CA2251394A1 - N-(amidinophenyl)-n'-(subst.)-3h-2,4-benzodiazepin-3-one derivatives as factor xa inhibitors - Google Patents

Abstract

The present application describes N-(amidinophenyl) cyclourea analogs of formula (I) which are useful as inhibitors of factor Xa.

Description

CA 022~l394 l998-l0-0~

W097138984 PCT~S97/06431 N-(AMIDINOPHENYL)-N'-(SUBST.)-3H-2,4-BENZODIAZEPIN-3-ONE DERIVATIVES
AS FACTOR XA INHIBITORS

FIELD OF THE INVENTION
This invention relates generally to N-~amidinophenyl~
cyclourea analogs which are inhibitors of factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION
Bovy et al, U.S. Patent No. 5, 430,043 describe phenyl amidines of the formula:

~ N~CO2R

which are reported to be platelet aggregation inhibitors.
However, no mention is made of inhibiting Factor Xa.
Himmelsbach et al, CA 2,105, 934, address cyclic ureas of the formula:
Rb--N~ ,N--Ra wherein, among the multitude of choices, X may be a carbonyl, Y may be an C2_4 alkylene, Ra may be A-B-C- and Rb may be -D-E-F. Group F is selected from -CO2R, phosphono, tetrazolyl, and 2~ RgCO-O-CHRg-O-CO-. The compounds described by the above formula are alleged to have aggregation inhibiting and/or fibrinogen binding properties. Factor Xa inhibiting is not discussed.
Lam et al, WO 94/19329, report cyclic carbonyls which may be cyclic ureas of the formula:

SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 o R22'N~N' R2R7a R4~R7 wherein at least one of R4, R4a, R7, and R7a is other than hydrogen. Compounds of this sort are said to be useful as HIV
protease inhibitors. N-(Amidinophenyl)cycloureas are not suggested as factor Xa inhibitors.
Currie et al, WO 96/36639, set forth amidine derivatives of the formula:
HLNI

NH2~~5L ~ HN X' wherein A may be a 6-membered cyclic urea, which may be useful as anti-platelet aggregation inhibitors. However, Y is nitrate, nitrite, or a nitric oxide donating group. The present compounds, in contrast, do not contain the nitric oxide donating groups of WO 96/36639.
Klinger et al, WO 94/21607, illustrate heterocyclic compounds of the formula:
,R R2 Z~ N~Y N ~CH2~W
A~B~z R3 wherein, upon judicious selection of variables, zl may be a carbonyl, A may be NR1, R1 may be an amidino-substituted phenyl, and B and z2 may each be CH2. However, the present compounds do not include the right-side chain shown above.
Mohan et al, WO 96/38421, describe N,N-di~arylmethyl)cyclic urea derivatives of the formula:

SUBSTITUTE SHEET (RULE 26) CA 022~1394 lsss-lo-o~

WO97/38984 PCT~S97/06431 N
R~ R7 wherein R7 and R8 may combine to form a benzene ring and the double bond shown may be absent, which may be useful as Factor Xa inhibitors. These compounds are preferably bis-amidino substituted. However, the presently claimed compounds are neither bis-benzyl nor bis-amidino substituted.
Chakravarty et al, WO 95/03044, discuss benzimidazoles substituted with phenoxyphenylacetic acid dervatives of the formula:
~ R16 ~12 R17 ~ N~o ~ R~' wherein R12 may be a substituted aryl group. But, this reference does not consider amidino-phenyl groups.
Furthermore, the present compounds do not contain the above variable Z, which is defined as a carbonyl, sulfonyl, or phosphoryl group.
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 amplif}ed 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, 5., Varadi, K.: Optimization of conditions for the catalytic - effect of the factor IXa-factor VIII Complex: Probable role of SU~ 1 UTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 the compl ex in th e ampl i fi ca t i on of bl ood coa gul a t i on .
Thromb. ~es. 1979, 15, 617-629), inhibition of factor Xa may be more efficient that inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.

SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel N-(amidinophenyl)cyclourea factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):

(p2) R1 R2a m D~r~ 1 ) n D~N~N--Z'A--B

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R1, R2, m and n are defined below, are effective factor Xa inhibitors.

SUBSTITUTE SHEET(RULE26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 DETAILED DESCRIPTION OF PREFERRED EMBO~IMENTS
[1] Thus, in a first embodiment, the present invention provides novel com~ounds of formula I:

R1 2 (F2)m D ~ \ ~ ~ ~)n D ~ N ~ N z,A ~ B
O
I

or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein;

one of D and D' is selected from CN, C(=NRll)NR12R13, NHC(=NRll)NRl2Rl3 NR12cH(=NR~ C(o)NR12R13, and (CH2)tNRl2Rl3 and the other is Hi Rl is selected from H, (CH2)roR3~ halo, Cl 4 alkyl, (CH2)rNR4R4 , (CH2)rCO2H, (CH2)rC(=o)R4~ (CH2)rNR4C(=o)R4 (CH2)rSo2R5~ and (CH2)rNR4So2R5i R2 is selected from H, =O, Cl_4 alkyl substituted with 0, 1, or 2 R7, C2_6 alkenyl substituted with 0, 1, or 2 R7, (CH2)roR3/ (CH2)rC(o)R4/ (CH2)roC(o)R4~ (CH2)rNR3R3 , (CH2)rNR3C(o)R4, (CH2)rSo2R5~ (CH2)rNR3So2R5, C3_10 carbocyclic residue substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;

R2a is absent;

alternatively, R2 and R2a may be present on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R10 or a 5-6 membered aromatic heterocycle containing 0-2 heteratoms selected from the group consisting of N, O, and S and substituted with 0-2 RlOai SUBSTITUTE SH'EET(RULE26) CA 022~1394 1998-lO-0~

W097138984 PCT~US97/06431 R3 and R3 are independently selected from H, Cl_4 alkyl, benzyl and phenyli R3 and R3 may be taken together to form a 5 or 6 membered ring substituted with 0-2 R6;

R4 and R4 are independently selected from H, oR3, Cl_4 alkyl, phenyl and NR3R3 ;

R5 is selected from Cl_4 alkyl, phenyl and NR3R3 ;

Z is selected from a bond, Cl_~ alkylene, (CH2) r~tCH2)r, (CH2)2NR3(CH2)r, (CH2)rC(O) (CH2)r, (CH2)rC(O)O(CH2)r, (CH2)20C(0)(CH2)r, (cH2)rc(o)NR3(cH2) (CH2)2NR3C(o)(CH2) r, (cH2)2oc(o)o(cH2)r~
(CH2)2oC(o)NR3(cH2)r~ (CH2)2NR3C(o)o(CH2)r, (CH2)2NR3C(o)NR3(CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSo2NR3(cH2)r~ (CH2)2NR3So2(CH2)r, and (CH2)2NR3SO2NR3(CH2)ri A is selected from:
C3_l0 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R6;

