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1. ZA1996/10704 - ISOXAZOLINE ISOTHIAZOLINE AND PYRAZOLINE FACTOR XA INHIBITORS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

FIELD OF THE INVENTION

This invention relates to isoxazolines,
isothiazolines and pyrazolines 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 benzamidine derivatives as Factor Xa inhibitors. The most active inhibitors were 3-amidino-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-amidinobenzyl) cycloalkanones, a, a' -bis- (4-aminobenzylidene) - and a, a' -bis- (3-aminobenzylidene) 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
Fibrinolvsis. vol. 4, 577-582(1993) and Hauptmann et al., Thromb. Haemostasis, vol. 63(2), 220-223(1990) report
-IA' testing of several synthetic compounds as Factor Xa inhibitors: Na-tosylglycyl-3-amidinophenylalanine methyl ester; 2,7-bis (4-amidinobenzylidene) -cycloheptanone- (1) ; Na-tosyl-4-amidinophenylalanine piperidide; Na-naphthylsulρhonylglycyl-4-amidinophenylalanine
piperidide; 4-methyl-l-N2- (methyl-1, 2 , 3 , 4-tethydro-8-quinolinesulphonyl-L-arginyl-2-piperidine carbonic acid; and D-phenylalanyl-L-propyl-L-arginine chloromethyl ketone.
Nagahara et al., J. Med. Chem., vol. 37, 1200-1207(1994) describes several dibasic
(amidinoaryl) ropanoic acid derivatives as Factor Xa inhibitors .
Daiichi EPA 0 540 051 Al, published May 5, 1993, discloses aromatic amidine derivatives, including amidino naphthylenes, amidino-indoles, ami,dino-benzimidazoles, 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 glycoprotein lib/Ilia fibrinogen receptor. The isoxazoles and isoxaolines of WO 95/14683 are represented by the formula:


The isoxazolines of WO 95/14682 are represented by the formula:

Copending, commonly assigned Z. A. Patent Application number 96/3391 filed 29 April 1996, discloses isoxazoline antagonists of the platelet glycoprotein

Ilb/IIIa fibrinogen receptor having the formula:


EP 53095 A and other references disclose various di-anilino-pyrazoline 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 isoxazoline,
isothiazoline or pyrazoline derivatives described as Factor Xa inhibitors.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula

I:

(U)u—V— (Z)u— (D)u


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
-C0-NH-(CH2)o- -C0-(CH2)o- -S02-NH-(CH2)o- -S02-(CH2)o- -NHS02- (CH2)0- provided m ≠ 0
-NHCO- (CH2)0-, provided m ≠ 0
-NH-(CH2)0-, provided m ≠ 0
-0-(CH )o-, provided m ≠ 0
-S-(CH2)0-, provided m ≠ 0
-CH=CH-(CH2)0- x is 0, S, NR15

Y is selected from



R1 is selected from
(CH2)P R5R6
C(NR14)NR5Rβ
NHC(NR1 )NR5Rβ
NHC(NR14)H
C0NR5R6

R2 is selected from
H
Cι-C6 alkyl Ci-Cδ alkoxy
C02R5
CONHR5
CONHCH2C02R5
CONH(CH2)q-R10
RlO
CO-R5
COC02R5
COCONHR5
SOnR5
S0NHR5
NHR7
CH=CHC02R5
CH=CHCONHR5
0-(CH2)n-R10
SOn-(CH2)n-R10
NH-(CH2)n-R10

U and R2 taken together provide a spiro compound of formula Ila and lib, or a compound of formula Ilia or Illb:



where W = CO , CH2 , CHOR5 and r = 1-3


where W = CO, CH2, CHOR5 and t = 0-2
R3 is selected from
(CH2)SNR5R6
C(NR1 )NR5R6
NHC(NR1 )NR5R6
NHC(NR14)H
CONR5R6

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-,
-(CH2)t-,
-SOn-,
-S02NHR4, provided D is absent
-NH-,
-NR7-,
-0- when present (i.e., when u = 1) is selected from



E is selected from N, NR5, 0, S;

J is selected from 0, NR7;

A is selected from CO, CH2, SO, S02

R4 is selected from
H
Cι-C6 alkyl
(CH2) n-phenyl
(CH2)n-CONHR5
(CH2 ) n-CONHR5CH2C02R5

R5 and R6 at each appearance are independently H
Cι-C6 alkyl
(CH2) n-phenyl

R7 is selected from
H
Cι-C6 alkyl S02R5
COR5
(CH2)r-Rl°
(CH2)n- henyi

is selected from
H
Cι-C6 alkyl
halogen
N02
CF3
OR5

is selected from
H
Ci-Cβ alkyl
halogen
N02
NHR7
S02NHR
CF3
OR5
C02R5
CONR5R7
CN
(CH2)pNR5R6
C(NR1 )NR5R6
NHC(NR1 )NR5R6
NHC(NR1 )H
SOn-R5
SOn-CF3
imidazole, pyrazole, 1,2, 3-triazole, 1,2,4-triazole and tetrazole, each optionally substituted with CF3, halogen, N02, C1-C5 alkyl, or C1-C5
alkoxy;

R10 is selected from


R11 is selected from H
Ci-Cβ alkyl (CH2) n-phenyl
COR5
C02R5

R12 is selected from
H
Ci-Cβ alkyl
Ci-Cβ alkoxy
halogen
N02
NHR7
CN

CF3
SONHR11

R13 is selected from
H

OH
Ci-Cio alkyl
Ci-Cio alkoxy
nitro
halo
CF3

R14 is selected from

H

OH
Ci-Cio alkyl
Ci-Cio alkoxy
C0 -Cι-Cιo alkyl

CO-Ci-Cio alkyl
CONH-Ci-Cio alkyl

CONH-phenyi
C02 (CH2) -phenyl;

R15 is selected from H
Ci-Cβ alkyl,
Ci-Cβ alkoxy
C0R14
CONHR14
CONHCH2C02R5
CONH(CH2)q-R10
(CH2)nR10
CO-R5
COC0R5
COCONHR5
S02NHR5

at each appearance each of the following are
independently:
m = 0-2
n = 0-4, except that in -SOn-, 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 NR15, Z and D are both absent,



then at least one of R1 and R3 must be
C(NR1 )NR5R6
NHC(NR1 )NR5R6 or
NHC(NR14)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, Ci-Cβ straight or branched alkoxy, S(0)n-alkyl where alkyl is Ci-Cβ straight or branched alkyl and n is 0-2,
morpholino, Ci-Cβ alkylacyloxy, NR5R7 where R5 and R7 are as defined in claim 1, CN, N02, and CF3;
the term "phenyi" means phenyi optionally
substituted with 1 to 3 substituents independently selected from halo, Ci-Ce straight or branched alkoxy, S(O) n-alkyl where alkyl is Ci-Ce straight or branched alkyl and n is 0-2, morpholino, Ci-Cβ alkylacyloxy, NR5R7 where R5 and R7 are as defined in claim 1, CN, N02, and CF3;
the terms "halo" and "halogen" mean chloro, fluoro, bromo and iodo.

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 isomers of olefins,

C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in 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-(CH2)o- -C0-(CH2)o- -S02-NH-(CH2)o- -S02-(CH2)o- -NH-(CH2)0- -0-(CH2)o-

X is 0

Y is selected from


R1 is selected from C(NR14)NR5R6
NHC(NR1 )NR5R6

R2 is selected from

H
Cχ-C6 alkyl
Ci-Cβ alkoxy
C0 R5
CONHR5
CONHCH2C02R5
CONH(CH2)q-R10
R10
CO-R5
COC02R5
COCONHR5
SOnR5
S02NHR5
NHR7
CH=CHC02R5
CH=CHCONHR5
0-(CH)n-R10 SOn- (CH) n-R10
NH- (CH ) n-R10

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


R10 is selected from



Of the preferred compounds, more preferred are those wherein, independently or concurrently:

U is -CO-NH-(CH2)o- Y is selected from


R1 is C(NR14)NR5R6

Z is absent or is present and is selected from
-0- and -NR7-.

Of the more preferred compounds, especially
preferred are those having the structures of V and VI:

wherein

R1 is C(NR14)NR5R6 and

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-Amidinophenyl) -5- [ (2-naphthylsulfonyl) amino] ethyl-isoxazoline

3- (3-amidinophenyl) -5- [ [ (2 ' -aminosulfonyl- [1,1']-biphenyl-4-yl ) -methyl] aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ [ (2 ' -aminosulfonyl- [1,1']-bipheny1-4-y1 ) methyl] aminocarbonyl] -5-(aminocarbonylmethyl) isoxazoline

3- (3-amidinophenyl) -7- (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) methyl [l-oxa-2 , 7-diazasp -o [4, 4] non-2-ene-6, 8-diones

3-amidinophenyl 3- (4-amidinophenyl) -5- [ (aminocarbonyl) isoxazolin-5-yl] aqetamide

4-amidinophenyl 3- (3-amidinophenyl) -5-[ (carbometoxy) isoxazolin-5-yl] acetamide

3- (3-amidinophenyl) -5- [ (4-amidinophenyl) aminocarbonyl] isoxazoline

3- (3-amidinophenyl) -5- [ (4-amidinophenyl) aminocarbonyl] -5-[ (carbomethoxymethyl) aminocarbonylmethyl] isoxazoline

3- (3-amidinophenyl) -5- [ (4-amidinophenyl) aminocarbonyl] -5-(carboxymethyl ) isoxazoline

3- (4-amidinophenyl) -5- [ (3-amidinophenyl) aminocarbonyl] -5-(carbomethoxymethy1 ) isoxazoline

3- (3-amidinophenyl) -5- [ (4-amidinophenyl ) methylaminocarbonyl] -5-(carbomethoxymethyl) isoxazoline 3- (3-amidinophenyl) -5- [ (4-benzenesulfonylpiperidin-l-yl) carbonyl] -5- (carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ [ (4-pyrimidin-5-yl)piperidin-l-yl] carbonyl] -5- (carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (4-benzenesulfonylphenyl-l-yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (4-amidinophenyl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [([1,1'] -biphenyl-4-yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [([1,1'] -biph.enyl-4-yl) aminocarbonyl] -5- (carboxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [([1,1'] -biphenyl-4-yl ) aminocarbonyl] -5- (aminocarbonylmethyl) isoxazoline

3- (3-amidinophenyl) -5- [([1,1'] -biphenyl-4-yl) aminocarbonyl] -5- (hydroxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3 ' -n-propyl-[1,1'] -biphenyl-4-yl) aminocarbonyl] -5-(carbomethoxymethy1) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -t-butylaminosulfonyl- [1,1' ]-biphenyl-4-yl) aminocarbonyl] -5-(carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -t-butylaminosulfonyl- [1,1'] biphenyl-4-yl) aminocarbonyl] -5-(aminocarbonylmethyl ) isoxazoline 3- (3-amidinophenyl) -5- [ (4 ' -amino- [1,1'] -biphenyl-4-yl ) aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -trifluoromethyl- [1,1' ]-biphenyl-4-yl) aminocarbonyl] -5- (carbomethoxymethy1 ) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1']-biphenyl-4-yl) aminocarbonyl) ] -5- (carbomethoxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1']-biphenyl-4-yl) aminocarbonyl] -5- (carboxyethyl ) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- :ι,i']-bipheny1-4-y1 ) aminocarbonyl] -5- .
(carbomethoxyethylene) isoxazoline

3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1-y1 ) pyrimidin-2 -yl] aminocarbonyl] -5- (aminocarbonylmethyl ) isoxazoline

3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1-yl ) pyrimidin-2-yl] aminocarbonyl] -5-(hydroxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1-yl ) pyrimidin-2-yl ] aminocarbonyl] -5-(methoxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ [5- (2 '-aminosulfonylphenyl-1-yDpyrimidin-2-yl] aminocarbonyl] -5- (methyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) minocarbonyl] -5- (carbomethoxymethyl) isoxazoline 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl- [1,1 ' ] -biphenyl-4-yl) aminocarbonyl] -5- (carboxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) aminocarbonyl] -5- (aminocarbonylmethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) aminocarbonyl) -5- (hydroxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) aminocarbonyl] -5-(carbomethoxymethylaminocarbonylmethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) aminocarbonyl] -5- [ (imidazole-4-yl) ethylaminocarbonylmethyl] isoxaaoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) aminocarbonyl] -5- (methoxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) aminocarbonyl] -5- (methyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1']-biphenyl-4-yl ) aminocarbonyl] -5-(carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1']-biphenyl-4-yl) aminocarbonyl] -5- (carboxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1'] biphenyl-4-yl) aminocarbonyl] -5-(aminocarbonylmethyl) isoxazoline 3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl [1, 1 ' ]-biphenyl-4-yl) aminocarbonyl] -5- (carbomethoxymethylaminocarbonylmethyl ) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1']-biphenyl-4-yl ) aminocarbonyl] -5- (hydroxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1']-biphenyl-4-yl ) aminocarbonyl] -5- (methoxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-methyl- [1,1' ] -biphenyl-4-yl ) aminocarbonyl] -5- (methyl ) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-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 ) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-fluoro- [1,1']-biphenyl-4-yl) aminocarbonyl] -5- (hydroxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-fluoro- [1,1']-biphenyl-4-yl) aminocarbonyl] -5- (methoxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-fluoro- [1,1' ] -biphenyl-4-yl ) aminocarbonyl] -5- (methyl ) isoxazoline

3- (3-amidinophenyl) -5- [ [2- (2 ' -aminosulfonylphenyl-1-yl) pyridin-5-yl] aminocarbonyl] -5-(carbomethoxymethyl) isoxazoline 3- (3-amidinophenyl) -5- [ [2- (2 ' -aminosulfonylphenyl-1-y1 ) yridin-5-y1] aminocarbonyl] -5- (carboxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ [2- (2 ' -aminosulfonylphenyl-1-yl ) yridin-5-yl] aminocarbonyl] -5- (aminocarbonylmethyl ) isoxazoline

3- (3 -amidinophenyl) -5- [ [2- (2 ' -aminosulfonylphenyl-1-yl)pyridin-5-yl] aminocarbonyl] -5- (hydroxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ [2- (2 ' -aminosulfonyl henyi-1-yl) pyridin-5-yl] aminocarbonyl] -5- ( ethoxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ [2- (2 ' -aminosulfonylphenyl-1-yl) pyridin-5-yl] aminocarbonyl] -5- (methyl) isoxazoline

3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1-yl) yridin-2-yl] aminocarbonyl] -5- ( carbomethoxymethyl) isoxazoline

3- (3 -amidinophenyl) -5- [ [5- (2 ' -aminosul fonylphenyl-1-yl) pyridin-2~yl] aminocarbonyl] -5- (carboxymethyl ) isoxazoline

3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1-yl)pyridin-2-yl] aminocarbonyl] -5-(aminocarbonylmethyl) isoxazoline

3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl] -5-(hydroxyethyl) isoxazoline 3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1-y1) pyridin-2-y1] aminocarbonyl] -5- (methoxyethyl) isoxazoline

3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1-yl)pyridin-2-yl] aminocarbonyl] -5- (methyl) isoxazoline

3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1-y1) pyrimidin-2-yl] aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ [5- (2 ' -aminosulfonylphenyl-1-y1) pyrimidin-2-y1] aminocarbonyl] -5- (carboxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [5- (2 ' -aminosulfonylphenyl-1-yl) yrimidin-2-yl] aminocarbonyl-5-carbomethoxymethyl-isoxazoline

3- (3-amidinophenyl) -5- [5- (2 ' -aminosulfonylphenyl-1-yl) yridin-2-yl] aminocarbonyl-5-carbo ethoxymethyl-isoxazoline

3- (3-amidinophenyl) -5- [2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl] aminocarbonyl-5- (tetrazol-1-yl) methyl-isoxazoline

3- (3-amidinophenyl) -5- [5- (2 ' -aminosulfonyIphenyl-1-yl)pyridin-2-yl]aminocarbonyl-5- (tetrazol-1-yl) methyl-isoxazoline

3- (3-amidinophenyl) -5- [5- (2 ' -aminosulfonylphenyl-1-yl) pyrimidin-2-yl] aminocarbonyl-5- (tetrazol-l-yl)methyl-isoxazoline 3- (3-amidinophenyl) -5- [2 * -trifluoromethyl- [1,1']-biphenyl-4-yl] aminocarbonyl-5- (tetrazol-1-yl) ethyl-isoxazoline

3- (3-amidinophenyl) -5- [5- (2 ' -trifluoromethylphenyl-1-yl) yridin-2-yl] aminocarbonyl-5- (tetrazol-1-yl )methyl-isoxazoline

3- (3-amidinophenyl) -5- [5- (2 ' -trifluoromethylphenyl-1-yl) yrimidin-2-yl] aminocarbonyl-5- (tetrazol-l-yl)methyl-isoxazoline

3- (3-amidinophenyl ) -5- [ 5- ( 2 ' -trifluoromethylsulfonylphenyl-l-yl)pyridin-2-yl]aminocarbonyl-5- (tetrazol-l-yl)methyl-isoxazoline

3- (3-amidinophenyl) -5- [5- (2 ' -trifluoromethylsulfonylphenyl-1-yl )pyrimidin-2-yl]aminocarbonyl-5- (tetrazol-l-yl) ethyl-isoxazoline

3- (3 -amidinophenyl) -5- [2 ' -aminosulfonyl-3-flouro- [1,1'] biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl) ethyl-isoxazoline

3- (3 -amidinophenyl) -5- [2 ' -aminosulfonyl-3-chloro- [1,1' ] biphenyl-4-yl] aminocarbonyl-5- (tetrazol-1-yl) methyl-isoxazoline

3- (3 -amidinophenyl) -5- [2 ' -trifluoromethyl-3-flouro-[1,1' ]-biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl) ethyl-isoxazoline

3- (3 -amidinophenyl) -5- [2 ' -trifluoromethyl-3-chloro-[1,1'] -biphenyl-4-yl] aminocarbonyl-5- (tetrazol-1-yl ) methyl-isoxazoline 3- (3-amidinophenyl) -5- [5- (2 ' -aminosulfonylphenyl-1-yl)pyridin-2-yl]aminocarbonyl-5-methoxymethyl-isoxazoline

3- (3-amidinophenyl) -5- [2 '-methylaminosulfonyl- [1,1']-biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl) methyl-isoxazoline

3- (3-amidinophenyl) -5- [5- (2 ' -methylaminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5- (tetrazol-1-yl) methyl-isoxazoline

3- (3-amidinophenyl) -5- [2 ' -methylsulfonyl- [1,1'] -biphenyl-4-yl] aminocarbonyl-5- (tetrazol-l-yl)methyl-isoxazoline

3- (3-amidinophenyl) -5- [2 ' -methylsulfonyl-fluoro- [1,1']-biphenyl-4-yl] aminocarbonyl-5- (tetrazol-l-yl) methyl-isoxazoline

3- (3-amidinophenyl) -5- [2 ' -methylsulfonyl-chloro- [1,1']-biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl) methyl-isoxazoline

3- (3-amidinophenyl) -5- [2 ' -trifluoromethylsulfonyl- [1,1']-biphenyl-4-yl] aminocarbonyl-5- (tetrazol-l-yl)methyl-isoxazoline

3- (3-amidinophenyl) -5- [2 ' -aminosulfonyl- [1, 1 ' ] -biphenyl-4-yl] aminocarbonyl-5- (imidazol-1-yl) methyl-isoxazoline

3- (3-amidinophenyl) -5- [2 ' -trifluoromethylsulfonyl-3-fluoro- [1,1' ] -biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl)methyl-isoxazoline

3- (3-amidinophenyl) -5- [2 ' -trifluoromethylsulfonyl-3-chloro- [1,1'] -biphenyl-4-yl] aminocarbonyl-5- (tetrazol-1-yDmethyl-isoxazoline 3- (3-amidinophenyl) -5- [2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl] aminocarbonyl-5- (imidazol-l-yl) ethyl-isoxazoline

3- (3-amidinophenyl) -4- (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl ) aminocarbonyl-5-methoxymethyl-isoxazoline

3- (3-amidinophenyl) -4- (2 '-aminosulfonyl- [1,1'] -biphenyl-4-yl)aminocarbonyl-5-trifluoromethyl-isoxazoline

3- (3-amidinophenyl) -5- (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl ) aminocarbonyl-4-methoxymethyl-isoxazoline

DETAILED DESCRIPTION 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 in 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 isoxazoline compounds of this invention utilizes a dipolar cycloaddition of nitrile oxides with appropriate dipolarophiles to prepare the isoxazoline rings present in compounds of Formula I (for reviews of 1,3 -dipolar cycloaddition chemistry, see 1,3-Dipolar Cycloaddition Chemistry (Padwa, ed. ) , Wiley, New York, 1984; Kanemasa and Tsuge, Heterocycles 1990, 2 , 719) . Scheme 1 shows a general synthesis of 3, 5-substituted-isoxazolines. An appropriately substituted hydroxylamine is treated with NCS in DMF according to the method of Liu, et al. (J. Orσ. Chem. 1980, 4ϋ, 3916). The resulting hydroximinoyl chloride is then dehydrohalogenated in situ using TEA to give a nitrile oxide, which undergoes a 1,3-dipolar cycloaddition to a suitably substituted alkene to afford the isoxazoline. Alternatively, the oxime may be oxidatively chlorinated, dehydrochlorinated and the resulting nitrile oxide trapped by a suitable alkene under phase transfer conditions according to the method of Lee (Synthesis 1982, 508). The isoxazoline 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 olefin as a dipolarophile. A mixture of regioisomers is formed and the regioisomers can be separated by column chromatography. An example is shown in Scheme 2. Optically active isoxazolines 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. Orσ. Chem. 52., 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 in formula (I) .

