, trifluoroacetic acid salt. 3- (3-Cyanophenyl)-5- [2'-t-Butylaminosulfonyl- [1,1']- bιphenyl-4-yl]oxymethyl-5-ethoxymethyl-ιsoxazolιne (0.18 g, 0.32 mmol) was dissolved in 50 mL of anhydrous methanol. It was cooled to -20°C and HCl gas was bubbled in until the solution was saturated. The mixture was sealed and allowed to stand at 0°C for 12h. The solvent was removed and the solid was dried under vacuum. The resulting solid was dissolved in 50 mL of anhydrous methanol, and ammonium carbonate (0.15 g, 1.6 mmol) was added. The mixture was stirred for 48 h. The solvent was removed. The solid was purified by by reversed phase HPLC (Ci 8 reversed phase column, 0.5% TFA in H 2 0/CH 3 CN) to give 0.13 g of the desired TFA salt (0.15 g) . iHN R (DMSO-d 6 ) : 51.09 (s, 3H) ; 3.40-3.58 (m, 4H) ; 3.68 (q, 2H); 4.17 (q, 2H);6.93 (d 2H) ; 7.15 (s, 2H) ; 7.28 (m, 3H) , 7.46-7.59(m, 2H) , 7.68 (t, IH) ; 7.83 (d, IH) ; 7.82-8.10 (m, 3H); 9.30 (s, 2H) ; 9.39 (s, 2H) . MS(ES + ) 509.4 (M+H) + . Example 10 and Example 11 3 - ( 3 -amιdmophenvl ) -4- ( 2 ' -ammosulfonyl- r i . l ' 1 -binhenyl - 4 -vl ) aminocarbonyl- 5- ethvl- isoxazolme . Tri f luoroacetic Acid Salt 3 - ( 3 -amid- onhenvl ) - 5- ( 2 ' -ammosulfonyl- r i , 1 ' 1 -binhenyl - 4-yl ) amιnocarbonvl-4-methvl-ιsoxaz [ olme . Trif luoroacetic Ac d Salt Part A. Preparation of 3-(3-cyanophenyl)-5-Carbomethoxy- 4-methyl-isoxazolme and 3- (3-cyanophenyl) -4- Carbomethoxy-5-methyl-isoxazolme To a dichloromethane ( lOOmL) solution of 3- cyanophenyl-oximmochloride (2.30 g, 13.65 mmol) and methyl crotonate (1.71 g, 17.05 mmol) was added tnetby1amine (1.39 g, 13.65 mmol) in dichloromethane (5mL) dropwise over 0.5 h. The reaction mixture was stirred at room temperature for 12 h. It was then concentrated to a viscous oil. Chromatography (silica gel, hexane : ethyl acetate 8:2) afforded the desired 4- methylcarboxylate-isoxazolme (0.82g, 25% yield) as a colorless o l. 1 HNMR(CDCl3) δ 1.47 (d, J = 9Hz, 3H) , 3.77 (s, 3H) , 4.09 (d, J = 4.2Hz, IH) , 5.15 (m, IH) , 7.54 (t, IH) , 7.68 (d, J = 7.8Hz, 2H) , 7.94 (d, J = 8Hz, 2H) . MS(ESI) 245, (M+H) + . The 5-methylcarboxylate isoxazolme was also obtained (0.53g, 16% yield) as a colorless o l. 1 HNMR(CDCl3) δ 1.42 (d, J = 8.5Hz, 3H) , 3.81 (s, 3H) , 3.96 (m, IH) , 4.83 (d, J = 4.5Hz, IH) , 7.55 (t, IH) , 7.70 (d, J - 8.0Hz, 2H) , 7.95 (d, J = 7.9Hz, 2H) . MS(ESI) 245, (M+H) + . Part B. Preparation of 3- (3-cyanophenyl)-4-CarboxylIC acid-5-methyl-isoxazolme The 4-ιsoxazolme ester was then carefully hydrolyzed (LiOH, leq.) m THF:water (4:1, 20 mL) to the carboxylic acid (0.75g, 97% yield). 1 HNMR(CDCl3) δ 1.50 (d, J = 8Hz, 3H) , 4.07 (d, J = 7 Hz, IH) , 5.18, (m, IH) , 7.50 (t, IH) , 7.68 (d, J = 8Hz, 2H) , 7.97 (d, J = 8Hz, 2H) . MS(ESI) 231 (M+H) + . Part C. Preparation of 3- (3-cyanophenyl) -4- (2 '-t- butylammosulfonyl- [1,1'] -biphenyl-4-yl)aminocarbonyl-5- methyl-isoxazolme Treatment of the acid from Part C with oxalyl chloride (leq) in dichloromethane followed by addition of a drop of DMF. Reaction mixture was stirred at room temperature for 1.5h and then concentrated to a yelloow oil. This was then redissolved in dichloromethane followed by treatment with 2 *-t-Butylammosulfonyl-4- ammo- [1, 1'] -biphenyl prepared as described in Example 4 (1 eq) and triethyl amine (3 eq. ) . The reaction mixture was stirred at room temperature overnight The reaction mixture was poured into water (lOOmL) and then extracted with ethyl acetate (2X100mL) , It was washed with brme (50mL) and dried (magnesium sulfate) . Evaporation of the solvent afforded crude amide which was purified (column chromatography, silica gel CH2Cl2:MeOH, 9:1) to give 0.35 g (20% yield) colorless oil. 1 HNMR(CDCl3) δ 1.01 (s, 9H) , 1.52 (d, J = 6.5Hz, 3H) , 3.70 (s, IH) , 4.18 (d, J = 5.4Hz, IH), 5.18 (m, IH) , 7.27 (dd, J = 3 and 8Hz, IH) , 7.43-7.54 (m, 7H) , 7.68 (d, J = 8.5Hz, IH) , 8.03 (ds, 2H), 8.17 (sd, 2H) . MS (DCI-NH3) 534 (M+NH4) + . Part D. Preparation of 3- (3-amidinophenyl)-4- (2 ' - ammosulfonyl- [1,1']-bιphenyl-4-yl)aminocarbonyl-5- methyl-isoxazolme The nitrile obtained m Part D was then subjected to the Pmner - amidme reaction protocol described previously to afford 0.15g (colorless crystals) of the desired benzamidine compound after reversed phase HPLC purification. 1 HNMR(DMSO d6) δ 1.44 (d, J = 7.5Hz, 3H) , 4.53 (d, J = 6Hz, IH) , 5.02 (m, IH) , 7.27-7.38 (m, 5H) , 7.55-7.63 ( , 3H) , 7.70 (t, 1H0, 7.80 (d, J = 8.5Hz, IH) , 7.91 (d, J = 8.2hz, IH), 8.00 (dd, J = 1.8 and 7.9Hz, IH), 9.10 (bs, 2H) , 9.44 (bs, 2H) , 10.30 (s, IH) . MS (ESI) 478.3, <M+H) + . Part E. Preparation of 3- (3-amidinophenyl) -5- (2 '- ammosulfonyl- [1,1']-biphenyl-4-yl)aminocarbonyl-4- methyl-isoxazolme This compound was obtained by the same procedure described above using 3- (3-cyanophenyl)-4-Carbomethoxy-5- methyl-isoxazolme as starting material. l-HNMR(DMSO d6) δ 1.38 (d, J = 7.7Hz, 3H) , 4.31 (m, IH) , 5.08 (d, J = 5.4Hz, IH), 7.23-7.38 (m, 5H) , 7.55-7.66 (m, 2H) , 7.69- 7.70 (m, 2H) , 7.88 (d, = 8Hz, IH) , 8.00 (d, j = 8 Hz, IH) , 8.10 (ds, 2H) , 9.20 (bs, 2H0, 9.40 (bs, 2H) , 10.3 (s, IH) . MS(ESI) 478.4, (M+H) + . Example 12 3- (3-amιdιnonhenvl) -5- \ (4- (2 ' -mtronhenoxv) )nhenyl-l- yll ammocarbonyl- 5 -methyl- isoxazolme, Trif luoroacetic Part A. Preparation of 4- (2'-nitrophenoxy)aniline To a stirred DMF (10 mL) solution of p-aminophenol (0.89 g, 8.16 mmol) was added anhydrous potassium carbonate (6.76 g, 48.96 mmol). The reaction mixture was stirred at room temperature for lh and then 2- fluoronitrobenzene (1.152 g, 8.16 mmol) aws added. The reddish brown solution was refluxed for 24h. The reaction mixture was cooled and then quenched with water (200mL) . It was extracted with EtOAc, washed with brme(50mL), and dried with magnesium sulfate. Evaporation of the solvent provided a crude material which was purified via column chromatography (silica gel 9 : 1, hexane : ethyl acetate) to a colorless oil 1.10 g (58% yield); 1 HNMR(CDCl3) δ 3.60 (bs, 2H) , 6.65 (d, J = 8.2Hz, 2H) , 6.88 (d, J = 8.0Hz, 2H), 7.06 (t, IH) , 7.40 (t, IH) , 7.98 (d, J = 8.0Hz, IH) . MS (DCI-NH3) 248 (M+NH4, 100). Part B. Preparation of 3- (3-amidinophenyl) -5- [ (4- (2 '- nitrophenoxy) )phenyl-1-yl]ammocarbonyl-5-methyl- lsoxazolme 3- (3-Cyanophenyl)-5-carboxylιc acιd-5-methyl- isoxazolme prepared by the same procedures described above aws coupled to 4- (2-nitrophenoxy)aniline from Part A as previously described. The resulting product was sub ected to standard Pmner reaction to give the desired amidme. 1 HNMR(DMSO d6) δ 7.74 (s, 3H) , 3.48 (d, J - 19Hz, IH) , 4.04 (d, J = 19Hz, IH) , 7.04 (dd, J = 2.5 and 8Hz, 3H), 7.33 (t, IH) , 7.64-7.77 (m, 3H) , 7.78 (d, J = 8.5Hz, IH) , 7.87 (d, J = 7.5Hz, IH) , 8.03 (t, 3H) , 9.20 (bs, 2H) , 9.41 (bs, 2H) , 10.2(s, IH) . MΞ(ESI) 460.2, (M+H, 100) . Example 13 3- (3-amιdιnonhenvl) -5- (3- fNN-ethyl (nyrιd-2-yl- methvl) 1 aminophenvl-1-vI) aminocarbonyl-5-methyl- isoxazolme. Trifluoroacetic Acid Salt Part A. Preparation of 3- [NN-ethyl (pyπd-2-yl- methyl) ] aniline The title compound was prepared three step sequence via a sequential reductive amination of 3- nitroamlme with 2-pyrιdme carboxaldehyde and acetaldehyde with sodium cycanoborohydride methanol, followed by catalytic (Pd/C) hydrogenation in 29% overall yield. 1 HNMR(CDCl3) δ 1.30 (t, 3H) , 3.60 (q, 2H) , 4.70 (s, 2H) , 6.91 (dd, IH) , 7.05-7.30 ( , 3H) , 7.50 (m, 2H) , 7.65 (t, IH) , 8.60 (d, IH) . MS(ES-I) 258, (M+H, 100) . Part B. Preparation of 3- (3-amidinophenyl) -5- (3- [NN- ethy1 (pyrid-2-y1-methyl) ]am opheny1-1-yl) aminocarbonyl- 5-methyl-ιsoxazolme, Trifluoroacetic Acid Salt 3- (3-Cyanophenyl) -5-carboxylιc acιd-5-methyl- lsoxazolme prepared by the same procedures described above was coupled to 3- [NN-ethyl (pyrid-2-yl- methyl) ]aniline from Part A as previously described. The resulting product was subjected standard Pmner reaction to give the desired amidme. 1 HNMR(DMSO d6> δ 1.12 (t, 3H) , 1.70 (s, 3H), 3.40 (-3.49 (dm, J = 19.6Hz, 3H) , 4.00 (d, J = 19.6 Hz, IH), 4.60 (s, 2H) , 6.34 (dd, J = 2.5 and 8Hz, IH) , 6.99 (t, IH) , 7.04 (d, J = 8.6Hz, IH) , 7.19 (s, IH) , 7.40 (d, J = 8.4HZ, IH) , 7.36 (m, IH) , 7.70 (t, IH) , 7.80 (m, 2H) , 8.05 (ds, 2H) , 8.58 (d, J = 4.4Hz, IH) , 9.06 (bs, 2H) , 9.40 (bs, 2H) , 9.80 (s, IH) . High resolution mass spectrum calcd. for C26 H 29 N 6θ2 457.235199, found 457.233965. The compounds of Tables 1-6 were prepared by the methods of Examples 1-13. The compounds in Tables 1-6 which have asymmetric centers are racemates except where indicated otherwise by (+) or (-) m the column headed o.r. (for optical rotation) m Table 2. TABLE 1 EX# B m (CH 2 ) n R 2 -U-V-Z-D MS 16 - 5 -B-(H ) 399.0 NH -C_ ■ Nw-_ϋV NH i 365.3 NH CH 2 C0 2 H -J- d -tf-NH, 409.2 " _5~ϊ. N NH m NH, 351.3 m 0 CH 2 CONHCH 2 Cθ2Me 480.5 m 0 777 m 2 77) CH 2 C0 Me 592.5 I-BU-HNO 2 S' 8 771 0 CH CO HCH 2 C02Me 593.3 9 771 0 CH 2 CONH(CH 2 ) - 308.2 4-ιmιdazole (M+2H) 2 ' m 0 CH2CONHCH 2 Cθ2Me 607.3 63 CH 2 C0 2 Me — 226.7 (M+2H) 2+ (M+2H) 2+ (M+2H) 2+ TABLE 2 (CH 2 )nR 2 1-2 EX o.r. (CH 2 ) π R 2 # 68 0 N N CH2C02Me 69 0 CH N CH2Cθ2Me 70 (+) 0 N N CH2C02Me 71 (-) 0 N N CH2Cθ2Me 151 CH2CONH2 o-Sθ2N e2 549.4 152 CH2CONH2 o-S02NHMe 535.4 153 CH2C02Me o-SMe 503.4 154 CH2Cθ2Me o-Sθ2Me 535.4 155 Cθ2Me o-Sθ2Me 535.4 156 CH2CONH2 o-Cθ2Me 500.3 157 CH2Cθ2Me o-Cθ2Me 515.4 158 CH2CONH2 o-SOMe 488.3 159 CH2θMe o-SQ2Me 507.4 160 CH2θMe o-Sθ2Et 521.4 161 CH2θMe o-Sθ2-n-Pr 535.4 162 CH2θMe o-S02-i-Bu 549.5 163 CH2-tetrazol-l-yl o-Sθ2Me 545.2 164 0 CH CH CH2-te-razol-l-yl o-Sθ2CF 3 165 (-) CH2-tetrazol-l-yl 0-CF3 535.4 166 (-) CH2-tetrazol-l-yl 0-CF3 536.3 167 CH2-tetrazol-l-yl 0-CF3 168 CH2-tetrazoH-yl 0-CF3 169 CH2-tetrazol-l-yl 0-CF3 170 CH2-iπ_idazol-l-yl 0-CF3 171 CH2-i idazol-l-yl o-Sθ2NH 2 TABLE 3 EX# U (CH 2 ) n R 2 V-(Z)u-(D)u MS (M + H) + 175 CONH CH 3 400.3 178 CONH CH 3 -Q-°X< 409.3 179 CONH CH 3 -ζ_ s °*xx 472.4 180 CONH CH 3 -o-°- 415.3 X3 181 CONH CH 3 -Q-< 416.4 X N-) 182 CONH CH 3 -o-° r 430.3 183 CONH CH 3 - "°- 430.3 ' y$ 184 CONH CH 3 508.4 185 CONH CH 2 OCH 3 523.3 187 CONH 456.4 13 CONH 457.4 190 CONH 366.2 192 CONH 536.2 CH2O CH2θEt χ χ 509.2 S0 2 >NH 2 200 CH2NH H 450.3 S0 2 NH 2 201 CH2NCOCF3 H -O-O 563.3 Sθ2 H 2 TABLE 4 EX# B MS (M + H) + 203 H fl-TS— T5 CH 3 OCH 2 508.4 O S0 2 NH 2 204 H tetrazole- 1 -y 1-CH - 546.4 206 H / Si(Et) 2 Me 564.4 ° S0 2 NH 2 210 5-CH OCH 3 522.3 EX# (M + H) + TABLE 6 PI R X MP(°C ) MS(M+H)* 219 H, CH 140 496.3 220 H, CH 240 508.3 (69%) 221 H^ CH 235 494.3 223 H, CH 175 526.4 224 H,N CH 2 OCH 3 CH 215 526.3 nn 225 -CH 3 CH 245 508.4 226 "^CF -CH 3 CH 238 494.2 Tables 7-15 identify additional representative compounds of this invention which can be prepared by the methods described above. The divalent radicals V m the compounds of Tables 7-11 have the following structures 1 , 4-phenylene pyrιdιn-2, 5-dιyl pyrιmιdιn-2, 5-dιyl F 2-fluoro-1, 4-phenylene -b Cl - 2-chloro-1, 4- phenylene -b CH 3 - 2-methyl-1, 4-phenylene 2, 5-thιophene -O- The pyrιdιn-2 , 5-dιyl and pyrιmιdιn-2, 5-dιyl radicals are bonded to the (Z) u -D moiety at the 5 position. The 2-substιtuted-l,4-phenylene radicals are bonded to the <Z) U -D moiety at the 4 position. The compounds of Tables 7-11 have the structures indicated by the formula "a" under each table heading. The corresponding compounds having the structures of formula "b" under each table heading can be obtained by substituting the appropriate starting material, as illustrated in Examples 10 and 11. TABLE 7 P a rt Cp d < C "2 ) nR- ( Z ) u - D Al CH 2 OMe 1-4-phenylene 2-aminosulfony1pheny1 CH 2 OEt -4-phenylene 2-aminosulfony1pheny1 CH 0-n-Pr 1- -phenylene 2-ammosulfonylphenyl CH 2 0-ι-Pr 1-4-phenylene 2-amιnosulfonylphenyl CH 2 0-n-Bu 1-4-phenylene 2-amιnosulfonylphenyl CH 2 0-ι-Bu 1 -4-phenylene 2-ammosulfonylphenyl CH 2 Ph 1-4-phenylene 2-amιnosulfonylphenvl CH2-pyrazol- 1 - -phenylene 2-ammosulfonylphen l 1-yl CH2-ιmιdazol- 1- -phenylene 2-ammosulfonylphenyl 1-yl CH 2 -tetrazol- 1-4-phenylene 2-aminosulfonylpheny1 1-yl CH2~cetrazol- 1-4-phenylene 2-aminos lfonylphenyl 2-yl CH2-crιazol- 1-4-phenylene 2-aπunosulfonylphenyl 1-yl 13 CH2OCH3 CH2SEt 1- -phenylene 2-amιnosulfonylphenyl 14 CH2OCH3 CH2SO2EC 1- -phenylene 2-ammosulfonylphen l 15 CH 2 OCH 3 CF 3 1-4-phenylene 2-aminosulfonylphenyl 16 CH2OCH3 CH3 1-4-phenylene 2-amιnosulfonylphenyl 17 CH?OCH 3 H 1-4-phenylene 2-amιnosulfonvlDhenvl A2 CH2OCH3 CH?O e pyrιdm-2 , 5- 2-amιnosulfonylphenyl diyl CH2OCH 3 CH-jOEt pyrιdm-2, 5- 2-ammosulfonylphenyl diyl CH2OCH3 CH 2 0-n-Pr pyrιdιn-2, 5- 2-amιnosulfonylphenyl diyl CH OCH. CH2θ-ι-Pr pyrιdιn-2 , 5- ?