B is selected from:
X-Y, NR3R3 , C(o)NR3R3 , S02NR3R3 , benzyl substituted with 0-2 R6, C3_10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R6;

X is selected from Cl_4 alkylene, -C(O)-, -C(o)CR3R3 -, -CR3R3 C(O)-, -C(O)0-, -C(o)oCR3R3 -, -CR3R3 C(O)O-, -OC(O)-, -oC(o)CR3R3 -, -CR3R3'oC(o)- -S(O) --S(o)pCR3R3 -, -CR3R3 S(O)p-, -S(0)2NR3-, -NR3S(0)2-, SUBSTITUTE SHEET (RULE 26) , . . ~ . , CA 022~1394 1998-lO-0~

W097/38984 PCT~S97/06431 -NR3S(o)2CR3R3 -, -CR3R3 S(0)2NR3-, -NR3S(0)2NR3-, -C(o)NR3-, -NR3C(o)-, -C(o)NR3CR3R3 -, -NR3C~o)CR3R3 -, -CR3R3 C(o)NR3-, -CR3R3 NR3C(o)-, -NR3C(o)o-, -oC(o)NR3-, -NR3C(o)NR3-, -NR3-, -NR3CR3R3 -, -CR3R3 NR3-, O, -CR3R3'o-, -oCR3R3 -, S, -CR3R3 S-, and -SCR3R3 -;

Y is selected from:
Cl_4 alkyl substituted with 0-2 R6 C3_10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R6;

R6 is selected from H, OH, CF3, (CH2)noR3~ halo, Cl 4 alkyl, CN, NO2, ~CH2)rNR3R3 ,(CH2)rC(o)R3, NR3C(o)R3 , NR3C(o)NR3R3 , So2NR3R3 , NR3So2NR3R3 , NR3So2-cl-4 alkyl, SO2-phenyl, and NR3So2R8;

R7 is selected from:
C3_10 carbocyclic residue substituted with 0-2 R6i and, 5-10 membered heterocyclic system cont~in'ng from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R6;

R8 is selected from:
C3_10 carbocyclic residue substituted with 0-2 R9; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R9;
R9 is selected from H, OH, (CH2)noR3~ halo, Cl_4 alkyl, CN, NO2, (CH2 ) rNR3R3, (CH2 ) rC (O) R3 ~ NR3C (o) R3, NR3C (o) NR3R3, So2NR3R3 , NR3So2NR3R3 , and NR3So2-Cl_4 alkyl;

R10 is selected from H, oR3, halo, Cl_4 alkyl, CN, NO2, NR3R3 , NR3C~o)R3 , NR3C(o)oR3 , NR3SO2-phenyl, and NR3So2-Cl_4 alkyl;

SUBSTITUTE SHEET(RULE26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 Rl0a if a substituent on nitrogen is selected from H and Cl_4 alkyl;

Rl0a if a substituent on carbon is selected from H, Cl_4 alkyl, MR3R3 , NR3C(o)R3 , NR3C(o)oR3 , NR3S02-phenyl, and NR3So2-Cl_4 alkyl;

Rll is selected from H, OH, Cl_6 alkyl, Cl_6 a~kylcarbonyl, Cl_6 alkoxy, Cl_4 alkoxycarbonyl, C6-lo aryloxy, C6-lo aryloxycarbonyl, C6_l0 arylmethylcarbonyl, Cl_4 alkylcarbonyloxy Cl_4 alkoxycarbonyl, C6_l0 arylcarbonyloxy Cl_4 alkoxycarbonyl, Cl_6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl Cl_4 alkoxycarbonyl;
Rl2 is selected from H, Cl_6 alkyl and (CH2)n-phenyl;

Rl3 is selected from H, Cl_6 alkyl and (CH2)n-phenyl;

n is selected from 0, l, 2, and 3;

m is selected from 0 and li p is selected from 0, l, and 2;
q is selected from l, 2, 3, 4, and 5; and, r is selected from 0, l, and 2.

[2] In a preferred embodiment, the present invention provides compounds o~ formula I wherein:

D is C(=NH)NH2 D' is Hi SUBSTITUTE SHEET (RULE 26) CA 022~1394 1sss-1o-o~

W097/38984 PCT~S97/06431 Rl is selected from H, (CH2)roR3, halo, (CH2)rNR4R4 , (CH2)rC02H, (CH2)rC(=o)R4, (CH2)rNR4C(=o)R4~ (CH2)rS02RS, and ICH2)rNHSO2R5i R2 is selected from H, =O, (CH2)roR3~ (CH2)rC(o)R4, (CH2)roC(o)R4~ (CH2)rNR3R3 , (CH2)rNR3C(o)R4~ (CH2)rSo2R5~
(CH2)rNR3So2R5~ C3_l0 carbocyclic residue substituted with 0-2 R6; and, 5-lO membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;

R4 and R4 are independently selected from H, oR3, Cl_4 alkyl, and NR3R3 ;

R5 is selected from Cl_4 alkyl and NR3R3 ;

Z is selected from a bond, Cl-4 alkylene, (CH2)rC(O)(CH2)r, (CH2)rC(o)NR3(CH2)r, (CH2)2NR3C(o) (CH2)r, (CH2)2oc(o)NR3(cH2)r~ (CH2)2NR3C(o)o(CH2)r, (cH2)2NR3c(o)NR3(cH2)r~ (cH2)rs(o)p(cH2)r~
(CH2)rSo2NR3(CH2)r, (CH2)2NR3So2(CH2)r, and (CH2)2NR3So2NR3(cH2)r; and, X is selected from Cl 4 alkylene, -C(O)-, -C(o)CR3R3 -, -CR3R3 C(O)-, -C(O)O-, -C(o)oCR3R3 -, -CR3R3 C(O)O-, -OC(O)-, -oC(o)CR3R3 -, -CR3R3 OC(O)-, -S(O)p-, -S(o)pCR3R3 -, -CR3R3 S(O)p-, -S(0)2NR3-, -C(o)NR3-, -NR3C(o)-, -NR3C(o)o-, -oC(o)NR3-, -NR3C(o)NR3-, -NR3-, -NR3CR3R3 -, -CR3R3 NR3-, O, -CR3R3'o- and -oCR3R3' [3] In a more preferred embodiment, the present invention provides compounds of formula I wherein:

Rl is selected from H, oR3, (CH2)0R3, halo, NR4R4 , (CH2)NR4R4 , C(=o)R4, (CH2)C(=o)R4, NHC(=o)R4, (CH2)NHC(=o)R4, So2R5, (CH2)So2R5, NHSo2R5, and (CH2)NHSo2R5;

SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 R2 is selected from H, =O, oR3, C(o)R4, (CH2)C(o)R4, oC(o)R4, NR4R4 , NR3C(o)R4, and NR4So2R5;

A is selected from:
C5-6 carbocyclic residue substituted with 0-1 R6, and 5-6 membered heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N and O
substituted with 0-1 R6;

B is selected from: Y, X-Y, and NR2R2a;

Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, l,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, l,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, l,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, isoindazole, and benzothiadiazole;
Y may also be selected from the following bicyclic heteroaryl ring systems:

~C N R ~ R4 N~ R4 R4~ ) N~N~ R4 ~11 K is selected from O, S, NH, and N;

SUBSTITUTE SHEET (RULE 26) CA 022~1394 1sss-1o-o~

W097/38984 PCT~S97/06431 X is selected from -CH2-, -C(O)-, -C(o)CHR3-, -CHR3C(o)-, -S(O)p-, -S(C)pCR3R3 -, -CHR3S(C)p-, -S(o)2NR3-, -C(o)NR3-, -NR3C(o)-, -NR3-, -NR3CHR3-, and -CHR3NR3;

R6 is selected from H, OH, CF3, (CH2)noR3~ halo, Cl_4 alkyl, CN, N02 , ( CH2 ) rNR3R3, ( CH2 ) rC ( O ) R3 ~ NR3C ( o ) R3, So2NR3R3, S02 -phenyl, NR3So2-Cl_4 alkyl, and NR3So2R8;

R8 is selected from:
Cs_6 carbocyclic residue substituted with 0-2 R9; and, 5-6 membered heterocyclic system cont~;ning from l-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R9;

R9 is selected from H, OH, (CH2)noR3~ halo, Cl_~ alkyl, CN, NO2, (CH2)rNR3R3 ,(CH2)rC(o)R3, NR3C(o)R3 , NR3C(o)NR3R3 , So2NR3R3 , NR3So2NR3R3 , and NR3So2-cl-4 alkyl; and, p is 2.

[4] In an even more preferred embodiment, the present invention provides compounds of formula I wherein:

Z is selected from a bond, Cl_4 alkylene, (CH2)rC(O)(CH2)r, (CH2) rC (o)NR3 (CH2) r/ (CH2) 2NR3C (O) (CH2) r/
(CH2)2NR3C(o)NR3(CH2)r, and (CH2)rS(CH2)r;

X is selected from -CH2-, -C(O)-, -C(O) CHR3-, -CHR3C(o)-, -S(O)p-, -S(o)pCR3R3 -, -CHR3S(o)p-, -S(o)2NR3-/ -C(o)NR3-, and -NR3C(o)-;

R6 is selected from H, OH, CF3, (CH2)noR3~ halo, Cl_4 alkyl, CN, NO2, (CH2)rNR3R3 ,(CH2)rC(o)R3, NR3C(o)R3 , So2NR3R3 , SO2-phenyl, and NR3So2-Cl_4 alkyl;

m is l; and, SU~S 111 UTE SHEET (RULE 26) .... .. . . . . . . . . .. ...... . .

CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 r is selected from 0 and l.

[5] In a further preferred embodiment, the present invention provides compounds of formula I wherein:

R3 and R3 are independently selected from H and Cl_4 alkyl;

Z is selected from a bond, Cl_4 alkylene, (CH2)rC(o)NR3(CH2) (CH2)2NR3C(o)(cH2)r~ and (CH232NR3C(o)NR3(CH2)r;

A is selected from phenyl substituted with 0-l R6 and a 6 membered heterocyclic system containing l N and 0-l O
atoms and substituted with 0-l R6;
X is selected from -CH2-, -S(O)p-, -S(O) pCR3R3 -, -S (O) 2NR3-, -C (O) NR3-, and ;

Y is selected from phenyl, i-propyl, quinolynyl, thiadizolyl, benzothiadiazolyl, thiophenyl, pyridyl, cyclohexyl, and naphthyl, each of which is substituted with 0-2 R6; and, n is selected from 0, l, and 2.

[6] In an even further preferred embodiment, the present invention provides compounds of formula I wherein:

R3 and R3' are independently selected from H and methyl;
Z is selected from a bond, CH2, -CH2CH2-, -CH2CH2CH2- and -CH2CH2CH2CH2-;

A is selected from phenyl substituted with 0-l R6, and piperidinyl substituted with 0-l R6; and, n is 2.

SUBSTITUTE SHEET(RUEE26) .... .

CA 022~1394 1sss-1o-o~

W097t38984 PCT~S97/06431 [7] In a particularly preferred embodiment, the present invention provides compounds selected from:

N-( 3-amidinophenyl)-N'-(( 4-((2-sulphonamido)phenyl)phenyl)-methyl)cycloheptylureai N-( 3-amidinophenyl)-N'-(l-benzylpiperidin-4-yl) cycloheptylurea;
N-( 3-amidinophenyl)-N'-(l-(picolin-2-yl)piperidin-4-yl) cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-(picolin-3-yl)piperidin-4-yl) cycloheptylurea;

N-( 3-amidinophenyl)-N'-(l- (picolin-4-yl)piperidin-4-yl) cycloheptylurea;

N- (3-amidinophenyl) -N'-(l- (a-phenethyl)piperidin-4-yl)cyclo-heptylurea;

N-(3-amidinophenyl)-N'-(l-((phenyl)methane)sulfonyl)-piperi-din-4-yl)cycloheptylurea N-(3-amidinophenyl) -N'-(l- (phenyl)sulfonylpiperidin-4-yl)-cycloheptylurea;

N-(3-amidinophenyl) -N'-(l- (quinolin-8-yl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-~3-amidinophenyl) -N'-(l- (2-fluorophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;
~5 N-(3-amidinophenyl) -N'-(l- (4-acetamidophenyl)sulfonyl-piperidin-4-yl)cycloheptylurea;

SUBSTITUTE SHEET(RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 N-(3-amidinophenyl)-N'~ (2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(3-aminophenyl)sulfonylpiperidin-4-5yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(4-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((2-aminophenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((2-acetamido-phenyl)methane~-sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(l-((thiophen-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((5-chlorothiophen-2-yl)sulfonyl)-20piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((5-carbomethoxythiophen-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

25N-(3-amidinophenyl)-N'-(l-((benzo-2,1,3-thiadiazo-4-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-((cyclohexyl)sulfamido)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(l-((isopropyl)sulfamido)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-((phenyl)sulfamido)piperidin-4-35yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-((isopropyl)sulfonyl)piperidin-4-yl)cycloheptylurea;

SIJ~S 111 U TE SHEET (RULE 26) CA 022~1394 1998-10-0~

WO 97/38984 rcT/usg7/06431 N-(3-amidinophenyl)-N'-(1-((5-amino-4-methylthiazol-2-yl)sulfonyl)piperidin-4-yl)cycloheptylureai N-(3-amidinophenyl)-N'-(1-((5-acetamido-4-methylthiazol-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(6-carbomethoxyphenyl-sulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(2-pyridylmethyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(3-pyridylmethyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(4-pyridylmethyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(phenyl-N''-methylsulfamido)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-((4-phenylsulfonylthiophen-2-yl)sulfonyl)-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(4-pyridylmethylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(thiophen-2-ylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(4-fluorobenzylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-~3-amidinophenyl)-N'-(2-pyridylsulfonyl)piperidin-4-yl)cycloheptylurea;