Scheme 1


Scheme 2



X = H, Ci
R = H, alkyl

Many isoxazoline compounds of this invention can use commercially available substituted alkenes as starting materials. Compounds with R2 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 isoxazoline ring is formed. Compounds with R2 is 0(CH2)nR> NH(CH2)nR, S(CH2)nR> where R is R5 or R10, 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 R2 is aromatics and heteroaromatics (R^) 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. 31, 4413-4416, 1990), or using palladium-catalyzed coupling of an a-stannyl acrylate to aryl iodides or triflates by Levin (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 is COCO2R or COCONHR can be prepared by the method discribed by Iwanowicz (Bioorα. & Med. Chem. Lett.. 2, 1607-1612, 1992).

Scheme 3



Scheme 4

Scheme 5

ets

Appropriately substituted crotonate ester can be used as starting material for 4, 5-disubstituted
isoxazolines. 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 (Svnlett , 660, 1994) .

Scheme 6



R = H, alkyl 2a 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. hem- - 4 , 3742, 1978) as shown in Scheme 8. The nitrile sulfide is generated by thermolysis of 5-substituted 1,3,4-oxthiazol-2-one.

Scheme 8



R' = Br, CN, R1

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 in 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 is then coupled with an appropiate amine using standard conditions for the formation of amide bonds. The nitrile is then converted to the amidine via the imidate or thioimidate under standard conditions. Some of the compounds are prepared following the procedures described in copending commonly-assigned US. Patent application USSN 08/337920. An example of these compounds is shown in Scheme 11. The 3-substituted-isoxazoline-5-ylcarboxylic acids or 3-substituted-isoxazoline-5-ylacetic 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 R1 is NHCH(NRS) in formula (I) may be prepared from amine derivatives by reaction of the amine with ethyl formimidate and N,N-dimethylpyrid:L-ne in refluxing ethanol. Compounds of this invention where Rl is
NHC (NR5)NR5R6 in formula (I) may be prepared from amine derivatives by reaction of the amine with either
formamidine sulfonic acid and N,N-dimethylpyridine in refluxing ethanol (Kim, et al. Tet . Lett . 29, 3183, 1988), or Bocprotected pyrazole carboxamidine in DMF (Bematowicz et al. Tet. Lett. 34, 3389, 1993).

Scheme 11


Scheme 12


The sulfone derivatives where U is -Sθ2-(CH2)o~ are prepared as exemplified by the reactions in Scheme 13. Methyl (triphenylphosphoranylidene) -acetate is reacted with acetyl chloride to give the desired allene. A sulfinic acid, prepared by hydrogen peroxide oxidation of the corresponding thiol, is added into the allene to give the desired alkene (Padwa, J. Orσ. 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. Vinyl sulfonyl chloride is brominated, then reacted with an amine (Barnett, Tet. Lett . , 651, 1968) . Halogen-metal exchange and alkylation with iodoacetate gives the desired substituted vinyl sulfonamide (Stetan, Chem, Ber. , 122, 169, 1889) which can be used in the previously described cycloaddition reactions.

Scheme 13


Scheme 14


Isoxazoline 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 isoxazoline 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 traping of the intermediate thiol with an appropriate benzylbro ide to afford the thioalkylphenylanalog.
Oxidation of the thio-compound with MCPBA or oxone affords the sulfoxide and or sulfone.

Scheme 15


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 Wittig reaction. The alkene-linked compounds can then be reduced to the corresponding alkyl-linked compounds. The alkyl-linked 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 amine intermediate is the converted to compounds with -NHSO2-, and -NHCO- using suitable sulfonyl or acyl chloride. The 5-hydroxymethylisoxazoline can be converted to the ether-linked compound by Mitsunobo reaction. The ether and amine linked compounds can also be prepared by
displacement of the allyl bromide shown in Scheme 17.

Scheme 16

Scheme 17


Compounds of this invention where U is -CO- can be prepared by palladium-catalyzed coupling reactions of organozinc reagents with acid chlorides (Jackson,
Synlet , 819-820, 1995 and Sato, Chem. Lett. ■ 1135, 1981) or by organimetallics of Zinc and .Copper described by Knochel (J. Orα. 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-Bro oaniline is protected as Boc-derivative and the coupled to 2- (t-butylamino) sulfonylphenylboronic acid under Suzuki conditions. 2- (t-Butylamino) sulfonylphenylboronic acid is prepared by the method described by Rivero (BJQQrg, Med, Chem, Lett,, 189, 1994).
Deprotection with TFA provides the aminobiphenyl
compound. The aminobiphenyl is the coupled to the core ring structures first as described above. The
Bromoaniline 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 peperidine derivative shown in Scheme 19. Compounds of this invention where -Z- is -NH-, -0-, and -S- can be prepared by the methods described in

Scheme 20.

Scheme 19


Scheme 20


Some of the compounds of this invention may also be prepared as shown in Scheme 21. Itaconic anhydride reacts with appropiate amine to give 3-carboxy-3- butenamide. The benzaldehyde oxime is oxidatively chlorinated and dehydrochlorinated. The resulting nitrile oxide then reacted with 3-carboxy-3-butenamide to yield the 3, 5, 5-trisubstituted isoxazoline which was then converted to the final benzamidine 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-brompyridine 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 isoxazoline by the same methods described above. An example of such a convertion is shown in Scheme 22 where n = 0-3.

Scheme 22



21 32 S3


Some of the spiro-compounds of this invention in formula (II) may be prepared as shown in Scheme 23.
Itaconyl chloride is reacted with appropiate amine to give the a-methylene-succinimide 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 in Scheme 24 can be reduced with LiBH4 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


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 vivo 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 vivo, 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, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic,
salicylic, sulfanilic, 2-acetoxybe.nzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, 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
stoichiometric 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 amine, e.g.,
dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine 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, unJL,ess otherwise
indicated, all temperatures are in degrees centigrade and parts and percentages are by weight.

Example 1

3-amidinophenyl-5- (4-amidinophenyl) aminocarbonyl-5-carbomethoxymethyl-isoxazoline, 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 N2 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%). iHNMR (DMSO): d 7.61 (t, IH) ; 7.85 (d, IH) ; 7.96 (d, IH) ; 8.00 (s, IH) ; .21 (s, IH) ; 11.61 (s, IH) .

Part B. Preparation of 3- (3-cyanophenyl) -5-carbomethoxy methyl-isoxazolin-5-ylcarboxylic acid

3-cyanobenzaldehyde oxime (26.9 g, 0.18 mol) and itaconic 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 N2 for 12h. The THF was removed in 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%). iHNMR (DMSO): d 3.12 ( , 2H); 3.63 (s, 3H) ; 3.66 (d, IH) ; 3.95 (d,
1H);7.68 (t, IH) ; 7.85 (d, IH) ; 7.95 (d, IH) ; 8.04 (d, IH) ; 8.12 (S, IH) .

Part C. Preparation of 3- (3-cyanophenyl) -5- (4-cyanophenyl) aminocarbonyl-5-carbomethoxymethyl-isoxazoline

3- (3-Cyanophenyl) -5-carbomethoxy methyl-isoxazolin-5-ylcarboxylic acid (1.00 g, 3.47 mmol), 4-cyanoaniline (0.41 g, 3.47 mmol), and (2- (lH-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (1.11 g, 3.47 mmol) were added together with DMF (25 mL) and triethylamine (2 mL) . The mixture was stirred at room temperature under N2 for 48 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic solution was washed with brine, dried over MgS04 and concentrated. It was then purified by chromatography (silica gel, 30-50% EtOAc in hexane) to give 0.33 g of the desired product (24%). MS 406,
(M+NH4)+. XHNMR (CDC13): 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-amidinophenyl) -aminocarbonyl-5-carbomethoxymethyl-isoxazoline, Bistrifluoroacetic Acid Salt

3- (3-Cyanophenyl) -5- (4-cyanophenyl) aminocarbonyl-5-carbomethoxymethyl-isoxazoline (0.63 g, 1.62 mmol) was dissolved in 10 mL of anhydrous methanol and 30 mL of CHCI3. The mixture was cooled in an ice-bath and HCl 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 H20/CH3CN to give 0.20 g of the
bisbenza idine TFA salt (20%). MS 423.2, (M+H)+; 212.1, (M+2H)2+. iHNMR (DMS0-d6): 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- (3-Amidinophenyl) -5- r (2-naphthylsulfonyl) aminolmethyl-isoxazoline Trifluoroacetic Acid Salt

Part A. Preparation of 3- (3-cyanophenyl) -5-hydroxymethyl-isoxazoline 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 N2 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%). XHNMR (DMS0-d6) : 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) ethylisoxazoline

3- (3 -Cyanophenyl) -5-hydroxymethylisoxazoline (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 N2 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 MgS04, and then the solvent was removed in vacuo to give 1.53 g (87%) of the desired compound as a white solid. 1HNMR (DMSO-d6) : 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 ( , 2H) , 8.55 (d, IH) .

Part C. Preparation of 3- (3-cyanophenyl) -5-azidomethyl-isoxazoline

3- (3-Cyanophenyl ) -5- (4-methylphenylsulfonyloxy)methylisoxazoline (1.00 g, 2.81 mmol) and sodium azide (0.55 g, 8.42 mmol) are dissolved in 10 mL of DMSO and stirred at RT under N2 for 72 h.

After diluting with water, the mixture was extracted with ethyl acetate, dried with MgS04, and then the solvent was removed in vacuo to give 0.64 g (100%) of the desired compound as a white solid. "HNMR (CDC13) : 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-aminomethyl-isoxazoline

3- (3-Cyanophenyl) -5-azidomethylisoxazoline (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 H2 for 4 h. The reaction mixture was filtered through celite and then the solvent was removed in vacuo to give 0.57 g (100%) of the desired compound as a white solid. ^ΗN R (CDC13) : d 2.90 ( , IH) , 3.06 (m, IH) , 3.18 (dd, IH) , 3.36 (dd, IH) , 4.88 ( , IH) , 7.32 (t, IH) , 7.48 Cd, IH) , 7.95 (m, 2H) .

Part E. Preparation of 3- (3-cyanophenyl) -5- [ (2-naphthylsulfonyl) amino] methylisoxazoline

3- (3 -Cyanophenyl) -5-aminomethylisoxazoline (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 N2 for 12h.
After diluting with saturated aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate, dried with MgS04, 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. HNMR (DMSO-d6) : 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 (m, 5H) , 8.12 (m, 3H) .

Part F. Preparation of 3- (3-amidinophenyl) -5- [ (2-naphthylsulfonyl) amino]methylisoxazoline Trifluoroacetic Acid Salt

3- (3-Cyanophenyl) -5- [ (2-naphthylsulfonyl) amino] ethylisoxazoline (0.30g, 0.77 mmol) was dissolved in 50 L of MeOH. The reaction mixture was cooled in an ice/salt bath (-5°C) , and HCl gas was bubbled-in for 2h. The mixture was sealed, allowed to warm to RT, and stirred for 12h. The solvent was removed in vacuo and the resulting solid was dried and used in the next step.

The imidate 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 H20/CH3CN to give 0.03 g of the benzamidine TFA salt (9.5%). MS 409.3, (M+H)\ XHNMR (DMSO-d6) : d 3.03 (t, 2H) , 3.22-3.58 ( , 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-amidinophenyl 13- (3-amidinophenyl) -5-Carbomethoxy-isoxazolin-5-yll acetamide, Bistrifluoroacetic Acid Salt

Part A. Preparation of N-4-cyanophenyl 3-carboxy-3-butenamide

Itaconic anhydride (0.56 g, 5.0 mmol) and 4-cyanoaniline (0.71 g, 6.0 mmol) were added together with 25 mL of CHCI3. The mixture was stirred at RT under 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+NH4)+.

Part B. Preparation of 4-cyanophenyl [3- (3-cyanophenyl) 5-carboxy-isoxazolin-5-yl] acetamide

N-4-cyanophenyl 3-carboxy-3-butenamide (1.06 g, 4.6 m o .) 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 N2. 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 brine, dried over MgSθ4 and concentrated to a solid. The solid was washed with CH2C12 to give 0.81 g off-solid (47%). MS 392,
(M+NH )+.

Part C. Preparation of 4-amidinophenyl [3- (3-a idinophenyl ) -5-Carbometoxy-isoxazolin-5-yl] acetamide, Bistrifluoroacetic Acid Salt

4-cyanophenyl [3- (3-cyanophenyl) -5-carboxy-isoxazolin- -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 in H2O/CH3CN to give 84 mg of the bisbenzamidine TFA salt (16%). MS 423.2, (M+H)+. XHNMR (DMSO-d6) : 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 ' -aminosulfonyl- \1.1 ' 1 -biphenyl- 4-yll aminocarbonyl-5-carbomethoxy methyl-isoxazoline, Trifluoroacetic Acid Salt

Part A. Preparation of 2- (t-butylamino) sulfonylphenylboronic acid

To a solution of 34.0 g (0.16 mol) of benzene-N- (t-butylsulfonamide in 500 mL of THF under N2 was added 160 mL (0.36 mol) of 2.25M n-butyllithium in hexane over 35 min, keeping the temperature between 0°-2°C. The reaction mixture was allowed to warm to room temperature over 1.5h, during which time a thJck precipitate formed. Triisopropylborate (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 min. 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 brine, dried over MgS04, and the solvents were removed in vacuo to yield 45 g of a thick oil. After addition of Toluene (45 L) , 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 in 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.

!HNMR (CDCI3): 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-butylaminosulfonyl-4-nitro- [1,1' ] -biphenyl

A mixture of 4.4 g (0.020 mol) of l-bromo-4-nitrobenzene and 5.14 g (0.020 mol) of 2-(t-butyla ino) sulfonylphenylboronic acid , 1.16 g of tetrakis (triphenylphosphine) palladium(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 N2 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, drieq. over MgS04 and concentrated. The resulting solid was recrystallized from EtOAc/hexane to afford 3.25 g of the desired biphenyl. (49%) . iHMR (CDCI3) : d l.07(s, 9H) ; 3.60 (br s, 2H) ; 7.29 (d, IH) ; 7.59 ( , 2H) ; 7.69 (d, 2H) ; 8.20 (d, 2H) ; 8.30 (d, 2H) .

Part C. Preparation of l-Bromo-4-t-butoxycarbonylaminobenzene

To a mixture of NaH (4.13, 0.14 mol) in THF was added 4-bromoaniline. The resulting mixture was refluxed under N2 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 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 NH4CI and saturated aqueous NaHCθ3, dried over MgS04, 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 (CDC13) : d 1.52 (s, 9H) ; 6.48 (br s, IH); 7.27 (d, 2H) ; 7.40 (d, 2H) .

Part D. Preparation of 2 ' -t-butylaminosulfonyl-4-amino- [1,1'] -biphenyl

Method A:
A suspension of 3.00 g (0.009 mol) of 2'-t-butylaminosulfonyl-4-nitro- [1, 1 '] -biphenyl and 0,30 g of 10% Pd/C in 90 mL of methanol was stirred at room temperature under H2 (gas) d atm) 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 filtrate was
concentrated. The crude product was recrystallized from benzene/hexane to give 2.32 g (85%) of the aniline.
iH MR (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-butylamino) sulfonylphenylboronic acid , 3.0 g of tetrakis (triphenylphosphine) palladium(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 N2 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 brine, dried over MgS04 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 aminobiphenyl 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 in 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. !H MR (DMSO-d6) : d 1.01(s, 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-butylaminosulfonyl- [1,1'] -biphenyl-4-yl] aminocarbonyl-5-carbomethoxy methyl-isoxazoline

3- (3-cyanophenyl) -5-carbomethα y methyl-isoxazolin-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 . The solvent was removed in 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-butylaminosulfonyl-4-amino- [1, 1' ] -biphenyl, TFA salt (0.60 g, 1.40 mmol) was added followed by triethylamine (1.5 mL, 10.4 mmol) . The reaction mixture was stirred at RT and the reaction was completed in less than 30 min. The mixture was diluted with ethyl acetate and the solution was washed with water and brine. It was dried over MgS04 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)+. ΪHNMR (CDC13): 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 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl] aminocarbonyl-5-carbo ethoxy methyl-isoxazoline

3- (3-Cyanophenyl) -5-N- [2 ' -t-butylaminosulfonyl- [1,1'] -biphenyl-4-yl]aminocarbonyl-5-carbomethoxy methylisoxazoline (1.12 g, 1.95 mmol) was refluxed with 25 ml of trifluoroacetic acid under N2 for l/2h. The TFA was removed in vacuo, the residue was dissolved in methylene chloride and then precipitated with ether to give l.O g Of white solid (99%). MS 519.2, (M+H)+. iHNMR (CDCI3) : 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 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl]aminocarbonyl-5-carbomethoxy methyl-isoxazoline, Trifluoroacetic Acid

Salt

3- (3-Cyanophenyl) -5-N- [2 ' -aminosulfonyl- [1,1']-biphenyl-4-yl] aminocarbonyl-5-carbomethoxy methylisoxazoline (1.2 g, 1.93 mmol) was dissolved in 90 mL of CHCI3 and 20 mL of MeOH. The reaction mixture was cooled in an ice-bath, and HCl gas was bubbled-in for 30 min 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 imidate 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 H20/CH3CN to give o.47 g of the benzamidine TFA salt (37%). MS 536.4, (M+H)+. iHNMR (DMSO-d6) : d 3.20 ( , 2H) ; 3.48 (s, 3H) ; 3.70-4.01 ( ,

2H) ; 7.20-7.32 (m, 4H) ; 7.52 (m, 2H) ; 7.72 (d, 2H) ; 7.8E

(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 ' -aminosulfonyl- [1,1']-biphenyl-4-yl) -methyl] aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline, trifluoroacetic acid salt (Ex.5)

3- (3-amidinophenyl) -7- (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) methyl [l-oxa-2 ,7-diazaspiro[4, 4]non-2-ene-6, 8-diones, trifluoroacetic acid salt (Ex.6)

Part A. Preparation of 2 ' -t-butylaminosulfonyl-4-amino ethyl- [1,1'] -biphenyl

2 ' -t-butylaminosulfonyl-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-bromosuccinamide (0.92 g, 5.18 mmol) and AIBN (0.10 g) in 50 mL of CC1 for 2h. The mixture was cooled and the precipitae was filtered-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 N2. The reaction mixture was cooled and pourted into water. It was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgS04. 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 H2 for 5 h. The resulting mixture was filtered through celite and washed with MeOH. The filtrate was concentrated and precipitated with Et2θ to give 1.32 g of white solid (72 %). MS (DCI) 336 (M+NH4)+, 319 (M+H)+.

Part B. Preparation of 3- (3-cyanophenyl) -5-N- [2 ' -t-butylaminosulfonyl- [1,1'] -biphenyl-4- ethyl] aminocarbonyl-5-carbomethoxy methyl-isoxazoline

This compound was prepared by the same method
described in Part G of Example 4 using 2 ' -t-butylaminosulfonyl-4-aminomethyl- [1, 1' ] -biphenyl and 3- (3-cyanophenyl) -5-carbomethoxy methyl-isoxazolin-5-ylcarboxylic acid as the starting materials. MS (DCI) 606 (M+NH4)+.

Part C. Preparation of 3- (3-amidinophenyl) -5- [ [ (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yL) -methyl] aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline, trifluoroacetic acid salt (EX 5) and 3- (3-amidinophenyl ) -7- (2 ' -aminosulfonyl- [1, 1 ' ] -biphenyl-4-yl) methyl [l-oxa-2, 7-diazaspiro[4, 4] non-2-ene-6, 8-diones, trifluoroacetic acid salt (EX 6).

3- (3-cyanophenyl) -5-N- [2 ' -t-butylaminosulfonyl- [1,1']-biphenyl-4-methyl] aminocarbonyl-5-carbomethoxy methyl-isoxazoline was subjected to the Pinner - 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 in H20 and CH3CN 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-benzenesulfonyIpheny1-1-yl) aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline, trifluoroacetic acid salt Part A: Preparation of 4-aminodiphenylsulphone

To a suspension of 4-nitrodiphenylsulphone (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) + . i-HNMR (DMSO-d6) : 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-benzenesulfonylphenyl-1-yl) aminocarbonyl] -5- ( carbomethoxymethyl) isoxazoline

This compound was prepared by the method described in Part C of Example 1 using 3- (3-cyanophenyl) -5-carbomethoxy methyl-isoxazolin-5-ylcarboxylic acid and 4-aminodiphenylsulphone as starting materails. MS 504.2, (M+H)+. XHNMR (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) isoxazoline, trifluoroacetic acid

This compound was prepared as described in Part D of Example 1. MS 521.2, (M+H)+.