-ammosul fonvlphenx 1 diyl CH2OCH3 CH2θ-n-Bu pyrιdιn-2, 5- 2-amιnosulfonylphenyl diyl CH 2 OCHj CH 0-l-Bu pyrιdιn-2, 5- 2-aminosulfonylphenyl diyl CH2OCH3 CH 2 Ph pyrιdιn-2, 5- 2-ammosulfonylphenyl diyl CH 2 OCHj CH 2 -pyrazol- pyrιdm-2 , 5- 2-ammosulfonylphenyl 1-yl diyl CH 2 OCH^ CH -ιmιdazol- pyrιdιn-2 , 5- 2-amιnosulfonylpheny1 1-yl diyl CH2OCH3 CH2-tetrazol- pyπdm-2 , 5- 2-ammosulfonylphenyl 1-yl diyl CH2OCH J CH 2 -tecrazol- pyrιdm-2 , 5- 2-ammosulfon lphenyl 2-yl diyl CH2OCH3 CH -tπazol- pyndιn-2, 5- 2-ammosulfonylphenyl 1-yl diyl CH2OCH3 CH 2 SEt pyridιn-2, 5- 2-ammosulfonylphenyl diyl CH2OCH3 CH2S0 2 E pyrιdm-2, 5- 2-aminosulfonylphenyl diyl CH 2 OCH 3 CF 3 pyrιdιn-2, 5- 2-ammosulfonylphenyl diyl CH2OCH3 CH3 pyrιdιn-2, 5- 2-ammosulfonylphenyl diyl CH OCH 3 pyrιdm-2, 5- 2-ammosulfonylphenyl diyl CH2OCH3 CH OMe pyrimidm- 2-amιnosulfonylphenyl 2,5-dιyl CH 2 OCH3 CH 2 OEt pynmidm- 2-ammosulfonylpneny1 2,5-dιyl CH 2 OCH-. CH 2 0-n-Pr pyπmidin- 2-ammosulfonylDheny1 2,5-dιyl CH 2 OCH 3 CH;0-ι-Pr pyrimid - lphenyl 2,5-dιyl CH 2 OCH. CH 0-n-Bu pyrirrαdm- 2-ammosulfonylphenyl 2,5-dιyl CH2OCH3 CH 2 0-ι-Bu pyrimidin- 2-ammosulfonylphenyl 2,5-dιyl CH2OCH3 CH 2 Ph pynmidm- 2-aminosulfony1pheny1 2,5-dιyl CH2OCH3 CH 2 -pyrazol- pyπmidin- 2-ammosulfonylphenyl 1-yl 2,5-dιyl CH2OCH3 CH2 - ιmιdazol - pyπmidin- 2-ammosulfonylphenyl 1 -yl 2,5-dιyl CH2OCH 3 CH2 - tetrazol - pyrimidin- 2-ammosulfonylphenyl 1-yl 2,5-dιyl CH2OCH3 CH 2 -tetrazol- pyrimidm- 2-ammosulfonylphenyl 2-yl 2,5-dιyl CH 2 OCH CH2 - t nazol - pynmidin- 2-ammosulfonylphenyl 1-yl ^,5-dιyl CH2OCH3 CH 2 SEt pyrimidin- 2-aminosulfonylphenyl 2,5-dιyl CH2OCH3 CH 2 S0 2 Et pyrimidm- 2-ammosulfonylphenyl 2,5-dιyl CH2OCH3 CF 3 pyπmidin- 2-amιnosulfonylphenyl 2,5-dιyl CH2OCH 3 CH3 pyrimidm- 2-amιnosulfonylphenyl 2,5-dιyl CH2OCH3 pyπmidin- 2-ammosulfonylphenyl 2,5-dιv] CH 2 OCH 3 CH 2 OMe 2-fluoro-l,4- -ammosulfonylphenyl phenylene CH2OCH3 CH 2 OEt 2-fluoro- , 4- 2-aminosulfon 1pheny1 phenylene CH2OCH3 CH 2 0-n-Pr 2-fluoro-1 , 4- -ammosulfonylphenyl phenylene CH2OCH3 CH 2 0-ι-Pr 2-fluoro-l,4- 2-ammosulfonylphenv1 phenylene CH?OCH. CH-O-n-Bu 2-fluoro-l , - -ammosulfonylphen\ 1 phenylene 2-ammosulfonylphenyl -ammosulfonylphenyl 2-ammosulfonylphenyl 2-aminosulfonylphenyl 2-amιnosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl -ammosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-amιnosulfonylphenyl 2-aminosulfonylphenyl 2-ammosulfonylphenyl -ammosulfonylphenyl 2-amιnosulfonylphenyl 2-amιnosulfonylphenyl -ammosulfonylphenvl 2-amιnosulfonvlohenvl CH 2 OCH] CH 2 Ph 2-chloro-l,4- 2-ammosulfonylpnenvl phenylene CH 2 OCH j CH 2 -pyrazo l - 2-chloro-l, 4- 2-amιnosulfonylphenγ1 1 -yl phenylene CH2OCH3 CH 2 - ιmιdazol - 2-chloro-l,4- 2-amιnosulfonylphenyl 1 -yl phenylenel CH 2 OCH3 CH 2 -tecrazol - 2-chloro-l , 4- 2-aminosulfony1pheny1 1 -yl phenylene CH 2 OCHj CH 2 -tet razol - 2-chloro-l , 4- 2-aminosulfonylphenyl 2 -y l phenylene CH2OCH3 CH 2 - t πazol - 2-chloro-l ,4- 2-am osulfonylphenyl 1 -yl phenylene CH2OCH 3 CH 2 SEt 2-chloro-l , 4- 2-aminosulfonylphenyl phenylene CH 2 OCHj CH 2 S0 2 EC 2-chloro-l, 4- 2-ammosulfonylphenyl phenylene CH2OCH3 CF3 2-chloro-l,4- 2-aminosulfonylphenyl phenylene CH 2 OCH 3 CH3 2-chloro-l,4- 2-aminosulfonylphenyl phenylene CH 2 OCH 3 H 2-chloro-l,4- 2-amιnosulfonylphenyl Dhenvleπe 1 , 4-phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-arrunosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1 ,4-phenylene 2-ammosulfonylphenyl 1, -phenylene 2-ammosulfonylphenyl 1, 4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-amιnosulfonylphenyl 1 , 4-phenylene 2-aminosulfony1pheny1 1 ,4-phenylene 2-amιnosulfonylphenyl 1 , -phenylene 2-ammosulfonylphenyl CH3 CH 2 -tetrazol- 1 , -phenylene 2-amιnosulf onylpheny 1 2-yl CH3 CH2-criazol- 1 ,4-phenylene 2-amιnosulfonylphenyl 1-yl 1 , 4 -phenylene 2 -ammosul fonylphenyl 1 , 4 -phenylene 2-ammosul fonylphenyl 1 , 4 -phenylene 2-aπunosul fonylphenyl 1 , 4 -phenylene 2 -ammosul fonylphenyl 1 , 4-phenylene 2-amιnosul fonylphenyl CH^ CH 2 OMe pyrιdm-2,5- 2 -ammosul f ony lpnenyl diyl CH3 CH 2 OEC pyrιdιn-2 , 5- 2-ammosul fonylphenyl diyl CH-< CH 0-n-Pr pyrιdιn-2 , 5- 2-amιnosulfonylphenyl diyl Crh CH 2 0-ι-Pr py ιdιn-2 , 5- 2-amιnosulfonylphenyl diyl CH 3 CH 2 0-n-Bu pyrιdm-2 , 5- 2 -ammosul fonylphenyl diyl CH3 CH 2 0-ι-Bu pyrιdιn-2 , 5- 2-amιnosul fonylphenyl diyl CH 3 CH 2 Ph pyrιdm-2 , 5- 2 -ammosul fonyl phenyl diyl CH3 CH -pyrazol- pyrιdm-2 , 5- 2-ammosulfonylphenyl 1-yl diyl CH3 CH -ιmιdazol- pyrιdm-2 , 5- 2-ammosulfonylphenyl 1-yl diyl CH3 CH 2 -tetrazol- pyrιdm-2 , 5- 2-ammosulf onylpheny 1 1-yl diyl CH3 CH 2 -tetrazol- pyrιdιn-2 , 5- 2-ammosulfonylphenvl 2-yl diyl CH 3 CH 2 -trιazol- pyrιdm-2 , 5- 2-ammosulfonylphenyl 1-yl diyl CH3 CH 2 SEC pyrιdιn-2 , 5- 2-ammosulfonylpnenyl diyl CH-, CH 7 SO? Et pyrιdι n- 2 , 5 - -aminosulfonvΪDheriv 1 diy l Cf- CF 3 pyr idm- 2 , 5 - -ammosulfonylphenyl diyl CH 3 Cl-h pyπdι n-2 , 5 - 2-aminosulfonylphenyl di yl CH3 pyπ dι n- 2 , 5 - 2-ammosulfonylphenyl divl CH3 CH 2 OMe pyrimidin- 2-aminosulfonylphenyl 2,5-dιyl CH3 CH 2 OEt pyπmidin- 2-aminosulfonylphenyl 2,5-diyl CH3 CH2θ-n-Pr pyrimidin- -aminosulfonylphenyl 2,5-diyl CH3 CH2θ-ι-Pr pyri idin- 2-aminosulfonylphenyl • 2,5-dιyl CHj CH 2 0-n-Bu pyπmidin- 2-aminosulfonyIpheny1 2,5-diyl CH3 CH2O-1-BU pyrimidin- 2-aminosulfonylphenyl 2,5-diyl CH3 CH 2 Ph pyrimidin- 2-amιnosulfonylphenyl 2,5-dιyl CH3 CH 2 -pyrazol- pyπmidm- 2-aminosulfonylphenyl 1-yl 2,5-dιyl CH3 CH 2 -lmidazol- pyrimidm- 2-amιnosulfonylphenyl 1-yl 2,5-diyl CH3 CH 2 -tetrazol- pyrimid - 2-aminosulfonylphenyl 1-yl 2,5-dιyl CH3 CH 2 -teCrazol- pyπmidin- 2-aminosulfonylphenyl 2-yl 2,5-dιyl CH-- CH 2 -tnazol- pyrimidin- 2-aminosul 1 1-yl 2,5-dιyl CH-. CH 2 SEC pyrimidm- -ammosulfonylphenyl 2,5-dιyl CH-. CH 2 SO ? Et pyri idin- 2-ammosulfonylphenyl 2,5-dιyl 15 CH3 CF3 pvrimidin- 2-amιnosulf onylphen.1 2.5-dιyl 16 CH3 CH3 pyrimidm- 2-amιnosulfonylpheny1 2,5-dιyl 17 CH3 H pyrimidm- 2-ammosulfonylphenyl 2,5-diyl B4 1 CH 3 CH 2 OMe 2-fluoro-1 , 4- 2-amιnosulfonylpheny1 phenylene 2 CH3 CH 2 OEt 2-fluoro-l,4- 2-ammosul fonylphenyl phenylene 3 CH CH 2 0-n-Pr 2-fluoro-1 , 4- 2-ammosulfonylphen 1 phenylene 4 CH3 CH 2 0-ι-Pr 2-fluoro-1 , 4- 2-amιnosulfonylpheny1 phenylene 5 CH3 CH 2 0-n-Bu 2-fluoro-l,4- 2 -ammosul fonylphenyl phenylene 6 CH 3 CH 2 0-ι-Bu 2-fluoro-l,4- 2-ammosul fonylphenyl phenylene 7 CH3 CH 2 Ph 2-fluoro-l,4- 2-aminosulfonylphenyl phenylene 8 CH3 CH 2 -pyrazol- 2-f luoro-1 , 4 - 2-ammosul fonylphenyl 1-yl phenylene 9 CH3 CH 2 -ιmιdazol- 2-fluoro-l , 4- 2-amιnosulfonylphenyl 1-yl phenylene 10 CH3 CH 2 -cetrazol- 2-f luoro-1 , 4- 2-ammosul fonylphenyl 1-yl phenylene 11 CH3 CH 2 -tetrazol- 2-fluoro-1 , 4- 2-am osulfonylphenyl 2-yl phenylene 12 CH3 CH 2 -trιazol- 2-fluoro-1, - 2-aminosulfonylphenyl 1-yl phenylene 13 CH3 CH2SEC 2-fluoro-l,4- 2-ammosulfonylphenyl phenylene 14 CH3 CH 2 S0 2 Et 2-fluoro-l,4- ?-aπunosulfonylphen 1 phenylene 15 CH3 CF3 2- f luoro-1 , 4 - 2-ammosul f onylohenv I phenylene CH3 CH-. 2-f luoro-1 , - 2-amιnos l fonylphenyl phenylene CH3 H 2-fluoro-1 ,4- 2-aminosulfonylphenyl phenylene CH3 CH 2 OMe 2-chloro-l , 4 - 2-ammosulf onylphenyl phenylene CH 3 CH 2 OEt 2-chloro-l,4- 2-aminosulfonylphenyl phenylene CH 3 CH 2 0-n-Pr -chloro-1 , 4 - 2-ammosulf onylphenyl phenylene CH3 CH 0-ι-Pr 2-chloro-l,4- 2-aminosulfonylphenyl phenylene CH CH 2 0-n-Bu 2-chloro-l,4- 2-amιnosulfonylphenyl phenylene CH3 CH 2 0-ι-Bu 2-chloro-l,4- 2-aminosulfonylphenyl phenylene CH3 CH 2 Ph 2-chloro-l , 4- 2-ammosulfonylphenyl phenylene CH 3 CH 2 -pyrazol- 2-chloro-l , 4- 2-ammosulfonylphenyl 1-yl phenylene CH3 CH 2 -ιmιdazol- 2-chloro-l , 4- 2-ammosulfonylphenyl 1-yl phenylene CH CH 2 -cetrazol- 2-chloro-l , 4- 2-ammosulfonylphenyl 1-yl phenylene CH3 CH 2 -tetrazol- 2-chloro-l , 4- 2-ammosulfonylphenyl 2-yl phenylene CH3 CH 2 -tπazol- 2-chloro-l , 4- 2-amιnosul fonylphenyl 1-yl phenylene CH3 CH 2 SEt 2-chloro-l , 4- 2-ammosulfonylphenyl phenylene CH3 CH 2 S0 2 Et 2-chloro-l , 4- 2-ammosulfonylphenyl phenylene CH3 CF3 2-chloro-l , 4- 2-ammosulfonylphenyl phenylene CH3 CH3 2-chloro-l , 4- 2-amιnosulfonylphenyl phenylene 17 CH-. 2-cnloro-l , - 2-ammosulfonylphenyl phenvlene Cl 1, 4-phenylene 2-ammosulfonylphenyl 1 , -phenylene 2-aminosulfonylphenyl 1 , -phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1, 4-phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 , -phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-aminosul onylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 , -phenylene 2-ammosulfonylphenyl 1, 4-phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1, 4-phenylene 2-aminosulfonylphenyl 1 , -phenylene 2-aminosulfonylphenyl , 4-phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-ammosulfonvlphenvl C2 CH 2 0Me pyπdm-2 , 5- 2-aminosulfonylphenyl diyl CH 2 OEt pyrιdιn-2 , 5- 2-ammosulfonylphenyl diyl CH 2 0-n-Pr pyrιdιn-2 , 5- 2-aminosulfonylphenyl diyl CH 0-ι-Pr pyπdm-2 , 5- 2-aminosulfony1pheny1 diyl CH 2 0-n-Bu pyrιdm-2 , 5- 2-ammosulfonylphenyl diyl CH ? 