SlJtlS i 11 UTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 N-(3-amidinophenyl)-N'-(2-trifluormethyl-phenylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(2-phenylisopropylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-((l-((phenyl)-l,l-dimethyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(methyl((phenyl-methane)carbamide)morpholin-3-yl))cycloheptylurea;

N-(3-amidinophenyl)-N'-(methyl((thiophen-2-yl)sulfonyl)morpholin-3-yl))cycloheptylurea N-(3-amidinophenyl)-N'-(methyl((phenyl-methane)sulfonyl)morpholin-3-yl))cycloheptylurea N-(3-amidinophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptylureai N-(3-amidinophenyl)-N'-((N-(benzyl)sulfonyl)-piperidin-3-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-((N-(thiophen-2-yl)sulfonyl)piperidin-3-yl)cycloheptylureai N-(3-amidinophenyl)-N'-(4-(2-sulfonamido-phenyl)phenyl)cycloheptylureai N-(3-amidinophenyl)-N'-(5-(2-sulfonamido-phenyl)pyridin-2-yl)cycloheptylurea; and, ~5 N-(3-amidinophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea;

SU~51ll~TE SHEET (RULE 26) CA 022~1394 1sss-1o-o~

W097/38984 PCT~S97/06431 or stereoisomers or pharmaceutically accepta~le salt forms thereof.

[8] In another preferred embodiment, the present invention provides compounds wherein:

n is 2; and, ~O R2 and R2a are on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 RlO or a 5-6 membered aromatic heterocycle containing 0-2 heteratoms selected from the group consisting of N, O, and S and substituted with 0-2 RlOa [9] In another more preferred embodiment, the present invention provides novel compounds of formula II:

D ~ N ~ N z- B
~
II
or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein;
~5 ring N contains 0-2 N atoms and is substituted with 0-2 RlO;
and, D is selected from CN, C(=NRll)NRl2Rl3~ NHC(=NRll)NRl2Rl3 NRl2CH(=NRll) C(o)NRl2Rl3~ and (CH2)tNRl2Rl3-[lO] In another even more preferred embodiment, the present invention provides compounds of formula II wherein:

SUtl:j 111 UTE SHEET (RULE 26) CA 022~1394 1998-lO-0~

W097/38984 PCTrUS97/06431 D is C(=NH)NH2;

Rl is selected from H, (CH2)roR3l halo, (CH2)rNR4R4 , (CH2)rCO2H, (CH2)rC~=O)R4~ (cH2)rNR4c(=o)R4~ (CH2)rSo2R5 and ( CH2)rNHSo2R5;

R4 and R4 are independently selected from H, oR3, C1_4 alkyl, and NR3R3 ;

R5 is selected from Cl_4 alkyl and NR3R3 ;

Z is selected from a bond, C1_4 alkylene, (CH2)rC(O)(CH2)r, (CH2)rC(o)NR3(cH2)r~ (CH2)2NR3C(o) (CH2)r, (CH2)2oc(o)NR3(cH2)r~ (CH2)2NR3C(o)o(cH2)r~
(CH2)2NR3C(o)NR3(CH2)r~ (cH2)rs~o)p(cH2)r~ and (CH2)rSo2NR3(CH2)ri and, X is selected from Cl_4 alkylene, -C(O)-, -C(O) CR3R3 -, -CR3R3 C(O)-, -C(O)O-, -C(o)oCR3R3 -, -CR3R3 C(O)O-, -OC(O)-, -oC(o)CR3R3 -, -CR3R3 OC(O)-, -S(O)p-, -S(o)pCR3R3 -, -CR3R3 S(O)p-, -C(o)NR3-, -NR3C(o)-, -NR3C(o)o-, -oC(o)NR3-, -NR3C(o)NR3-, -NR3- -NR3CR3R3'--CR3R3 NR3-, O, -CR3R3 O-, and -3CR3R3 -.

~11] In another further preferred embodiment, the present invention provides compounds of formula II, wherein:

30 Z is selected from a bond, C1_4 alkylene, C(o)NR3(cH2)r~ S(0)2, S(0)2CH2, and (CH2)rSo2NR3(cH2)r;

A is selected from phenyl substituted with 0-1 R6 and 6 membered heterocyclic system containing 1 N and substituted with 0-1 R6; and, SUBSTITUTE SHEET(RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 X is selected from C1 4 alkylene, -C(O)-, -C(O) CR3R3 -, -CR3R3 C (O) -, -S (O) p-, -S (O) pCR3R3 -, -C (O) NR3-, and, -NR3-[12] In another even further preferred embodiment, the present invention provides compounds selected from:

1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;

1,2,4,5-tetrahydro-2-(thiopen-2-yl)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;

1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one; and, 1,2,4,5-tetrahydro-2-(thiophen-2-yl)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one.

In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.

In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.

SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-0~

DEFINITIONS
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom 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 synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., =O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, "Cl_6 alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyli "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the ~ike.
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, "carbocycle" or "carbocyclic residuell is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which SUOSTITUTE SHEET (RULE 26 CA 022~1394 1sss-1o-o~

W097l38984 PCT~S97/06431 results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S
and O atoms in the heterocycle exceeds l, then these heteroatoms are not adjacent to one another. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to lO-membered bicyclic heterocyclic aromatic ring which consists ofcarbon atoms and from l to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the heterocycle is not more than l.
Examples of heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H,6H-l,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-l,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, benzothiadiazolyl, carbazolyl, 4aH-carbazolyl, ~-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, l,2,3-oxadiazolyl, l,2,4-oxadiazolyl, l,2,5-oxadiazolyl, l,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, l,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, l,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoy~. Also included are fused ring and spiro compounds containing, for exam.ple, the above heterocycles.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and ~nim~ls without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound 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, SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid 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.
"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a m~mm~l ian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is ~;n;stered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl 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. Preferred prodrugs are amidine prodrugs whereïn D is C(=NRll)NH2, and Rll is selected from OH, Cl_4 alkoxy, C6_10 aryloxy, Cl_4 alkoxycarbonyl, C6_l0 aryloxycarbonyl, C6_10 arylmethylcarbonyl, Cl_4 alkylcarbonyloxy Cl_4 alkoxycarbonyl, and C6_l0 arylcarbonyloxy Cl_4 alkoxycarbonyl. More preferred SUBSTITUTE SHEET(RULE 26) CA 022~1394 1998-10-0~

WO97/38984 PCT~S97/06431 prodrugs are where Rll is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

SYNTHESIS
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 methods described below. Each of the references cited below are hereby incorporated herein by reference. All the temperatures are reported herein in degrees Celsius.
The compounds of Formula ~ can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the SUBSTITUTE SHEET (RULE 26) trained practitioner is Greene and Wuts (~rotective Groups In Organic Synthesis, Wiley and Sons, 1991).
Two general approaches can be used for the preparation of the cyclic ureas of this invention. The first involves bimolecular cyclizations to the cyclic urea, as outlined in Scheme I, the second uses the internal unimolecular cyclizations of Scheme II.