Example 8

3- (3-amidinophenyl) -5- (2 ' -aminosulfonyl- fl.1 ' 1 -biohenyl-4-yl)aminocarbonyl-5-(tetrazol-l-yl)methyl-isoxazoline. Trifluoroacetic Acid Salt Part A. Preparation of 3- (3-cyanophenyl) -5-Carbomethoxy-5- (tetrazol-l-yl) ethyl-isoxazoline

1H-Tetrazole(0.89 g, 14.0 mmol) and K2CO3 were added together with 50 mL of DMF. Methyl 2- (bromo ethyl) acrylate (2.5 g, 14.0 mmol) was added. The mixture was stirred at room temperature under N2 for 12h. The mixture was poured into water and extracted with EtOAc. The combined organic solution was washed with brine, dried over MgS04, 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 L) . To the above mixture was added dropwise bleach (25 mL of 0.67M solution) . The resulting mixture .was stirred at room temperature under N2 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 MgS04, and concentrated. It was purified by chromatography (silica gel, 5-15% EtOAc in CH2CI2) 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. iHNMR (DMSO-dβ) : 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-Carboxylic acid-5- (tetrazol-1-yl)methyl-isoxazoline

3- (3-Cyanophenyl) -5-Carbomethoxy-5- (tetrazol-1-yl-methyl) -isoxazoline (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 N2 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 brine, dried over MgS04, and concentrated to a white solid (1.54 g) . iHNMR (DMS0-d6) : δ 3.70-4.02 (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-Butylaminosulfonyl- [1,1'] -biphenyl-4-yl] aminocarbonyl-5- (tetrazol-l-yl)methyl-isoxazoline

3- (3-Cyanophenyl) -5-Carboxylic acid-5- (tetrazol-1-yD ethyl-isoxazoline (0.55 g, 1.84 mmol) was refluxed with CH3CN (20 mL) and S0C12 (1.34 mL, 18.4 mmol) under 2 for lh. The solvent was removed. Residual SOCI2 was removed by dissolving in toluene and then removing the solvent to dryness. The resulting solid was dissolved in CH2CI2 (20 mL) . 2 '-t-Butylaminosulfonyl-4-amino- [1,1* ]-biphenyl prepared as described in Example 4 (0.28 g, 0.92 mmol) was added followed by Et3N (1.5 mL, 18.4 mmol) . The mixture was stirred at room temperature under N2 for 1/2 h. It was diluted with CH2CI2 and washed with water and brine. It was dried over MgSθ4 and concentrated. The desired product was the purified by chromatography (silica gel, 20% EtOAc in CHC12) to give 0.59 g off-white solid. XHNMR (DMSO-dδ) : δl.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 '-aminosulfonyl- [1,1'] -biphenyl-4-yl] aminocarbonyl-5-(tetrazol-l-yl)methyl-isoxazoline, Trifluoroacetic Acid

Salt 3-(3-Cyanophenyl)-5- [2 '-t-Butylaminosulfonyl- [1,1' ] -biphenyl-4-yl] aminocarbonyl-5- (tetrazol-1-yl) methylisoxazoline (β.41 g, 0.70 mmol) was dissolved in
anhydrous CHCI3 (20 mL) and anhydrous CH3OH (5 mL) . HCl gas was bubbled-in until the solution was saturated (about 15 min) . 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 imidate formed above was dissolved in 20 mL of anhydrous CH3OH. 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 CH3CN/H2O/TFA, and purifed by reversed phase HPLC (Cis reversed phase column, 0.5% TFA in H2O/CH3CN) to give the desired TFA salt (0.15 g) .
!HNMR (DMSO-d6) : δ 3.89-4.16 (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 ( , 3H) ; 9.12 (s, 2H) ; 9.41 (s, 2H) ; 9.43 (s, IH) . MS(ES+) 546.3 (M+H)+.

Example 9

3- (3-amidinophenyl) -5- (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl)oxymethyl-5-ethoxymethyl-isoxazoline.
Trifluoroacetic Acid Salt

Part A. Preparation of 3- (3-cyanophenyl) -5-ethoxymethyl-5- (4-bromophenoxy)methyl-isoxazoline

Sodium hydride (0.74 g of 60% oil dispersion, 18.4 mmol) was washed with Petrolium ether and then suspended in 50 L of THF. To it was added 4-bromophenol (2.89 g, 16.7 mmol) . The mixture was stirred at room temperature for 15 min, and methyl 2- (bromomethyl) acrylate (2.99 g, 16.7 mmol) was added. The mixture was stirred at room temperature under N2 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 and concentrated to 3.93 g of methyl 2- [ (4-bromophenoxy) ethyl] acrylate.
Methyl 2- [ (4-bromophenoxy) methyl] acrylate (2.01 g, 7.4 mmol) was dissolved in 50 mL of THF. The mixture was cooled at -78°C under N2 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 brine. It was dried over MgS04 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 etcher and then suspended in 30 mL 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 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 MgS04, 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 N2 for 12 h. It was diluted with EtOAc and washed with brine. 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-isoxazoline.

Part B. Preparation of 3- (3-cyanophenyl)-5- [2 '-t-Butyla inosulfonyl- [1,1'] -biphenyl-4-yl] oxymethyl-5-ethoxymethyl-isoxazoline

3- (3-Cyanophenyl) -5-ethoxymethyl-5- (4-bromophenoxy)methyl-isoxazoline ( 0.48 g, 1.15 mmol), 2- (t-butylaminosulfonyIphenyl 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 min and tetrakis (triphenylphosphine) palladium was added. The mixture was refluxed under 2 for 12 h. The solvents were removed. The resulting material was dissovled in EtOAc and washed with water and brine. It was dried over MgS04, concentrated chromatographed on silica gel (3:1 hexane/EtOAc) to give 0.18 g of the desired product. 1HNMR (CDCI3) : δ l.00 (s, 9H) ; 1.21(t,

3H) ; 3.43 ( , 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 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl] oxymethyl-5-ethoxymethyl-isoxazoline, trifluoroacetic acid salt.

3- (3-Cyanophenyl)-5-[2 ' -t-Butylaminosulfonyl- [1,1' ]-biphenyl-4-yl] oxymethyl-5-ethoxymethyl-isoxazoline (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 (Cis reversed phase column, 0.5% TFA in H2O/CH3CN) to give 0.13 g of the desired TFA salt (0.15 g) . iH MR (DMSO-de) : δl.09 (s, 3H) ; 3.40-3.58 (m, 4H) ; 3.68 (q,

2Hj; 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 ( +H)+.

Example 10 and Example 11

3- (3-amidinophenyl) -4- (2 ' -aminosulfonyl- ri.1 ' 1 -biohenyl-4-yl)aminocarbonyl-5-methyl-isoxazoline, Trifluoroacetic Acid Salt
3- (3-amidinophenyl) -5- (2 '-aminosulfonyl- f1.1' ] -biphenyl-4-yl) aminocarbonyl-4-methyl-isoxazoline, Trifluoroacetic Aςid Salt

Part A. Preparation of 3- (3-cyanophenyl) -5-Carbomethoxy-4-methyl-isoxazoline and 3- (3-cyanophenyl) -4-Carbomethoxy-5-methy1-isoxazoline

To a dichloromethane ( lOOmL) solution of 3-cyanophenyl-oximinochloride (2.30 g, 13.65 mmol) and methyl crotonate (1.71 g, 17.05 mmol) was added
triethylamine (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-isoxazoline (0.82g, 25% yield) as a colorless oil. 1HNMR(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
isoxazoline was also obtained (0.53g, 16% yield) as a colorless oil . 1HNMR (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-isoxazoline

The 4-isoxazoline ester was then carefully
hydrolyzed (LiOH, leq.) in THF:water (4:1, 20 mL) to the carboxylic acid (0.75g, 97% yield). ^-HNMR CDCls) 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-butylaminosulfonyl- [1,1'] -biphenyl-4-yl)aminocarbonyl-5-methyl-isoxazoline

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-Butylaminosulfonyl-4-a ino- [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 brine (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. iHNMR CDCIs) 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 ' -aminosulfonyl- [1, 1 ' ] -biphenyl-4-yl) aminocarbonyl-5- ethyl-isoxazoline

The nitrile obtained in Part D was then subjected to the Pinner - amidine reaction protocol described
previously to afford 0.15g (colorless crystals) of the desired benzamidine compound after reversed phase HPLC purification. 1HNMR(DMSO de) 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 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) aminocarbonyl-4-methyl-isoxazoline

This compound was obtained by the same procedure described above using 3- (3 -cyanophenyl ) -4-Carbomethoxy-5-methyl-isoxazoline as starting material. 1HNMR(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, j = 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-amidinophenyl) -5- f (4- (2 ' -nitrophenoxy) )phenyl-l-yllaminocarbonyl-5-methyl-isoxazoline, Trifluoroacetic Acid Salt 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 brine (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); 1HNMR(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) ) henyi-1-yl] aminocarbonyl-5-methyl-isoxazoline

3- (3-Cyanophenyl) -5-carboxylic acid-5-methylisoxazoline prepared by the same procedures described above aws coupled to 4- (2-nitrophenoxy) aniline from Part A as previously described. The resulting product was subjected to standard Pinner reaction to give the desired amidine. 1HNMR(DMSO άe ) 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) . MS(ESI) 460.2, (M+H, 100).

Example 13 3- (3-amidinophenyl) -5- (3- NN-ethvl (pyrid-2-yl-methyl) 1 aminophenyl-1-yl) aminocarbonyl-5-methylisoxazoline. Trifluoroacetic Acid Salt

Part A. Preparation of 3- [NN-ethyl (pyrid-2-yl-methyl) ] aniline

The title compound was prepared in three step sequence via a sequential reductive amination of 3-nitroaniline with 2-pyridine carboxaldehyde and
acetaldehyde with sodium cycanoborohydride in methanol, followed by catalytic (Pd/C) hydrogenation in 29% overall yield. -H MRCCDCls) 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(ESJ) 258, (M+H, 100).

Part B. Preparation of 3- (3-amidinophenyl) -5- (3- [NN-ethyl (pyrid-2-yl-methyl) ] aminophenyl-1-yl) aminocarbonyl-5-methyl-isoxazoline, Trifluoroacetic Acid Salt

3- (3-Cyanophenyl) -5-carboxylic acid-5-methylisoxazoline 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 Pinner reaction to give the desired amidine. iHNMRfDMSO dδ) 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 C26H29N6O2
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 (-) in the column headed o.r. (for optical rotation) in Table 2.

TABLE 1



EX# B m (CH2)nR2 -U-V-Z-D MS

16 -c-N-Q-O 399.0




-C- H-O=/-^ N NHH2 365.2



NH
in 0 CH2CO HCH2C02Me -C-N- "^ NH, 480.5


O

II
—C-N NH
m 0 CH2C02Me 374.2



m 0 CH2C02Me -c-fj- O 457.4

in 0 CH2C02H -C-N^O^O 443.4

CH2CONH2 -C-N-Qr- 442.4

m 0 CH2CH2OH -C- - ~0 429.3

m 0 CH2C02Me C-N- ~ ~NH2 236.8
(M+2H) +


4 -imidazole (M+2H)2+



O II

CH2Cθ2Me 537.2
H2 θ2S




(M+2H)2+

TABLE 2



1-2

EX o.r. m (CH2)nR2 R12 MS

# (M + H) +

68 0 N N CH2C02Me 0-SO2NH2 538.2 69 0 CH N CH2C02Me 0-SO2NH2 537.2

70 (+) 0 N N CH2C02Me 0-SO2NH2 538.2

71 (-) 0 N N CH2Cθ2Me 0-SO2NH2 538.2 72 0 CF CH CH2Cθ2Me 0-SO2NH2 554.2

73 0 CF CH CH2C02H 0-SO2NH2 540.2

74 0 CH CH H 0-SO2NH2 464.2

75 0 CH N CH3 0-SO2NH2 479.3

76 0 CH CH CH3 0-SO2NH2 478.2

77 0 CH N CH2θMe 0-SO2NH2 509.2

78 0 N N CH2SEt 0-SO2NH2 540.3

79 0 N N CH2Sθ2Et 0-SO2NH2 572.4

80 0 CH N CH2S02Et 0-SO2NH2 571.3

81 0 CH CH CH2Sθ2Et 0-SO2NH2 570.4

8 0 CH CH CH2-tetrazol-l-yl 0-SO2NH2 546.3

82 0 CH CH CH2-teoazol-l-yl * o-S02NH-t-Bu 602.3

83 0 CH CH CH2-tetrazol-2-yl 0-SO2NH2 546.5

84 0 CH CH CH2-tetrazol-2-yl oSθ2NH-t-Bu 602.6

85 0 CH N CH2CO2H 0-SO2NH2 523.1

86 (-) 0 CH N CH2C02Me 0-SO2NH2 537.1

87 (+) 0 CH N CH2C02Me 0-SO2NH2 537.3

88 0 N N CH2θMe 0-SO2NH2 510.3

89 0 N N CH2θEt 0-SO2 H2 524.3

90 0 CH N CH2θEt o-Sθ2NH2 523.3

91 0 CH CH CH2CONH2 0-SO2NH2 520.6

92 0 CH CH CH2θMe 0-SO2 H2 508.3

93 0 CH CH CH2θEt 0-SO2NH2 522.3

94 (-) 0 CH CH CH2θEt 0-SO2NH2 522.4

95 (+) 0 CH CH CH2θEt 0-SO2NH2 522.4

96 (+) 0 CH CH CH2θEt oSCriNH-t-Bu 578.5

97 0 CH N CH2CO2H o-Sθ2NH2 524.4 98 0 CH CH CH2θ-i-Pen 0-SO2NH2 564.4

99 0 CH CH CH2Br 0-SO2NH2 556.3

100 0 CH CH CH2Br o-S02NH-t-Bu 612.4

101 0 CH CH CH2θEt o-S02 fHMe 536.4

102 (-) 0 CH N CH2θEt 0-SO2NH2 523.3

103 (-) 0 CH N CH2θEt o-S02NH-t-Bu 579.3

104 0 CH CH CH2θ-n-Pr 0-SO2NH2 536.4

105 0 CH CH CH2θ-n-Bu 0-SO2NH2 550.5

106 0 CH N CH2SEt 0-SO2NH2 539.3

107 0 CH CH CF3 o-S02NH-t-Bu 588.2

108 0 CH CH CF3 0-SO2NH2 532.3

109 (-) 0 CH CH CH2-tetrazol-l-yl * 0-SO2NH2 546.4

110 (+) 0 CH CH CH2-tetrazol-l-yl 0-SO2NH2 546.2

111 (-) 0 CC1 CH CH2-tetrazol-l-yl 0-SO2NH2 580.1

112 0 CC1 CH CH2-teoazol-l-yl 0-SO2NH2 580.1

113 0 CF CH CH2-tettazol-l-yl 0-SO2NH2 564.4

114 (-) 0 CF CH CH2-tetrazol-l-yl 0-SO2NH2 564.4

115 0 CH N CH2-tetrazol-l-yl o-S02NH-t-Bu 603.5

116 0 CH N CH2-tettazol- -y1 0-SO2NH2 547.4

117 (-) 0 CH N CH2-tetιazol-l-yl 0-SO2NH2 547.4

118 0 CH CH CH2CH2θMe 0-SO2NH2 522.4

119 0 CH CH CH2CH2θMe o-Sθ2NH-t-Bu 578.5

120 (-) 0 CH N CH2-tetrazol-l-yl o-Sθ2NH-t-Bu 603.6

121 0 CH CH CH2Ph 0-SO2 H2 554.3

122 0 CH CH CH2θ-i-Pr 0-S02NH2 536.3

123 (-) 0 CH N CH2θMe 0-SO2NH2 509.3

124 (-) 0 CH N CH2θMe o-S02NH-t-Bu 565.4 125 0 CH N CH2-tetrazol-l-yl o-S02NHMe 561.6

126 (-) 0 CH N CH2-tetrazol-l-yl o-S02NHMe 561.6

127 (-) 0 CH CH CH2-tetrazol-l-yl o-Sθ2NH-n-Pr 588.6

128 0 CH CH CH2-tetrazol-l-yl o-Sθ2NH-n-Pr 588.4

129 (-) 0 CH CH CH2-tetrazol-l-yl o-S02NHMe 560.4

130 0 CH CH CH2I 0-SO2NH2 604.3

131 0 CH CH CH2-l-(4,5- o-S02NHMe 612.2
di doroimidazole)
132 0 N N CH2-tetrazol-l-y! 0-SO2NH2 548.4

133 CH CH Cθ2Me 0-SO2NH2 536.3

134 CH CH Cθ2Me o-S02NH-t-Bu 592.4

135 CH N C02H 0-SO2NH2 523.4

136 (-) N N CO2H 0-SO2NH2 524.3

137 (-) CH N CO2H 0-SO2NH2 523.4

138 N N CO2H 0-SO2NH2 524.4

139 0 CH CH CH2C02Me o-OMe 487.3

140 0 CH CH CH2Cθ2Me m-OMe 487.3

141 0 CH CH CH2CONH2 o-OMe 472.2

142 0 CH CH CH2CONH2 m-OMe 472.2

143 0 CH CH CH2Cθ2Me -CF3 525.2

144 0 CH CH CH2CONH2 m-CF3 510.2

145 0 CH CH CH2CONH2 w-S02Me 535.3

146 0 CH CH CH2CONH2 o-Me 456.5

147 0 CH CH CH2Cθ2Me o-Me 471.5

148 0 CH CH CH2CONH2 m-Me 456.5

149 0 CH CH CH2C02Me m-Me 471.5

150 0 CH CH CH2Cθ2Me m-S02NH2 536.5 151 0 CH CH CH2CONH2 o-S02NMe2 549.4

152 0 CH CH CH2CONH2 o-S02NHMe 535.4

153 0 CH CH CH2Cθ2Me σ-SMe 503.4

154 0 CH CH CH2Cθ2Me o-Sθ2Me 535.4

155 1 CH CH Cθ2 e o-S02Me 535.4

156 0 CH CH CH2CONH2 o-C02Me 500.3

157 0 CH CH CH2Cθ2Me o-C02Me 515.4

158 0 CH CH CH2CONH2 o-SOMe 488.3

159 0 CH CH CH2θMe o-S02Me 507.4

160 0 CH CH CH2θMe o-S02Et 521.4

161 0 CH CH CH2θMe o-S02-n-Pr 535.4

162 0 CH CH CH2θMe o-S02-i-Bu 549.5

163 0 CH CH CH2-tetιazol-l-yl o-S02Me 545.2

164 0 CH CH CH2-tetrazol-l-yl 0-SO2CF3
165 (-: ) 0 CH CH CH2-tetrazol-l-yl 0-CF3 535.4

166 (- ) 0 N CH CH2-tetrazol-l-yl 0-CF3 536.3

167 0 N N CH2-tettazol-l-yl 0-CF3
168 0 CC1 CH CH2-tetrazol-l-yl 0-CF3
169 0 CF CH CH2-tetrazol-l-yl 0-CF3
170 0 CH CH CH2-imidazol-l-yl 0-CF3
171 0 CH CH CH2-imidazol- 1 -yl 0SO2NH

A9&E 3
(CH2)nR2

EX# U ϊH2)nR2 V-(Z)u-(D)u MS
(M + H) +

172 CONH CH2OMe 526.4
S02NH2



175 CONH CH3 -O-O 400.3

176 CONH CH3 -O-G 400.2



178 CONH CH3 -Q-» X 409.3

179 CONH CH3 — 472.4
Q-SOΪNH



182 CONH CH3 -o° 430.3



186 CONH CH2OCH3 494.3
^
SO2NH2

187 CONH CH3 456.4
> (^0



507.4

189 CONH CH3 - ό
366.2

190 CONH CH3
o-H

191 CONH CH3 429.4
0- 5




198 CH20 H O 451.2
S02NH2



201 CH2NCOCF3 563.3


202 CH2CO 463.3
-OO S02NH2

TABLE 4


EX# B MS
(M + H) +



204 H tetrazole- l-yl-CH2- 546.4




206 H // %. Si(Et)2Me 564.4
° SO2NH2


TABLE 5

EX# tructures MS
(M + H)'

S5- TABLE 6



ΕxF PI R MP(°C) MS(M+H)+



NH
222 w' CH2OCH3 N 81 528.4

223 CH2OCH3 CH 175 526.4


N NHH
224 ^'"nf CH2°CH3 CH 215 526.3
NH
225 H:NΛIOΓ "CH3 CH 245 508.4

NH
226 HN Of CH 238 494.2
OH "CH3


Tables 7-15 identify additional representative compounds of this invention which can be prepared by the methods described above.