0-ι-Bu pyrιdm-2 , 5- 2-amιnosuifonylphenyl diyl CH 2 Ph pyπdιn-2,5- '-ammosulfonylpnen 1 diyl H CH 2 -pyrazol- pyrιdm-2,5- 2-am nosulfonylphenyl 1-yl diyl H CH2-ιmιdazol- pyrιdm-2,5- 2-aminosulfonylphenyl 1-yl diyl H CH 2 -t-etrazol- pyndιn-2,5- 2-amιnosulfonylphenyl 1-yl diyl H CH 2 --etrazol- pyrιdm-2,5- 2-ammosulfonylphenyl 2-yl diyl H CH 2 -tπazol- pyrιdm-2,5- 2-ammosulfonylpneny1 1-yl diyl H CH SEt pyrιdιn-2,5- 2-ammosulfonylphenyl diyl H CH 2 S0 2 EC pyrιdιn-2,5- 2-amiπosulfonylpneny1 diyl CFi pyrιdιn-2 , 5- 2-ammosulfonylphenyl diyl CH 3 pyrιdm-2 , 5- 2-amιnosulfonylphenyl diyl pyrιdιn-2, 5- 2-ammosulfonylphenyl diyl CH 2 OMe pyπmidm- 2-aminosulfonyIpheny1 2,5-dιyl CH OEt pyπmidm- 2-aminosulfonylphenyl 2,5-diyl CH 2 0-n-Pr pyπmidin- 2-ammosulfonylphenyl 2,5-dιyl CH?0-ι-Pr pyπmidm- 2-aminosulfonylphenyl 2,5-dιyl CH 2 0-n-Bu pyrimidm- 2-amιnosulfonylpnenyl 2,5-dιyl CH?0-ι-Bu pyπmidm- 2-amιnosulfonylpnem 1 2, 5-diyl CH 2 Ph pyrimidin- 2-aminosulfonylphenyl 2,5-dιyl H CH 2 -pyrazol- pyrimidm- 2-amιnosulfonylphenyl 1-yl 2,5-dιyl H CH 2 -ιmidazol- pyrimidm- 2-ammosulfonylphenyl 1-yl 2,5-dιyl H CH 2 -tecrazol- pyrimidm- 2-amιnosulfonylphenyl 1-yl 2,5-dιyl H CH 2 -tetrazol- pyrimidm- 2-ammosulfonylphenyl 2-yl 2,5-dιyl H CH2-trιazol- pyrimidm- 2-amιnosulfonylphenyl 1-yl 2,5-dιyl H CH2SE pyrimidin- 2-amιnosulfonylphenyl 2,5-dιyl H CH 2 Sθ2E pyrimidm- 2-aminosulfonylphenyl 2,5-diyl H CF3 pyrimidm- 2-aminosulfonylphenyl 2,5-diyl H CH3 pyrimidm- 2 -am osul fonylphenyl 2,5-diyl H H pyrimidin- 2-ammosulfonylphenyl 2,5-diyl H CH 2 OMe 2-fluoro-1 , 4- 2-ammosulfonylphenyl phenylene H CH2θEt 2-f luoro-1 , 4- 2-ammosulfonylphenyl phenylene H CH2θ-n-Pr 2-fluoro-1 , 4- 2-amιnosulfonylpnenyl phenylene H CH 2 0-ι-Pr 2-fluoro-l,4- 2-ammosulfonylphenyl phenylene H CH 2 0-n-Bu 2-fluoro-l,4- 2-ammosulfonylphenyl phenylene H CH 2 0-ι-Bu 2-fluoro-l,4- 2-ammosulfonylphenyl phenylene H CH 2 Ph 2-f luoro-1 , 4- 2-arnιnosul fonylphenyl phenylene H CH 2 -pyrazol- 2-f luoro-1 , 4- 2-ammosulf onylphen.1 1-yl phenylene CH 2 -ιmιdazol - 2-fluoro-l,4- 2-aminosulfonylpheπ. _ 1-vl phenylene 10 CH2~tetrazol- 2-fluoro-1, - 2-ammosulfonylphenyl 1-yl phenylene 11 CH 2 -tetrazol- 2-fluoro-l,4- 2-aminosulfonylphenyl 2 -y l phenylene CH 2 - C πazol - 2- luoro-1 ,4- 2-ammosulfonylphenyl 1 -y l phenylene 13 CH 2 SEt 2-fluoro-1 , 4- 2-ammosulfonylphenyl phenylene 14 CH 2 S0 2 EL 2-fluoro-1 , 4- 2-aminosulfonylphenyl phenylene 15 CF 2-fluoro-1 , 4- 2-aminosulfonylphenyl phenylene 16 CHT 2-fluoro-l,4- -aminosulfony1pheny1 phenvlene 17 2-fluoro-1 ,4- 2-ammosulfonylphenyl phenylene :5 CH O e 2-chloro-l, - 2-aminosulfonylphenγ1 phenylene CH OEt 2-chloro-l, 2-aminosulfonylphenyl phenylene CH 2 0-n-Pr 2-chloro-l , 4 2-aminosulfony1pheny1 phenylene CH2θ-ι-Pr 2-chloro-l , 4 2-aminosulfonylphenvl phenylene CH 2 0-n-Bu 2-chloro-l , 4- 2-aminosulfonylphenyl phenylene CH 2 0-ι-Bu 2-chloro-l, 4 -aminosulfonylphenyl phenylene CH 2 Ph 2-chloro-l , 4 2-aminosulfonylphenvl phenylene CH 2 -pyrazol- 2-chloro-l, 2-aminosulfonylphe 1 -yl phenylene CH 2 -ιmιdazol - 2-chloro-l, 4 -aminosulfonvlphen 1 1-yl phenylene 10 H CH 2 -cecrazol- ?-chloro-l , - 2-amιnosul fonylphenyl 1-yl phenylene 11 H CH2-t_etrazol- 2-chloro-l , 4- 2-ammosulfonylpnenyl 2-yl phenylene 12 H CH 2 -trιazol- 2-chloro-l, 4- 2-amιnosulfonylphenyl 1-yl phenylene 13 H CH 2 SEt 2-chloro-l , 4- 2-ammosulfonylphenyl phenylene 14 H CH S0 2 Et 2-chloro-l,4- 2-ammosulfonylphenyl phenylene 15 H CFj 2-chloro-l, - 2-amιnosulfonylphenyl phenylene 16 H CH3 2-chloro-l , 4- 2-ammosulf onylpneny 1 phenylene 17 H H 2-chloro-l , 4- 2-amιnosulfonylphenyl phenylene C6 1 H CH2θMe 2-methyl -1 , 4 - 2-ammosulfonylphenyl phenylene 2 H CH2θEt 2-methyl-l , 4- 2-amιnosulfonylphenyl phenylene 3 H CH2θ-n-Pr 2-methyl-l, 4- 2-aminosulfonylphenyl phenylene 4 H CH 2 0-ι-Pr 2-methyl -1 , 4 - 2-ammosulfonylphenyl phenylene 5 H CH2θ-n-Bu 2-methyl-1, - 2-amιnoεulfonylpnenyl phenylene 6 H CH 2 0-ι-Bu 2-methyl-l ,4- 2-amιnosulfonylphenyl phenylene 7 H CH 2 Ph 2-methyl-l, 4- 2-ammosulfonylphenyl phenylene 8 H CH 2 -pyrazol- 2-methyl -1 , 4- 2-ammosulfonylphenyl 1-yl phenylene 9 H CH2-ιmιdazol- 2-methyl-l , 4- 2-amιπosulfonylpneny 1 1-yl phenylene 10 H CH 2 -tetrazol- 2-methyl-1 , 4- 2-aminosul lpπenyl 1-yl phenylene H CH 2 -tetrazol - 2-methyl -1 , - 2 -aminosul fo lphen 1 2-yl phenylene H CH2-tπazol- 2-meth l-l , 4 - 2-ammosulfonylphenyl 1-yl phenylene H CH 2 SEt 2-methyl-l, 4- 2-ammosulfonylphenyl phenylene H CH 2 S0 2 Et 2-methyl-l, 4- 2-aminosulfonylphenyl phenylene H CF3 2-methyl-l , 4- 2-ammosul onylphenyl phenylene H CH3 2-methyl-l , 4- 2-ammosulfonylphenyl phenylene H H 2-methyl-l , - 2-amιnosulfonylphenyl phenylene H CH 2 OMe 1 , 4-phenylene 2- trifluoromethylphenyl H CH 2 OEt 1, -phenylene 2- tπfluoromethylphenyl H CH 2 0-n-Pr 1 ,4-phenylene 2- tr1f1uorome hy1pheny1 H CH 2 0-ι-Pr 1,4-phenylene 2- tr1f1uoromethy1pheny1 H CH 2 0-n-Bu 1 , 4-phenylene 2- rif luoromethylphenyl H CH 2 0-ι-Bu 1,4-phenylene 2- tπf luoromechyl phenyl H CH 2 Ph 1,4-phenylene 2- tr1f1uoromechy1pheny1 H CH 2 -pyrazol- 1 , 4-phenylene 2- 1-yl trifluoromethylphenyl H CH 2 -ιmιdazol- 1 , 4-phenylene 2- 1-yl trifluoromethylphenyl H CH 2 -cetrazol- 1 , 4-phenylene 2- 1-yl trifluoromethylpnenyl H CH 2 -tecrazol- 1 , -phenylene 2- 2-vl trifiuorornethylphe 1 H CH -t nazol - 1 , 4 -phenylene ~> - 1-yl trifluoromethylphenyl H CH 2 SEt 1,4-phenylene 2- πfluoromethylphenyl H CH 2 S0 2 Et 1,4-phenylene 2- trifluoromethylphenyl H CF3 1 , 4-phenylene 2- trifluoromethylphenyl H CH 3 1,4-phenylene 2- trifluoromethylphenyl H H 1,4-phenylene 2- trifluoromethylphenyl H CH 2 OMe pyrιdm-2,5- 2- diyl trifluoromethylpnenyl H CH OEt pyrιdιn-2,5- 2- diyl trifluoromethylphenyl H CH 2 0-n-Pr pyπdιn-2,5- 2- diyl trifluoromethylphenyl H CH 2 0-ι-Pr pyrιdιn-2,5- 2- diyl trifluoromethylphenyl H CH 2 0-n-Bu pyrιdιn-2,5- 2- diyl trifluoromethylphenyl H CH 2 0-ι-Bu pyrιdm-2,5- 2- diyl trifluoromethylphenyl H CH 2 Ph pyrιdm-2,5- 2- diyl trifluoromethylphenyl H CH 2 -pyrazol- pyrιdm-2,5- 2- 1-yl diyl trifluoromethylphenyl H CH 2 -ιmιdazol- pyπdm-2,5- 2- 1-yl diyl trifluoromethylphenyl H CH 2 -tetrazol- pyrιdm-2,5- 2- 1-yl diyl trifluoromethylpnenyl H CH 2 -tetrazol- pyrιdm-2,5- 2- 2-yl diyl t 1fluoromethylphenyl H CH 2 -trιazol- pvrιdm-2,5- 2- 1-yl diyl trifluorometnylpne 1 13 CH ? SEt pyrιdm-2, 5- diyl trif luor ome thv 1 phenyl 14 CH 2 S0 2 Et pyrιdιn-2 , 5- i. - diyl tri luoromethylphenyl 15 CF-, pyrιdιn-2, 5- . - diyl trif luoromethylphenyl 16 CHj pyπdm-2, 5- 2 - diyl trif luoromethylphenyl 17 pyrιdm-2, 5- 2- diyl tri f luoromethv 1 phenv 1 D3 CH ? OMe pyπmidm- 2,5-dιyl trifluoromethylphenyl CH 2 OEt pyπmidin- 2- 2,5-dιyl trifluoromethylphenyl CH 2 0-n-Pr pyπmidin- 2- ^,5-dιyl trifluoromethylphenyl CH 2 0-ι-Pr pyrimidin- 2- 2,5-dιyl trifluoromethylphenyl CH 2 0-n-Bu pyrimid - 2- 2,5-dιyl trifluoromethylphenyl CH 0-ι-Bu pynmidin- ._- 2,5-dιyl trifluoromethylphenyl CH 2 Ph pyrimidm- 2- 2,5-dιyl tπfluoromethylphenyl CH 2 -pyrazol- pyrimidin- 2- 1-yl 2,5-dιyl tπfluoromethylphenyl CH -ιmιdazol- pyπmidin- 2- 1-yl 2,5-dιyl tπfluoromethylphenyl 10 CH 2 -tetrazol- pyπmidin- 1-yl 2,5-dιyl trifluoromethylphenyl CH 2 -tetrazol- pyπmidin- ._- 2-yl 2,5-dιy trifluorometnylphenvl CH 2 -tr azol- pynmidin- 1-yl 2,5-dιyl trifluoromethylphenyl 13 CH 2 SEt pynmidin- 2,5-dιyl trifluoro et.Tv lpnenv 1 H CH S0 2 Et pvπmidin- 2- 2,5-dιyl trifluoromethylphenyl H F3 pyrimid - 2 - 2,5-dιyl trifluoromethylphenyl H CH3 pyrimidm- 2- 2,5-dιyl trifluoromethylphenyl H H pyrimid - 2- 2 , 5-dιyl tr fluoromethylphenyl H CH 2 OMe 2-fluoro-1, - 2- phenylene trifluoromethylphenyl H CHpOEt 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl H CH 2 0-n-Pr 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl H CH 2 0-ι-Pr 2-fluoro-l,4- 2- henylene trifluoromethylphenyl H CH 2 0-n-Bu 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl H CH 2 0-ι-Bu 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl H CH 2 Ph 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl H CH 2 -pyrazol- 2-fluoro-1 ,4- 2- 1-yl phenylene trifluoromethylphenyl H CH 2 -ιmιdazol- 2-fluoro-1, - 2- 1-yl phenylene trifluoromethylphenyl H CH 2 -tetrazol- 2-fluoro-1, 4- 2- 1-yl phenylene trifluoromethylphenyl H CH 2 -tetrazol- 2-fluoro-1,4- 2- 2-yl phenylene trifluoromethylphenyl H CH 2 -triazol- 2-fluoro-1 , 4- 2- 1-yl phenylene trifluoromethylphenyl H CH 2 SEt 2-fluoro-l,4- 2- phenylene trifluorometnylphenyl H CH 2 S0 2 Et 2-fluoro-l,4- 2- phenylene trifluorometnylpnenv 1 15 CF 2-fluoro-1 , 4- phenylene trifluoromethylphenyl 16 CH 3 2-fluoro-1 , - _.~ phenylene trifluoromethylphenyl 17 2- luoro-1, 4- 2- phenylene trifluoromethylphenyl D5 CH 2 OMe 2-chloro-l,4- phenylene trifluoromethylphenyl CH 2 OEt 2-chloro-l , 4- 2- phenylene rifluoromethylphenyl CH 2 0-n-Pr 2-chloro-l,4- 2- phenylene trifluoromethylphenyl CH 2 0-ι-Pr 2-chloro-l , 4- 2- phenylene t lfluoromethylphenyl CH 0-π-Bu 2-chloro-l, 4- phenylene trifluoromethylphenyl CH 2 0-ι-Bu 2-chloro-l, 4- 2- phenylene trifluoromethylphenyl CH 2 Ph 2-chloro-l,4- 2- phenylene trifluoromethylphenyl CH 2 -pyrazol- 2-chloro-l,4- _.- 1-yl phenylene trifluoromethylphenyl CH 2 -ιmιdazol- 2-chloro-l, 4- 2- 1-yl phenylene trifluoromethylphenyl 10 CH -tetrazol- 2-chloro-l , 4- 2- 1-yl phenylene trifluoromethylphenyl 11 CH -tetrazol- 2-chloro-l ,4- 2- 2-yl phenylene trifluoromethylphenyl 12 CH -triazol- 2-chloro-l, - 2- 1-yl phenylene trifluoromethylphenyl 13 CH 2 SEt 2-chloro-l , 4- 2- phenylene rifluoromethylphenyl 14 CH 2 S0 2 Et 2-chloro-l, 4- 2- phenylene trlf1uoromethy1pheny1 15 CF-. 2-chloro-l,4- __,~ phenylene trif1uoromethv1Dheπv1 H CH3 2-chloro-l,4- 2- phenylene trifluoromethylphenyl H H 2-chloro-l,4- 2- phenylene trifluoromethylphenyl H CH 2 OMe 2-methyl-l,4- 2- phenylene trifluoromethylphenyl H CH 2 OEt 2-methyl-l, 4- 2- phenylene trifluoromethylphenyl H CH 2 0-n-Pr 2-methyl-l , - 2- phenylene trifluoromethylphenyl H CH 0-ι-Pr 2-methyl-l,4- 2- phenylene trifluoromethylphenyl H CH 2 0-n-Bu 2-methyl-1 ,4- 2- phenylene trifluoromethylphenyl H CH 2 0-ι-Bu 2-methyl-l, 4- 2- p * henylene tri f luoromethylphenyl H CH 2 Ph 2 -methyl - l , 4 - 2 - phenylene trifluoromethylphenyl H CH 2 -pyrazol- 2-methyl-l , - 2- 1-yl phenylene trifluoromethylphenyl H CH 2 -ιmιdazol- 2-methyl-l , 4- 2- 1-yl phenylene trifluoromethylphenyl H CH 2 -tetrazol- 2-methyl-l, - 2- 1-yl phenylene trifluoromethylphenyl H CH 2 -tetrazol- 2-methyl-1, 4- 2- 2-yl phenylene trifluoromethylphenyl H CH 2 -trιazol- 2-methyl-l,4- 2- 1-yl phenylenel trifluoromethylphenyl H CH 2 SEt 2-methyl-l, 4- 2- phenylene trifluoromethylpnenyl H CH 2 S0 2 Et 2-methyl-l,4- 2- phenylene tri luoromethylphenyl H CF3 2-methyl-l,4- 2- phenylene trifluoromethy Iphen 1 H CH3 2-methvl-l,4- 2- phenvlene trifluoromethylpnenv H H 2 -methy l - l , 4 - 2 - phenylene tr fluoromethylphenyl H CH 2 OMe 1 , 4-phenylene 2- trif1uoro ethoxypheny1 H CH 2 OEt 1,4-phenylene 2- trif1uoromethoxypheny H CH 2 0-n-Pr 1 , 4-phenylene 2- trif1uoromethoxypheny1 H CH 2 0-ι-Pr 1 ,4-phenylene 2- tπfluoromethoxypheny1 H CH 2 0-n-Bu 1,4-phenylene 2- trifluoromethoxypheny1 H CH 2 0-ι-Bu 1,4-phenylene 2- trifluorome hoxypheny] H CH 2 Ph 1,4-phenylene 2- tπfluoromethoxyphenyl H CH 2 -pyrazol- 1 , 4-phenylene 2- 1-yl trifluoromethoxyphenyl H CH 2 -imιdazol- 1 , 4-phenylene 2- 1-yl trifluoromethoxyphenyl H CH -tetrazol- 1 ,4-phenylene 2- 1-yl trifluoromethoxyphenyl H CH 2 -tetrazol- 1 , 4-phenylene 2- 2-yl trifluoromethoxyphenyl H CH 2 -tπazol- 1 , 4-phenylene 2- 1-yl trifluoromethoxyphenyl H CH 2 SEt 1,4-phenylene 2- trifluoromethoxyphenyl H CH 2 S0 2 Et 1,4-phenylene 2- trifluoromethoxyphen l H F 1 ,4-phenylene 2- tπfluoromethoxyphenyl H CH3 1 , -phenylene 2 - trifluoromethoxyphenyl H H 1 , -phenylene 2- ^ trifluoromethoxyphen', 1 E2 CH-OMe pyrιdm-2,5- diyl trifluoromethoxyphen> ± diyl trifluoromethoxyphenyl CH 0-n-Pr pyrιdm-2,5- diyl trlf1uo omethoxypheny1 CH 2 0-ι-Pr pyrιdιn-2,5- 2- diyl trifluoromethoxyphenyl CH 2 0-n-Bu pyrιdm-2,5- 2- diyl trifluoromethoxyphenyl CH 2 0-ι-Bu pvrιdιn-2,5- 2- diyl t lf1uorome hoxypheny1 CH Ph pyrιdιn-2,5- 2- diyl trifluoromethoxyphenyl CH 2 -pvrazol- pyrιdιn-2,5- 2- 1-yl diyl trifluoromethoxyphenyl CH -ιmιdazo] - pyrιdιn-2 , 5- 2- 1-yl diyl trlf1uoromethoxypheny1 10 CH 2 -tetrazol- pyrιdιn-2, 5- 2- 1-yl diyl tπfluoromethoxyphenyl 11 CH 2 -tetrazol- pyrιdιn-2, 5- 2- 2-yl diyl trifluoromethoxyphenyl 12 CHj-tnazol- pyrιdιn-2 , 5- 2- 1-yl diyl trifluoromethoxyphenyl 13 CH 2 SEt pyrιdm-2, 5- 2- diyl trifluoromethoxyphenyl 14 CH 2 S0 2 Et pyrιdιn-2, 5- 2- diyl trifluoromethoxyphenyl 15 CF 3 pyrιdιn-2, 5- 2- diyl trifluoromethoxyphenyl 16 CH 3 pyrιdm-2 , 5- 2- diyl trifluoromethoxyphenyl 17 pvπdm-2, 5- - divl trifluorometnoxvoheni 1 E3 CHiOMe p yπmidm- trifluoromethoxyphenyl 2- trif1uoromethoxypheny 1 2- trlf1uorome hoxypheny1 2- tπfluoromethoxyphenyl _.