SUBSTITUTE SHEET (RULE 26) WO 97t38984 PCT/US97/06431 Scheme I: Bimolecular cyclization routes to a cyclic urea precursor to Fo Route A

~NCO ~ NH2 H2N \ / OCN
~Z-A-B \,~ OR ~/ Z-A-B

'1~ \ L.G\~H2)n L.G.

\~ (R2)m R ~\--(CH2)n ~N~N~

Route B
/~ Cyclic urea precursor (R2) / to Formulal R1 ~ CH2)n / O
r ~NH HN~
Q~ Z-A-B L.G L.G.~

(R2)m R1 ~\ (CH2)n ~ OR r~N~ G
Q~ P.G. + H2N~z A B
R1 (R2)m P G'l~Z A B

SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 Route A of Scheme I illustrates the bis-alkylation of an N,N'-disubstituted urea with an alkane substituted at both termini with an appropriate leaving group (L.G.), such as a halogen or sulfonate ester. The flexibility of this approach also allows for the bis-alkylation with an alkene or R2-substituted alkane which is again substituted at both termini with an appropriate leaving group (L.G.). Such alkylation agents are either commercially available, e.g. 1,4-dibromobutane and its lower homologs, found in the literature, e.g. the isopropylidene ether of 1,4-diiodido-2,3-dihydroxybutane (Deluca and Magnus, J. Chem. Soc. ( Perkin Trans. I), 2661(1991), and Hoye and Suhadolnik, Tetrahedron, 42 (11) 2855 (1986)), or can be prepared by a practitioner skilled in the art using standard chemical methods.
The N,N'-disubstituted urea can be generated from two primary amines, one of which must be a Q,R1-substituted aniline wherein Q is a functional group from which an amidine could be readily generated such as nitrile; in some special cases Q may be tolerated as a mono- or di- acyl or carbamoyl protected amidine. The second primary amine, H2N-Z-A-B, may be any amine deemed appropriate within the limits of Formula 1. This amine may be commercially available, e.g.
1-benzyl-4-aminopiperidine, found in the literature, e.g. 1-t-butoxycabonyl-4-aminopiperidine (Mach et al.,~. Med. C~em., 36(23), 3707 (1993)), or can be prepared by a practitioner skilled in the art utilizing standard chemical methods.
The two primary amines described above can be assembled to the desired N,N'-disubstituted urea by selecting one for transformation to the corresponding isocyanate in situ by stirring with phosgene or its equivalent such as trichloromethyl chloroformate or p-nitrophenylchloroformate in the presence of a trialkylamine base and a dry, aprotic solvent such as dimethylformamide, dioxane, benzene or a chlorinated alkane. The temperature of this reaction may be varied from -10 C to the reflux point of the solvent (Takeda et al., Tetrahedron Lett., 24(42) 4569 (1983), Cortez et al., Synth. Commun., 21(2) 285 (1991)). Alternatively the desired isocyanate may be commercially available, such as SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 3-cyanophenyl isocyanate, in which case convenience dictates that this substrate be used. Conditions for direct reaction of a preformed isocyanate are similar to those described above with the caveat that the phosgene equivalent is necessary, and the trialkylamine base may be omitted (Shiau et al., J.
Heterocyclic Chem., 26, 595(1989)).
Ring formation in Route A is achieved by alkylation of the N,N'-disubstituted urea with the dihalogenated (Curtis, Aust. J. Chem., 41 585 (1988), Htay et al., Tetrahedron Lett., 79 (1976), Sulsky et al., Synth. Commun., 19, 1871 (1989)) or disulfonated (Ayyana et al., Chem. Ind. (London), 599 (1988)) alkylating agent described above. Typically, the disubstituted urea is added at ambient temperature or lower to a mixture of at least two equivalents of strong base such as sodium hydride, potassium t-butoxide or an alkyl lithium in an appropriate anhydrous solvent such as tetrahydrofuran, dimethylformamide, t-butanol, toluene or dimethylsulfoxide.
After deprotonation is complete, a solution of the alkylating agent in the selected solvent is added slowly to the disubstituted urea at ambient temperature or lower; when the addition is completed, the reaction may be continued at ambient temperature or lower or heated up to the reflux temperature of the solvent, depending upon the reactivity of the alkylating agent/disubstituted urea pair and the patience of the practitioner.
Route B of Scheme I illustrates use of an appropriately substituted diamine and phosgene or its equivalent to generate a cyclic urea precursor to Formula 1. The required diamine can be generated by two approaches. The first approach utilizes a Q,R1-substituted aniline which is conjoined with an N-acyl or N-carbamoyl protected secondary amine where G is a halogen or sulfonate ester leaving group for a standard alkylation of the Q,R1-substituted aniline or G could be an aldehyde suitable for reductive alkylation of the Q,R1-substituted aniline. The second approach to diamine formationconjoins an N-acyl or N-carbamoyl protected N-alkylated Q,R1-substituted aniline, where G is as described above, with primary amine H2N-Z-A-B by a standard or reductive alkylation.

SUBSTITUTE SHEET(RULE26) .. , . . , . . . .. ~ ....

CA 022~l394 lsss-lo-o~

WO97/38984 PCT~S97/06431 Both protected secondary amines are available by similar chemistry. The selected aniline or primary amine H2N-Z-A-B is protected with a N-acyl or N-carbamoyl protecting group according to a method specified in Greene and Wuts; N-t-butoxy carbamoyl is useful for this application. This protected amine can then be cleanly mono-alkylated with one of the dihalogenated or disulfonylated alkylating agents recommended for Route A (Reed et al., Tetrahedron Lett., 79 (45) 5725 (19~8)). Alternatively, the protected amine can be mono-alkylated with a protected halo alcohol. Both alkylations arereadily achieved in anhydrous aprotic solvents such as toluene, tetrahydrofuran, dimethylformamide or dimethylsulfoxide at temperatures ranging from -78 C to the reflux temperature of the selected solvent with a strong base such as sodium hydride, potassium t-butoxide or an alkyl lithium. In the case where G is a protected alcohol, the protecting group is removed and an aldehyde generated by Moffatt oxidation (Pfitzner and Moffatt, J. Amer. Chem. Soc., 87 5661 (1965)) or through use of pyridinium chlorochromate (Corey and Suggs, Tetrahedron Lett., 2647 (1975)) or pyridinium dichromate in dichloromethane (Coates and Corrigan, Chem. Ind. ~London), 1594 (1969)).
The required diamine can then be prepared by stirring the alkylating agent with the primary amine component either neat or in an aprotic solvent such as toluene, tetrahydrofuran, dimethylformamide or dimethylsulfoxide. The temperature of this reaction may range from -78 C to the reflux temperature of the selected solvent. A strong base such as sodium hydride, potassium t-butoxide or an alkyl lithium or a weaker trialkylamine base may be used, depending upon the reactivity of the two components. As an alternative, when G is an aldehyde, a reductive alkylation of the primary amine component is possible. The direct method involves the use of a borohydride reducing agent, most preferably sodium or lithium cyanoborohydride, in a mixture of aldehyde and amine components in an alcoholic solvent (Borch et al., J. Amer.
Chem. Soc., 93 2897 (1971)). A stepwise method involves generation of an intermediate imine/enamine by azeotropic S(J~ ITE SHEET (RULE 26) CA 022~1394 lsss-lo-o~