The divalent radicals V in the compounds of Tables 7-11 have the following structures

1,4-phenylene

pyridin-2 , 5-diyl

pyrimidin-2 , 5-diyl

F

2-fluoro-l,4-phenylene -t Cly

2-chloro-l,4-phenylene -t CHy3

2-methyl-l, 4-phenylene -o-2, 5-thiophene -O-

The pyridin-2 , 5-diyl and pyrimidin-2 , 5-diyl radicals are bonded to the (Z)U~D moiety at the 5 position. The 2-substituted-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

Part Cpd (CH2)nR2 (Z)u-D
Al CH2OCH3 CH2θMe 1-4-phenylene 2-aminosulfonylphenyl CH2OCH3 CH2θEt 1-4-phenylene 2-aminosulfonylphenyl CH2OCH3 CH20-n-Pr 1-4-pheny1ene 2-aminosulfonyIphenyl CH2OCH3 CH20-i-Pr 1-4-phenylene 2-aminosulfonyIphenyl CH2OCH3 CH2θ-n-Bu 1-4-phenylene 2-aminosulfonyIphenyl CH2OCH3 CH2θ-i-Bu 1-4-phenylene 2-aminosulfonyIpheny1 CH2OCH3 CH2Ph 1-4-phenylene 2-aminosulfonylphenyl CH2OCH3 CH2-pyrazol- 1-4-phenylene 2-aminosulfonyIphenyl
1-yl
CH2OCH3 CH2~imidazol- 1-4-phenylene 2-aminosulfonylphenyl
1-yl
10 CH2OCH3 CH2-tetrazol- 1-4-phenylene 2-aminosulfonyIpheny1
1-yl
11 CH2OCH3 CH2-tetrazol- 1-4-phenylene 2-aminosulfonylphenyl
2-yl
12 CH2OCH3 CH2-triazol- 1-4-phenylene 2-aminosulfonylphenyl
1-yl
13 CH2OCH3 CH SEt 1-4-phenylene 2-aminosulfonylphenyl 14 CH2OCH3 CH2S02Et 1-4-phenylene 2-aminosulfonylphenyl 15 CH2OCH3 CF3 1-4-phenylene 2-aminosulfonylphenyl 16 CH2OCH3 CH3 1-4-phenylene 2-aminosulfony1pheny1 17 CH2OCH3 H 1- -phenylene 2-aminosulfonylphenyl

A2 CH2OCH3 CH2OMe pyridin-2 ,5- 2-aminosulfonylphenyl
diyl
CH2OCH3 CH2OEt pyridin-2,5- 2-aminosulfonylphenyl
diyl
CH2OCH3 CH20-n-Pr pyridin-2, 5- 2-aminosulfonylphenyl
diyl CH OCH3 CH2θ- i -Pr pyridin-2 , 5 - 2-aminosulfonyIpheny1
diyl
CH2OCH3 CH2θ-n-Bu pyridin-2, 5- 2-aminosulfonyIphenyl
diyl
CH2OCH3 CH2θ- i -Bu pyridin-2 , 5- 2-aminosulfonylphenyl
diyl
CH2OCH3 CH2Ph pyridin-2, 5- 2-aminosulfonylphenyl
diyl
8 CH2OCH3 CH2-pyrazol- pyridin-2, 5- 2-aminosulfonylphenyl
1-yl diyl
9 CH2OCH3 CH2 -imidazol- pyridin-2, 5- 2-aminosulfonylphenyl
1-yl diyl
10 CH2OCH3 CH2-tetrazol- pyridin-2, 5- 2 -aminosulfonylphenyl
1-yl diyl
11 CH2OCH3 CH2-tetrazol- pyridin-2 , 5- 2-aminosulfonylphenyl
2-yl * diyl
12 CH2OCH3 CH2-triazol- pyridin-2, 5- 2 -aminosulfonylphenyl
1-yl diyl
13 CH2OCH3 CH2SEt pyridin-2, 5- 2-aminosulfonyIpheny1
diyl
14 CH2OCH3 CH2S02 E pyridin-2, 5- 2-aminosulfonylphenyl
diyl
15 CH OCHi CF3 pyridin-2, 5- 2-aminosulfonylphenyl
diyl
16 CH2OCH3 CH3 pyridin-2 , 5- 2-aminosulfonylphenyl
diyl
17 CH2OCH3 H pyridin-2, 5- 2-aminosulfonyIphenyl
diyl
A3 1 CH2OCH3 CH2θMe pyrimidin- 2-aminosulfonylphenyl
2 , 5-diyl
CH2OCH3 CH2OEt pyrimidin- 2-aminosulfonylphenyl
2 , 5-diyl
CH2OCH3 CH20-n-Pr pyrimidin- 2-aminosulfonyIphenyl
2 , 5 -diyl
CH2OCH3 CH 0- i -Pr pyrimidin- 2-aminosulfonyIphenyl
2, 5-diyl CH2OCH3 CH20-n-Bu pyrimidin- 2-aminosul fonyIpheny1
2, 5-diyl
CH2OCH3 CH20- i -Bu pyrimidin- 2-aminosulfonyIphenyl
2, 5-diyl
CH20CH3 CH2Ph pyrimidin- 2-aminosulfonyIphenyl
2, 5-diyl
CH20CH3 CH2 -pyrazol - pyrimidin- 2-aminosulfonylphenyl
1 -yl 2, 5-diyl
CH20CH3 CH2 -imidazol - pyrimidin- 2-aminosulfonylphenyl
1 -yl 2, 5-diyl
10 CH2OCH3 CH2 -tetrazol - pyrimidin- 2-aminosulfonyIphenyl
1 -yl 2, 5-diyl
11 CH20CH3 CH -tetrazol - pyrimidin- 2-aminosulfonylphenyl
2 -yl 2, 5-diyl
CH20CH3 CH2 - triazol - pyrimidin- 2-aminosulfonyIphenyl
1 -yl 2, 5-diyl
13 CH2OCH3 CH2 SEt pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
14 CH2OCH3 CH2S02Et pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
15 CH2OCH3 CF3 pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
16 CH2OCH3 CH3 pyrimidin- 2-aminosulfonylphenyl
2 , 5-diyl
17 CH2OCH3 pyri idin- 2-aminosulfonylphenyl
2, 5-diyl
A4 1 CH2OCH3 CH2θMe 2-fluoro-1 , 4- 2-aminosulfonylphenyl
phenylene
CH2OCH3 CH20Et 2-fluoro-l ,4- 2-aminosulfonylphenyl
phenylene
CH2OCH3 CH 0-n-Pr 2-fluoro-1, 4- 2-aminosulfonyIphenyl
phenylene
CH2OCH3 CH20-i-Pr 2-fluoro-l, 4- 2-aminosulfonyIphenyl
phenylene
CH2OCH3 CH2θ-n-Bu 2-fluoro-1 , 4- 2-aminosulfonylphenyl
phenylene 6 CH2OCH3 CH2θ-i-Bu 2-fluoro-l,4 2-aminosulfony1pheny1
phenylene
7 CH2OCH3 CH2?h 2-fluoro-l, 4 2-aminosulfonylphenyl
phenylene
8 CH2OCH3 cH2_pyιazol- 2-fluoro-l,4 2-aminosulfonylphenyl
1-yl phenylene
9 CH OCH3 CH2-imidazol- 2-fluoro-l,4 - 2-aminosulfonyIphenyl
1-yl phenylene
10 CH2OCH3 CH2-tetrazol- 2-fluoro-l,4 - 2-aminosulfonyIphenyl
1-yl phenylene
11 CH2OCH3 CH2-tetrazol- 2-fluoro-l,4 2-aminosulfonyIpheny1
2-yl phenylene
12 CH2OCH3 CH2-triazol- 2-fluoro-l,4 2-aminosulfonylphenyl
1-yl phenylene
13 CH2OCH3 CH2SEt 2-fluoro-l, 4 2-aminosulfonylphenyl
phenylene
14 CH2OCH3 CH2S02Et 2-fluoro-l, 4 - 2-aminosulfonylphenyl
phenylene
15 CH2OCH3 CF3 2-fluoro-l, 4 2-aminosulfonylphenyl
phenylene
16 CH2OCH3 CH3 2-fluoro-l, 2-aminosulfonylphenyl
phenylene
17 CH2OCH3 2-fluoro-l,4 2-aminosulfonylphenyl
phenylene
A5 CH2OCH3 CH 0Me 2-chloro-l , 4- 2 -aminosulfonylphenyl
phenylene
CH2OCH3 CH2OEt 2-chloro-l, 4- 2-aminosulfonylphenyl
phenylene
CH2OCH3 CH20-n-Pr 2-chloro-l, - 2-aminosulfonyIphenyl
phenylene
CH2OCH3 CH20-i-Pr 2-chloro-l,4- 2-aminosulfonylphenyl
phenylene
CH2OCH3 CH20-n-Bu 2-chloro-1,4- 2-aminosulfonyIphenyl
phenylene
CH2OCH3 CH20-i-Bu 2 -chloro-1, 4- 2-aminosulfonylphenyl
phenylene 7 CH2OCH3 CH2 Ph 2-chloro-l, 4- 2-aminosulfonyIphenyl
phenylene
8 CH2OCH3 CH2-pyrazol- 2-chloro-l,4- 2-aminosulfonylphenyl
1-yl phenylene
9 CH2OCH3 CH2 -imidazol- 2-chloro-l, 4- 2-aminosulfonylphenyl
1-yl phenylenel
10 CH2OCH3 CH2-tetrazol- 2-chloro-l, 4- 2-aminosulfonyIphenyl
1-yl phenylene
11 CH2OCH3 CH2-tetrazol- 2-chloro-l,4- 2-aminosulfonyIphenyl
2-yl phenylene
12 CH2OCH3 CH2-triazol- 2-chloro-l , 4- 2-aminosulfonylphenyl
1-yl phenylene
13 CH2OCH3 CH2SEt 2-chloro-l,4- 2-aminosulfonyIpheny1
phenylene
14 CH2OCH3 CH2S02Et 2-chloro-l,4- 2-aminosulfonylphenyl
φhenylene
15 CH2OCH3 CF3 2-chloro-l,4- 2-aminosulfonylphenyl
phenylene
16 CH2OCH3 CH3 2-chloro-l,4- 2-aminosulfonylphenyl
phenylene
7 CH2OCH3 2-chloro-l, 4- 2-aminosulfonylphenyl
phenylene
1 CH3 CH2OMe 1, 4-phenylene 2-aminosulfonyIpheny1

2 CH3 CH20Et 1 , 4-phenylene 2-aminosulfonyIpheny1

3 CH3 CH20-n-Pr 1, 4-phenylene 2-aminosulfonylphenyl

4 CH3 CH20- i -Pr 1 , 4-phenylene 2-aminosulfonyIpheny1

5 CH3 CH20-n-Bu 1, 4-phenylene 2-aminosulfonylphenyl

6 CH3 CH 0- i -Bu 1 , 4-phenylene 2-aminosulfonyIphenyl

7 CH3 CH2Ph 1, 4-phenylene 2-aminosulfonylphenyl

8 CH3 CH2 -pyrazol - 1, 4-phenylene 2-aminosulfonylphenyl
1-yl
9 CH3 CH2 -imidazol 1 , 4-phenylene 2-aminosulfonyIphenyl
1-yl
L O CH3 CH2 -tetrazol 1, 4-phenylene 2-aminosulfonyIphenyl
1 -yl 11 CH3 CH2-tetrazol- 1 , 4-phenylene 2-aminosulfonyIphenyl
2-yl
12 CH3 CH2-triazol- 1, 4-phenylene 2-aminosulfonyIphenyl
1-yl
13 CH3 CH2SEt 1, 4-phenylene 2-aminosulfonyIphenyl 14 CH3 CH2S02Et 1, 4-phenylene 2-aminosulfonylphenyl 15 CH3 CF3 1 ,4-phenylene 2-aminosulfonyIpheny1 16 CH3 CH3 1 , 4-phenylene 2-aminosulfonylphenyl 17 CH3 H 1, 4-phenylene 2-aminosulfonyIphenyl

B2 CH3 CH20Me pyridin-2, 5- 2-aminosulfonylphenyl
diyl
2 CH3 CH2OEt pyridin-2, 5- 2-aminosulfonylphenyl
diyl
3 CH3 CH20-n-Pr pyridin-2, 5- 2-aminosulfonyIpheny1
diyl
4 CH3 CH 0-i-Pr pyridin-2, 5- 2-aminosulfonylphenyl
diyl
5 CH3 CH2θ-n-Bu pyridin-2, 5- 2-aminosul fonyIpheny1
diyl
6 CH3 CH20-i-Bu pyridin-2, 5- 2-aminosul fonylphenyl
diyl
7 CH3 CH2Ph pyridin-2, 5- 2-aminosulfonylphenyl
diyl
8 CH3 CH2~pyrazol- pyridin-2, 5- 2-aminosulfony1pheny1
1-yl diyl
9 CH3 CH2-imidazol- pyridin-2 , 5- 2-aminosulfonylphenyl
1-yl diyl
10 CH3 CH2 -tetrazol - pyridin-2, 5- 2-aminosulfonylphenyl
1-yl diyl
11 CH3 CH2-tetrazol- pyridin-2 , 5- 2-aminosulfonylphenyl
2-yl diyl
12 CH3 CH -triazol- pyridin-2, 5- 2-aminosulfonylphenyl
1-yl diyl
13 CH3 CH2SEt pyridin-2, 5- 2-aminosulfonylphenyl
diyl 14 ' CH3 CH2 S02Et pyridin-2 , 5- 2 -aminosul fonylphenyl
diyl
15 CH3 CF3 pyridin-2, 5- 2 -aminosulfonyIphenyl
diyl
16 CH3 CH3 pyridin-2, 5- 2-aminosulfonylphenyl
diyl
17 CH3 pyridin-2 , 5- 2 -aminosulfonyIphenyl
diyl
B3 CH3 CH2θMe pyrimidin- 2 -aminosulfonyIphenyl
2, 5-diyl
CH3 CH OEt pyrimidin- 2-aminosulfonyIphenyl
2, 5-diyl
CH3 CH 0-n-Pr pyrimidin- 2-aminosulfony1pheny1
2 , 5-diyl
CH3 CH20-i-Pr pyrimidin- 2-aminosulfonyIphenyl
*2, 5-diyl
CH< CH20-n-Bu pyrimidin- 2 -aminosulfonylphenyl
2, 5-diyl
CH3 CH2θ-i-Bu pyrimidin- 2-aminosulfonyIphenyl
2 , 5-diyl
CH3 CH2Ph pyrimidin- 2-aminosulfonyIphenyl
2, 5-diyl
CH3 CH2~pyrazol- pyrimidin- 2-aminosulfonyIpheny1
1-yl 2 , 5-diyl
CH3 CH2-imidazol- pyrimidin- 2-aminosulfonylphenyl
1-yl 2, 5-diyl
10 CH3 CH2-tetrazol- pyrimidin- 2 -aminosulfonyIpheny1
1-yl 2, 5-diyl
11 CH3 CH2-tetrazol- pyrimidin- 2-aminosulfonyIphenyl
2-yl 2, 5-diyl
12 CH3 CH2-triazol- pyrimidin- 2-aminosulfonylphenyl
1-yl 2, 5-diyl
13 CH3 CH2SEt pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
14 CH-< CH2S02Et pyrimidin- 2-aminosulfonyIpheny1
2, 5-diyl 15 CH3 CF3 pyrimidin- 2-aminosulfonylpheny1
2, 5-diyl
16 CH3 CH3 pyrimidin- 2-aminosulfonyIphenyl
2 , 5-diyl
17 CH3 H pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
B4 CH3 CH2OMe 2-fluoro-1, 4- 2-aminosulfonyIphenyl
phenylene
CH3 CH2OEt 2-fluoro-l,4-- 2-aminosulfonyIphenyl
phenylene
CH3 CH2θ-n-Pr 2-fluoro-l,4 2-aminosulfonyIphenyl
phenylene
CH3 CH20-i-Pr 2-fluoro-l,4 2-aminosulfonylphenyl
phenylene
CH3 CH20-n-Bu 2-fluoro-l,4 2-aminosulfonyIphenyl
phenylene
CH3 CH2θ-i-Bu 2-fluoro-l,4 2-aminosulfonyIpheny1
phenylene
CH3 CH2Ph 2-fluoro-l,4 - 2-aminosulfonylphenyl
phenylene
CH3 CH2-pyrazol- 2-fluoro-l, 4 2-aminosulfonylphenyl
1-yl phenylene
CH3 CH2-imidazol- 2-fluoro-l,4 2-aminosulfonyIphenyl
1-yl phenylene
10 CH3 CH2~tetrazol- 2-fluoro-l,4 2-aminosulfonylphenyl
1-yl phenylene
11 CH3 CH2-tetrazol- 2-fluoro-l,4 2-aminosulfonyIphenyl
2-yl phenylene
12 CH3 CH2~triazol- 2-fluoro-l,4 2-aminosulfonyIphenyl
1-yl phenylene
13 CH3 CH2SEt 2-fluoro-l,4 - 2-aminosulfonyIphenyl
phenylene
14 CH3 CH2S02Et 2-fluoro-l,4 - 2-aminosulfonylphenyl
phenylene
15 CH3 CF3 2-fluoro-l,4 2-aminosulfonyIphenyl
phenylene 16 CH3 CH3 2-fluoro-l , 4- 2-aminosulfonylphenyl
phenylene
17 CH3 2-fluoro-l,4- 2-aminosul fonylphenyl
phenylene
CH3 2-chloro-l, 4 2-aminosulfonyIphenyl
phenylene
CH3 CH2OEt 2-chloro-l, 4 2 -ammosulfonylphenyl
phenylene
CH3 CH20-n-Pr 2-chloro-l,4 2-aminosulfonylphenyl
phenylene
CH3 CH 0-i -Pr 2-chloro-l,4 2-aminosulfony1pheny1
phenylene
CH3 CH20-n-Bu 2-chloro-l , 4 2-aminosulfonyIphenyl
phenylene
CH3 CH20- i -Bu 2-chloro-l, 4 2-aminosulfonyIphenyl
phenylene
2-chloro-l,4 2 -aminosulfonylphenyl
phenylene
CH3 CH2~pyrazol- 2-chloro-l,4 - 2-aminosulfonylphenyl
1-yl phenylene
CH3 CH2 -imidazol- 2-chloro-l , 4 2-aminosulfonylphenyl
1-yl phenylene
10 CH3 CH2-tetrazol- 2-chloro-l,4 2-aminosulfonylphenyl
1-yl phenylene
11 CH3 CH2~tetrazol- 2-chloro-l, 4 2-aminosulfonyIpheny1
2-yl phenylene
12 CH3 CH2-triazol- 2-chloro-l,4 2-aminosulfonylphenyl
1-yl phenylene
13 CH3 CH2SEt 2-chloro-l,4 2-aminosulfonylphenyl
phenylene
14 CH3 CH2S02Et 2-chloro-l,4 - 2-aminosulfonylphenyl
phenylene
15 CH3 CF3 2-chloro-l,4 2-aminosulfonylphenyl
phenylene
16 CH3 CH3 2-chloro-l , 4 2-aminosul fonyIpheny1
phenylene 17 CH3 2 -chloro-l , 4 - 2 -aminosul f onylphenyl
phenylene
1 H CH2OMe 1 , 4-phenylene 2-aminosulfonyIphenyl

2 H CH2θE 1,4-phenylene 2-aminosulfonylphenyl

3 H CH2θ-n-Pr 1, 4-phenylene 2-aminosulfonylphenyl „4 H CH20-i-Pr 1, 4-phenylene 2-aminosulfonylphenyl

5 H CH20-n-Bu 1, 4-phenylene 2-aminosulfonyIphenyl

6 H CH20-i-Bu 1 , 4-phenylene 2-aminosulfonyIpheny1

7 H CH2Ph 1, 4-phenylene 2-aminosulfonylphenyl

8 H CH2-pyrazol- 1, 4-phenylene 2-aminosulfonylphenyl
1-yl
9 H CH2-imidazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
10 H CH2-tetrazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
11 H CH2 -tetrazol- 1 , I-phenylene 2-aminosulfonylphenyl
2-yl
12 H CH2 -triazol - 1, 4-phenylene 2-aminosulfonyIphenyl
1 -yl
13 H CH SEt 1 , 4-phenylene 2-aminosulfonyIphenyl