- trifluoromethoxyphenyl _ - trifluoromethoxyphenyl 2- trifluoromethoxyphenyl 2- tπfluoromethoxyphenyl 10 2- tπfluoromethoxyphenyl 11 2- trifluoromethoxyphenyl 12 2- trifluoromethoxyphenyl 13 2- tπfluoromethoxyphenyl 14 2- trifluoromethoxyphenyl 15 2- trifluoromethoxyphenyl 16 2- trifluoromethoxyphenyl 17 2- E4 trifluoromethoxyphenyl trifluorometnoxvpneπvl CH;0-n-Pr 2-fluoro-l, 4- phenylene trifluoromethoxyphenyl 2-f luoro-1 , 4- _.- phenylene trifluoromethoxyphenyl CH 2 0-n-Bu 2-fluoro-l,4- 2- phenylene trlf1uoromethoxypheny1 CH-O-i-Bu 2-fluoro-1 , 4- 2- phenylene trifluoromethoxyphenyl CH 2 Ph 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl 2-fluoro-1 , 4- phenylene trifluoromethoxyphenyl 2-fluoro-l,4- 2- phenylene tπfluoromethoxyphenyl 10 2-fluoro-1 , 4- 2- phenylene trifluoromethoxyphenyl 11 2-fluoro-1, 4- phenylene trifluoromethoxyphenyl 12 2-fluoro-1 , 4- 2- phenylene trlf1uoromethoxypheny1 13 2-fluoro-1 ,4- 2- phenylene trlf1uorome hoxypheny1 14 2-fluoro-1 , 4- 2- phenylene trlf1uoromethoxypheny1 15 CF 2-fluoro-1 , 4- _ ~>- phenylene trifluoromethoxyphenyl 16 CH. 2-fluoro-1, 4- 2- phenylene tπfluoromethoxyphenyl 17 2-fluoro-1, 4- 2- phenylene tπfluoromethoxyphenyl E5 1 CH 2 OMe 2-chloro-l , - 2- phenylene trifluoromethoxyphenyl CH 2 OEt ?-chloro-l , 4- 2- phenylene trlfluoromethoxvpnenyl CH 2 0-n-Pr 2-chloro-l ,4- phenylene tπfluoromethoxvpnenv 1 11 - CH 2 0- ι -Pr 2-chloro-l ,4- phenylene trifluoromethoxyphenyl CH 2 0-n-Bu 2-chloro-l , 4- ^ _ phenylene trifluoromethoxyphenyl CH 2 0-ι -Bu 2-chloro-l , 4- 2- phenylene trifluoromethoxyphenyl CH 2 Ph 2-chloro-l ,4- 2- phenylene rifluoromethoxyphenyl CH 2 -pyrazol - 2-chloro-l, 4- 2- 1 -yl phenylene trifluoromethoxyphenyl CH 2 -ιmιdazol - 2-chloro-l, - 2- 1 -yl phenylene t if1uoromethoxypheny1 10 CH 2 -tetrazol - 2-chloro-l , 4- 2- 1 -yl phenylene tπfluoromethoxyphenyl 11 CH 2 -tetrazol - 2-chloro-l , 4- 2- 2 -yl phenylene trlf1uoromethoxypheny1 12 CH 2 -trιazol- 2-chloro-l, 4- 2- 1-yl phenylene trifluoromethoxyphenyl 13 CH 2 SEt 2-chloro-l,4- 2- phenylene trifluoromethoxyphenyl 14 CH 2 S0 2 Et 2-chloro-l,4- 2- phenylene trifluoromethoxyphenyl 15 CF-j 2-chloro-l , 4- 2- phenylene trifluoromethoxyphenyl 16 CH 3 2-chloro-l,4- 2- phenylene rifluoromethoxypnenyl 17 2-chloro-l , 4- 2- phenylene trifluoromethoxyphenyl E6 CH 2 OMe 2-methyl-l ,4- 2- phenylene trifluoromethoxyphenyl CH 2 0Et 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl CH 2 0-n-Pr 2-methyl-l, 4- phenylene trifluoromethoxyphenyl CH 2 0-ι-Pr 2-methyl-l , 4- phenylene tri f l uoromethoxvpfienyl 5 H CH 0-π-Bu 2 -methyl - 1 , - 2 - phenylene trifluoromethoxyphenyl 6 H CH 2 0-ι-Bu 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl 7 H CH 2 Ph 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl 8 H CH 2 -pyrazol- 2-methyl-l , 4- 2- 1-yl phenylene trifluoromethoxyphenyl 9 H CH 2 -imιdazol- 2-methyl-l, 4- 2- -yl phenylene trifluoromethoxyphenyl 10 H CH 2 -tetrazol- 2-methyl-l ,4- 2- 1-y phenylene trifluoromethoxyphenyl 11 H CH 2 -tetrazol- 2-methyl-l , 4- 2- 2-yl phenylene trifluoromethoxyphenyl 12 H CH 2 -trιazol- 2-methyl-l , - 2- 1-yl phenylene trifluoromethoxyphenyl 13 H CH 2 SEt 2-methyl-l,4- 2- phenylene trifluoromethoxyphenyl 14 H CH 2 S0 Et 2-methyl-l,4- 2- phenylene trifluoromethoxyphenyl 15 H CF 3 2-methyl-l,4- 2- phenylene trifluoromethoxyphenyl 16 H CH 3 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl 17 H H 2-methyl-l, - 2- _ ^ _ ^ phenylene trifluoromethoxyphenyl Fl 1 H CH 2 OMe 1, 4-phenylene 2-trifluoromethyl- sulfonyl-phenyl 2 H CH 2 OEt 1, 4-phenylene 2-trifluoromethyl- sulfonyl-pheny1 3 H CH2θ-n-Pr 1, 4-phenylene 2-trifluoromethyl- sulfonyl-phenyl 4 H CH 2 0-ι-Pr 1,4-phenylene 2-trifluoromethyl- sulfony1-pheny1 5 H CH 2 0-n-Bu , 4-phenylene 2-trifluoromethyl- sulfon 1-oheny 1 CH 2 0-ι-Bu 1,4-phenylene 2-trifluoromethyl- sulfonyl-pheny1 CH 2 Ph 1 , -phenylene 2-1rlf1uoromethy1- sulfonyl-phenyl CH 2 -pyrazol- 1 , 4-phenylene 2-trifluoromethyl- 1-yl sulfonyl-phenyl CH 2 -ιmιdazol- 1 ,4-phenylene 2-trifluoromethyl- 1-yl sulfony1-phenyl 10 CH 2 -cetrazol- 1 , -phenylene 2-trifluoromethyl- 1-yl sulfonyl-phenyl 11 CH 2 -tetrazol- 1 , 4-phenylene 2-1rlf1uo omethy1- 2-yl sulfonyl-phenyl 12 CH 2 -trιazol- 1 , 4-phenylene 2-trifluoromethyl- 1-yl sulfonyl-phenyl 13 CH 2 SEt 1 , 4-phenylene 2-1rlf1uoromethy1- sulfonyl-phenyl 14 CH 2 S0 2 Et l , -phenylene 2-trifluorome hy1- sulfonyl-phenyl 15 CF 3 1 , 4-phenylene 2-trifluoromethyl- sulfonyl-phenyl 16 CH 3 1 , 4-phenylene 2-trifluoromethyl- sulfony1-pheny1 17 1 , 4-phenylene 2-1rlf1uoromethy1- sulfonvl-ohenvl F2 CH 2 OMe pyrιdm-2, 5- 2-trifluoromethyl- diyl sulfonyl-pheny1 CH 2 OEt pyridm-2, 5- 2-trifluoromethyl- diyl sulfonyl-phenyl CH 0-n-Pr pyrιdιn-2, 5- -trifluoromethyl- diyl sulfonyl-phenyl CH 0-ι-Pr pyπdm-2, 5- 2-trifluoromethyl- diyl sulfonyl-pheny1 CH;0-n-Bu pyrιdιn-2 , 5- 2-trifluoromethy1- diyl sulfony1-pheny1 CH?0-ι-Bu pyrιdm-2, 5- 2-trifluoromethyl divl sul onvl -pnenyl CH 2 Ph pyridιn-2 , 5- 2-trifluoromethyl- diyl sulfonyl-pheny1 CH 2 -pyrazol- pyrιdιn-2 ,5- 2- rifluoromethyl- 1-yl diyl sulfonyl-phenyl CH 2 -ιmidazol- pyrιdm-2 , 5- 2-trifluorome hyl- 1-yl diyl sulfonyl-phenyl 10 CH 2 -tetrazol- pyrιdιn-2, 5- 2-trifluoromethyl- 1-yl diyl sulfonyl-phenyl 11 CH 2 -tetrazol- pyridm-2 , 5- 2-trifluoromethyl- 2-yl diyl sulfonyl-phenyl 12 CH 2 -trιazol- pyrιdin-2,5- 2- rifluorome hyl- 1-yl diyl sulfonyl-pheny1 13 CH 2 SEt pyrιdm-2 , 5- 2-trifluoromethy1- diyl sulfonyl-phenyl 14 CH 2 S0 2 Et pyrιdm-2 , 5- 2-trifluoromethyl- diyl sulfonyl-phenyl 15 CF 3 pyrιdm-2 , 5- 2-trifluoromethyl- diyl sulfonyl-phenyl 16 CH 3 pyrιdm-2, 5- 2-trif1uoromethyl- diyl sulfonyl-phenyl 17 H pyridιn-2,5- 2-trifluoromethyl- divl sulfonyl-phenyl F3 1 CH 2 OMe pyrimid - 2-trifluoromethyl- 2,5-diyl sulfon l-phenyl CH 2 OEt pyπmidin- 2-trifluoromethyl- 2,5-diyl sulfonyl-phenyl CH 2 0-n-Pr pyrimidin- 2-trifluoromethyl- 2,5-diyl sulfonyl-phenyl CH 2 0-ι-Pr pyrimidm- 2-trifluoromethyl- 2,5-dιyl sulfonyl-phenyl CH ? 0-n-Bu pyrimidin- 2-1rlf1uoromethy1- 2,5-dιyl sulfonyl-phenyl CH 2 0-ι-Bu pyπmidin- 2-trifluoromethyl ■ 2,5-dιyl sulfonyl-pheny1 CH ? Ph pyrimidin- 2-tri luorome hyl ■ 2,5-dιyl sulfonyl-phenyl CH 2 -pyrazol- pvrimidin- 2-trιfluorome hyl- 1-yl 2,5-dιyl sulfonyl-phenyl CH 2 -ιmιdazol- pyrimidm- 2-trifluoromethy1- 1-yl 2,5-dιyl sulfonyl-phenyl 10 CH 2 -tetrazol- pyπmidm- 2-1rlf1uoromethy1- 1-yl 2,5-dιyl sulfonyl-phenyl 11 CH 2 -tetrazol- pyπmidm- 2-trifluoromethy1- 2-yl 2,5-dιyl sulfonyl-phenyl 12 CHj-triazol- pyrimidin- 2-tπf1uoromethy1- 1-yl 2,5-dιyl sulfonyl-pheny1 13 pyrimidm- 2-trifluoromethyl- 2,5-dιyl sulfonyl-pheny1 14 CH2Sθ2Et pyrimid - 2-trifluoromethyl- 2,5-dιyl sulfonyl-phenyl 15 CF 3 pyπmidin- 2-trifluoromethyl- ^,5-dιyl sulfonyl-phenyl 16 CH 3 pyπmidm- 2-trifluoromethyl- 2,5-dιyl sulfonyl-phenyl 17 pyrimidin- 2-trifluoromethy1- 2,5-dιyl sulfonyl-pheny1 F4 CH 2 OMe 2-fluoro-1, 4- 2- rifluoromethyl- phenylene sulfony1-pheny1 CH 2 OEt 2-fluoro-1, 4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 0-n-Pr 2-fluoro-1,4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 2 0- ι -Pr 2-fluoro-1 , 4- 2-trifluoromethyl- phenylene sulfony1-pneny1 CH 2 0-n-Bu 2-fluoro-1,4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 2 0- ι -Bu 2-fluoro-1 , 4- 2-trifluoromethyl- phenylene sulfonyl-phen 1 CH?Ph 2-fluoro-1 , 4- 2-trifluoromethyl- phenylene sulfonyl-pheny1 CH2 -pyrazol - 2-fluoro-1 , 4- -trifluoromethy 1- 1 -y l phenylene sulfonvl-ohenvl CH2-ιmιdazol - 2-fluoro-l,4- 2-trifluoromethy1- 1-yl phenylene sulfonyl-phenyl 10 CH 2 -tetrazol - 2-fluoro-1 , 4- 2-trifluoromethyl- 1-yl phenylene sulfonyl-pheny1 11 CH;-tetrazol- 2-fluoro-1 ,4- 2-trif1uoromethyl- 2-yl phenylene sulfonyl-phenyl 12 CH 2 -tπazol- 2-fluoro-1 ,4- 2- rif1uoromethy1- 1-yl phenylene sulfonyl-phenyl 13 CH 2 SEt 2-fluoro-1 , 4- 2-tri luoromethyl- phenylene sulfony1-phenyl 14 CH 2 S0 2 Et 2-fluoro-1 , 4- 2-trifluoromethyl- phenylene sulfonyl-phenyl 15 CF 3 2-fluoro-1, 4- 2-trifluorome hyl- phenylene sulfony1-pheny1 16 CH-. 2-fluoro-1 , - 2-trifluoromethy1- βhenylene sulfonyl-phenyl 17 2-fluoro-1,4- 2-trifluoromethyl- phenylene sulfonvl-ohenvl F5 CH 2 OMe 2-chloro-l,4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 2 OEt 2-chloro-l , 4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 2 0-n-Pr 2-chloro-l , 4- 2- rifluoromethyl- phenylene sulfonyl-pheny1 CH 2 0-ι-Pr 2-chloro-l , 4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 2 0-n-Bu 2-chloro-l , 4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 2 0-ι-Bu 2-chloro-l , 4- 2-tri luorome hyl- phenylene sulfonyl-phenyl CH 2 Ph 2-chloro-l ,4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 2 -pyrazol - 2-chloro-l , 4- 2-trifluoromethyl ■ 1-yl phenylene sulfonyl-phenyl CH 2 -ιmιdazol - 2-chloro-l , 4- 2-trifluorome hyl■ 1-yl phenylene sulfonvi-phenvl 1 0 CH,. - tet razol - 2 -chloro- l , 4 - 2-trifluoromethyl- 1 -yl phenylene sulfonyl-pheny1 11 CH 2 - tet razol - 2-chloro-l , - 2-trifluoromethyl- 2 -yl phenylene sulfonyl-phenyl CH 2 - t πazol - 2-chloro-l , 4- 2-trifluoromethyl- 1 -y l phenylene sulfonyl-pheny1 13 CH 2 SEt 2-chloro-l,4- 2-trιfluoro; -thyl- phenylene sulfonyl-pheny1 14 CH 2 S0 2 Et 2-chloro-l , - 2-trifluoromethyl- phenylene sulfonyl-phenyl 15 CF 3 2-chloro-l , 4- 2-trifluorome hyl- phenylene sulfonyl-phenyl 1 6 CH 3 2-chloro-l , 4- 2-tri luoromethyl- phenylene sulfonyl-pheπyl 2-chloro-l , - 2-trifluoromethyl- ghenylene sulfonvl-ohenvl F6 CH 2 OMe 2-methyl-l, 4- 2-trifluorome hyl- phenylene sulfonyl-phenyl CH 2 OEt 2-methyl-l , 4- 2-1rif1uoromethy1- phenylene sulfonyl-phenyl CH 2 0-n-Pr 2-methyl-l,4- 2-tri luoromethyl- phenylene sulfonyl-phenyl CH 2 0-i-Pr 2-methyl-l , 4- 2-tr f1uoromethyl- phenylene