W097l38984 PCT~S97/06431 removal of water from a heated mixture of aldehyde and primary amine component in a suitable solvent such as benzene at reflux temperature. The imine/~n~mine intermediate can then be isolated and reduced by palladium catalyst under an atmosphere of hydrogen gas at ambient pressure or higher or reduced by borohydride reagents under conditions similar to those preferred for the direct method. The required diamine is generated by removal of the protecting group according to a method recommended in Greene and Wuts.
The diamine formed above is reacted with phosgene or its equivalent such as trichloromethyl chloroformate or p-nitrophenylchloroformate in the presence of an excess of a trialkylamine base and a dry, aprotic solvent such as dimethylformamide, dioxane, toluene, benzene or a chlorinated alkane to form a cyclic urea precursor to Formula 1. The temperature of this reaction may be varied from -10 C to the reflux point of the solvent.

SUBSTITUTE SHEET(RULE 26) . . . . . ..

CA 0225l394 l998-l0-05 W097/38984 PCT~S97/06431 .C~h ~ UnLmolecular cyclization routes to cyclic urea precursors to Formula l.
Route C (R2) Rl Rl \~CH2) 0H or -O-P.G. Q~/=~NH2 ~ NH OCN~
Q ~ + Z-A-B (R )m L.G~C H2) OH or -O-P.G .

(R2)m R 1 \,CH2) n 0H or -O-P.G .

Q~ 'I~ Z-A-B 1 (R )\

Route D Q ~ ~ \ Z-A-B
HO-or P.G;-O (R )m ~ O
R ~ C H2)n Cyclic urea precursor H2N \
Z-A-B
(R2)m R HO- or P.G.-O ~ \ (CH2)n (R )m /= ~\ NCO HN L.G~CH2)~,0H or -O-P.G.
Q ~ + ~Z-A-B

Two alternatives, Route C and Route D, for the preparation of precursors of Formula 1 by a unimolecular cyclization method are outlined in Scheme II. In Route C one begins by alkylating a Q,Rl-substituted aniline with a halogenated alkylalcohol, such as 4-bromobutan-1-ol or its SUBSTITUTE SHEET (RULE 263 CA 022~1394 1sss-1o-o~

W097/38984 PCT~S97/06431 homologs, or a protected version of the same, such as tne methoxymethyl ether of 4-bromobutan-l-ol, either neat or in an anhydrous solvent such as dimethylformamide, benzene, tetrahydrofuran, hexamethylphosphorotriamide, or dimethylsulfoxide. This reaction may be furthered by heating the mixture up to the reflux point of the solvent. Depending upon the reactivity of the substrate no base, or a strong base, such as sodium hydride, potassium t-butoxide or an alkyl lithium, or a weak base, such as potassium carbonate or a trialkylamine, may be necessary. The alkylation product is then reacted with an isocyanate OCN-Z-A-B generated from the amine NH2-Z-A-B by the same method described above for Route A
of Scheme I to give a product alcohol or protected alcohol which can be transformed to a halogenated or sulfonyl ester analog for cyclization to a cyclic urea precursor to Formula 1.
Following deprotection according to an appropriate method found in Greene and Wuts (if necessary), halogenation of the primary alcohol can be carried out with a variety of reagents such as neat thionyl chloride, triphenylphosphine in carbon tetrachloride (Lee and Downie, Tetrahedron, 23 359 (1967)), or triphenylphosphine with N-chloro- or N-bromosuccinimide in dimethylformamide. The alternative sulfonyl ester is also readily prepared from an appropriate sulfonyl chloride, such as the commercially available p-toluenesulfonyl chloride or methanesulfonyl chloride, in a variety of anhydrous aprotic solvents, such as pyridine, benzene, tetrahydrofuran or a chlorinated hydrocarbon, with or without cooling, and with or without a trialkylamine base.
Ring closure to a cyclic urea precursor to Formula l has been observed to occur spontaneously in some cases, but may be furthered in an anhydrous solvent such as dimethylformamide, benzene, tetrahydrofuran, hexamethylphosphorotriamide, or dimethylsulfoxide, by heating the mixture up to the reflux point of the solvent. Depending upon the reactivity of the substrate no base, or a strong base, such as sodium hydride, potassium t-butoxide or an alkyl lithium, or a weak base, such as potassium carbonate or a trialkylamine, may be necessary.

SU~:i 111 UTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 Route D of Scheme II may be advantageous over Route C for the availability of starting materials such as the commercially produced l-benzyl-4-aminopiperidine for NH2-Z-A-B
component, 2-bromoethanol for the halo alcohol component, and 3-cyanophenyl isocyanate for the isocyanate component. In any respect, the chemistry described in Route C is applicable to an analogous reaction in Route D with modifications appropriate for the particular materials involved.
In Formula 1 the radical Z serves as a linking group interposed between the cyclic urea structure and radical A-B.
For the purposes of this discussion it is recognized that there are variations of Z, that is where Z = a bond or Cl_4 alkylene or a portion of the defined linkage , that for synthetic purposes are best incorporated as a substituent of A. It is also assumed for the purpose of this discussion that the analog of A used throughout may contain an orthogonal protecting group, which is compatible with the chemistry suggested. Furthermore, this protecting group may be removed to reveal a substituent that can be used to generate a group X.

Schome III: Preparation of H2N-Z-A, where Z = -CH2CH2-O-functional group.

H2N~"~O-PG.
BocHN Oco2(cH2)rA A-(CH2)r~C(O)CI
2 BocHN~ OH
A-(CH2),C,(~ 1 ~CH2)rL-G
BocHN A(CH2),NR3C(O)CI
OC(O)(CH2),A BocHN O(CH2),A
BocHN~ oC(o)NR3(CH ) A

The preparation of Z outlined in Scheme III begins with the O-protected derivative of 2-aminoethanol. The t-butyldimethylsilyl analog is recommended for this purpose and is know in the literature (see W0 9504277 and WO 9205186).

SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 However, a worker skilled in the art would recognize that the approaches discussed herein are not limited to this particular analog of 2-aminoethanol. O-Protected 2-aminoethanol can then be protected as the N-t-butoxycarbonyl analog and selectively o-deprotected according to procedures found in Greene and Wuts. The resulting 2-(N-t-butoxycarbamoyl)ethanol (1) can then be reacted with various analogs of A to give the desired group Z.
Product 2 is the result of reaction of the chlorocarbonate analog of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 to ambient temperature. The carbonyl chloride analog of A (A(CH2)rOC(O)Cl) is avaialable by reaction of an appropriate alcohol analog of A with phosgene or one of its equivilents in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 to ambient temperature.
Product 3 is prepared by reaction of the acid chloride of an appropriate acid analog of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 to ambient temperature. The acid chloride can be obtained by reaction of the acid analog of A with phosphorous oxychloride, phosphorous pentachloride, thionyl chloride or oxalyl chloride with or without a non-polar aprotic solvent such as a chlorocarbon, benzene or toluene at temperatures ranging from O C to the reflux point of the solvent or neat reagent.
Product 4 can be prepared by the reaction of a carbamoyl chloride analog of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging'from -78 C to ambient temperature. The carbamoyl chloride analog of A (A(CH2)rNR3C(O)Cl) is avaialable by reaction of an appropriate amine analog of A with phosgene or one of its equivilents in a variety of aprotic solvents, such as a SUBSTITUTE StlEET (RULE 26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 C to ambient temperature.
Product 5 is available by the reaction of an analog of A
substituted with an appropriate leaving group with the alkoxide generated from 2 by treatment of 2 with a stong base such as sodium or potassium hydride or a thallium alkoxide in an aprotic solvent such as dimethylformamide, tetrahydrofuran or dimethylsulfoxide at a temperature ranging from 0 to 120-C
The leaving group of A is most conviently generated from an appropriate alcohol analog of A. The alcohol function can be used to prepare a sulfonate ester from a sulfonyl chloride in a cholorocarbon solvent with a trialkylamine base or in pyridine; alternatively the halogen can be generated from a variety of reagents, triphenyl phosphine and carbon tetrabromide, phosphorous pentabromide or chloride, and thionyl chloride, to name a few.

Scheme IV: Preparation of H2N-Z-A, where Z = -CH2CH2-NR3-functional group.

NH ~o,pG

A(CH=~,PG C NR3Co2(CH )A

PG O~NR3Co2(CH2),A ~O-PG ~\NR3Co2(CH2),A

A-(CH2),~ 6 ~CH2);CH=O or A-(CH2),L.G.
PG-~A(CH2)rNR3C(O)CI
--NR3Co2(CH2),A PG-O~NR3Co2(CH2),A

NR3Co2(CH2),A
The series of analogs in Scheme IV can be prepared from the protected amino alcohol 6 to give products 7 to 12 by methods similar to some of those described for Scheme III.
Compound 6 is prepared from 2-amino-(O-t-butyldimethyl-silyl)ethanol by reductive amination of the primary amine by a variety of methods. The primary amine may be reacted with an SU~:~ 111 UTE SHEET (RULE 26) CA 022~1394 1sss-1o-o~

W097/38984 PCT~S97/06431 aldehyde or ketone under dehydrating conditions to form an imine or ~n~mine intermediate which is then reduced to the N-alkyl derivative using palladium catalyst under an atmosphere of hydrogen in an appropriate solvent.
Alternatively, reductive alkylation can be effected by a mixture of the ketone or aldehyde and the amine with lithium or sodium cyanoborohydride in methanol or ethanol as solvent.
It is to be understood that products 7 to 12 need to have the terminal protected oxygen transformed to the primary amine either at this stage or after elaboration with group B. This can conveniently be achieved by deprotection of the primary alcohol. The alcohol function can then be used to prepare a sulfonate ester from a sulfonyl chloride in a chlorocarbon solvent with a trialkylamine base or in pyridine;
alternatively a halogen can be generated from a variety of reagents, triphenyl phosphine and carbon tetrabromide, phosphorous pentabromide or chloride, and thionyl chloride, to name a few. The resulting leaving group is then displaced with a mixture of sodium azide in dimethylformamide at an elevated temperature to form the primary azide. The azide can then be reduced to the amine by catalytic hydrogenation in an alcoholic solvent with palladium catalyst under an atmosphere of hydrogen gas at pressures ranging from ambient to 65 psi;
an alternative method for effecting this transformation involves refluxing the azide intermediate with triphenylphosphine in benzene or toluene and hydrolyzing the resulting intermediate with aqueous acid.
Product 7 of Scheme IV is the result of the reaction of the chlorocarbonate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 C to ambient temperature. Product 8 is prepared by the reaction of the acid chloride of an appropriate acid analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 C to ambient temperature. Product 9 can be prepared by the reaction of a carbamoyl chloride analog of A

SUBSTITUTE SHEET(RUEE26) CA 022~1394 1sss-1o-o~

W097/38984 PCT~S97/06431 with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 to ambient temperature.
Product lO may be obtained from 7 by two routes, conventional alkylation or reductive alkylation. If 6 is a primary amine, then reductive alkylation is recommended. The primary amine 6 may be reacted with an aldehyde or ketone analog of A under dehydrating conditions to form an imine or 10 ~n~mi ne intermediate which is then reduced to the N-alkyl derivative using palladium catalyst under an atmosphere of hydrogen in an appropriate solvent. Alternatively, reductive alkylation can be effected by a mixture of the ketone or aldehyde and the amine with lithium or sodium cyanoborohydride lS in methanol or ethanol as solvent. The aldehyde or ketone analog of A is readily accessible from the appropriate alcohol by Swern, Moffat or Jones oxidation. In the case where 6 is a secondary amine product lO is available by the reaction of an analog of A substituted with an appropriate leaving group with 7 in the presence of a weak base such as a trialkylamine or solid sodium or potassium carbonate in an aprotic solvent such as dimethylformamide, acetone, tetrahydrofuran or dimethylsulfoxide at a temperature ranging from 0 to 120-C.
Product ll is prepared by the reaction of the sulfonyl chloride of an appropriate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78- to ambient temperature. The sulfonyl chloride analog of A is available via the sulfonic acid of A
which can be prepared by heating a halogen analog of A in a aqueous sodium sulfite. The sulfonyl chloride of A can be prepared by reacting the sulfonic acid with phosphorous oxychloride, phosphorous pentachloride, thionyl chloride or oxalyl chloride with or without a non-polar aprotic solvent such as a chlorocarbon, benzene or toluene at temperatures ranging from O C to the reflux point of the solvent or neat reagent. Product 12 is prepared by the reaction of the sulfamoyl chloride of an appropriate analog of A with 6 in a SUBSTITUTE SHEET (RULE 26) W097/38984 PCT~S97/06431 variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from -78 C to ambient temperature.