14 H CH2S02 Et 1, 4-phenylene 2-aminosulfonylphenyl

15 H CF3 1, 4-phenyiene 2-aminosulfonylphenyl

16 H CH3 1 , 4-phenylene 2-aminosulfonylphenyl

17 H H 1, 4-phenylene 2-aminosulfonylphenyl
CH2OMe pyridin-2 , 5- 2-aminosulfonyIpheny1
diyl
CH2OEt pyridin-2 , 5- 2-aminosulfonylphenyl
diyl
CH20-n-Pr pyridin-2 , 5- 2-aminosulfonyIpheny1
diyl
CH20-i-Pr pyridin-2,5- 2-aminosulfonylphenyl
diyl
CH20-n-Bu pyridin-2 , 5- 2-aminosulfonylphenyl
diyl
CH20-i-Bu pyridin-2, 5- 2-aminosulfonylphenyl
diyl CH2Ph pyridin-2 , 5 2-aminosulfonyIpheny1
diyl
CH2-pyrazol- pyridin-2, 5 2-aminosulfonyIpheny1
1-yl diyl
CH2-imidazol- pyridin-2, 5 2-aminosulfonyIphenyl
1-yl diyl
10 CH2-tetrazol- pyridin-2, 5 2-aminosulfonyIpheny1
1-yl diyl
11 CH2-tetrazol- pyridin-2 , 5 2-aminosulfonylphenyl
2-yl diyl
12 CH2~triazol- pyridin-2 , 5 2-aminosulfonyIphenyl
1-yl diyl
13 CH2SEt pyridin-2,5 2-aminosulfonylphenyl
diyl
14 CH2S02Et pyridin-2 , 5 2-aminosulfonylphenyl
* diyl
15 CF3 pyridin-2 , 5 2-aminosulfonylphenyl
diyl
16 CH3 pyridin-2, 5 2-aminosulfonyIpheny1
diyl
17 H pyridin-2 , 5 2-aminosulfonylphenyl
diyl
C3 CH OMe pyrimidin- 2 -aminosulfonylphenyl
2, 5-diyl
CH2OEt pyrimidin- 2-aminosulfonyIphenyl
2, 5-diyl
CH20-n-Pr pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
CH20-i-Pr pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
CH20-n-Bu pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
CH20-i-Bu pyrimidin- 2-aminosulfonyIpheny1
2, 5-diyl
CH2Ph pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
-9< CH2-pyrazol- pyrimidin- 2-aminosul fonyIpheny1
1-yl 2, 5-diyl
CH2 -imidazol - pyrimidin- 2-aminosulfonylphenyl
1-yl 2, 5-diyl
10 CH2-tetrazol- pyrimidin- 2-aminosulfonyIphenyl
1-yl 2, 5-diyl
11 CH2-tetrazol- pyrimidin- 2-aminosulfonyIphenyl
2-yl 2, 5-diyl
12 CH2-triazol- pyrimidin- 2-aminosulfonylphenyl
1-yl 2, 5-diyl
13 CH2SEt pyrimidin- 2 -aminosulfonyIphenyl
2, 5-diyl
14 CH2S02Et pyrimidin- 2-aminosulfonyIpheny1
2, 5-diyl
15 CF3 pyrimidin- 2-aminosulfonylphenyl
1 , 5-diyl
16 CH3 pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
17 H pyrimidin- 2-aminosulfonylphenyl
2, 5-diyl
C4 CH2OMe 2 -fluoro-1, 4 2-aminosulfonylphenyl
phenylene
CH2OEt 2 -fluoro-1, 4 - 2-aminosulfonylphenyl
phenylene
CH 0-n-Pr 2 -fluoro-1 , 4 2-aminosulfonyIpheny1
phenylene
CH20-i-Pr 2 -fluoro-1, 4 - 2-aminosulfonyIphenyl
phenylene
CH2θ-n-Bu 2 -fluoro-1,4 2-aminosulfonylphenyl
phenylene
CH20-i-Bu 2 -fluoro-1,4 2-aminosulfonyIpheny1
phenylene
CH Ph 2 -fluoro-1,4 - 2-aminosulfonyIphenyl
phenylene
CH2~pyrazol- 2 -fluoro-1, 4 2-aminosulfonylphenyl
1-yl phenylene CH2 -imidazol- 2-fluoro-1, 4- 2-aminosulfonylphenyl
1-yl phenylene
10 CH2-tetrazol- 2-fluoro-l, 4- 2-aminosulfonylphenyl
1-yl phenylene
11 CH2-tetrazol- 2-fluoro-l, 4- 2-aminosulfonylphenyl
2-yl phenylene
12 CH2-triazol- 2-fluoro-1, 4- 2-aminosulfonylphenyl
1-yl phenylene
13 CH2SEt 2-fluoro-1,4- 2-aminosulfonylphenyl
phenylene
14 CH S02Et 2-fluoro-1 , 4- 2-aminosulfonylphenyl
phenylene
15 CF3 2-fluoro-1, 4- 2 -aminosulfonyIphenyl
phenylene
16 CH-i 2-fluoro-1 , 4- 2-aminosulfonylphenyl
phenylene
17 2-fluoro-1, 4- 2-aminosulfonylphenyl
phenylene
C5 CH2OMe 2-chloro-l , 4- 2-aminosulfonylphenyl
phenylene
CH2θEt 2-chloro-l, 4- 2-aminosulfonylphenyl
phenylene
CH2θ-n-Pr 2-chloro-l , 4- 2-aminosulfonylphenyl
phenylene
CH20-i-Pr 2-chloro-l , 4- 2 -aminosulfonylphenyl
phenylene
CH2θ-n-Bu 2-chloro-l, 4- 2-aminosulfonylphenyl
phenylene
CH2θ-i-Bu 2-chloro-l , 4- 2-aminosulfonylphenyl
phenylene
CH Ph 2-chloro-l,4- 2-aminosulfonylphenyl
phenylene
CH2-pyrazol- 2-chloro-l, 4- 2-aminosulfonylphenyl
1 -yl phenylene
CH2 -imidazol- 2-chloro-l, 4- 2-aminosulfonylphenyl
1-yl phenylene 10 CH -tetrazol- 2-chloro-l,4 2-aminosul fonylphenyl
1-yl phenylene
11 CH2-tetrazol- 2-chloro-l,4 2-aminosulfonyIpheny1
2-yl phenylene
12 CH2-triazol- 2-chloro-l, 4' 2-aminosulfonylphenyl
1-yl phenylene
13 CH2SEt 2-chloro-l,4' 2-aminosulfonylphenyl
phenylene
14 CH2S02Et 2-chloro-l,4' 2-aminosulfonyIphenyl
phenylene
15 CF3 2-chloro-l, 4 2-aminosulfonyIpheny1
phenylene
16 CH3 2-chloro-l,4 2-aminosulfonylphenyl
phenylene
17 H 2-chloro-l, 4 2-aminosulfonyIphenyl
phenylene
C6 CH2θMe 2-methy1-1, 4 2-aminosulfonyIphenyl
phenylene
CH2OEt 2-methyl-l, 4 2-aminosulfonylphenyl
phenylene
CH20-n-Pr 2-methyl-l , 4 2-aminosulfonylphenyl
phenylene
CH 0-i-Pr 2-methy1-1, 4 - 2-aminosulfonylphenyl
phenylene
CH20-n-Bu 2-methy1-1, 4 2-aminosulfonylphenyl
phenylene
CH20-i-Bu 2-methyl-l, 4 2-aminosulfonyIphenyl
phenylene
CH2Ph 2-methyl-l, 4 2-aminosulfonylphenyl
phenylene
CH2-pyrazol- 2-methyl-l, 4 2-aminosulfonyIpheny1
1-yl phenylene
CH2-imidazol- 2-methyl-l, 4 2-aminosulfonylphenyl
1-yl phenylene
10 CH2-tetrazol- 2-methyl-l, 4 2 -aminosulfonylphenyl
1-yl phenylene 11 CH2-tetrazol- 2-methyl-l, 4- 2-aminosulfonyIphenyl
2-yl phenylene
12 CH2-triazol- 2-methyl-l, 4- 2-aminosulfonylphenyl
1-yl phenylene
13 CH SEt 2-methyl-l, 4- 2-aminosulfonyIphenyl
phenylene
14 CH S02Et 2-methyl-l, 4- 2-aminosulfonyIphenyl
phenylene
15 CF3 2-methyl-l, 4- 2-aminosulfonylphenyl
phenylene
16 CH3 2-methyl-l, 4- 2-aminosulfonylphenyl
phenylene
17 2-methyl-l, 4- 2-aminosulfonylphenyl
phenylene
Dl CH2OMe 1 , 4-phenylene
trifluoromethylphenyl
CH2OEt 1 , 4-phenylene 2- trifluoromethylphenyl
CH2θ-n-Pr 1,4-phenylene 2- trifluoromethylphenyl
CH20-i-Pr 1, 4-phenylene 2- trifluoromethylphenyl
CH20-n-Bu 1 , 4-phenylene 2- trifluoromethylphenyl
CH20-i-Bu 1 , 4-phenyiene 2- trifluoromethylphenyl
CH2Ph 1 , 4-phenylene 2- trifluoromethylphenyl
CH2~pyrazol- 1 , 4-phenyiene 2- 1-yl trifluoromethylphenyl
CH2-imidazol- 1,4-phenylene 2- 1-yl trifluoromethylphenyl

10 CH2_tetrazol- 1,4-phenylene 2- 1-yl trifluoromethylphenyl

11 CH2~tetrazol- 1, 4-phenylene 2- 2-yl trifluoromethylphenyl 12 CH2-triazol- 1,4-phenylene
1-yl trifluoromethyIpheny1

13 CH2SEt 1, 4-phenyiene 2 - trifluoromethylphenyl

14 CH2S02Et 1, 4-phenylene 2- trifluoromethylphenyl

15 CF3 1 , 4-phenyiene 2- trifluoromethylphenyl

16 CH3 1, 4-phenylene 2- trifluoromethylphenyl

17 1 , 4-phenylene 2- trifluoromethylphenyl

D2 CH2OMe pyridin-2, 5- diyl trifluoromethylphenyl
CH2OEt pyridin-2, 5- 2- * diyl trifluoromethylphenyl
CH20-n-Pr pyridin-2, 5- 2- diyl trifluoromethylphenyl
CH 0-i-Pr pyridin-2, 5- 2- diyl trifluoromethylphenyl
CH 0-n-Bu pyridin-2, 5- 2- diyl trifluoromethylphenyl
CH20-i-Bu pyridin-2 , 5- 2- diyl trifluoromethylphenyl
CH2Ph pyridin-2, 5- 2- diyl trifluoromethylphenyl
CH2-pyrazol- pyridin-2 , 5- 2- 1-yl diyl trifluoromethylphenyl
CH2 -imidazol- pyridin-2, 5- 2- 1-yl diyl trifluoromethylphenyl

10 CH2-tetrazol- pyridin-2, 5- 2- 1-yl diyl trifluoromethylphenyl

11 CH2-tetrazol- pyridin-2, 5- 2- 2-yl diyl trifluoromethylphenyl

12 CH2-triazol- pyridin-2 , 5- 2- 1-yl diyl trifluoromethylphenyl 13 CH SEt pyridin-2 , 5- diyl trifluoromethylphenyl

14 pyridin-2 , 5- 2- diyl trifluoromethylphenyl

15 CF3 pyridin-2, 5- 2- diyl tri fluoromethylphenyl

16 CH3 pyridin-2, 5- 2- diyl trifluoromethyIphenyl

17 H pyridin-2,5- 2- diyl trifluoromethylphenyl

D3 CH2OMe pyrimidin- 2, 5-diyl trifluoromethylphenyl
CH2OEt pyrimidin- 2- 2, 5-diyl trifluoromethylphenyl
CH20-n-Pr pyrimidin- 2- '2, 5-diyl trifluoromethylphenyl
CH 0-i-Pr pyrimidin- 2- 2, 5-diyl tri fluoromethylphenyl
CH20-n-Bu pyrimidin- 2- 2, 5-diyl trifluoromethyIphenyl
CH2θ-i-Bu pyrimidin- 2- 2, 5-diyl trifluoromethylphenyl
CH2Ph pyrimidin- 2- 2, 5-diyl trifluoromethyIphenyl
CH2-pyrazol- pyrimidin- 2- 1-yl 2, 5-diyl trifluoromethyIpheny1
CH2-imidazol- pyrimidin- 2- 1-yl 2, 5-diyl trifluoromethylphenyl

10 CH2-tetrazol- pyrimidin- 2- 1-yl 2, 5-diyl trifluoromethyIphenyl

11 CH2-tetrazol- pyrimidin- 2- 2-yl 2, 5-diyl trifluoromethylphenyl

12 CH2-triazol- pyrimidin- 2- 1-yl 2 , 5-diyl trifluoromethylphenyl

13 CH2SEt pyrimidm- 2- 2, 5-diyl trifluoromethylphenyl 14 H CH2S02Et pyrimidin- 2- 2, 5-diyl trifluoromethyIpheny1

15 CF3 pyrimidin- 2- 2, 5-diyl trifluoromethylphenyl

16 CH3 pyrimidin- 2- 2, 5-diyl trifluoromethylphenyl

17 H pyrimidin- 2- 2, 5-diyl trifluoromethylphenyl

D4 CH2OMe 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl
CH2θEt 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl
CH 0-n-Pr 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl
CH20-i-Pr 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl
CH20-n-Bu 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl
CH20-i-Bu 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl
CH2Ph 2-fluoro-l,4- 2- phenylene trifluoromethyIphenyl
CH2-pyrazol- 2-fluoro-l,4- 2- 1-yl phenylene trifluoromethyIphenyl
CH2-imidazol- 2-fluoro-l,4- 2- 1-yl phenylene trifluoromethylphenyl

10 CH2-tetrazol- 2-fluoro-l,4- 2- 1-yl phenylene trifluoromethylphenyl

11 CH2~tetrazol- 2-fluoro-l,4- 2- 2-yl phenylene trifluoromethylphenyl

12 CH2-triazol- 2-fluoro-l,4- 2- 1-yl phenylene trifluoromethyIphenyl

13 CH2SEt 2-fluoro-l,4- 2- phenylene trifluoromethyIphenyl

14 CH2S02Et 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl 15 CF3 2-fluoro-l,4- phenylene trifluoromethylphenyl

16 CH3 2-fluoro-1 , 4- 2 - phenylene trifluoromethylphenyl

17 2-fluoro-l,4- 2- phenylene trifluoromethylphenyl

D5 CH2OMe 2-chloro-l, 4- phenylene trifluoromethyIpheny1
CH2OEt 2-chloro-l, 4- 2 - phenylene trifluoromethylphenyl
CH20-n-Pr 2-chloro-l, 4- 2- phenylene trifluoromethylphenyl
CH20-i-Pr 2-chloro-l,4- 2- phenylene trifluoromethylphenyl
CH20-n-Bu 2-chloro-l,4- 2- phenylene trifluoromethylphenyl
CH20-i-Bu 2-chloro-l, 4- 2- phenylene trifluoromethylphenyl
CH2Ph 2-chloro-l, 4- 2- phenylene trifluoromethyIphenyl
CH2-pyrazol- 2-chloro-l, 4- 2- 1-yl phenylene trifluoromethylphenyl
CH2-imidazol- 2-chloro-l,4- 2- 1-yl phenylene tri fluoromethylphenyl

10 CH2-tetrazol- 2-chloro-l,4- 2- 1-yl phenylene trifluoromethylphenyl

11 CH2~tetrazol- 2-chloro-l, 4- 2- 2-yl phenylene trifluoromethylphenyl

12 CH2-triazol- 2-chloro-l,4- 2- 1-yl phenylene trifluoromethylphenyl

13 CH2SEt 2-chloro-l,4- 2- phenylene trifluoromethyIphenyl

14 CH S02Et 2-chloro-l, 4- 2- phenylene trifluoromethyIphenyl

15 CF3 2-chloro-l,4- 2- phenylene trifluoromethylphenyl 16 CH3 2-chloro-l , 4- 2- phenylene trifluoromethylphenyl

17 2-chloro-l , 4- 2- phenylene trifluoromethylphenyl

D6 CH2OMe 2-methyl-l, 4- 2- phenylene trifluoromethylphenyl
CH2θEt 2-methyl-l, 4- 2- phenylene trifluoromethylphenyl
CH20-n-Pr 2-methyl-1,4- 2- phenylene trifluoromethylphenyl
CH20-i-Pr 2-methyl-l , 4- 2- phenylene trifluoromethylphenyl
CH2θ-n-Bu 2-methy1-1,4- 2- phenylene trifluoromethylphenyl
CH20-i-Bu 2-methy1-1,4- 2- phenylene trifluoromethylphenyl
CH Ph 2-methyl-l, 4- 2- phenylene trifluoromethylphenyl
CH -pyrazol- 2-methyl-l, 4- 2- 1-yl phenylene trifluoromethylphenyl
CH -imidazol- 2-methyl-l, 4- 2- 1-yl phenylene trifluoromethylphenyl

10 CH2-tetrazol- 2-methyl-l, 4- 2- 1-yl phenylene trifluoromethylphenyl

11 CH2-tetrazol- 2-methy1-1,4- 2- 2-yl phenylene trifluoromethylphenyl

12 CH2-triazol- 2-methyl-l, 4- 2- 1-yl phenylenel trifluoromethylphenyl

13 CH2SEt 2-methyl-l, 4- 2- phenylene trifluoromethylphenyl

14 CH2S02Et 2-methy1-1,4- 2- phenylene trifluoromethylphenyl

15 CF3 2-methyl-l, 4- 2- phenylene trifluoromethyIphenyl

16 CH3 2-methyl-l, 4- 2- phenylene trifluoromethylphenyl 17 H 2-- ethyl-1, 4- phenylene trifluoromethylphenyl

El CH2OMe 1, , 4-phenylene 2 - trifluoromethoxyphenyl
CH OEt 1, ,4-phenylene 2- trifluoromethoxyphenyl
CH20-n-Pr 1, ,4-phenylene 2- trifluoromethoxyphenyl
CH20-i-Pr 1, , 4-phenylene 2- trifluoromethoxyphenyl
CH20-n-Bu 1, , 4-phenylene 2- trifluoromethoxyphenyl
CH20-i-Bu 1, , 4-phenylene 2- trifluoromethoxyphenyl
CH2Ph 1, , 4-phenyiene 2- •
trifluoromethoxyphenyl
cH2- yiazol- 1, , 4-phenyiene 2- 1-yl trifluoromethoxyphenyl
CH2-imidazol- 1, , 4-phenylene 2- 1-yl tri fluoromethoxyphenyl

10 CH2-tetrazol- 1 , , 4-phenylene 2- 1-yl trif1uoromethoxypheny1

11 CH2-tetrazol- 1. , 4-phenylene 2- 2-yl trifluoromethoxyphenyl

12 CH2-triazol- 1 , , 4-phenylene 2- 1-yl trifluoromethoxyphenyl

13 CH2SEt 1, , 4-phenylene 2- trifluoromethoxyphenyl

14 CH2S02Et 1, , 4-phenylene 2- trifluoromethoxyphenyl

15 CF3 1, , 4-phenylene 2- trifluoromethoxyphenyl

16 CH3 1, , 4-phenylene 2- trifluoromethoxyphenyl

17 H 1 , -phenylene 2- trifluoromethoxyphenyl E2 CH2OMe pyridin-2 , 5
diyl trifluoromethoxyphenyl
CH2OEt pyridin-2, 5 2- diyl trifluoromethoxyphenyl
CH 0-n-Pr pyridin-2,5 2- diyl trifluoromethoxyphenyl
CH20-i-Pr pyridin-2, 5 2- diyl trifluoromethoxyphenyl
CH 0-n-Bu pyridin-2, 5 2- diyl trifluoromethoxyphenyl
CH20-i-Bu pyridin-2 , 5 2- diyl trifluoromethoxyphenyl
CH2Ph pyridin-2, 5 2- diyl trifluoromethoxyphenyl
CH2-pyrazol- pyridin-2, 5 2- 1-yl * diyl trifluoromethoxyphenyl
CH -imidazol- pyridin-2, 5 2- 1-yl diyl trifluoromethoxyphenyl

10 CH2-tetrazol- pyridin-2, 5 2- 1-yl diyl trifluoromethoxyphenyl

11 CH2-tetrazol- pyridin-2 , 5 2- 2-yl diyl trifluoromethoxyphenyl

12 CH2-triazol- pyridin-2, 5 2- 1-yl diyl trifluoromethoxyphenyl

13 CH2SEt pyridin-2 , 5 2- diyl trifluoromethoxyphenyl

14 CH2S02Et pyridin-2 , 5 2- diyl trifluoromethoxyphenyl

15 CF3 pyridin-2, 5 2- diyl trifluoromethoxyphenyl

16 CH3 pyridin-2, 5 2- diyl trifluoromethoxyphenyl

17 H pyridin-2, 5 2- diyl trifluoromethoxyphenyl

E3 CH2OMe pyrimidin- 2- 2, 5-diyl tri fluoromethoxyphenyl CH2OEt pyrimidin- 2- 2, 5-diyl trifluoromethoxyphenyl
CH20-n-Pr pyrimidin- 2- 2, 5-diyl tri fluoromethoxyphenyl
CH2θ-i-Pr pyrimidin- 2- 2, 5-diyl trifluorome hoxyphenyl
CH2θ-n-Bu pyrimidin- 2- 2, 5-diyl trifluoromethoxyphenyl
CH20-i-Bu pyrimidin- 2- 2, 5-diyl trifluoromet o yphenyl
CH2Ph pyrimidin- 2- 2, 5-diyl trifluoromethoxyphenyl
CH2-pyrazol- pyrimidin- 2- 1-yl 2, 5-diyl trifluoromethoxyphenyl
CH2-imidazol- pyrimidin- 2- 1-yl 2, 5-diyl trifluoromethoxyphenyl

10 CH2-tetrazol- pyrimidin- 2- 1-yl 2, 5-diyl trifluoromethoxyphenyl

11 CH2-tetrazol- pyrimidin- 2- 2-yl 2, 5-diyl trifluoromethoxyphenyl

12 CH2-triazol- pyrimidin- 2- 1-yl 2, 5-diyl trifluoromethoxyphenyl

13 CH2SEt pyrimidin- 2- 2, 5-diyl trifluoromethoxyphenyl

14 CH2S0 Et pyrimidin- 2- 2, 5-diyl trifluoromethoxyphenyl

15 CF3 pyrimidin- 2- 2, 5-diyl trifluoromethoxyphenyl

16 CH3 pyri idin- 2- 2, 5-diyl trifluoromethoxyphenyl

17 H pyrimidin- 2- 2, 5-diyl trifluoromethoxyphenyl

E4 CH2OMe 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl
CH2OEt 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl CH2θ-n-Pr 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl
CH20-i -Pr 2-fluoro-l, 4- 2- phenylene trifluoromethoxyphenyl
CH2θ-n-Bu 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl
CH20- i -Bu 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl
CH Ph 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl
CH2-pyrazol- 2-fluoro-l,4- 2- 1-yl phenylene trifluoromethoxyphenyl
CH2-imidazol- 2-fluoro-l,4- 2- .1-yl phenylene trifluoromethoxyphenyl

10 CH2-tetrazol- 2-fluoro-l, 4- 2- 1-yl ]5henylene trifluoromethoxyphenyl

11 CH2-tetrazol- 2-fluoro-l,4- 2- 2-yl phenylene trifluoromethoxyphenyl

12 CH -triazol- 2-fluoro-l,4- 2- 1-yl phenylene trifluoromethoxyphenyl

13- CH2SEt 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl

14 CH2S02Et 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl

15 CF3 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl

16 CH3 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl

17 2-fluoro-l,4- 2- phenylene trifluoromethoxyphenyl

E5 CH2OMe 2-chloro-l,4- phenylene trifluoromethoxyphenyl
CH2OEt 2-chloro-l,4- 2- phenylene trifluoromethoxyphenyl
CH2θ-n-Pr 2-chloro-l,4- 2- phenylene trifluoromethoxyphenyl CH20-i-Pr 2-chloro-l, 4- 2- phenylene trifluoromethoxyphenyl
CH20-n-Bu 2-chloro-l, 4- 2- phenylene trifluoromethoxyphenyl
CH20-i-Bu 2-chloro-l, 4- 2- phenylene trifluoromethoxyphenyl
CH2Ph 2-chloro-l, 4- 2- phenylene trifluoromethoxyphenyl
CH2-pyrazol- 2-chloro-l,4- 2- 1-yl phenylene trifluoromethoxyphenyl
CH -imidazol- 2-chloro-l,4- 2- 1-yl phenylene trifluoromethoxyphenyl

