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1. WO1997023212 - ISOXAZOLINE, ISOTHIAZOLINE AND PYRAZOLINE FACTOR Xa INHIBITORS

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[ EN ]

WE CLAIM :

1. Compounds of Formula I:


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

U when present (i.e., when u=1) is selected from
-CO-NH-(CH2)o- -CO-(CH2)o- -SO2-NH-(CH2)o- -SO2-(CH2)o- -NHSO2-(CH2)o- , provided m ≠ 0
-NHCO-(CH2)o-, provided m ≠ 0
-NH-(CH2)o-, provided m ≠ 0
-O-(CH2)o-, provided m ≠ 0
-S-(CH2)o-, provided m ≠ 0
-CH=CH-(CH2)o- X is O, S, NR15

Y is selected from

R1 is selected from
(CH2)PNR5R6
C(NR14)NR5R6
NHC(NR14)NR5R6
NHC(NR14)H
CONR5R6

R2 is selected from
H
C1-C6 alkyl
C1-C6 alkoxy
CO2R5
CONHR5
CONHCH2CO2R5
CONH(CH2)q-R10
R10
CO-R5
COCO2R5
COCONHR5
SOnR5
SO2NHR5
NHR7
CH=CHCO2R5
CH=CHCONHR5
O-(CH2)n-R10
SOn-(CH2)n-R10
NH-(CH2)n-R10

U and R2 taken together provide a spiro compound of formula IIa and IIb, or a compound of formula IIIa or IIIb:


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(NR14)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:



Z when present (i.e., when u = 1) is selected from a single bond,
-CO-,
-(CH2)t-,
-SOn-,
-SO2NHR4, provided D is absent
-NH-,
-NR7-,
-O-

D when present (i.e., when u = 1) is selected from



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

J is selected from O, NR7;

A is selected from CO, CH2, SO, SO2

R4 is selected from
H
C1-C6 alkyl
(CH2)n-phenyl
(CH2)n-CONHR5
(CH2)n-CONHR5CH2CO2R5

R5 and R6 at each appearance are independently H
C1-C6 alkyl
(CH2)n-phenyl R7 is selected from

H
C1-C6 alkyl
SO2R5
COR5
(CH2)r-R10
(CH2)n-phenyl

R8 is selected from

H
C1-C6 alkyl
halogen
NO2
CF3
OR5

R9 is selected from H
C1-C6 alkyl
halogen
NO2
NHR7
SO2NHR11
CF3
OR5
CO2R5
CONR5R7
CN
(CH2)pNR5R6
C(NR14)NR5R6
NHC(NR14)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
C1-C6 alkyl
(CH2)n-Phenyl
COR5
CO2R5

R12 is selected from

H
C1-C6 alkyl
C1-C6 alkoxy
halogen
NO2
NHR7
CN

CF3
SONHR11

R13 is selected from

H

OH
C1-C 1 0 alkyl
C1-C10 alkoxy nitro
halo
CF3

R14 is selected from H OH
C1-C 1 0 alkyl
C1-C10 alkoxy CO2-C1-C10 alkyl
CO-C1-C10 alkyl
CONH-C1-C10 alkyl
CONH-phenyl
CO2(CH2)n-phenyl;

R15 is selected from
H
C 1 -C6 alkyl,
C1-C6 alkoxy
CO2R14
CONHR14
CONHCH2CO2R5
CONH(CH2)q-R10
(CH2)nR10
CO-R5
COCO2R5
COCONHR5
SO2NHR5

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,

Y is
and V is
,
then at least one of R1 and R3 must be C(NR14)NR5R6
NHC(NR14)NR5R6 or
NHC(NR14)H.

Compounds of claim 1 wherein:

U is present and is selected from -CO-NH-(CH2)o- -CO-(CH2)o- -SO2-NH-(CH2)o- -SO2-(CH2)o- -NH-(CH2)o- -O-(CH2)o-

X is O

Y is selected from


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

R2 is selected from
H
C1-C6 alkyl
C1-C6 alkoxy
CO2R5
CONHR5
CONHCH2CO2R5
CONH(CH2)q-R10
R10
CO-R5 COCO2R5
COCONHR5
SOnR5
SO2NHR5
NHR7
CH=CHCO2R5
CH=CHCONHR5
O-(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


3. Compounds of claim 2 wherein:

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
-O- and -NR7-.

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



wherein

R1 is C(NR14)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[1-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)methylaminocarbonyl]-5-(carbomethoxymethyl)isoxazoline

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

3-(3-amidinophenyl)-5-[[(4-pyrimidin-5-yl)pipendin-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-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- (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']-biphenyl-4-yl)aminocarbonyl]-5-(carboxyethyl)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)pyrimidin-2-yl]aminocarbonyl]-5-(hydroxyethyl)isoxazoline

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

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

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

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

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)methyl-isoxazoline

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

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

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)methyl-isoxazoline

3-(3-amidinophenyl)-5-[2'-aminosulfonyl-3-flouro-[1,1']- biphenyl-4-yl]aminocarbonyl-5-(tetrazol-1-yl)methyl- 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)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'-methylaπμnosulfonyl-[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)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']-biphenyl-4-yl]aminocarbonyl-5-(tetrazol-1-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-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)-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-(lmidazol-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-yl)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 method of treating or preventing a thromboembolic disorder in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of any of claims 1 through 5.