sulfonyl-phenyl CH 2 0-n-Bu 2-methyl-l , 4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 2 0-i-Bu 2-methyl-l, 4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 2 Ph 2-methyl-l , 4- 2-trifluoromethyl- phenylene sulfonyl-phenyl CH 2 -pyrazol- 2-methyl-l, 4- 2-trifluoromethyl- 1-yl phenylene sulfonyl-phenyl CH 2 -ιmιdazol- 2-methyl-l , 4- 2-trifluoromethyl- 1-yl phenylene sulfonyl-phenyl 10 CH 2 -tetrazol - 2-methyl-l, 4- 2-trifluoromethyl ■ 1-yl phenylene sulfonyl-phenyl 2-me hoxyphenyl 2-methoxyphenyl 2-methoxypheny1 2-methoxyphenyl 2-methoxyphenyl 2-methoxyphenyl 2-m thoxyphenyl 2-me hoxyphenyl 2-me hoxyphenyl 10 2-methoxyphenyl 11 2-methoxyphenyl 12 2-methoxyphenyl 13 2-methoxyphenyl 14 2-methoxypheny1 15 2-methoxyphenyl 16 2-methoxyphenyl 17 2-methoxyphenyl G3 2-methoxvphenv1 ■ 12C- CH OEt pyπmidin- 2-methoxyphenyl 2,5-dιyl CH 2 0-n-Pr pyrimidm- 2-methoxyphenyl 2,5-dιyl CH 2 0-ι-Pr pynmidin- 2-me hoxyphenyl 2,5-dιyl CH 0-n-Bu pyπmidm- 2-methoxyphenyl 2,5-dιyl CH 2 0-ι-Bu pynmidm- 2-methoxyphenyl 2,5-dιyl CH 2 Ph pyrimidm- 2-methoxyphenyl 2,5-dιyl CH 2 -pyrazol- pyrimidm- 2-methoxyphenyl 1-yl 2,5-dιyl CH2 _ ιmιdazol- pyπmidin- 2-methoxypheny1 1-yl ^,5-dιyl 10 CH -tetrazol- pyπmidm- 2-methoxyphenyl 1-yl 2,5-dιyl 11 CH 2 -tetrazol- pyrimidin- 2-methoxyphenyl 2-yl 2,5-dιyl 12 CH 2 -trιazol- pyri idin- 2-methoxyphenyl 1-yl 2,5-dιyl 13 CH 2 SEt pyrimidm- 2-methoxypheny1 2,5-dιyl 14 CH 2 S0 2 Et pyrimidin- 2-methoxyphenyl 2,5-dιyl 15 CF 3 pyrimidin- 2-methoxyphenyl 2,5-dιyl 16 CH 3 pyrimidm- 2-me hoxyphenyl 2,5-dιyl 17 pyrimidm- 2-methoxypheny1 2,5-dιvl G4 CH2θMe 2-fluoro-l,4- 2-methoxyphenyl phenylene CH 2 OEt 2-fluoro-1 , 4- 2-me hoxyphenvi phenylene 12: 10 11 12 13 14 15 16 17 G5 CH 2 0-ι-Pr 2-chloro-l , 4- 2-methoxyphenyl phenylene CH 2 0-n-Bu 2-chloro-l ,4- 2-methoxyphenyl phenylene CH 2 0-ι-Bu 2-chloro-l ,4- 2-methoxyphenyl phenylene CH 2 Ph 2-chloro-l ,4- 2-methoxyphenyl phenylene CH 2 -pyrazol- 2-chloro-l , 4- 2-methoxyphenyl 1-yl phenylene CH 2 -ιmιdazol - 2-chloro-l , 4- 2-methoxyphenyl 1-yl phenylene 10 CH 2 -tetrazol- 2-chloro-l, 4- 2-methoxyphenyl 1-yl phenylene 11 CH 2 -tetrazol- 2-chloro-l ,4- 2-methoxyphenyl 2-yl [5henylene 12 CH 2 -trιazol- 2-chloro-l , 4- 2-methoxyphenyl 1-yl phenylene 13 CH 2 SEt 2-chloro-l ,4- 2-methoxyphenyl phenylene 14 CH 2 S0 2 Et 2-chloro-l , 4- 2-methoxyphenyl phenylene 15 CF 3 2-chloro-l , 4- 2-methoxypheny1 phenylene 16 CH 3 2-chloro-l , - 2-me hoxyphenyl phenylene 17 2-chloro-l,4- 2-methoxyphenyl phenylene G6 CH2θMe 2-methyl-l , 4- 2-methoxyphenyl phenylene CH2θEt 2-methyl-l , 4- 2-methoxyphenyl phenylene CH 2 0-n-Pr 2-methyl-l , 4- 2-methoxyphenyl phenylene CH?0-ι-Pr 2-methvl-l , 4- 2-methoxypheny phenylene CH 2 0-n-Bu 2-methyl-l , 4- 2-methoxyphen 1 phenylene CH 2 0-ι-Bu 2-methyl-l , 4- 2-methoxyphenyl phenylene CH 2 Ph 2-methyl-l , 4- 2-methoxypheny1 phenylene CH 2 -pyrazol- 2-methyl-l, - 2-methoxyphenyl 1-yl phenylene CH 2 -ιmidazol- 2-methyl-l , 4- 2-methoxyphenyl 1-yl phenylene 10 CH 2 -tetrazol- 2-methyl-l , 4- 2-methoxyphenyl 1-yl phenylene 11 CH -tetrazol - 2-methyl-l , - 2-methoxyphenyl 2-yl phenylene CH 2 -trιazol- 2-methyl-l , 4- 2-methoxyphenyl 1-yl phenylene 13 CH 2 SEt 2-methyl-l, 4- 2-methoxyphenyl phenylene 14 CH 2 S0 2 Et 2-methyl-l, 4- 2-methoxyphenyl phenylene 15 CF 3 2-methyl-l, - 2-methoxyphenyl phenylene 16 CH 3 2-methyl-l , - 2-methoxyphenyl phenylene 17 2-methyl-l , - 2-methoxyphenyl phenylene HI CHpOMe phenyl 2- methylsulfonylphenyl CH 2 0Et phenyl 2- methylsulfonylphenyl CH 2 0-n-Pr phenyl 2- methylsulfonylphenyl CH 2 0-ι-Pr phenyl " methylsulfonylphenyl CH?0-n-Bu phenyl methylsulfonylphenyl methylsulfonylphenyl 2- methylsulfonylphenyl 2- methylsulfonylphenyl 2- methylsulfonylphenyl 10 2- methylsulfonylphenyl 11 2- methylsulfonylphenyl 12 2- methylsulfonylphenyl 13 _.- methylsulfonylphenyl 14 2- methylsulfonylphenyl 15 2- methylsulfonylphenyl 16 2- methylsulfonylphenyl 17 2- methylsulfonylphenyl t methylsulfonylphenyl 2- me hyIsulfonylphenyl 2- diyl methylsulfonylphenyl CH 2 0-ι-Pr pyrιdιn-2, 5- 2- diyl methylsulfonylphenyl CH2θ-n-Bu pyrιdιn-2, 5- diyl methylsulfonylphenyl CH 2 0-ι-Bu pyridm-2 , 5- _.- diyl methylsulfonylphen l CH 2 Ph pvrιdιn-2 , 5- diyl methylsulfonylphenyl CH2-pyrazol- pyrιdm-2 , 5- 2- 1-yl diyl methylsulfonylphenyl CH2-ιmιdazol - pyrιdm-2 , 5- 2- 1-yl diyl methylsulfonylphenyl 10 CH 2 -tetrazol- pyrιdm-2 , 5- 2- 1-yl diyl methylsulfonylphenyl 11 CH 2 -tetrazol- pyrιdιn-2, 5- 2- 2-yl diyl methylsulfonylphenyl 12 CH 2 -tπazol- pyrιdιn-2 , 5- - 1-yl diyl methylsulfonylphenyl 13 CH 2 SEt pyrιdιn-2, 5- 2- diyl methylsulfonylphenyl 14 CH 2 S0 2 Et pvrιdιn-2, 5- _.- diyl methylsulfonylphenyl 15 CF 3 pyrιdιn-2, 5- diyl methylsulfonylphenyl 16 CH 3 pyridιn-2, 5- i. - diyl methylsulfonylphenyl 17 pyrιdm-2 , 5- 2- diyl methvlsulfonvlohenvl H3 CH OMe pyπmidin- 2,5-dιyl methylsulfonylphenyl CH 2 OEt pyrimidm- 2- 2,5-dιyl methylsulfonylphenyl CH 0-n-Pr pyπmidm- _.- 2,5-dιy me hylsulfonylphenyl CH 2 0-ι-Pr pyπmidin- 2- 2,5-dιyl methylsulfonylphenyl CH 2 0-n-Bu pyπmidin- 2- CH 2 0-ι-Bu pyrimidin- 2,5-dιyl me hylsulfonylphenyl CH?Ph pyπmidin- 2,5-dιyl methylsulf nylphenv 1 CH 2 -pyrazol - pyrimidin- 1-yl 2,5-dιyl methylsulfonylphenyl CH -ιmιdazol- pyrimidm- 2- 1-yl 2,5-dιyl methylsulfonylphenyl 10 CH -tetrazol- pyri idm- Λ_.- 1-yl 2,5-dιyl methy1sulfony1phenv1 11 CH -tetrazol- pyrimidm- 2- 2-yl 2,5-dιyl methylsulfonylphenyl 12 CH 2 -trιazol- pyπmidm- 2- 1-yl 2,5-dιyl methylsulfonylphenyl 13 CH 2 SEt pyπmidm- - 2,5-dιyl methylsulfonylphenyl 14 CH 2 S0 2 Et pyrimidin- 2- 2,5-dιyl methylsulfonylphenyl 15 CF 3 pyrimidin- 2- • 2,5-dιyl methylsulfonylphenyl 16 CH 3 pyπmidin- 2- 2,5-dιyl methylsulfonylphenyl 17 H pynmidm- 2- 2,5-dιyl methylsulfonylphenyl H4 CH 2 0Me 2-fluoro-1, 4- 2- phenylene methylsulfonylphenyl CH 2 0Et 2-fluoro-l,4- ._* phenylene methylsulfonylphenyl CH 2 0-n-Pr 2-fluoro-1 ,4- - phenylene methylsulfonylphenyl CH 2 0-ι-Pr 2-fluoro-1 , 4- phenylene methylsulfonylphenyl CH 2 0-n-Bu 2-fluoro-1 , 4- _. - phenylene methylsulfonylphenyl CH 2 0-ι-Bu 2-fluoro-l, 4- 2- phenylene methylsulfonylphenyl CH 2 Ph 2-fluoro-1 , 4- phenylene methylsulfonylphenvl CH 2 -pyrazol- 2-fluoro-1, 4- 1-yl phenylene methylsulfonvlDnen> 1 H CH 2 -ιmidazol- 2- f luoro-1 , 4- 2- 1-yl phenylene methylsulf onylphenyl H CH 2 -tetrazol- 2- f luoro-1 , 4- 2- 1-yl phenylene methylsul fonylphenyl H CH 2 -tetrazol- 2-f luoro-1 , 4- 2- 2-yl phenylene methylsul fonylphenyl H CH 2 -trιazol- 2-f luoro-1 , 4- 2- 1-yl phenylene methylsulfonylphenyl H CH 2 SEt 2-fluoro-l,4- 2- phenylene methylsulfonylphenyl H CH S0 2 Et 2-fluoro-l,4- 2- phenylene methylsulfonylphenyl H CF 3 2-fluoro-l,4- 2- phenylene methylsulfonylphenyl H CHj 2-fluoro-l,4- 2- phenylene methylsulfonylphenyl H H 2-fluoro-l,4- 2- phenylene methylsulfonylphenyl H CH 2 OMe 2-chloro-l, 4- 2- phenylene methylsulfonylphenyl H CH 2 OEt 2-chloro-l,4- 2- phenylene methylsulfonylphenyl H CH 0-n-Pr 2-chloro-l, 4- 2- phenylene methylsulfonylphenyl H CH 0-ι-Pr 2-chloro-l , 4- 2- phenylene methylsulfonylphenyl H CH 2 0-n-Bu 2-chloro-l , 4- 2- phenyleπe methylsulfonylphenyl H CH 2 0-i-Bu 2-chloro-l,4- 2- phenylene methylsulfonylphenyl H CH 2 Ph 2-chloro-l,4- 2- phenylene methylsulfonylphenyl H CH2-pyrazol- 2-chloro-1 , - 2- 1-yl phenylene methylsulfonylphenyl H CH2-ιmidazol- 2-chloro-l , - 2- 1-yl phenylene methylsulfonylphenyl 10 CH 2 -tetrazol- 2-chloro-l ,4- 1-yl phenylene methylsulfonylphenyl 11 CH 2 -tetrazol- ?-chloro-l , - 2- 2-yl phenylene me hylsulfonylphenyl 12 CH 2 -trιazol- 2-chloro-l,4- 2- 1-yl phenylene me hylsulfonylphenyl 13 CH 2 SEt 2-chloro-l, 4- 2- phenylene methylsulfonylphenyl 14 CH 2 S0 2 Et 2-chloro-l , - 2- phenylene methylsulfonylphenyl 15 CF 3 2-chloro-l ,4- _,- phenylene methylsulfonylphenyl 16 CH 3 2-chloro-l , 4- 2- phenylene methylsulfonylphenyl H 2-chloro-l , - 2- fthenylene methylsulfonylpheny H6 CH2θMe 2-methyl-l, - phenylene methylsulfonylphenyl CH 2 OEt 2-methyl-l,4- 2- phenylene methylsulfonylphenyl H CH 2 0-n-Pr 2-methyl-l, 4- 2- phenylene methylsulfonylphenyl CH 2 0-ι-Pr 2-methyl-l,4- 2- phenylene methylsulfonylphenyl H CH 2 0-n-Bu 2-methyl-l,4- 2- phenylene methylsulfonylphenyl H CH 2 0-ι-Bu 2-methyl-l,4- 2- phenylene me hylsulfonylphenyl CH 2 Ph 2-methyl-l, 4- 2- phenylene methylsulfonylphenyl CH 2 -pyrazol- 2-methyl-l, ■ 2- 1-yl phenylene methylsulfony1phenvl CH 2 -ιmιdazol- 2-methyl-l , 4- 2- 1-yl phenylene methylsulfonylphenyl 10 CH 2 -tetrazol- 2-methyl-l,4• _.- 1-yl phenylene methylsulfonylphenyl Jl 2 , 5-thιophene 2-aminosulfonylpneny 1 , -thιophene 2-amιnosulfonylphenyl 2 , 5-thιophene 2-amιnosulfonylphenyl 2 , 5-thιophene 2-ammosulfonylphenyl , 5-thιophene 2-ammosulfonylphenyl 2 , 5-thιophene 2-aminosulfonylphenyl 2, 5-thιophene 2-ammosulfonylphenyl 2, 5-thιophene 2-amιnosulfonylphenyl 2, 5-thιophene 2-aminosulfonylphenyl 1-yl 10 CH 2 -tetrazol - 2 , 5-thιophene 2-amιnosulfonylphenyl 1-yl 2 , 5-thιophene 2-amιnosulf onylphenyl 2 , 5-thιophene 2-ammosulfonylphenyl 2 , 5-thιophene 2-ammosulfonylphenyl 2 , 5-thιophene 2-amιnosul fonylphenyl 2 , 5-thιophene 2-amιnosul fonylphenyl 2 , 5-thιophene 2-amιnosul fonylphenyl 2 , 5-thιophene 2-amιnosul fonylphenyl TABLE 8 Part Cpd (CH 2 ) n R J (Z) u -D 1 CH 2 0 e phenyl 2 -ami nosul fonylphenyl CH 2 OEt phenyl 2-ammosulf 1 phenyl 2-aminosulfonylphenyl phenyl 2-aminosulfonylphenyl phenyl 2-aminosulfony1pheny1 phenyl 2-amιnosulfonylphenyl phenyl 2-aminosulfonylphenyl phenyl 2-ammosulfonylphenyl phenyl 2-aminosulfonylphenyl phenyl 2-aminosulfonylphenyl phenyl 2-aminosulfonylphenyl phenyl 2-aminosulfonylphenyl phenyl 2-aminosulfonylphenyl phenyl 2-aminosulfony1phenyl phenyl 2-aminosulfonylphenyl phenyl 2-aminosulfonylphenyl phenyl 2-am osulfonylphenyl pyπdιn-2, 5-dιyl 2-ammosulfonylphenyl pyrιdm-2,5-dιyl 2-ammosulfonylphenyl pyrιdιn-2, 5-dιyl 2- minosulfony1pheny1 pyrιdm-2, 5-dιyl 2-aminosulfonylphenyl pyrιdιn-2, 5-dιyl 2-aminosulfonylphenyl pyrιdm-2,5-diyl 2-amιnosulfonylphenyl pyrιdιn-2, 5-dιyl 2-ammosulfonylphenyl pyrιdm-2, 5-dιyl 2-ammosulfonylphenyl pyrιdm-2,5-diyl 2-aminosulfonylphenyl pyrιdιn-2, 5-dιyl 2-amιnosulfonylphenyl pyrιdm-2, 5-dιyl 2-ammosulfonylphenyl pyπdm-2,5-dιyl 2-aminosulfonv1pheny1 pyrιdιn-2,5-dιyl 2-ammosulfonylphenyl pyrιdm-2 , 5-dιyl 2-aminosulfony1pheny1 pyrιdm-2 , 5-dιvl 2-ammosulfonylphenyl pyrιdm-2 , 5-dιvl 2 -ami nosul fonyl phenyl pyridm-2,5-d yl 2 -aminosul f onvlphe 1 pyrιmιdm-2, 5-dιyl 2 -aminosul f on lpnenyl pyrιmιdιn-2 , 5-dιyl 2-ammosulfonylphenyl pyrιmιdm-2 , 5-dιyl 2-ammosulfonylphenyl pyπmιdm-2 , 5-dιyl 2 -aminosul fonylphenyl pyrιmιdιn-2 , 5-dιyl 2-ammosulfonylphenyl pyrιmιdm-2 , 5-dιyl 2 -ami nosul fonyl phenyl pyrιmιdm-2 , 5-dιyl 2-ammosulfonylphenyl pyπmιdm-2, 5-dιyl 2 -ami nosul fonyl phenyl pyrιmιdιn-2 , 5-dιyl 2 -ammosul fonyl phenyl pyπmιdm-2 , 5-dιyl 2 -aminosul fonylphenyl pyrιmιdιn-2 , 5-dιyl 2 -aminosul fonylphenyl pyrιmιdιn-2 , 5-dιyl 2-ammosulfonylphenyl pyri idin -2 , 5 -diyl 2 -aminosul fonylphenyl pyrιmιdιn-2, 5-dιyl 2 -aminosulf onylphenyl pyrιmιdιn-2 , 5-dιyl 2-ammosulfonylphenyl pyrιmιdιn-2 , 5-dιyl 2 -aminosul fonylphenyl pyrιmιdιn-2 , 5-dιyl 2-amιnosulfonylphenyl TABLE 9 Part Cpά (CH 2 ) n R' V (Z)„-D CH3 CH 2 OMe phenyl aminosul ony lpneny 1 CH", CH 2 OEt phenyl aminosulfonylphenyl CH 3 CH 2 0-n-Pr phenyl _.