10 CH2-tetrazol- 2-chloro-l,4- 2- 1-yl phenylene trifluoromethoxyphenyl

11 CH2-tetrazol- 2-chloro-l,4- 2- 2-yl ]5henylene trifluoromethoxyphenyl

12 CH2-triazol- 2-chloro-l,4- 2- 1-yl phenylene trifluoromethoxyphenyl

13 CH2SEt 2-chloro-l,4- 2- phenylene trifluoromethoxyphenyl

14 CH S02Et 2-chloro-l,4- 2- phenylene trifluoromethoxyphenyl

15 CF3 2-chloro-l,4- 2- phenylene trifluoromethoxyphenyl

16 CH3 2-chloro-l,4- 2- phenylene trifluoromethoxyphenyl

17 H 2-chloro-l,4- 2- phenylene trifluoromethoxyphenyl- E6 CH2OMe 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl
CH2OEt 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl
CH 0-n-Pr 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl
CH20-i-Pr 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl CH2θ-n-Bu 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl
CH20- i -Bu 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl
CH2Ph 2-methyl-1,4- 2- phenylene trifluoromethoxyphenyl
CH2-pyrazol- 2-methyl-l, 4- 2- 1-yl phenylene trifluoromethoxyphenyl
CH2-imidazol- 2-methyl-l, 4- 2- 1-yl phenylene trifluoromethoxyphenyl

10 CH2-tetrazol- 2-methyl-l, 4- 2- 1-yl phenylene trifluoromethoxyphenyl

11 CH2~tetrazol- 2-methyl-l, 4- 2- 2-yl phenylene trifluoromethoxyphenyl

12 CH2~triazol- 2-methyl-l, 4- 2- 1-yl phenylene trifluoromethoxyphenyl

13 CH2SEt 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl

14 CH2S02Et 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl

15 CF3 2-methy1-1,4- 2- phenylene trifluoromethoxyphenyl

16 CH3 2-methy1-1, - 2- phenylene trifluoromethoxyphenyl

17 2-methyl-l, 4- 2- phenylene trifluoromethoxyphenyl

Fl CH2OMe 1,4-phenylene 2-trifluoromethylsulfonyl-phenyi
CH2OEt 1, 4-phenylene 2-trifluoromethylsulfonyl-phenyi
CH2θ-n-Pr 1, 4-phenylene 2-trifluoromethylsulfonyl-phenyi
CH20-i-Pr 1,4-phenylene 2-trifluoromethylsulfonyl-phenyi
CH20-n-Bu 1, 4-phenylene 2-trifluoromethylsulfonyl-phenyi Ch*2θ-i-Bu 1 , 4 -phenylene 2-trifluoromethylsulfonyl-phenyi
CH2Ph 1 , 4-phenylene 2-tri luoromethylsulfonyl-phenyi
CH2-pyrazol- 1, 4-phenylene 2-trifluoromethyl¬

1-yl sulfonyl-phenyi
CH2 -imidazol- 1 , 4-phenylene 2-trifluoromethyl¬

1-yl sulfonyl-phenyi

10 CH2-tetrazol- 1, 4-phenylene 2-trifluoromethy1- 1-yl sulfonyl-pheny1

11 CH2-tetrazol- 1, 4-phenylene 2-trifluoromethyl- 2-yl sulfonyl-phenyl

12 CH2-triazol- 1 , 4-phenylene 2-trifluoromethyl¬

1-yl sulfonyl-phenyi

13 CH2SEt 1 , 4-phenylene 2-trifluoromethyl- sulfonyl-phenyi

14 CH2S02Et 1 , 4-phenyiene 2-trifluoromethylsulfonyl -phenyi

15 CF3 1, 4-phenylene 2-trifluoromethy1- sulfonyl-pheny1
CH3 1, 4-phenylene 2-trifluoromethyl- sulfonyl-phenyl

17 1,4-phenylene 2-trifluoromethyl- sulfonyl-pheny1

F2 CH2OMe pyridin-2,5- 2-trifluoromethyldiyl sulfonyl-phenyi
CH20Et pyridin-2,5- 2-trifluoromethyldiyl sulfonyl-phenyi
CH20-n-Pr pyridin-2,5- 2-trifluoromethyldiyl sulfonyl-phenyi
CH20-i-Pr pyridin-2,5- 2-trifluoromethyldiyl sulfonyl-phenyi
CH20-n-Bu pyridin-2,5- 2-trifluoromethyldiyl sulfonyl-phenyi
CH20-i-Bu pyridin-2,5- 2-trifluoromethyldiyl sulfonyl-phenyi CH2Ph pyridin-2 , 5- 2-trifluoromethyldiyl sulfonyl-phenyi
CH2~pyrazol- pyridin-2, 5- 2-trifluoromethyl¬

1-yl diyl sulfonyl-phenyi
CH2-imidazol- pyridin-2, 5- 2-trifluoromethy1- 1-yl diyl sulfonyl-phenyi

10 CH2~tetrazol- pyridin-2, 5- 2-trifluoromethyl¬

1-yl diyl sulfonyl-phenyi

11 CH2-tetrazol- pyridin-2 , 5- 2-trifluoromethyl¬

2-yl diyl sulfonyl-phenyi

12 CH2-triazol- pyridin-2 , 5- 2-trifluoromethyl- 1 -yl diyl sulfonyl- heny1

13 CH SEt pyridin-2 , 5- 2-trifluoromethyl- diyl sulfonyl-phenyi

14 CH2S02Et pyridin-2 , 5- 2-trifluoromethyl¬

* diyl sulfonyl-phenyi

15 CF3 pyridin-2 , 5- 2-trifluoromethyldiyl sulfonyl-phenyi

16 CH3 pyridin-2 , 5- 2-trifluoromethyldiyl sulfonyl-phenyi

17 pyridin-2 , 5- 2-trifluoromethyl- ≤Li i sulfonyl-phenyl

F3 CH2θMe pyrimidin- 2-trifluoromethyl- 2, 5-diyl sulfonyl-phenyl
CH2OEt pyrimidin- 2-trifluoromethyl- 2, 5-diyl sulfonyl-pheny1
CH20-n-Pr pyrimidin- 2-trifluoromethyl¬

2, 5-diyl sulfonyl-phenyi
CH20-i-Pr pyrimidin- 2-trifluoromethyl¬

2, 5-diyl sulfonyl-phenyi
CH2θ-n-Bu pyrimidin- 2-trifluoromethyl- 2, 5-diyl sulfonyl-phenyi
CH20-i-Bu pyrimidin- 2-trifluoromethyl- 2, 5-diyl sulfonyl-phenyl
CH2Ph pyrimidin- 2-trifluoromethyl¬

2, 5-diyl sulfonyl-phenyi CH2~pyrazol- pyrimidin- 2-trifluoromethyl¬

1-yl 2, 5-diyl sulfonyl-phenyi
CH2-imidazol- pyrimidin- 2-trifluoromethy1- 1-yl 2, 5-diyl sul fonyl-phenyi

10 CH2-tetrazol- pyrimidin- 2-trifluoromethyl¬

1-yl 2, 5-diyl sulfonyl-phenyi

11 CH2-tetrazol- pyrimidin- 2-trifluoromethyl¬

2-yl 2, 5-diyl sulfonyl-phenyi

12 CH2-triazol- pyrimidin- 2-trifluoromethyl¬

1-yl 2, 5-diyl sulfonyl-phenyi

13 CH2SEt pyrimidin- 2-trifluoromethyl¬

2, 5-diyl sulfonyl-phenyi

14 CH2S02Et pyrimidin- 2-trifluoromethyl¬

2, 5-diyl sulfonyl-phenyi

15 CF3 pyrimidin- 2-trifluoromethy1- V. , 5-diyl sulfonyl-phenyi
CH3 pyrimidin- 2-trifluoromethyl¬

2, 5-diyl sulfonyl-phenyi

17 pyrimidin- 2-trifluoromethy1- 2, 5-diyl sulfonyl-phenyi

F4 CH2OMe 2-fluoro-l,4- 2 -trifluoromethyl - phenylene sulfonyl-phenyl
CH OEt 2-fluoro-l,4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH20-n-Pr 2-fluoro-l,4- 2-trifluoromethy1- phenylene sul fonyl-phenyi
CH20-i-Pr 2-fluoro-l,4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH2θ-n-Bu 2-fluoro-l, - 2-trifluoromethylphenylene sulfonyl-phenyi
CH20-i-Bu 2-fluoro-l,4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH2Ph 2-fluoro-l,4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH2-pyrazol- 2-fluoro-l, 4- 2-trifluoromethyl- 1-yl phenylene sulfonyl-pheny1 CH2-imidazol- 2-fluoro-l,4- 2-trifluoromethyl¬

1-yl phenylene sulfonyl-phenyi
10 CH2-tetrazol- 2-fluoro-l,4- 2-trifluoromethyl¬

1-yl phenylene sulfonyl-phenyi
11 CH2-tetrazol- 2-fluoro-l,4- 2-trifluoromethyl¬

2-yl phenylene sulfonyl-phenyi
12 CH2-triazol- 2-fluoro-l, 4- 2-trifluoromethyl¬

1-yl phenylene sulfonyl-phenyi

13 CH SEt 2-fluoro-l,4- 2-trifluoromethylphenylene sulfonyl-phenyi

14 CH2S02Et 2-fluoro-l,4- 2-trifluoromethyl- phenylene sulfonyl-phenyl

15 CF3 2-$luoro-l,4- 2-trifluoromethyl- phenylene sulfonyl-phenyi

16 CH3 2-fluoro-l,4- 2-trifluoromethyl¬

]3henylene sulfonyl-phenyi

17 2-fluoro-l,4- 2-trifluoromethyl- phenylene sulfonyl-phenyl

F5 CH2OMe 2-chloro-l,4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH2OEt 2-chloro-l,4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH20-n-Pr 2-chloro-l,4- 2-trifluoromethyl- phenylene sulfonyl-phenyl
CH2θ-i-Pr 2-chloro-l,4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH20-n-Bu 2-chloro-l,4- 2 -trifluoromethylphenylene sulfonyl-phenyi
CH 0-i-Bu 2-chloro-l, 4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH2Ph 2-chloro-l,4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH2-pyrazol- 2-chloro-l,4- 2-trifluoromethyl¬

1-yl phenylene sulfonyl-phenyi
CH2-imidazol- 2-chloro-l,4- 2-trifluoromethyl¬

1-yl phenylene sulfonyl-phenyi 10 CH2-tetrazol- 2-chloro-l , 4- 2-trifluoromethyl¬

1-yl phenylene sulfonyl-phenyi
11 CH2-tetrazol- 2-chloro-l , 4- 2-trifluoromethyl- 2-yl phenylene sulfonyl-pheny1
12 CH2~triazol- 2-chloro-l, 4- 2-trifluoromethyl¬

1-yl phenylene sulfonyl-phenyi
13 CH2 SEt 2-chloro-l,4- 2-trifluoromethyl - phenylene sulfonyl-phenyi
14 CH S0 Et 2-chloro-l,4- 2-trifluoromethylphenylene sulfonyl-phenyi

15 CF3 2-chloro-l , 4- 2-trifluoromethylphenylene sulfonyl-phenyi

16 CH3 2-chloro-l,4- 2-trifluoromethyl- phenylene sulfonyl-phenyi

17 2-chloro-l , 4- 2-trifluoromethyl- fthenylene sulfonyl-phenyi

F6 CH2OMe 2-methyl-l, 4- 2-trifluoromethyl- phenylene sulfonyl-phenyi
CH2OEt 2-methyl-l, 4- 2-trifluoromethylphenylene sulfony1-phenyl
CH20-n-Pr 2-methyl-l, 4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH20-i-Pr 2-methyl-l, 4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH20-n-Bu 2-methyl-l, 4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH2θ-i-Bu 2-methyl-l, 4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH2Ph 2-methy1-1,4- 2-trifluoromethylphenylene sulfonyl-phenyi
CH2-pyrazol- 2-methyl-l, 4- 2-trifluoromethyl¬

1-yl phenylene sulfonyl-phenyi
CH2-imidazol- 2-methyl-l, 4- 2-trifluoromethyl- 1-yl phenylene sulfonyl-phenyi

10 CH2-tetrazol- 2-methyl-l, - 2-trifluoromethyl- 1-yl phenylene sulfonyl-pheny1
-US 11 H CH2-tetrazol- 2-methyl-l , 4- 2-trifluoromethyl¬

2-yl phenylene sulfonyl-phenyi

12 H CH -triazol- 2-methyl-l, 4- 2-trifluoromethyl¬

1-yl phenylene sulfonyl-phenyi

13 H CH2ΞEt 2-methyl-l, 4- 2-trifluoromethylphenylene sulfonyl-phenyi

14 H CH2S02Et 2-methyl-l, 4- 2-trifluoromethylphenylene sulfonyl-phenyi

15 H CF3 2-methyl-l, 4- 2-trifluoromethylphenylene sulfonyl-phenyi

16 H CH3 2-methyl-l , 4- 2-trifluoromethylphenylene sulfonyl-phenyi

17 H H 2-methyl-l, 4- 2-trifluoromethylphenylene sulfonyl-phenyi

Gl 1 H CHOMe phenyi 2-methoxyphenyl

2 H CH2OEt * phenyi 2-methoxyphenyl

3 H CH20-n-Pr phenyi 2-methoxyphenyl

4 H CH20-i-Pr phenyi 2-methoxyphenyl

5 H CH20-n-Bu phenyi 2-methoxyphenyl

6 H CH2θ-i-Bu phenyi 2-methoxyphenyl

7 H CH Ph phenyi 2-methoxyphenyl

8 H CH2~pyrazol- phenyi 2-methoxyphenyl
1-yl
9 H CH2~imidazol- phenyi 2-methoxyphenyl
1-yl
10 H CH2~tetrazol- phenyi 2-methoxyphenyl
1-yl
11 H CH2~tetrazol- phenyi 2-methoxyphenyl
2-yl
12 H CH2-triazol- phenyi 2- ethoxypheny1
1-yl
13 H CH SEt phenyi 2-methoxyphenyl

14 H CH2S02Et phenyi 2-methoxyphenyl

15 H CF3 phenyi 2-methoxyphenyl

16 H CH3 phenyi 2-methoxyphenyl

17 H H phenyi 2 -methoxyphenyl G2 CH2OMe pyridin-2 , 5- 2-methoxyphenyl
diyl
CH2OEt pyridin-2, 5- 2-methoxyphenyl
diyl
CH2θ-n-Pr pyridin-2, 5- 2-methoxyphenyl
diyl
CH 0-i~Pr pyridin-2, 5- 2-methoxypheny1
diyl
CH 0-n-Bu pyridin-2, 5- 2-methoxypheny1
diyl
CH20-i-Bu pyridin-2 , 5- 2-methoxyphenyl
diyl
CH2Ph pyridin-2 , 5- 2-methoxyphenyl
diyl
cH2-pyrazoi- pyridin-2 , 5- 2-methoxyphenyl
1-yl * diyl
CH2-imidazol- pyridin-2 , 5- 2-methoxypheny1
1-yl diyl
10 CH2-tetrazol- pyridin-2 , 5- 2-methoxyphenyl
1-yl diyl
11 CH2-tetrazol- pyridin-2 , 5- 2-methoxyphenyl
2-yl diyl
12 CH2-triazol- pyridin-2 , 5- 2-methoxyphenyl
1-yl diyl
13 CH2SEt pyridin-2 , 5- 2-methoxyphenyl
diyl
14 CH2S02Et pyridin-2 , 5- 2-methoxyphenyl
diyl
15 CF3 pyridin-2 , 5- 2-methoxyphenyl
diyl
16 CH3 pyridin-2, 5- 2-methoxyphenyl
diyl
17 H pyridin-2, 5- 2-methoxyphenyl
diyl
CH20Me pyrimidin- 2-methoxyphenyl
2, 5-diyl CH2OEt pyrimidin- 2-methoxyphenyl
2, 5-diyl
CH20-n-Pr pyrimidin- 2-methoxyphenyl
2, 5-diyl
CH20-i-Pr pyrimidin- 2-methoxyphenyl
2, 5-diyl
CH 0-n-Bu pyrimidin- 2-methoxyphenyl
2, 5-diyl
CH20-i-Bu pyrimidin- 2-methoxyphenyl
2, 5-diyl
CH2Ph pyrimidin- 2-methoxyphenyl
2, 5-diyl
CH2~pyrazol- pyrimidin- 2-methoxyphenyl
1-yl 2, 5-diyl
CH2-imidazol- pyrimidin- 2 -methoxyphenyl
1-yl "2, 5-diyl
10 CH2-tetrazol- pyrimidin- 2-methoxyphenyl
1-yl 2, 5-diyl
11 CH2~tetrazol- pyrimidin- 2-methoxyphenyl
2-yl 2, 5-diyl
12 CH2-triazol- pyrimidin- 2-methoxyphenyl
1 -yl 2, 5-diyl
13 CH SEt pyrimidin- 2-methoxyphenyl
2, 5-diyl
14 CH2 S02 Et pyrimidin- 2-methoxyphenyl
2, 5-diyl
15 CF3 pyrimidin- 2-methoxyphenyl
2, 5-diyl
16 CH3 pyrimidin- 2-methoxyphenyl
2, 5-diyl
17 pyrimidin- 2-methoxyphenyl
2 , 5-diyl
G4 CH2OMe 2-fluoro-l,4- 2-methoxyphenyl
phenylene
CH20Et 2-fluoro-l,4- 2 -methoxyphenyl
phenylene CH20-n-Pr 2-fluoro-l,4- 2-methoxyphenyl
phenylene
CH20-i -Pr 2-fluoro-l, 4- 2-methoxyphenyl
phenylene
CH2θ-n-Bu 2-fluoro-l,4- 2-methoxyphenyl
phenylene
CH20-i -Bu 2-fluoro-l,4- 2 -methoxyphenyl
phenylene
CH2Ph 2-fluoro-l , 4- 2-methoxyphenyl
phenylene
CH2~pyrazol- 2-fluoro-l,4- 2-methoxyphenyl
1-yl phenylene
CH2-imidazol- 2-fluoro-l,4- 2-methoxyphenyl
1-yl phenylene
10 CH2-tetrazol- 2-fluoro-l,4- 2-methoxyphenyl
1-yl ]5henylene
11 CH2-tetrazol- 2-fluoro-l,4- 2-methoxyphenyl
2-yl phenylene
12 CH2-triazol- 2-fluoro-l,4- 2-methoxyphenyl
1-yl phenylene
13 CH2SEt 2-fluoro-l,4- 2-methoxyphenyl
phenylene
14 CH2S02Et 2-fluoro-l,4- 2 -methoxyphenyl
phenylene
15 CF3 2-fluoro-l,4- 2-methoxyphenyl
phenylene
16 CH3 2-fluoro-l,4- 2-methoxyphenyl
phenylene
17 2-fluoro-l,4- 2-methoxyphenyi
phenylene
G5 CH2θMe 2-chloro-l,4- 2-methoxyphenyl
phenylene
CH2θEt 2-chloro-l,4- 2-methoxyphenyl
phenylene
CH20-n-Pr 2-chloro-l,4- 2-methoxyphenyl
phenylene CH20-i-Pr 2-chloro-l, 4- 2-methoxyphenyl
phenylene
CH 0-n-Bu 2-chloro-l, 4- 2-methoxyphenyl
phenylene
CH20-i-Bu 2-chloro-l, 4- 2-methoxyphenyl
phenylene
CH2Ph 2-chloro-l , 4- 2-methoxyphenyl
phenylene
CH2-pyrazol- 2-chloro-l,4- 2-methoxyphenyl
1-yl phenylene
CH2 -imidazol- 2-chloro-l,4- 2-methoxyphenyl
1-yl phenylene
10 CH2-tetrazol- 2-chloro-l , 4- 2-methoxyphenyl
1-yl phenylene
11 CH2-tetrazol- 2-chloro-l,4- 2-methoxyphenyl
2-yl βhenylene
12 CH2-triazol- 2-chloro-l,4- 2-methoxyphenyl
1-yl phenylene
13 CH2SEt 2-chloro-l,4- 2 -methoxyphenyl
phenylene
14 CH2S02Et 2-chloro-l,4- 2-methoxyphenyl
phenylene
15 CF3 2-chloro-l,4- 2-me hoxyphenyl
phenylene
16 CH3 2-chloro-l,4- 2-methoxyphenyl
phenylene
17 H 2-chloro-l,4- 2-methoxyphenyi
phenylene
G6 CH20Me 2-methyl-l, 4- 2-methoxyphenyl
phenylene
CH 0Et 2-methy1-1,4- 2-methoxyphenyl
phenylene
CH20-n-Pr 2-methyl-l, 4- 2-methoxyphenyl
phenylene
CH20-i-Pr 2-methyl-l, 4- 2-methoxyphenyl
phenylene CH20-n-Bu 2-methyl-l, 4- 2-methoxyphenyl
phenylene
CH20-i-Bu 2-methyl-l, 4- 2-methoxyphenyl
phenylene
CH2Ph 2-methyl-l, 4- 2-methoxyphenyl
phenylene
CH -pyrazol- 2-methyl-l, 4- 2-methoxypheny1
1-yl ~ phenylene
CH -ιmidazol- 2-methyl-l, 4- 2-methoxyphenyl
1-yl phenylene
10 CH2-tetrazol- 2-methyl-l, 4- 2-methoxyphenyl
1-yl phenylene
11 CH2-tetrazol- 2-methyl-l, 4- 2-methoxyphenyl
2-yl phenylene
12 CH2-triazol- 2-methyl-l, 4- 2 -methoxyphenyl
1-yl phenylene
13 CH SEt 2-methyl-l, 4- 2-methoxyphenyl
phenylene
14 CH2S02Et 2-methyl-l, 4- 2-methoxyphenyl
phenylene
15 CF3 2-methy1-1,4- 2-methoxyphenyl
phenylene
16 CH3 2-methyl-l, 4- 2-methoxyphenyl
phenylene
17 H 2-methyl-l, 4- 2-methoxypheny1
phenylene
HI CH20Me phenyi 2- ethylsulfonylphenyl
CH2OEt phenyi 2- methylsulfonyIphenyl
CH20-n-Pr phenyi 2- methylsulfonylphenyl
CH20- i -Pr phenyi 2- methylsulfonylphenyl
CHpO-n-Bu phenyi 2- methylsulfonyIpheny1 CH20-i -Bu phenyi 2 - methylsulfonyIphenyl
CH2Ph phenyi 2- methylsul fonylphenyl
CH2-pyrazol- phenyi 2 - 1-yl methylsulfonyIphenyl
CH2-imidazol- phenyi 2- 1-yl methylsulfonyIphenyl

