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

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[ EN ]

CLAIMS

1. Compounds of Formula I:

(U), V— (Z)u— (D)



(I)

including pharmaceutically acceptable salts and prodrug forms thereof, and all stereoisome *ric forms thereof and mixtures of such stereoisomeric forms, wherein:

U when present (i.e., when u=l) is selected from
-CO-NH-(CH2)o- -C0-(CH2)o- -S02-NH-(CH2)o- -S02-(CH2)o- -NHSO2- (CH2)0-' provided m ≠ 0
-NHC0-(CH2)o-' provided m ≠ 0
-NH-(CH2)o-/ provided m ≠ 0
-0-(CH2)o-> provided m ≠ 0
-S-(CH )0-/ provided m ≠ 0
-CH=CH-(CH2)0- X is 0, S, NR15

Y is selected from

R1 is selected from
(CH2)PNR5R6
C(NR1 )NR5Rβ
NHC(NR14)NR5Rβ
NHC(NR14)H
CONR5R6

R2 is selected from
H
Cι-C6 alkyl
Ci-Cζ alkoxy
C02R5
CONHR5
CONHCH2C02R5
CONH(CH2)q-R10
R10
CO-R5
COC02R5
COCONHR5
SOnR5
S02NHR5
NHR7
CH=CHC02R5
CH=CHCONHR5
0-(CH2)n-R10
SOn-(CH2)n-RlO
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(NR14)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-,
-SO2NHR4, 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, CH , SO, S02

R4 is selected from
H
Ci-Cδ alkyl
(CH2) n-phenyl
(CH2)n-CONHR5
(CH2) n-C0NHR5CH2CO2R5

R5 and R6 at each appearance are independently H
Cι-C6 alkyl
(CH2) n- henyl R7 is selected from H
Cι-C6 alkyl
S02R5
COR5
(CH2)r-R10
(CH2) n-phenyl

R8 is selected from

H
Ci-Cβ alkyl
halogen
N02
CF3
OR5

R9 is selected from

H
Cι-C6 alkyl
halogen
N02
NHR7
SO2NHR11
CF3
OR5
C02R5
CONR5R7
CN
(CH2)pNR5R6
C(NR1 )NR5R6
NHC(NR1 )NR5R6
NHC(NR14)H
SOn-R5
SOn-CF3 imidazole, pyrazole, 1, 2,3-triazole, 1,2,4-triazole and tetrazole, each optionally substituted with CF3, halogen, NO2, C1-C5 alkyl, or C1-C5
alkoxy;

R10 is selected from



R11 is selected from H
Cι-C6 alkyl
(CH2 ) n-phenyl
COR5
C02R5

R12 is selected from

H
Cι-C6 alkyl
C1-C6 alkoxy
halogen
N02
NHR7
CN

CF3
SONHR11

R13 is selected from H OH
C1-C10 alkyl
C1-C10 alkoxy nitro
halo
CF3

R14 is selected from H OH
C1-C10 alkyl
C1-C10 alkoxy CO2-C1-C10 alkyl
CO-C1-C10 alkyl
CONH-C1-C10 alkyl
CONH-phenyl
C02 (CH2) n-phenyl;

R15 is selected from
H
Ci-Cβ alkyl,
Ci-Cβ alkoxy
C02R14
CONHR14
CONHCH2C02R5
CONH(CH2)q-R10
(CH2)nR10
CO-R5
COCO2R5
COCONHR5
S02NHR5

at each appearance each of the following are
independently:
m = 0- -2
n = 0- - 4 except that in -SOn-, n = 0-2;
0 = 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.

Compounds of claim 1 wherein:

U is present and is selected from -C0-NH-(CH2)o- -C0-(CH2)o- -S02-NH-(CH2)o- -S02~(CH2)o- -NH-(CH2)o- -0-(CH2)o-

X is 0

Y is selected from


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

R2 iε selected from
H
Cι-C6 alkyl
Ci-Ce alkoxy
C0R5
CONHR5
CONHCH2C02R5
CONH(CH2)q-R10
R10
CO-R5 C0C02R5
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


Compounds of claim 2 wherein:

U is -CO-NH-(CH2;
Y is selected from


R1 is C(NR1 )NR5R6

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

4. Compounds of claim 3 having the structures of V and VI:


wherein

R1 is C (NR1 ) NR5R6 and

D is selected from


V is selected from the following:

5. A compound of claim 1 selected from the group consisting of the following compounds, including
pharmaceutically acceptable salt and prodrug forms thereof, and all stereoisomeric forms thereof and mixtures of such stereoisomeric forms:

3- (3-Amidinophenyl) -5- [ (2-naphthylsulfonyl)amino]methyl-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']-biphenyl-4-yl) methyl] aminocarbonyl] -5-(aminocarbonylmethyl) isoxazoline

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

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

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- (carbomethoxymethyl) isoxazoline

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

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

3- (3-amidinophenyl) -5- [ [ (4-pyrimidin-5-yl) piperidin-1-yl] carbonyl] -5- (carbomethoxymethyl) isoxazoline

3- (3-amidinophenyl) -5- [ (4-benzenesulfonylphenyl-1-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' ] -biphenyl-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- (carbomethoxymethyl) 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-y1) 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- (carbomethoxymethyl) 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']-bipheny1-4-yl ) aminocarbonyl] -5- (carboxyethy1) isoxazoline

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

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

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

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

3- (3-amidinophenyl) -5- [ (2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl) aminocarbonyl] -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) ethylaminocarbonylmethy1] isoxazoline

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- ( -amidinophenyl) -5- [ (2 ' -aminosulfonyl-3-fluoro- [1,1']-biphenyl-4-yl) aminocarbonyl] -5-(carbomethoxy ethy1) 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-y1] aminocarbonyl] -5- (carbomethoxymethyl) isoxazoline

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

3- (3-amidinophenyl) -5- [ [2- (2 ' -aminosulfonyIphenyl-1-y1 ) pyridin-5-y1] aminocarbonyl] -5-(aminocarbonylmethyl) isoxazoline

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

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

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

3- (3 -amidinophenyl ) -5- [ [5- (2 ' -aminosul fonylphenyl-1-yl ) yr idin- 2-yl] aminocarbonyl] -5- ( hydroxyethyl ) isoxazoline

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

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

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

3- (3-amidinophenyl) -5- [5- (2 ' -aminosulfonylphenyl-1-yl) pyridin-2-yl] aminocarbonyl-5-carbomethoxymethyl-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 ' -aminosulfonylphenyl-1-yl)pyridin-2-yl]aminocarbonyl-5- (tetrazol-1-yl) ethylisoxazoline

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

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

3- (3-amidinophenyl) -5- [5- (2 ' -trif uoromethylphenyl-1-yl)pyridin-2-yl] aminocarbonyl-5- (tetrazol-1-yl) methylisoxazoline

3- (3-amidinophenyl) -5- [5- (2 ' -trifluoromethylphenyl-1-yl)pyrimidin-2-yl] aminocarbonyl-5- (tetrazol-1-yl) methylisoxazoline

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

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

3- (3-amidinophenyl) -5- [2 ' -aminosulfonyl-3-flouro- [1,1' ] biphenyl-4-yl]aminocarbonyl-5- (tetrazol-1-yl) ethylisoxazoline 3- (3-amidinophenyl) -5- [2 ' -aminosulfonyl-3-chloro- [1,1']-bipheny1-4-y1] aminocarbonyl-5- (tetrazol-1-yl) ethyl-isoxazoline

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

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

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

3- (3-amidinophenyl) -5- [2 ' -methylsulfonyl-fluoro- [1,1']-bipheny1-4-y1] aminocarbonyl-5- (tetrazol-1-y1) ethyl-isoxazoline

3- (3-amidinophenyl) -5- [2 ' -methylsulfonyl-chloro- [1,1'] biphenyl-4-y1] aminocarbonyl-5- (te razol-1-yl) ethyl-isoxazoline 3- (3-amidinophenyl) -5- [2 ' -trifluoromethylsulfonyl- [1,1'; biphenyl-4-y1 ] aminocarbonyl-5- (tetrazol-1-y1 ) 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-yl) methyl-isoxazoline

3- (3-amidinophenyl) -5- [2 ' -aminosulfonyl- [1,1'] -biphenyl-4-yl] aminocarbonyl-5- (imidazol-1-yl) methyl-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-y1) aminocarbonyl-4-methoxymethyl-isoxazoline

6. Pharmaceutical composition comprising a
therapeutically effective amount of a compound of any of claims 1 through 5 and a pharmaceutically acceptable carrier.
7. A compound of any of claims 1 through 5, for use in a method of treating or preventing a thromboembolic disorder in a mammal which comprises administering to the mammal a therapeutically effective amount of the compound.

8. A composition of claim 6 substantially as herein described.

D ECEMBER 1996

S
A
EYS