- ammosulfonylphenyl CH 3 CH 2 0-ι-Pr phenyl Δ ~ aminosulfony1pheny1 CH 3 CH?0-n-Bu phenyl Δ ~» ~ aminosulfony1pheny1 CH 3 CH 2 0-ι-Bu phenyl 2- aminosulfonylphenyl CH 3 CH 2 Ph phenyl 2- aminosulfonylphenyl phenyl 2- am osulfonylphenyl phenyl 2- am osulfonylphenyl phenyl 2- a inosulfonylphenyl phenyl 2- aminosulfonylphenyl phenyl 2- aminosulfony1phenyl phenyl 2- aminosulfonylphenyl phenyl Δ ~)- ammosulfonylphenyl CH 3 CF 3 phenyl 2- ammosulfonylphenyl CH 3 CH3 phenyl Δ - aminosulfony1pheny1 CH 3 phenyl 2- aminosulfonvlphenvl CH 2 O e phenyl aminosulfonylpheny 1 CH ? OEt phenyl z - aminosulfonylphenyl CH 2 0-n-Pr phenyl aminosul fonylphenyl CH 2 n-ι-Pr phenyl 2- ami nos ul f ony 1 pheny 1 CH 2 0-n-Bu phenyl 2- ammosul fonylphen l CH 2 0-ι-Bu phenyl aminosulfonylphenyl CH 2 Ph phenyl 2- aminosulfonylphenyl CH 2 -pyrazol- phenyl 2- 1-yl aminosulfony1pheny1 CH 2 -ιmιdazol- phenyl 2- 1-yl ammosulfonylphenyl 10 CH 2 -tetrazol- phenyl 2- 1-yl ammosulfonylphenyl 11 CH -tetrazol- phenyl 2-yl aminosulfonylphenyl 12 CH -trιazol- phenyl 2- 1-yl aminosulfonylphenyl 13 CH 2 SEt phenyl 2- ammosulfonylphenyl 14 CH S0 2 Et phenyl 2- a inosulfonylphenyl 15 CF 3 phenyl aminosul fonylphenyl 16 CHi phenyl z - ammosul fonylphenyl 17 phenyl z - aminosul fonylphenyl TABLE 10 Cpd »15 (CH 2 ) n R^ (Z) u -D CH-, CH 2 OMe 1 , -phenylene aminosulfonylphenyl CH 3 CH 2 OEt 1 , 4-phenylene 2- ammosulfonylphenyl CH 3 CH 2 0-n-Pr 1 ,4-phenylene 2- aminosulfonylphenyl CH. CH 2 0-ι-Pr 1 , 4-phenylene — ammosulfonylphenyl CH 3 CH 2 0-n-Bu 1 ,4-pheaylene 2- aminosulfonylphenyl CH 3 CH 2 0-ι-Bu 1 , -phenylene 2- aminosulfonylphenyl CH 3 CH 2 Ph 1 , 4-phenylene 2- aminosulfonylphenyl CH 3 CH 2 -pyrazol- 1 , 4-phenylene 2- 1-yl aminosulfonylphenyl CH 3 CH 2 -ιmιdazol- 1 , 4-phenylene 2- 1-yl am osulfonylphenyl 10 CH 3 CH 2 -tetrazol- 1 , 4-phenylene 2- 1-yl aminosulfony1pheny1 11 CH 3 CH 2 -tetrazol- 1 , 4-phenylene 2- 2-yl aminosulfon lphen l 12 CH 3 CH 2 -trιazol- 1 , 4-phenylene Z ~ 1-yl ammosulfonylphenyl 13 CH- CH 2 SEt 1 , -phenylene Δ - aminosulfonylphenyl 14 CH 5 CH 2 S0 2 Et 1 , -phenylene 2- aminosulfonylphenyl CH3 CF , 1 , -phenylene aminosulfonylphenyl CH 3 CH 3 1 , 4-phenylene 2- aminosulfonylphenyl CH3 1 , 4-phenylene Δ ~ aminosulfonylphenyl CH2CF3 CH 2 OMe 1 , 4-phenylene 2- aminosulfonylphenyl CH 2 CF 3 CH 2 OEt 1 , 4-phenylene 2- aminosulfonylphenyl CH 2 CFj CH^O-n-Pr 1 , 4-phenylene 2- aminosulfony1pheny1 CH 2 CF CH 2 0-ι-Pr 1 , 4-phenylene 2- ammosulfonylphenyl CH 2 CF 3 CH 2 0-n-Bu 1 , 4-phenylene _.- aminosulfonylphenyl CH CF CH 2 0-ι-Bu 1 , 4-phenylene 2- ammosulfonylphenyl CH 2 CF 3 CH 2 Ph 1 , 4-phenylene 2- ammosulfonylphenyl 1 , 4-phenylene 2- aminosulfonylphenyl 1 , 4-phenylene 2- aminosulfonylphenyl 1 , 4-phenylene 2- ammosulfonylphenyl 1 , 4-phenylene 2- aminosulfony1pheny1 1 , 4-phenylene 2- aminosulfonylphenyl 1 , 4-phenylene 2- ammosulfonylphenyl CH2CF3 CH 2 S0 2 Et 1 , -phenylene 2- aminosulfonylphenvl CH2CF3 CF-Ϊ 1 , 4-phenylene 2 - ammosul f onylpneny 1 33 CH2CF3 CH3 1 , 4 -phenylene 2- am osul fonylphenyl 34 CH 2 CF 3 1 , 4 -phenylene 2- aminosul fonvlohenvl TABfrE Part Cpd (CH 2 ) (Z) u -D CH 2 OMe 1 , 4 -phenylene 2 -aminosul fonylphenyl CH 2 OEt 1 , 4-phenylene 2 -aminosul fonylphenyl CH 2 0-n-Pr 1 , 4-phenylene 2-amιnosulfonylphenyl CH 2 0-i-Pr 1 , -phenylene 2-ammosulfonylphenyl CH 2 0-n-Bu 1 , 4 -phenylene 2 -ammosul fonylphenyl CH 2 0-i-Bu 1 , -phenylene 2 -am osul fonylphenyl CH 2 Ph 1 , -phenylene 2 -aminosul fonylphenyl CH 2 -pyrazol- 1 , 4 -phenylene 2 -aminosul fonylphenyl 1-yl CH 2 NH CH 2 -ιmidazol- 1,4-phenylene 2-aminosulfonylphenyl 1-yl 10 CH 2 NH CH 2 -tetrazol- 1 ,4-phenylene 2-ammosulfonylphenyl 1-yl 1 , 4-phenylene 2-amιnosulfonylphenyl 1 , 4 -phenylene 2-ammosulfonylphenyl 1 , 4 -phenylene 2-ammosulfonylphenyl 1 , 4 -phenylene 2 -ammosul fonylphenyl 1 , 4 -phenylene 2 -aminosul fonylphenyl 1 , 4-phenylene 1 1 , 4 -phenvlene 2 -ami nos l fonyl hen l 1 , 4-phenylene 2-amιnosulfonylphen 1 1 , 4-phenylene 2-ammosulfonylphenyl 1 , 4-pnenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 , -phenylene 2-ammosulfonylphenyl , -phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 ,4-phenylene 2-amιnosulfonylpnenyl 1, 4-phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1 ,4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl , 4-phenvlene 2-ammosulfonylphenyl CH 2 CH 2 CH 2 0Me 1 , -phenylene 2-aminosulfonylphenyl CH 2 CH 2 CH 2 0Et 1 , 4-phenylene 2-aminosulfonylphenyl CH 2 CH 2 CH 2 0- n- Pr 1 , 4-phenylene 2-aminosulfonylphenyl CH 2 CH 2 CH 2 0- ι - Pr 1 , 4-phenylene 2-aminosulfonylphenyl CH 2 CH 2 CH 2 0-n-Bu 1 , 4-phenylene 2-aminosulfonylphenyl CH 2 CH 2 CH 2 0- ι -Bu 1 , 4-phenylene 2-aminosulfonylphenyl CH 2 CH CH 2 Ph 1 , 4-phenylene 2-amιnosulfonylphenyl CH 2 CH 2 CH 2 -pyrazol - 1 , 4-phenylene 2-amιnosulfonylphenyl 1-yl CH 2 CH 2 CH 2 -ιmιdazol- 1 , -phenylene 2-amιnosulfonvlphenv 1-yl CH 2 CH CH 2 -tetrazol- 1 , 4-pnenylene 2-aminosulfonylpnen 1 1-yl 1 , 4 -phenylene 2 -ammosul fonylphenyl 1 , 4-phenylene 2-amιnosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1 , 4- henylene 2-aminosulfonylphenyl 1, 4-phenylene 2-aminosulfonylphenyl , 4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 , -phenylene 2-amιnosulfonylphenyl 1, 4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 ,4-phenylene 2-aminosulfonylphenyl 1 , 4-phenylene 2-amιnosulfonylphenyl 1 , -phenylene 2-aminosulfonylphenyl 1, 4-phenylene 2-amιnosulfonylphenyl 1 , 4-phenylene 2-amιnosulfonylphenyl 1 , 4-phenylene 2-ammosulfonylphenyl 1 , 4-phenylene 2-aminosulfonylphenyl 1 , -phenylene 2-ammosulfonylphenyl 1 , -phenylene 2-aminosulfonvlphenvl S0 2 CH 2 CH 2 OMe 1 , 4-phenylene 2-aminosulfony1phenv1 S0 2 CH 2 CH 2 0Et 1 , 4-phenylene /-ammosulfonylphenyl Ξ0 2 CH 2 CH 2 0-n-Pr 1 ,4-phenylene 2-ammosulfonylphenyl S0 2 CH 2 CH 0-ι-Pr 1 , -phenylene 2-aminosulfonylpheny1 SO7CH; CH 2 0-n-Bu 1 , -phenylene 2-aminosulfonylphenyl 2 -amιnosul fonylpheny l 2 -aminosul f ony Ipheny 1 2-ammosul f onylpheny 1 2 -ammosul fonylphenyl 2-amιnosulfonylphenyl -aminosulfonylphenyl 2-ammosulfonylphenyl 2-ammosulfonylphenyl -aminosulfonylphenyl 2-aminosulfonylpheny1 2- minosulfony1pheny1 2-aminosulfonvlphenvl 2-aminosulfonylphenyl 2-aminosulfony1pheny1 2-ammosulfonylphenyl 2-amιnosulfonylphenyl 2-ammosulfonylphenyl 2-amιnosulfonylphenyl 2-ammosulfonylphenyl 2-aminosulfonylphenyl 2-ammosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylpheny1 2-amιnosulfonylphenyl 2-aminosulfonylphenvl 2-aminosulfonv1ohenv! 15 CH 2 0 CF 1 , 4 -phenylene 2-ammosul fonylphenyl 16 CH 2 0 CH3 1 , -phenylene 2-aminosul fonylphenyl 17 CH 2 0 H 1 , 4 -phenylene 2 -aminosul fonyl henv 1 TABLE 12 Cpd. # m -σ-v-z-D TABLE 13 Cpd. # n -α-v-z-D 0 0 CH=C Cpd (CH 2 ) n R 2 (Z) u -D 2-aminosu_fonylphenyl 2-ammosulfonylphenyl 2-aminosulf onylphenyl 2-aminosulfonylphenyl 2-aminosulfonylpheny] 2-an_inosulfonylphenyl 2-aminosulfonylphenyl 2-aπ_inosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-an_inosulfonylphenyl 2-aminosulf onylphenyl 2-aminosulfonylphenyl Cpd (CH 2 )nR 2 (Z) u -D 2-ammosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aπ_mosι_lfonylphenyl 2-aminosulfonylphenyl 2-ammosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-am_nosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-a-ninosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl Cpd (CH 2 ) n R^ (Z) u - D 1 CH 2 OMe 2 CH 2 OEt 3 CH 2 0-n-Pr 4 CH 2 0-i-Pr 5 CH 2 0-n-Bu 6 CH 2 0-i-Bu 7 CH 2 Ph 8 CH2-pyrazol-l-yl 9 CH 2 -in_idazol-l-yl 10 CH2-tetrazol-l-yl 11 CH2-tetrazol-2-yl 12 CH 2 -tπazol-l-yl 13 CH 2 SEt 14 CH 2 S0 2 Et 15 CF 3 16 CH 3 17 H 1-17 Cod (CH 2 ) n R 2 (Z) u -D 2-amιnosu-fonylphenyl 2-ammosulfonylphenyl 2-amιnosulfonylphenyl 2-aminosulfonylphenyl Cpd (CH 2 )„R 2 (Z)u-D 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylpheπyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-an-inosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl 2-aminosulfonylphenyl phenyl 2-amωosulfonylphenyl phenyl 2-amιnosulfonylphenyl phenyl 2-amιπosu-fonylphenyl Utility The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders m mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, lsche ic sudden death, transient lschemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, pulmonary embolisms. The anticoagulant effect of compounds of this invention is due to inhibition of Factor Xa. The activated factor Xa, whose manor practical role is the generation of thrombin by the limited proteolysis of prothrombm, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothro b nase complex (Factor Xa, Factor V, Ca2+ and phosphol pid) . Since it is calculated that one molecule of Factor Xa can generate 138 molecules of thrombin ( Elodi , S. , Varadi , K. : Optimization of condi tions for the catalytic effect of the factor IXa- factor VIII COomplex: Probable role of the complex in the amplifi cation of blood coagulation . Thromb. Res . 1979, 15 , 61 7-629) , inhibition of factor Xa may be more efficient that inactivation of thrombin in interrupting the blood coagulation system. The effectiveness of the compounds of the invention as inhibitors of Factor Xa was determined using purified human Factor Xa and synthetic substrate. The rate of Factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, Ki . Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5 % PEG 8000. The Michaelis constant, K m , for substrate hydrolysis was determined at 25 °C using the method of Lineweaver and Burk. Values of Ki were determined by allowing 0.2 - 0.5 nM human Factor Xa (Enzyme Research Laboratories, South Bend, IN) to react with the substrate (0.20 mM - 1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate Ki values. v 0 -v s I v s Ki (1 + S/Km) where: vo is the velocity of the control in the absence of inhibitor; v s is the velocity in the presence of inhibitor; I is the concentration of inhibitor; Ki is the dissociation constant of the enzyme: inhibitor complex; S is the concentration of substrate; Km is the Michaelis constant. The antithrombotic effect of the compounds of this invention can be demonstrated in a rat vena cava thrombosis model. In this model Male Sprague-Dawley rats weighing 350-450 grams anesthetized with a mixture of xylazine (10 mg/kg l.m.) and ketamine (110 mg/kg l. .) are used. A carotid artery, a jugular vein and a femoral vein are cannulated for blood sampling, drug infusion and hypotonic saline injection, respectively. The abdominal vena cava is isolated and all its .side-branches are ligated beneath the left renal vein. Thrombus formation is induced by rapid injection of 1 ml hypotonic saline (0.225%) into the vena cava. This is followed 15 seconds later by a 15-minute stasis of an isolated segment (about 1 cm) of the vena cava. The formed thrombus in the vena cava is removed and immediately weighed. Test compounds or vehicle are given as continuous intravenous infusions or orally starting 1 hour before the injection of hypotonic saline. Arterial blood samples (1.5 ml) for the determination of clotting times are collected before and 1 hour after the infusion or oral dosing of test compounds or vehicle. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression. The compounds of this invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thro bolytic or fibrmolytic agents. The compounds are administered to a mammal m a therapeutically effective amoun . By "therapeutically effective amount" is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease. By "administered in combination" or "combination therapy" is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially m any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and hepann, as well as other Factor Xa inhibitors such as those described m the publications identified above under Background of the Invention. The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include the various known non-steroidal anti- inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulmdac, lndomethacm, mefenamate, droxicam, diclofenac, sulfmpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA) , and piroxicam. Other suitable anti-platelet agents include ticlopidme, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidme is also a preferred compound since it is known to be gentle on the gastro-mtestinal tract n use. Still other suitable platelet inhibitory agents include thro boxane- A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof. The term thrombin inhibitors (or anti-thrombin agents) , as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombm-mediated processes, such as thrombm-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasmmogen activator ιnhιbιtor-1 and/or serotonin) and/or fibrin formation are disrupted. Such inhibitors include boroarginme derivatives ajid boropeptides, hirudm and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginme derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a- aminoboronic acid derivatives of lysme, ornithme, argmine, homoarginme and corresponding isothiouronium analogs thereof. The term hirudm, as used herein, includes suitable derivatives or analogs of hirudm, referred to herein as hirulogs, such as disulfatohirud . Boropeptide thrombin inhibitors include compounds described in Kettner et al. , U.S. Patent No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginme derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471 651 A2, the disclosures of which are hereby incorporated herein by reference, in their entirety. The term thrombolytics (or flbnnolytic) agents (or thrombolytics or flbrmolytics) , as used herein, denotes agents that lyse blood clots (thrombi) . Such agents include tissue plasmmogen activator, anistreplase, urokmase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to amsoylated plasmmogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by reference herein, in their entirety. The term urokmase, as used herein, is intended to denote both dual and single chain urokmase, the latter also being referred to herein as prourokmase. Administration of the compounds of Formula I of the invention in combination with such, additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety. The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of Factor Xa. Such compounds may be provided m a commercial kit, for example, for use in pharmaceutical research involving Factor Xa. The compounds of the present invention may also be used in diagnostic assays involving Factor Xa. Dosaσe and Formulation The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered m intravenous (bolus or infusion), mtraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill m the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind pf concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient,and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder. By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 g/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/mmute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. Compounds of this invention can be administered in mtranasal form via topical use of suitable mtranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration m liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The compounds of the present invention can also be administered m the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and mult1lamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamme, or phosphatidylcholines. Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylasparta idephenol, or polyethyleneoxide- polylysme substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful m achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslmked or amphipathic block copolymers of hydrogels. Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizmg agents such as sodium bisulfite, sodium sulfite, or ascqrbicacid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol . Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences. Mack Publishing Company, a standard reference text in this field. Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate. Soft Gelatin Capsules A mixture of active ingredient m a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried. Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. Iπiectab e A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient m 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized. Suspension An aqueous suspension is prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin. Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present m an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant m an amount of about 1 to 5 milligrams per dosage unit. Where the compounds of Formula I are administered m combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight. Where the compounds of Formula I are admmstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I. Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered m combination. Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined m a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced) . For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained- release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. TJie polymer coating serves to form an additional barrier to interaction with the other component.

Claims: WE CLAIM : 1. Compounds of Formula I: including pharmaceutically acceptable salts and prodrug forms thereof, and all stereoisomeric forms thereof and mixtures of such stereoisomeric forms, wherein: U when present (i.e., when u=l) is selected from -CO-NH- (CH 2 ) 0 - -C0- ( CH 2 ) o - -S0 2 -NH- ( CH 2 ) o - -S0 2 -(CH 2 ) o - -NHSO 2 - (CH 2 ) 0 - , provided m ≠ 0 -NHCO- (CH 2 ) 0 -» provided m ≠ 0 -NH-(CH 2 ) 0 -' provided m ≠ 0 -0-(CH 2 ) o - provided m ≠ 0 -S-(CH2) 0 -» provided m ≠ 0 -CH=CH- ( CH 2 ) 0 - Y is selected from R 1 is selected from C(NR 14 )NR 5 R 6 NHC(NR 1 )NR5R6 NHC(NR 14 )H CONR 5 R 6 R 2 is selected from H Cι-C 6 alkyl Ci-Cβ alkoxy C0 2 R 5 CONHR 5 CONHCH 2 C0 2 R 5 CONH(CH 2 )q-R 10 R 10 CO-R 5 COC0 2 R 5 COCONHR 5 SO n R 5 S0 2 NHR 5 NHR 7 CH=CHC0 2 R 5 CH=CHCONHR 5 0-(CH 2 ) n -Rl O SO n -(CH 2 ) n -R 10 NH- (CH 2 ) n -R 10 U and R 2 taken together provide a spiro compound of formula Ila and lib, or a compound of formula Ilia or Illb: where W = CO , CH 2 , CHOR 5 and r = 1- 3 where W = CO, CH 2 , CHOR 5 and t 0-2 R 3 is selected from (CH 2 ) s Nϊ. 5 F. 6 C(NR 14 )NR 5 R 6 NHC(NR 14 )NR 5 R 6 NHC(NR 14 )H CONR 5 R 6 V is selected from the following when Z and D are both absent: V is selected from the following when Z and/or D are present: when present (i.e., when u = 1) is selected from a single bond, -CO-, -(CH 2 ) t -, -so n -, -S0 2 NHR 4 , provided D is absent -NH-, -NR 7 -, -0- D when present (i.e., when u = 1) is selected from E is selected from N, NR 5 , 0, S; J is selected from 0, NR 7 ; A is selected from CO, CH 2 , SO, SO 2 R 4 is selected from H Cι-C 6 alkyl (CH 2 ) n - henyl (CH 2 ) n -CONHR 5 (CH 2 ) n -CONHR 5 CH 2 C0 2 R 5 R 5 and R 6 at each appearance are independently H Cι-C 6 alkyl (CH 2 ) n-phenyl imidazole, pyrazole, 1, 2 , 3-trιazole, 1, 2, 4-trιazole and tetrazole, each optionally substituted with CF 3 , halogen, N0 2 , C 1 -C 5 alkyl, or C 1 -C 5 alkoxy; R 10 is selected from R 11 is selected from H Cι-C 6 alkyl (CH 2 ) n - Phenyl COR 5 C0 2 R 5 R 12 is selected from H Cι-C 6 alkyl Ci-Cβ alkoxy halogen N0 2 NHR 7 CN CF 3 SONHR 11 R 13 is selected from H OH Ci-Cio alkyl Ci-Cio alkoxy ni ro halo CF 3 R 14 is selected from H OH Ci-Cio alkyl Ci-Cio alkoxy CO2-C1-C10 alkyl CO-C1-C10 alkyl CONH-C1-C10 alkyl CONH-phenyl C0 2 (CH2)n-phenyl; R 15 is selected from H Cι-C 6 alkyl, Ci-Cβ alkoxy C0 2 R 14 CONHR 14 CONHCH 2 C0 2 R 5 CONH(CH 2 ) q -R 10 ( CH 2 ) n R 10 CO-R 5 COC0 2 R 5 COCONHR 5 S0 2 NHR 5 at each appearance each of the following are independently: m = 0-2 n = 0-4, except that in -SO n ~, n = 0-2; provided that, when X is NR 15 , Z and D are both absent, then at least one of R 1 and R 3 must be C(NR 1 )NR 5 R β NHC(NR 1 )NR5R6 or NHC(NR 14 )H. Compounds of claim 1 wherein: U is present and is selected from -C0-NH- ( CH 2 ) o - -C0- ( CH 2 ) o - -S0 2 -NH- ( CH 2 ) o - -S0 2 - ( CH 2 ) o- -NH- ( CH 2 ) 0 - -0- ( CH 2 ) o - Y is selected from R 1 is selected from C(NR 1 )NR 5 R 6 NHC(NR 14 )NR 5 R 6 R 2 is selected from H Cι-C 6 alkyl C1-C6 alkoxy C0 2 R 5 CONHR 5 CONHCH 2 C0 2 R 5 CONH(CH 2 ) q -R 10 RlO CO-R 5 C0C0 R 5 COCONHR 5 SO n R 5 S0 2 NHR 5 NHR 7 CH=CHC0 2 R 5 CH=CHCONHR 5 0-(CH) n -R 10 SO n -(CH) n -Rl0 NH- (CH) n -R 10 V is selected from the following when Z and/or D are present: V is selected from the following when Z and D are both absent : D when present (i.e., when u = 1) is selected from R 10 is selected from Compounds of claim 2 wherein: Y is selected from Z is absent or is present and is selected from -O- and -NR 7 -. 