10 CH2-tetrazol- phenyi 2- 1-yl methylsulfonylphenyl

11 CH2-tetrazol- phenyi 2- 2-yl ethylsulfonylphenyl

12 CH2~triazol- phenyi 2- 1-yl methylsulfonyIphenyl

13 CH2SEt phenyi 2- • methylsulfonylphenyl

14 CH2S02Et phenyi 2- methylsulfonylphenyl

15 CF3 phenyi 2- methylsulfonylphenyl

16 CH3 phenyi 2- methylsulfonylphenyl

17 H phenyi 2- methylsulfonylphenyl

H2 CH2OMe pyridin-2 , 5- 2- diyl methylsulfonyIphenyl
CH OEt pyridin-2, 5- 2- diyl methylsulfonylphenyl
CH20-n-Pr pyridin-2 , 5- 2- diyl methylsulfonylphenyl
CH2θ-i-Pr pyridin-2, 5- 2- diyl methylsulfonylphenyl
CH2θ-n-Bu pyridin-2, 5- 2- diyl methylsulfonylphenyl
CH20-i-Bu pyridin-2 , 5- 2- diyl methylsulfonylphenyl CH2 Ph pyridin-2, 5- diyl methylsulfonyIphenyl
CH2-pyrazol- pyridin-2 , 5- 2- 1-yl diyl methylsulfonylphenyl
CH2 -imidazol- pyridin-2, 5- 2- 1-yl diyl methylsul fonylphenyl

10 CH2-tetrazol- pyridin-2, 5- 2- 1-yl diyl methylsulfonyIphenyl

11 CH -tetrazol- pyridin-2, 5- 2- 2-yl diyl methylsulfonylphenyl

12 CH -triazol- pyridin-2 , 5- 2- 1-yl diyl methylsulfonylphenyl

13 CH SEt pyridin-2 , 5- 2- diyl methylsulfonyIphenyl
CH2S02Et pyridin-2 , 5- 2- diyl methylsulfonyIphenyl

15 CF3 pyridin-2 , 5- 2- diyl methylsul fonylphenyl

16 CH3 pyridin-2 , 5- 2- diyl methylsulfonylphenyl

17 pyridin-2, 5- 2- diyl methylsul fonylphenyl

H3 CH2θMe pyrimidin- 2- 2, 5-diyl methylsulfonylphenyl
CH2OEt pyrimidin- 2- 2, 5-diyl methylsulfonylphenyl
CH20-n-Pr pyrimidin- 2- 2, 5-diyl methylsulfonylphenyl
CH20-i-Pr pyrimidin- 2- 2, 5-diyl ethylsulfonyIphenyl
CH20-n-Bu pyrimidin- 2- 2, 5-diyl methylsulfonylphenyl
CH20-i-Bu pyrimidin- 2- 2, 5-diyl methylsulfonylphenyl
CH2Ph pyrimidin- 2- 2, 5-diyl methylsulfonylphenyl CH2-pyrazol- pyrimidin- 2- 1-yl 2, 5-diyl methylsulfonyIpheny1
CH2-imidazol- pyrimidm- 2- 1-yl 2, 5-diyl methylsulfonyIpheny1

10 CH2-tetrazol- pyrimidin- 2- 1-yl 2, 5-diyl methylsulfonyIphenyl

11 CH2-tetrazol- pyrimidin- 2- 2-yl 2, 5-diyl methylsulfonylphenyl

12 CH -triazol- pyrimidin- 2- 1-yl 2, 5-diyl methylsul fonylphenyl

13 CH SEt pyrimidin- 2- 2, 5-diyl methylsulfonyIphenyl

14 CH2S02Et pyrimidin- 2- 2, 5-diyl methylsulfonyIphenyl

15 CF3 pyrimidin- 2- 1 , 5-diyl methylsulfonylphenyl

16 CH3 pyrimidin- 2- 2, 5-diyl methylsulfonyIpheny1

17 H pyrimidin- 2- 2, 5-diyl methylsulfonylphenyl

H4 CH2OMe 2-fluoro-l, 4- 2- phenylene methylsulfonylphenyl
CH2OEt 2-fluoro-l,4- 2- phenylene methylsulfonyIphenyl
CH20-n-Pr 2-fluoro-1 , 4- 2- phenylene methylsulfonyIpheny1
CH20-i-Pr 2-fluoro-l , 4- 2- phenylene methylsulfonyIpheny1
CH20-n-Bu 2-fluoro-l , 4- 2- phenylene methylsulfonylphenyl
CH 0-i-Bu 2-fluoro-l,4- 2- phenylene methylsulfonyIphenyl
CH2Ph 2-fluoro-l,4- 2- phenylene methylsulfonylphenyl
CH2-pyrazol- 2-fluoro-l,4- 2- 1-yl phenylene methylsulfonylphenyl CH2-imidazol- 2-fluoro-l, 4- 2- 1-yl phenylene methylsulfonylphenyl

10 CH2~tetrazol- 2-fluoro-l,4- 2- 1-yl phenylene methylsul fonylphenyl

11 CH2~tetrazol- 2-fluoro-l, 4- 2- 2-yl phenylene methylsulfonylphenyl

12 CH2~triazol- 2-fluoro-l,4- 2 - 1-yl phenylene methylsulfonylphenyl

13 CH SEt 2-fluoro-1 , 4- 2 - phenylene methylsulfonyIphenyl

14 CH2S02Et 2-fluoro-l, 4- 2- phenylene methylsulfonyIphenyl

15 CF3 2-fluoro-l,4- 2- phenylene methylsulfonylphenyl

16 CH3 2-fluoro-l, 4- 2- £>henylene methylsulfonylphenyl

17 2 -f luoro-1 , 4 - 2- phenylene methylsulfonylphenyl

H5 CH2OMe 2-chloro-l,4- 2- phenylene methylsulfonylphenyl
CH2OEt 2-chloro-l, 4- 2- phenylene methylsulfonyIpheny1
CH20-n-Pr 2-chloro-l,4- 2- phenylene methylsulfonyIphenyl
CH20-i-Pr 2-chloro-l, 4- 2- phenylene methylsulfonyIphenyl
CH20-n-Bu 2-chloro-l, 4- 2- phenylene methylsulfonylphenyl
CH20-i-Bu 2-chloro-l, 4- 2- phenylene methylsulfonylphenyl
CH Ph 2-chloro-l,4- 2- phenylene methylsulfonyIphenyl
CH2-pyrazol- 2-chloro-l, 4- 2 - 1-yl phenylene methylsulfonyIphenyl
CH2-imidazol- 2-chloro-l,4- 2- 1-yl phenylene methylsulfonylphenyl
-121 10 CH2~tetrazol- 2-chloro-l, 4- 1-yl phenylene methylsulfonylphenyl

11 CH2-tetrazol- 2-chloro-l,4- 2- 2-yl phenylene methylsulfonyIphenyl

12 CH2-triazol- 2-chloro-l, 4- 2- 1-yl phenylene methylsulfonylphenyl

13 CH2SEt 2-chloro-l, 4- 2- phenylene methylsulfonylphenyl

14 CH2S02Et 2-chloro-l, 4- 2- phenylene methylsulfonyIphenyl

15 CF3 2-chloro-l , 4- 2- phenylene methylsulfonyIphenyl

16 CH3 2-chloro-l, - 2- phenylene methylsul fonylphenyl

17 2-chloro-l,4- 2- flhenylene methylsulfonyIphenyl

H6 CH20Me 2-methyl-1, 4- phenylene methylsulfonyIphenyl
CH2OEt 2-methy1-1,4- 2- phenylene methylsulfonyIphenyl
CH20-n-Pr 2-methyl-l, 4- 2- phenylene methylsul fonylphenyl
CH20-i-Pr 2-methyl-l, 4- 2- phenylene methylsulfonylphenyl
CH20-n-Bu 2-methyl-l, 4- 2- phenylene methylsulfonylphenyl
CH20-i-Bu 2-methyl-l, 4- 2- phenylene methylsulfonyIphenyl
CH Ph 2-methyl-l, 4- 2- phenylene methylsulfonylphenyl
CH2-pyrazol- 2-methyl-l, 4- 2- 1-yl phenylene methylsulfonylphenyl
CH2 -imidazol- 2-methyl-l, 4- 2- 1-yl phenylene methylsulfonyIpheny1

10 CH2-tetrazol- 2-methyl-l, 4- 2- 1-yl phenylene methylsulfonylphenyl 11 H CH -tetrazol- 2-methyl-1, 4- 2- 2-yl phenylene methylsulfonyIpheny1

12 H CH2-triazol- 2-methyl-1,4- 2- 1-yl phenylene methylsulfonylphenyl

13 H CH SEt 2-methyl-l, 4- 2- phenylene methylsulfonyIphenyl

14 H CH S02Et 2-methyl-l, 4- 2- phenylene methylsulfonylphenyl

15 H CF3 2-methyl-l, 4- 2- phenylene methylsul fonylphenyl

16 H CH3 2-methyl-l, 4- 2- phenylene methylsulfonylphenyl

17 H H 2 -methyl-1,4- 2- phenylene methylsulfonylphenyl

11 1 H CH2OMe 1,4-phenylene 2-nitrophenoxy

2 H CH OEt 1, 4-phenylene 2-nitrophenoxy
3 H CH20-n-Pr 1, 4-phenylene 2-nitrophenoxy
4 H CH20-i-Pr 1, 4-phenylene 2-nitrophenoxy
5 H CH2θ-n-Bu 1, 4-phenylene 2-nitrophenoxy
6 H CH20-i-Bu 1, -phenylene 2-nitrophenoxy
7 H CH2Ph 1 , 4-phenyiene 2-nitrophenoxy
8 H CH2-pyrazol- 1, 4-phenylene 2-nitrophenoxy
1-yl
9 H CH2 -imidazol- 1 , 4-phenyiene 2-nitrophenoxy
1-yl
10 H CH2-tetrazol- 1 , 4-phenylene 2-nitrophenoxy
1-yl
11 H CH -tetrazol- 1, 4-phenylene 2-nitrophenoxy
2-yl
12 H CH2-triazol- 1, 4-phenylene 2-nitrophenoxy
1-yl
13 H CH2SEt 1 , 4-phenylene 2-nitrophenoxy
14 H CH S02Et 1, 4-phenylene 2-nitrophenoxy
15 H CF3 1, 4-phenylene 2-ni rophenoxy
16 H CH3 1, 4-phenylene 2-nitrophenoxy
17 H H 1 , 4-phenylene 2-nitrophenoxy Jl 1 H CH2OMe 2, 5-thiophene 2 -aminosulfonylphenyl

2 H CH2θEt 2, 5-thiophene 2 -aminosulfonylphenyl

3 H CH20-n-Pr 2, 5-thiophene 2 -aminosulfonyIphenyl

4 H CH20- i -Pr 2 , 5-thiophene 2-aminosulfonyIpheny1

5 H CH 0-n-Bu 2, 5-thiophene 2-aminosulfonylphenyl

6 H CH20-i -Bu 2 , 5-thiophene 2-aminosulfonylphenyl

7 H CH2Ph 2, 5-thiophene 2-aminosulfonylphenyl

8 H CH -pyrazol - 2 ,5-thiophene 2-aminosulfonylphenyl
1 -yl
9 H CH2 -imidazol 2 , 5-thiophene 2-aminosulfonylphenyl
1 -yl
10 H CH -tetrazol 2, 5-thiophene 2-aminosulfonylphenyl
1 -yl
11 H CH2 -tetrazol 2, 5-thiophene 2-aminosulfonyIphenyl
2 -yl
12 H CH2 -triazol - 2 , 5-thiophene 2-aminosulfonyIphenyl
1 -yl
13 H CH2 SEt 2, 5-thiophene 2-aminosulfonyIphenyl

14 H CH2 S02 Et 2, 5-thiophene 2-aminosulfonylphenyl

15 H CF3 2, 5-thiophene 2-aminosulfonylphenyl

16 H CH3 2, 5-thiophene 2-aminosulfonylphenyl

17 H H 2 , 5-thiophene 2-aminosulfonylphenyl

TABLE 8


Part Cpd (CH2)nR2 (Z)u-D
CH2OMe phenyi 2-aminosulfonylphenyl
CH2OEt phenyi 2-aminosulfonylphenyl 3 CH20-n-Pr phenyl 2-aminosulfonyIphenyl

4 CH20-i-Pr phenyi 2-aminosulfonyIpheny1

5 CH20-n-Bu phenyi 2-aminosulfonylphenyl

6 CH20-i-Bu phenyi 2-aminosulfonylphenyl

7 CH2Ph phenyi 2-aminosulfonyIpheny1

8 CH2-pyrazol-l -yl phenyi 2-aminosulfonyIpheny1

9 CH2-imidazol-•1- phenyi 2-aminosulfonylphenyl yi
10 CH2-tetrazol--1- phenyi 2-aminosulfonylphenyl yi
11 CH2-tetrazol--2- phenyi 2-aminosulfonyIpheny1 yi
12 CH2-triazol-l -yl phenyi 2-aminosulfonylphenyl

13 CH2SEt phenyi 2-aminosulfonyIphenyl

14 CH2S02Et phenyi 2-aminosulfonylphenyl

15 CF3 phenyi 2-aminosulfonylphenyl

16 CH3 phenyi 2-aminosulfonylphenyl

17 H phenyi 2-aminosulfonyIphenyl

1 CH2OMe pyridin-2 , 5-diyl 2-aminosulfonyIphenyl

2 CH2OEt pyridin-2 , 5-diyl 2-aminosulfonyIphenyl

3 CH 0-n-Pr pyridin-2 , 5-diyl 2 -aminosulfonyIphenyl

4 CH20-i-Pr pyridin-2 , 5-diyl 2-aminosulfonylphenyl

5 CH20-n-Bu pyrj .din-2, 5-diyl 2-aminosulfonyIpheny1

6 CH20-i-Bu pyridin-2 , 5-diyl 2-aminosulfonylphenyl

7 CH2Ph pyridin-2 , 5-diyl 2 -aminosul fonylphenyl

8 CH2-pyrazol-l -yl pyrj '.din-2, 5-diyl 2-aminosulfonyIphenyl

9 CH2-imidazol-1- pyridin-2 , 5-diyl 2-aminosulfonylphenyl yi
10 CH -tetrazol-1- pyridin-2 , 5-diyl 2-aminosulfonyIphenyl yi
11 CH2-tetrazol-2- pyridin-2 , 5-diyl 2-aminosulfonyIpheny1 yi
12 CH2-triazol-l -yl pyridin-2 , 5-diyl 2-aminosulfonyIpheny1

13 CH2SEt pyridin-2 , 5-diyl 2-aminosulfonylphenyl

14 CH2S02Et pyridin-2 , 5-diyl 2-aminosulfonylphenyl

15 CF3 pyridin-2 , 5-diyl 2-aminosulfonyIphenyl 16 CH3 pyridin-2 , 5-diyl 2 -aminosulfonylphenyl

17 H pyridin-2 , 5-diyl 2-aminosulfonyIphenyl

1 CH2OMe pyrimidin-2 , 5-diyl 2-aminosulfonyIphenyl

2 CH2OEt pyrimidin-2 , 5-diyl 2-aminosulfonyIphenyl

3 CH2θ-n-Pr pyrimidin-2 , 5-diyl 2-aminosulfonyIpheny1

4 CH20-i-Pr pyrimidin-2 , 5-diyl 2-aminosulfonylphenyl

5 CH2θ-n-Bu pyrimidin-2 , 5-diyl 2-aminosulfonyIpheny1

6 CH20-i-Bu pyrimidin-2 , 5-diyl 2-aminosulfonyIpheny1

7 CH Ph pyrimidin-2 , 5-diyl 2-aminosulfonylphenyl

8 CH2-pyrazol-l -yl pyrimidin-2 , 5-diyl 2-aminosulfonylphenyl

9 CH2-imidazol-1- pyrimidin-2 , 5-diyl 2-aminosulfonyIphenyl
yi
10 CH2-tetrazol-1- pyrimidin-2 , 5-diyl 2-aminosulfonylphenyl
yi
11 CH2-tetrazol-2- pyrimidin-2 , 5-diyl 2-ammosulfonylphenyl
yi
12 CH2-triazol-l -yl pyrimidin-2 , 5-diyl 2-aminosulfonyIphenyl

13 CH2SEt pyrimidin-2 , 5-diyl 2-aminosul fonylphenyl

14 CH2S0 Et pyrimidin-2 , 5-diyl 2-aminosul fonylphenyl

15 CF3 pyrimidin-2 , 5-diyl 2-aminosulfonylphenyl

16 CH3 pyrimidin-2 , 5-diyl 2-aminosulfonyIphenyl

17 H pyrimidin-2 , 5-diyl 2-aminosulfonylphenyl

TABLE 9


P a rt C p d ( CH2 ) nR2 ( Z ) u- D
CH3 CH2OMe phenyi 2- aminosulfonylphenyl CH3 CH2OEt phenyi 2- aminosulfonyIphenyl

CH3 CH 0-n-Pr phenyi 2- aminosulfonylphenyl

CH3 CH20-i-Pr phenyi 2- aminosul fonylphenyl

CH3 CH20-n-Bu phenyi 2- aminosulfonyIpheny1

CH3 CH20-i-Bu phenyi 2- aminosulfonyIphenyl

CHj CH2Ph phenyi 2- aminosulfonyIpheny1

CH3 CH2-pyrazol- phenyi 2- 1-yl aminosulfonylphenyl

CH3 CH2-imidazol- phenyi 2- 1-yl * aminosulfonylphenyl

10 CH- CH2-tetrazol- phenyi 2- 1-yl aminosulfonyIphenyl

11 CH3 CH2~tetrazol- phenyi 2- 2-yl aminosul fonylphenyl

12 CH3 CH2-triazol- phenyi 2- 1-yl aminosulfony1pheny1

13 CH3 CH2SEt phenyi 2- aminosulfonylphenyl

14 CH3 CH2S02Et phenyi . —
aminosulfonylphenyl

15 CH3 CF3 phenyi 2- aminosulfonylphenyl

16 CH3 CH3 phenyi 2- aminosulfonyIphenyl

17 CH3 H phenyi 2- aminosulfonylphenyl

B 1 CH2OMe phenyi
aminosulfonyIphenyl
CH OEt phenyi 2- aminosulfonylphenyl CH20-n-Pr phenyi 2- aminosulfonylphenyl
CH20-i-Pr phenyi 2- aminosulfonylphenyl
CH2θ-n-Bu phenyi 2- aminosulfonyIphenyl
CH20-i-Bu phenyi 2- - aminosul fonylphenyl
CH2Ph phenyi 2- aminosulfonyIphenyl
CH2~pyrazol- phenyi 2- 1-yl aminosulfonyIphen 1

CH2~imidazol- phenyi 2- 1-yl aminosulfonylphenyl

10 CH2~tetrazol- phenyi 2- 1-yl * aminosulfonylphenyl

11 CH2~tetrazol- phenyi 2- 2-yl aminosulfonylphenyl

12 CH2-triazol- phenyi 2- 1-yl aminosulfonylphenyl

13 CH2SEt phenyi 2- aminosulfonyIpheny1

14 CH2S02Et phenyi 2- aminosulfonylphenyl

15 CF3 phenyi 2- aminosulfonylphenyl

16 CH3 phenyi 2- aminosulfonylphenyl

17 H phenyi 2- aminosulfony1pheny1

TABLE 10

C p d .1 5 ( CH2 ) nR2 V ( Z ) u - D
CH3 CH2OMe 1, , 4-phenylene 2- aminosulfonyIphenyl

CH3 CH2OEt 1, , 4-phenylene 2- 'aminosulfonyIphenyl

CH3 CH20-n-Pr 1, .4-phenylene 2- aminosulfonylphenyl

CH3 CH20-i-Pr 1, , 4-phenylene 2- aminosulfonylphenyl

CH3 CH 0-n-Bu 1, , 4-pheaylene 2- aminosul fonylphenyl

CH3 CH20-i-Bu 1, , 4-phenylene 2- aminosulfonylphenyl

CH3 CH2Ph 1, , 4-phenylene 2- aminosulfonyIphenyl

CH3 CH2-pyrazol- 1, , 4-phenylene 2- 1-yl aminosulfonylphenyl

CH3 CH2-imidazol- 1, , 4-phenylene 2- 1-yl aminosulfonyIphenyl

10 CH3 CH2-tetrazol- 1, , 4-phenylene 2- 1-yl aminosulfony1pheny1

11 CH3 CH2-tetrazol- 1, , 4-phenylene 2- 2-yl aminosulfonylphenyl

12 CH3 CH2-triazol- 1, , 4-phenylene 2- 1-yl aminosulfonylphenyl

13 CH3 CH2SEt 1, , 4-phenylene 2- aminosulfonylphenyl

14 CH3 CH2S02Et 1, , 4-phenylene 2- aminosulfonyIpheny1 CH3 CF3 1 , 4 -phenylene
aminosul f ony Ipheny 1

CH3 CH3 1 , 4 -phenylene 2- aminosul f onylphenyl

CH3 1 , 4 -phenylene 2- aminosulf ony Iphenyl

CH2CF3 CH2OMe 1, 4-phenylene 2- aminosul fonylphenyl CH2CF3 CH OEt 1, 4-phenylene 2- aminosulfonylphenyl CH2CF3 1,4-phenylene 2- aminosulfonylphenyl CH CF3 CH20-i-Pr 1, 4-phenylene 2- aminosulfonylphenyl

CH2CF3 CH20-n-Bu 1 , 4-phenylene 2- aminosulfonyIphenyl CH2CF3 CH20-i-Bu 1 , 4-phenylene 2- aminosulfonylphenyl

CH2CF3 CH2Ph 1, 4-phenylene 2- aminosulfonylphenyl

CH2CF3 CH2-pyrazol- 1 ,4-phenylene 2- 1-yl aminosulfonyIphenyl

CH2CF3 CH2-imidazol- 1 , 4-phenylene 2- 1-yl aminosulfonylphenyl

CH2CF3 CH2-tetrazol- 1, 4-phenylene 2- 1-yl aminosulfonyIphenyl

CH2CF3 CH2-tetrazol- 1 , 4-phenylene 2- 2-yl aminosulfonyIpheny1 CH2CF3 CH -triazol- 1, 4-phenylene 2- 1-yl aminosulfonyIpheny1 CH2CF3 CH SEt 1,4-phenylene 2- aminosulfonyIpheny1 CH2CF3 CH S02Et 1, 4-phenylene 2- aminosulfonylphenyl CH2CF3 CF3 1, 4-phenylene 2- aminosulfonyIpheny1 33 CH2CF3 CH3 1, 4 -pheny lene 2- aminosulf onylphenyl
34 CH2CF3 1 , 4 -phenylene 2 - aminosulf onylphenyl

TABLE 11


Part Cpd U (CH2)nR's (Z)
A 1 CH2NH CH2OMe 1, 4-phenylene 2-aminosulfonylphenyl

2 CH2NH CH2OEt 1 , 4-phenylene 2-aminosulfonylphenyl

3 CH2NH CH20-n-Pr 1,4-phenylene 2-aminosulfonylphenyl

4 CH2NH CH2θ-i-Pr 1, 4-phenyiene 2 -aminosulfonyIpheny1

5 CH2 H CH2θ-n-Bu 1 , 4 -phenylene 2 -aminosulfonylphenyl

6 CH2NH CH20-i-Bu 1 , 4-phenylene 2-aminosul fonylphenyl

7 CH2NH CH2Ph 1 , 4-phenylene 2-aminosulfonylphenyl

8 CH NH CH2-pyrazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
9 CH2 H CH2-imidazol- 1, 4-phenylene 2-aminosulfonylphenyl
1-yl
10 CH2 H CH2-tetrazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
11 CH2NH CH2-tetrazol- 1, 4-phenylene 2-aminosulfonyIphenyl
2-yl
12 CH2 H CH2-triazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
13 CH2 H CH2SEt 1 , 4-phenylene 2-aminosulfonylphenyl

14 CH2 H CH2S02Et 1 , 4-phenylene 2-aminosulfonylphenyl

15 CH2NH CF3 1 , 4-phenylene 2-aminosulfonylphenyl

16 CH2 H CH3 1 , 4-phenylene 2-aminosulfonylphenyl

17 CH2NH H 1 , 4-phenylene 2 -aminosulfonylphenyl 1 CH2CO CH2OMe 1, 4-phenylene 2 -aminosul fonylphenyl

2 CH2CO CH2OEt 1 , 4-phenylene 2 -aminosulfonyIpheny1

3 CH2CO CH20-n-Pr 1 , 4-phenylene 2-aminosulfonyIphenyl

4 CH2CO CH20-i-Pr 1, 4-phenylene 2-aminosul fonylphenyl

5 CH2CO CH20-n-Bu 1, 4-phenylene 2-aminosulfonylphenyl

6 CH2CO CH20-i-Bu 1 , 4-phenyiene 2-aminosulfonyIpheny1

7 CH2CO CH2Ph 1 , 4-phenylene 2-aminosulfonylphenyl

8 CH2CO CH2-pyrazol- 1 , 4-phenylene 2-aminosulfonyIphenyl
1-yl
9 CH2CO CH2-ιmidazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
10 CH2CO CH2-tetrazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
11 CH2CO CH2-tetrazol- 1 , 4-phenylene 2-aminosulfonyIphenyl
2-yl
12 CH2CO CH2~triazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
13 CH CO CH2SEt 1 , 4-phenylene 2-aminosulfonyIpheny1

14 CH2CO CH S02Et 1 , 4-phenylene 2-aminosulfonylphenyl

15 CH2CO CF3 1 , 4-phenylene 2-aminosulfonylphenyl

16 CH2CO CH3 1 , 4-phenylene 2-aminosulfonylphenyl

17 CH2CO H 1, 4-phenylene 2-aminosulfonylphenyl

1 CH2CH2 CH2OMe 1, 4-phenylene 2-aminosulfonyIphenyl

2 CH2CH2 CH2OEt 1, 4-phenylene 2-aminosulfonylphenyl

3 CH2CH2 CH20-n-Pr 1, 4-phenylene 2-aminosulfonyIpheny1

4 CH2CH2 CH20-i-Pr 1, 4-phenyiene 2 -aminosulfonylphenyl

5 CH2CH2 CH20-n-Bu 1, 4-phenylene 2-aminosulfonylphenyl

6 CH2CH2 CH20-i-Bu 1, 4-phenylene 2-aminosulfonylphenyl

7 CH2CH2 CH2Ph 1, 4-phenylene 2-aminosulfonylphenyl

8 CH2CH2 CH2-pyrazol- 1,4-phenylene 2-aminosulfonylphenyl
1-yl
9 CH2CH2 CH2-imidazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
10 CH2CH2 CH2-tetrazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl 11 CH2CH2 CH2-tetrazol- 1, 4-phenylene 2-aminosulfonylphenyl
2-yl
12 CH2CH2 CH2-triazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
13 CH2CH2 CH SEt 1, 4-phenylene 2-aminosulfonylphenyl 14 CH2CH2 CH2S02Et 1, 4-phenylene 2-aminosulfonylphenyl 15 CH2CH2 CF3 1, 4-phenylene 2-aminosulfonyIphenyl 16 CH2CH2 CH3 1, 4-phenylene 2-aminosulfonyIphenyl 17 CH CH2 H 1 , 4-phenyiene 2-aminosulfonylphenyl

1 S02NH CH2OMe 1,4-phenylene 2-aminosulfonyIphenyl

2 S02NH CH2OEt 1 , 4-phenyiene 2-aminosulfonylphenyl

3 S02 H CH20-n-Pr 1,4-phenylene 2-aminosulfonylphenyl

4 S0 NH CH20-i-Pr 1, 4-phenylene 2-aminosulfonylphenyl

5 S02NH CH20-n-Bu 1 , 4-phenyiene 2-aminosulfonylphenyl

6 S02NH CH20-i-Bu 1 , 4-phenylene 2-aminosulfonylphenyl

7 S02NH CH2Ph 1, 4-phenylene 2-aminosulfonylphenyl

8 S02NH CH2~pyrazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
9 S0 NH CH2-imidazol- 1 , 4-phenylene 2-aminosulfonylphenyl
1-yl
10 S02NH CH2-tetrazol- 1, 4-phenylene 2-aminosulfonylphenyl
1-yl
11 S02NH CH2-tetrazol- 1 , 4-phenylene 2 -aminosulfonylphenyl
2-yl
12 S02 H CH2-triazol- 1 , 4-phenylene 2 -aminosulfonyIpheny1
1-yl
13 S02NH CH2SEt 1 , 4-phenylene 2-aminosulfonyIphenyl

14 S0 NH CH2S02Et 1 , 4-phenylene 2 -aminosul fonylphenyl

15 S02 H CF3 1 , 4-phenyiene 2-aminosulfonylphenyl

16 SO2NH CH3 1, 4-phenylene 2-aminosulfonyIphenyl

17 S0NH H 1, 4-phenylene 2-aminosulfonylphenyl

S02CH2 CH OMe 1 , 4-phenylene 2 -aminosulfonylphenyl S02CH2 CH2OEt 1 , 4-phenylene 2-aminosulfonylphenyl S02CH2 CH20-n-Pr 1 , 4-phenylene 2-aminosulfonylphenyl S02CH2 CH 0-i-Pr 1, 4-phenylene 2-aminosulfonylphenyl S02CH2 CH20-n-Bu 1 , 4-phenylene 2-aminosulfonylphenyl 6 S02CH2 CH20-i-Bu 1 , 4-phenylene 2-aminosulfonylphenyl

7 S02CH2 CH2Ph 1 , 4-phenylene 2-aminosulfonyIphenyl

8 S02CH2 CH2-pyrazol- 1. , 4-phenylene 2-aminosulfonylphenyl
1-yl
9 S02CH2 CH2-imidazol- 1, , 4-phenylene 2-aminosulfonyIphenyl
1-yl
10 S02CH2 CH2-tetrazol- 1, , 4-phenylene 2-aminosulfonyIphenyl
1-yl
11 S02CH2 CH2-tetrazol- 1, , 4-phenylene 2-aminosulfonylphenyl
2-yl
12 S02CH2 CH -triazol- 1, , 4-phenylene 2 -aminosulfonylphenyl
1-yl
13 S02CH2 CH2ΞEt 1, ,4-phenylene 2-aminosulfonylphenyl

14 S0 CH2 CH2S02Et 1, , -phenylene 2-aminosulfonyIphenyl

15 S02CH2 CF3 1, , 4-phenylene 2-aminosulfonyIphenyl

16 S02CH2 CH3 1, , 4-phenylene 2-aminosulfonyIphenyl

17 S02CH2 H 1, , 4-phenylene 2-aminosulfonylphenyl

1 CH20 CH OMe 1, , 4-phenylene 2-aminosulfonyIpheny1

2 CH20 CH20Et 1, , 4-phenylene 2-aminosulfonylphenyl

3 CH20 CH20-n-Pr 1, ,4-phenylene 2-aminosulfonyIpheny1

4 CH20 CH20-i-Pr 1, , 4-phenylene 2-aminosulfonylphenyl

5 CH20 CH20-n-Bu 1, , 4-phenyiene 2-aminosulfonyIphenyl

6 CH 0 CH20-i-Bu 1, .4-phenylene 2-aminosulfonyIphenyl

7 CH20 CH Ph 1, , 4-phenyiene 2-aminosulfonylphenyl

8 CH20 CH -pyrazol- 1, 4-phenylene 2-aminosulfonyIphenyl
1-yl
9 CH20 CH2-imidazol- 1, 4-phenylene 2-aminosulfonyIphenyl
1-yl
10 CH20 CH2~tetrazol- 1, 4-phenylene 2-aminosulfonyIphenyl
1-yl
11 CH20 CH2-tetrazol- 1, 4-phenylene 2-aminosulfonyIpheny1
2-yl
12 CH20 CH2-triazol- 1, 4-phenylene 2-aminosulfonylphenyl
1-yl
13 CH20 CH2SEt 1, 4-phenylene 2-aminosulfonylphenyl

14 CH20 CH2S02Et 1, 4-phenylene 2-aminosulfonyIphenyl 15 CH20 CF3 1 , 4-phenylene 2 -aminosulf onylphenyl

16 CH20 CH3 1, 4 -phenylene 2 -aminosulf onylphenyl

17 CH20 H 1, 4-phenylene 2-aminosulf onylphenyl

TABLE 12


Cpd.# ■U-V-Z-D


TABLE 13

Cpd,
# n U-V-Z-D


1 0 C02Me
-Mc-rO~Q S02NH2




S SOO NH



37 0 0 CH=CHCONH- (CH2 ) 2 -4 - imidazole


TABLE 14 -


Cpd (CH2)nR2 (Z)u-D
1 CH2OMe phenyi 2-aminosulfonylphenyl

2 CH2OEt phenyi 2-aminosulfonylphenyl

3 CH20-n-Pr phenyi 2-aminosulfonylphenyl

4 CH20-i-Pr phenyi 2-aminosulfonylphenyl

5 CH20-n-Bu phenyi 2-aminosulfonylphenyl

6 CH20-i-Bu phenyi 2-aminosulfonylphenyl

7 CH2Ph phenyi 2-aminosulfonylphenyl

8 CH -pyrazol-l-yl phenyi 2-aminosulfonylphenyl

9 CH -imidazol-l-yl phenyi 2-aminosulfonylphenyl

10 CH -tetrazol-l-yl phenyi 2-aminosulfonylphenyl

11 CH2-tetrazol-2-yl phenyi 2-aminosulfonylphenyl

12 CH -triazol-l-yl phenyi 2-aminosulfonylphenyl

13 CH2SEt phenyi 2-aminosulfonylphenyl 14 CH2S02Et phenyi 2-aminosulfonylphenyl

15 CF3 phenyi 2-aminosulfonylphenyl

16 CH3 phenyi 2-aminosulfonylphenyl

17 H phenyi 2-aminosulfonylphenyl

TABLE 15



1-15

Cpd (CH2)nR2 V (Z)u-D

1 CH2OMe phenyi 2-aminosulfonylphenyl

2 CH2OEt phenyi 2-aminosulfonylphenyl

3 CH20-n-Pr phenyi 2-aminosulfonylphenyl

4 CH20-i-Pr phenyi 2-aminosulfonylphenyl

5 CH20-n-Bu phenyi 2-aminosulfonylphenyl

6 CH 0-i-Bu phenyi 2-aminosulfonylphenyl

7 CH2Ph phenyi 2-aminosulfonylphenyl

8 CH -pyrazoM-yl phenyi 2-aminosulfonylphenyl

9 CH -imidazol-l-yl phenyi 2-aminosnlfonylphenyl

10 CH -tetrazoH-yl phenyi 2-aminαsulfonylphenyl

11 CH -tetrazol-2-yl phenyi 2-aminosulfonylphenyl

12 CH2-triazol-l-yl phenyi 2-aminosulfonylphenyl

13 CH2SEt phenyi 2-aminosulfonylphenyl

14 CH2S02Et phenyi 2-aminosulfonylphenyl

15 CF3 phenyi 2-aminosulfonylphenyl

16 CH3 phenyi 2-aminosulfonylphenyl

17 H phenyi 2-aminosulfonylphenyl

TABLE 16

1-16

Cpd (CH2)„R2 V (Z)„-D

1 CH2OMe phenyi 2-aminosulfonylphenyl

2 CH2OEt phenyi 2-aminosulfonylphenyl

3 CH20-n-Pr phenyi 2-aminosulfonylphenyl

4 CH20-i-Pr phenyi 2-aminosulfonylphenyl

5 CH20-n-Bu phenyi 2-aminosulfonylphenyl

6 CH20-i-Bu phenyi 2-aminosulfonylphenyl

7 CH2Ph phenyi 2-aminosulfonylphenyl

8 CH -pyrazol-l-yl phenyi 2-aminosιιlfonylphenyl

9 CH - imidazol- 1-yl phenyi 2-aminosulfonylphenyl

10 CH -tetrazol-l-yl phenyi • 2-aminosulfonylphenyl

11 CH -tetrazol-2-yl phenyi 2-aminosulfonylphenyl

12 CH -triazol-l-yl phenyi 2-aminosulfonylphenyl

13 CH2SEt phenyi 2-aminosulfonylphenyl

14 CH2S02Et phenyi 2-aminosulfonylphenyl

15 CF3 phenyi 2-aminosulfonylphenyl

16 CH3 phenyi 2-aminosulfoπylphenyl

17 H phenyi 2-aminosulfonylphenyl

TABLE 17



1-17

Cpd (CH2)nR2 V (Z)u-D

1 CH2O e phenyi 2-aminosulfonylphenyl

2 CH2OEt phenyi 2-aminosulfonylphenyl

3 CH20-n-Pr phenyi 2-aminosulfonylphenyl

4 CH20-i-Pr phenyi 2-aminosulfonylphenyl 5 CH20-n-Bu phenyi 2-aminosulfonylphenyl

6 CH20-i-Bu phenyi 2-aminosulfonylphenyl

7 CH2Ph phenyi 2-aminosulfonylphenyl

8 CH2-pyrazol-l-yl phenyi 2-aminosulfonylphenyl

9 CH2- imidazol- 1-yl phenyi 2-aminosulfonylphenyl

10 CH2-tetrazol-l-yl phenyi 2-aminosulfonylphenyl

11 CH2-tetrazol-2-yl phenyi 2-aminosulfonylphenyl

12 CH2-triazol-l-yl phenyi 2-aminosulfonylphenyl

13 CH2SEt phenyi 2-aminosulfonylphenyl

14 CH2S02Et phenyi 2-aminosulfonylphenyl

15 CF3 phenyi 2-aminosulfonylphenyl

16 CH3 phenyi 2-aminosulfonylphenyl

17 H phenyi 2-aminosulfonylphenyl

TABLE 18


Cpd (CH2)nR2 V (Z)u-D

1 CH2OMe phenyi 2-aminosulfonylphenyl

2 CH2OEt phenyi 2-aminosulfonylphenyl

3 CH20-n-Pr phenyi 2-aminosulfonylphenyl

4 CH20-i-Pr phenyi 2-aminosulfonylphenyl

5 CH20-n-Bu phenyi 2-aminosulfonylphenyl

6 CH20-i-Bu phenyi 2-aminosulfonylphenyl

7 CH2Ph phenyi 2-aminosnlfonylphenyl

8 CH2-pyrazol-l-yl phenyi 2-aminosulfonylphenyl

9 CH -imidazol-l-yl phenyi 2-aminosulfonylphenyl

10 CH2-tetrazol-l-yl phenyi 2-aminosulfonylphenyl

11 CH2-tetrazol-2-yl phenyi 2-aminosulfonylphenyl

12 CH2-triazol-l-yl phenyi 2-aminosulfonylphenyl

13 CH2SEt phenyi 2-aminosulfonylphenyl

14 CH2S02Et phenyi 2-aminosulfonylphenyl 15 CF3 phenyi 2-aminosulfonylphenyl
16 CH3 phenyi 2-aminosulfonylphenyl
17 H phenyi 2-aminosulfonylphenyl

Utility

The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in 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, ischemic sudden death, transient ischemic 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 major practical role is the generation of thrombin by the limited proteolysis of prothrombin, 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 prothrombinase complex (Factor Xa, Factor V, Ca2+ and phospholipid) . Since it is calculated that one molecule of Factor Xa can generate 138 molecules of thrombin {Elodi , S. , Varadi , K. : Optimization of
conditions for the catalytic effect of the factor IXa-factor VIII COomplex: Probable role of the complex in the amplification 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 wers made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5 % PEG 8000. The Michaelis constant, Km, 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.

vo- s

s Ki (1 + s/κm)

where :
v0 is the velocity of the control in the absence of inhibitor;

vs 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 i.m.) and ketamine (110 mg/kg i.m.) 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 thrombolytic or fibrinolytic agents.
The compounds are administered to a mammal in a therapeutically effective amount. 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 in 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 heparin, as well as other Factor Xa inhibitors such as those described in 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, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, 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 ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include thromboxane-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 thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the
aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. Such inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. 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 boroarginine 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 fibrinolytic) agents (or thrombolytics or fibrinolytics) , as used herein, denotes agents that lyse blood clots (thrombi) . Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term
anistreplase, as used herein, refers to anisoylated plasminogen 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 urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

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 in 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.

Dosaαe 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 in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or
intramuscular form, all using dosage forms well known to those of ordinary skill in 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 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 g/kg/minute 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 intranasal form via topical use of suitable intranasal 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 in 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 in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as
cholesterol, stearylamine, 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,
polyhydroxypropyl ethacrylami e-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.
Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release o£ a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon
caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked 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. Antioxidizing 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 in 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.
Injectable
A parenteral composition suitable for
administration by injection is prepared by stirring 1.5% by weight of active ingredient in 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 in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit. Where the compounds of Formula I are administered in 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 "ormula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.
Where the compounds of Formula I are adminstered 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 in 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 in 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. TJJe polymer coating serves to form an additional barrier to interaction with the other component .