4. Compounds of claim 3 having the structures of V and VI: R 1 :vι: wherein D is selected from V is selected from the following: 5. A compound of claim 1 selected from the group consisting of the following compounds, including pharmaceutically acceptable salt and prodrug forms thereof, and all stereoisomeric forms thereof and mixtures of such stereoisomeric forms: 3- (3-Amidinophenyl) -5- [ (2-naphthylsulfonyl)ammo]methyl- isoxazolme 3- (3-amidinophenyl) -5- [ [ (2 '-ammosulfonyl- [1,1']- bιphenyl-4-yl)-methyl]aminocarbonyl]-5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl) -5- [ [ (2 '-ammosulfonyl- [1,1']- bipheny1-4-y1)methyl]aminocarbonyl]-5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -7- (2'-ammosulfonyl- [1,1']-biphenyl- 4-yl)methyl[l-oxa-2,7-dιazaspιro[4,4]non-2-ene-6,8-dιones 3-amidinophenyl 3-(4-amidinophenyl) -5- [ (aminocarbonyl)isoxazolin-5-yl]acetamide 4-amidinophenyl 3- (3-amidinophenyl) -5- [ (carbometoxy) isoxazolm-5-yl]acetamide 3- (3-amidinophenyl) -5- [ (4- amidinophenyl)aminocarbonyl]isoxazolme 3- (3-amidinophenyl) -5- [ (4-amιdmophenyl)aminocarbonyl] -5- [ (carbomethoxymethyl)ammocarbonylmethyl] isoxazolme 3- (3-amidinophenyl) -5- [ (4-amidinophenyl)aminocarbonyl] -5- (carboxymethyl) isoxazolme 3- (4-amidinophenyl) -5- [ (3-amidinophenyl)aminocarbonyl]-5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl)-5- [ (4- amidmophenyl)met ylaminocarbonyl] -5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl) -5- [ (4-benzenesulfonylpιperιdm-l- yl)carbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [ (4-pyrimidm-5-yl)pιpendm-l- yl]carbonyl]-5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (4-benzenesulfonylphenyl-1- yl)aminocarbonyl]-5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl) -5- [ (4-amιdmophenyl)aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl)-5- [([1,1']-bιphenyl-4- yl)aminocarbonyl]-5- (carbomethoxymethyl)isoxazolme 3- (3-amidinophenyl) -5- [ ( [1,1 ' ] -bιphenyl-4- yl)aminocarbonyl] -5- (carboxymethyl)isoxazolme 3- (3-amidinophenyl)-5- [ ( [1,1 ' ] -biphenyl-4- yl)aminocarbonyl]-5- (ammocarbonylmethyl)isoxazolme 3- (3-amidinophenyl) -5- [ ( [1,1' ]-bιphenyl-4- yl)aminocarbonyl] -5- (hydroxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3 ' -n-propyl- [1,1'] -bιphenyl-4-yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 * -t-butylammosulfonyl- [1,1']- bipheny1-4-y1) aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -t-butylammosulfonyl- [1,1']- bιphenyl-4-yl) aminocarbonyl] -5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (4 ' -amino- [1,1'] -b phenyl-4- yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3-(3-amιdmophenyl) -5-[ (2 ' -trifluoromethyl- [1, 1' ] - bιphenyl-4-yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1']- bipheny1-4-y1) aminocarbonyl) ] -5- (carbomethoxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-methyl- [1,1']- bιphenyl-4-yl)aminocarbonyl] -5- (carboxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1']- bιphenyl-4-yl)aminocarbonyl] -5- (carbomethoxyethylene) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1- yl)pyrimidin-2-yl]aminocarbonyl] -5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2'-ammosulfonylphenyl-1- yl)pyrimidm-2-yl]aminocarbonyl] -5- (hydroxyethyl) isoxazolme 3- (3-amidinophenyl) -5-[ [5- (2'-aminosulfonylphenyl-1- yl)pyrlmidin-2-y1]aminocarbonyl]-5- (methoxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2'-aminosulfonylphenyl-1- yl;pyrimidm-2-yl]aminocarbonyl] -5- (methyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 '-ammosulfonyl- [1,1 ' ] -biphenyl- 4-yl)aminocarbonyl] -5-(carbomethoxymethyl)isoxazoline 3- (3-amidinophenyl) -5- [ (2' -ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl] -5- (carboxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2' -ammosulfonyl-[1,1' ]-biphenyl- 4-yl)aminocarbonyl]-5- (ammocarbonylmethyl)isoxazolme 3- (3-amidinophenyl) -5- [ (2'-ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl)-5- (hydroxyethyl)isoxazolme 3- (3-amidinophenyl)-5- [ (2' -ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl] -5- (carbomethoxymethylaminocarbonylmethyl)isoxazolme 3- (3-amidinophenyl) -5- [ (2 '-ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl]-5-[ (ιmidazole-4- yl)ethyla mocarbonylmethyl]isoxazolme 3- (3-amidinophenyl)-5-[ (2'-ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl]-5- (methoxyethyl) isoxazolme 3- (3-amidinophenyl)-5-[ (2 ' -ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl] -5- (methyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1']- biphenyl-4-yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -amιnosulfonyl-3-methyl- [1,1']- bιphenyl-4-yl)aminocarbonyl] -5- (carboxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 * -aminosulfonyl-3-methyl- [1,1']- biphenyl-4-yl) aminocarbonyl] -5- (ammocarbonylmethyl) isoxazoline 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl [1, 1 ' ] - biphenyl-4-y1) aminocarbonyl] -5- (carbomethoxymethylaminocarbonylmethyl) isoxazoline 3- (3-amidinophenyl) -5- [ (2 ' -amιnosulfonyl-3-methyl- [1,1']- biphenyl-4-yl)aminocarbonyl] -5- (hydroxyethyl) isoxazoline 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-methyl- [1,1']- biphenyl-4-yl)aminocarbonyl] -5- (methoxyethyl) isoxazoline 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1']- bιphenyl-4-yl)aminocarbonyl] -5- (methyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -ammosulfonyl-3-fluoro- [1,1']- biphenyl-4-yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-fluoro- [1,1']- biphenyl-4-yl)aminocarbonyl] -5- (carboxymethyl) isoxazoline 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-fluoro- [1,1']- biphenyl-4-yl) aminocarbonyl] -5- (aminocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-fluoro- [1,1']- bιphenyl-4-yl) aminocarbonyl] -5- (hydroxyethyl) isoxazol e 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-fluoro- [1,1']- biphenyl-4-yl)aminocarbonyl] -5- (methoxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ (2 ' -amιnosulfonyl-3-fluoro- [1,1']- bιphenyl-4-yl) aminocarbonyl] -5- (methyl) isoxazolme 3- (3-amidinophenyl) -5- [ [2- (2 ' -aminosulfonylphenyl-1- yl)pyrιdm-5-yl]aminocarbonyl] -5- (carbomethoxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [2- (2 ' -aminosulfonylphenyl-1- yl)pyrιdm-5-yl] aminocarbonyl] -5- (carboxymethyl) isoxazoline 3- (3-amidinophenyl) -5- [ [2- (2 ' -aminosulfonylphenyl-1- y1)pyπdm-5-y1]aminocarbonyl] -5- (ammocarbonylmethyl) isoxazoline 3- (3-amidinophenyl) -5- [ [2- (2 '-aminosulfonylphenyl-1- yl)pyridin-5-y1]aminocarbonyl] -5- (hydroxyethyl) isoxazoline 3- (3-amidinophenyl) -5- [ [2- (2 ' -amιnosulfonylphenyl-1- y1)pyrldin-5-y1]aminocarbonyl] -5- (methoxyethyl) isoxazoline 3- (3-amidinophenyl) -5- [ [2- (2 ' -aminosulfonylphenyl-1- yl)pyπdιn-5-yl]aminocarbonyl] -5- (methyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -ammosulfonylphenyl-1- yl)pyrldm-2-yl] aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline 3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1- yl)pyrιdm-2-yl]aminocarbonyl] -5- (carboxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -ammosulfonylphenyl-1- yl)pyrιdm-2-yl] aminocarbonyl] -5- (ammocarbonylmethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1- yl)pyrιdm-2-yl] aminocarbonyl] -5- (hydroxyethyl) isoxazoline 3- (3-amidinophenyl) -5- [ [5- (2 * -aminosulfonylphenyl-1- yl)pyrιdm-2-yl]aminocarbonyl] -5- (methoxyethyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1- yDpyridin-2-yl]aminocarbonyl] -5- (methyl) isoxazolme 3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1- y1)pyrimidin-2-yl]aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline 3- (3-amidinophenyl) -5- [ [5- (2 ' -ammosulfonylphenyl-1- y1)pyrimidin-2-y1]aminocarbonyl] -5- (carboxymethyl) isoxazolme 3- (3-amidinophenyl) -5- [5- (2 ' -ammosulfonylphenyl-1- y1)py imidm-2-y1]aminocarbonyl-5-carbomethoxymethyl- isoxazoline 3- (3-amidinophenyl) -5- [5- (2 ' -aminosulfonylphenyl-1- y1)pyridin-2-y1]aminocarbonyl-5-carbomethoxymethyl- isoxazolme 3- (3-amidinophenyl) -5- [2 '-ammosulfonyl- [1,1'] -biphenyl- 4-yl]aminocarbonyl-5- (tetrazol-l-yl)methyl-ιsoxazol e 3- (3-amidinophenyl) -5- [5- (2 ' -aminosulfonylphenyl-1- yl)pyrιdιn-2-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl¬ isoxazolme 3- (3-amidinophenyl) -5- [5- (2 ' -aminosulfonylphenyl-1- yl)pyrimidm-2-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl- isoxazolme 3- (3-amidinophenyl) -5- [2 '-trifluoromethyl- [1,1']- biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl¬ isoxazolme 3- (3-amidinophenyl) -5- [5- (2 '-trif uoromethylphenyl-1- yDpyπdm-2-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl¬ isoxazolme 3- (3-amidinophenyl)-5- [5- (2*-trifluoromethylphenyl-1- yl)pyrιmιdm-2-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl¬ isoxazolme 3-(3-amidinophenyl)-5- [5- (2'- trifluoromethylsulfonylphenyl-1-yl)pyrιdιn-2- yl]aminocarbonyl-5- (tetrazol-1-yl)methyl-isoxazoline 3- (3-amidinophenyl) -5- [5-(2' - trifluoromethylsulfonylphenyl-1-yl)pyrimid -2- yl]aminocarbonyl-5- (tetrazol-l-yl)methyl-ιsoxazolιne 3- (3-amidinophenyl) -5- [2 '-amιnosulfonyl-3-flouro- [1,1']- bιphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl¬ isoxazolme 3- (3-amidinophenyl) -5- [2' -aminosulfonyl-3-chloro- [1,1']- bιphenyl-4-yl]aminocarbonyl-5-(tetrazol-1-yl)methyl¬ isoxazolme 3- (3-amidinophenyl) -5- [2 '-trifluoromethyl-3-flouro- [1,1'] -biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1- yl)methyl-isoxazolme 3-(3-amidinophenyl) -5-[2'-trifluoromethyl-3-chloro- [1,1'] -biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1- yl)methyl-isoxazolme 3- (3-amidinophenyl) -5- [5- (2 '-aminosulfonylphenyl-1- yl ) pyrιdm-2-yl]amιnocarbonyl-5-methoxyιrtethyl-ιsoxazolιne 3-(3-amidinophenyl) -5-[2'-methylaπμnosulfonyl- [1,1']- bipheny1-4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl- isoxazolme 3- (3-amidinophenyl) -5- [5- (2 '-methylammosulfonylphenyl-1- yl)pyrιdm-2-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl¬ isoxazolme 3- (3-amidinophenyl) -5-[2'-methylsulfonyl- [1,1']-biphenyl- 4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl-isoxazolme 3- (3-amidinophenyl) -5- [2 '-methylsulfonyl-fluoro-[1,1']- biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl¬ isoxazolme 3- (3-amidinophenyl) -5- [2'-methylsulfonyl-chloro- [1,1']- biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl¬ isoxazolme 3- (3-amidinophenyl) -5- [2 '-trif1uoromethylsulfonyl- [1,1']- bipheny1-4-yl]aminocarbonyl-5- (tetrazol-1-yl) ethyl- isoxazolme 3- (3-amidinophenyl) -5- [2 '-ammosulfonyl- [1,1']-bip enyl- 4-yl]aminocarbonyl-5- (ιmιdazol-1-yl)methyl-isoxazolme 3- (3-amidinophenyl) -5- [2 '-trifluoromethylsulfonyl-3- fluoro- [1,1'] -biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1- yl)methyl-isoxazolme 3- (3-amidinophenyl) -5- [2 ' -trifluoromethylsulfonyl-3- chloro- [1,1'] -bιphenyl-4-yl]aminocarbonyl-5- (tetrazol-1- yl)methyl-isoxazolme 3- (3-amidinophenyl) -5- [2' -ammosulfonyl- [1,1'] -biphenyl- 4-yl] minocarbonyl-5- (lmidazol-1-yl)methyl-isoxazoline 3- (3-amidinophenyl) -4- (2'-ammosulfonyl- [1,1']-biphenyl- 4-yl)ammocarbonyl-5-methoxymethyl-ιsoxazolme 3- (3-amidinophenyl) -4- (2 '-ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl-5-trifluoromethyl-isoxazolme 3- (3-amidinophenyl) -5- (2 '-ammosulfonyl- [1,1']-biphenyl- 4-yl)aminocarbonyl-4-methoxymethyl-isoxazol e 6. Pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1 through 5 and a pharmaceutically acceptable carrier. 7. A method of treating or preventing a thromboembolic disorder in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of any of claims 1 through 5.

Inventors: GALEMMO ROBERT ANTHONY JR, PRUITT JAMES RUSSELL, QUAN MIMI LIFEN, STOUTEN PETRUS F W, WITYAK JOHN, GALEMMO, ROBERT, ANTHONY, JR., PRUITT, JAMES, RUSSELL, QUAN, MIMI, LIFEN, STOUTEN, PETRUS, F., W., WITYAK, JOHN
Applicants: DU PONT MERCK PHARMA, THE DU PONT MERCK PHARMACEUTICAL COMPANY
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61P7, C07D231, C07D261, C07D275, C07D403, C07D413, C07D417, C07D498