Scheme V: Preparation of com~sl~n~c of Formula l where Z =
-(CH2)1_2C(O)~O(CH2)r-, ~(CH2)l 2C(o)-NR3(cH2)r- and -(CH2)2S02-NR3(CH2)r~
(R2)m (R2)m ,\ ~ ~. T ,\--lcH2,n o ~ (CH2)~ 2 OH~ ~ (CH2)l 2 Cl (R2)m R~ CH2)n (R2~m (CH2)1 2 SO2CI T ~ ~
17 ~N~ (CHz)~ 2 O(CH2)rA
OR
~ CH )n ~_ ~ CH2)n~

Scheme V outlines the preparation of variations of Z that are not readily prepared by the strategies in Schemes III and IV. Compound 13 is available by the routes developed in Schemes I and II by replacing the primary amine NH2ZAB with O-t-butyldimethylsilyl-2-aminoethanol or its propanol homolog.
Jones oxidation of 13 gives corresponding carboxylic acid which is then transformed to the acid chloride 14 by one of the methods outlined in the preceding discussion. The ester 15 is prepared by reaction of 14 with an alcohol derivative of A under conditions similar to those detailed for the preparation of ester 2 in Scheme III. The amide 16 is available by the reaction of 14 with an amine derived from A

SUBSTITUTE SHEET(RULE26) CA 022~1394 1sss-1o-o~

W097/38984 PCT~S97/06431 under conditions similar to those used for the formation of amide 8 found in Scheme IV. The sulfonyl chloride 17 of Scheme V is prepared by the alcohol to halide to sulfonic acid to sulfonyl chloride route discussed for the sulfonyl analogs of Scheme IV. Reaction of 17 with an amine derivative of A
under conditions used for the formation of ll in Scheme IV
gives the sulfonamide 18 of Scheme V.

Scheme VI: Methods to incorporate B where B = X-Y.
(R2) (RZ)m R1 ~\ (CH2)n R1 ~\ (CH2)n Q~ ~1~ \Z-A Q~'~N~N\Z A B

OR

PG-NH-Z-A ~ PG-NH-Z-A-B

In Scheme VI two approaches to the incorporation of group B are outlined; in each case it is assumed that the starting structures are suitably protected to accommodate the chemistry that follows. It is also understood that both approaches may not be equivilent and, for purposes of compatibility with the chemistry that fol~ows, one approach may have certain advantages over the other. It is further assumed that groups A and B have been selected to be derivatives of A and B that contain functionality suitable for the chemistry contemplated. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis.
The required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-0~

WO97/38984 PCT~S97/06431 in the art of organic synthesis. In the tables that follow the chemistry required to effect the coupling of A to B is outlined.

Table l: Preparation of Amide, Ester, Urea, Sulfonamide and Sulf~;de linkages between A ~nd B.
then the reactive to give the Rxn. substituent of following product No. if A contains: Y is: A-X-Y:
l A-NHR3 as a ClC(O)-Y A-NR3-C(o)-Y
substituent 2 a secondary NH ClC(O)-Y A-C(O)-Y
as part of a ring or chain 3 A-OH as a ClC(O)-Y A-O-C(O)-Y
substituent 4 A-NHR3 as a ClC(O)-CR3R3 -Y A-NR3-C(o)-CR3R3 -Y
substituent a secondary NH ClC(O)-CR3R3 -Y A-C(o)-CR3R3 -Y
as part of a ring or chain 6 A-OH as a ClC(O)-CR3R3 -Y A-o-C(o)-CR3R3 -Y
substituent 7 A-NHR3 as a ClC(O)NR3-Y A-NR3-C(o)NR3-Y
substituent 8 a secondary NH ClC~O)NR3-Y A-C(o)NR3-Y
as part of a ring or chain 9 A-OH as a ClC(O)NR3-Y A-o-C(o)NR3-Y
substituent l0 A-NHR3 as a ClSO2-Y A-NR3-So2-Y
substituent ll a secondary NH ClS02-Y A-SO2-Y
as part of a ring or chain 12 A-NHR3 as a ClSO2-CR3R3 -Y A-NR3-So2-CR3R3 -Y
substituent SUBSTITUTE SHEET (RULE 26) CA 022~l394 l998-lO-0~

W097/38984 PCTrUS97/06431 13 a secondary NH ClS02-CR3R3 -Y A-So2-CR3R3 -Y
as part of a rinq or chain 14 A-NHR3 as a ClS02-NR3-Y A-NR3-So2-NR3-Y
substituent a secondary NH ClS02-NR3-Y A-S02-NR3-Y
as part of a ring or chain 16 A-C(O)Cl HO-Y as a A-C(O)-O-Y
substituent 17 A-C(O)Cl NHR3-Y as a A-C(o)-NR3-Y
substituent 18 A-C(O) Cl a secondary NH as A-C(O)-Y
part of a ring or chain 19 A-CR3R3 C(O) C1 HO-Y as a A-CR3R3 C(O)-O-Y
substituent A-CR3R3 C(O)Cl NHR3-Y as a A-CR3R3 C(o)-NR3-Y
substituent 21 A-CR3R3 C(O) Cl a secondary NH as A-C(R3)2C(O)-Y
part of a ring or chain 22 A-S02Cl NHR3-Y as a A-So2-NR3-Y
substituent 23 A-S02Cl a secondary N~ as A-S02-Y
part of a ring or chain 24 A-CR3R3 S02Cl NHR3-Y as a A-CR3R3 So2-NR3-Y
substituent 25 A-CR3R3 S02Cl a secondary NH as A-CR3R3 S02-Y
part of a ring or chain The chemistry of Table 1 can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20 C to the reflux point of the solvent and with or without a trialkylamine base.

SUBSTITUTE SHEET(RULE26) . . --CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 Table 2: Preparation of ketone linkages between A and B.
then the reactive to give the Rxn. substituent of following product No. if A contains: Y is: A-X-Y:
1 A-C(O)Cl BrMg-Y A-C(O)-Y
2 A-CR3R3 C(O)Cl BrMg-Y A-CR3R3 2C(O)-Y
3 A-C(O)C1 BrMgCR3R3 -Y A-C(o)CR3R3 -Y
4 A-CR3R3 C(O)Cl BrMgCR3R3 -Y A-CR3R3 C(o)CR3R3 -y The coupling chemistry of Table 2 can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0 C to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temeprature (-20 C or lower) and with a large excess of acid chloride orwith catalytic or stoichiometric copper bromide-dimethyl sulfide complex in dimethyl sulfide as a solvent or with a varient thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout ~Org. Syn. Col.
Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)3 according to Fiandanese et al.(Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33(31), (1992) 4437).
Table 3: Preparation of ether and thioether l;nkAge~ between A and B
then the reactive to give the Rxn. substituent of following No. if A contains: Y is: product A-X-Y:
1 A-OH Br-Y A-O-Y
2 A-CR3R3 -OH Br-Y A-CR3R3 O-Y
3 A-OH Br-CR3R3 -Y A-oCR3R3 -Y
- 4 A-SH Br-Y A-S-Y

SUtl~ JTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 A-CR3R3 -SH Br-Y A-CR3R3 S-Y
6 A-SH Br-CR3R3 -Y A-SCR3R3 -Y

The ether and thioether linkages of Table 3 can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.

Table 4: Preparation of -SO- and -S02- linkages from thioethers of Table 3.
and it is oxidized and it is oxidized with m-chloroper-with Alumina (wet)/ benzoic acid (Satoh if the Oxone (Greenhalgh, et al., Chem. Lett.
Rxn. starting Synlett,(1992) 235) (1992) 381, the No. material is: the product is: product is:
1 A-S-Y A-S(O)-Y A-S02-Y
2 A-CR3R3 S-Y A-CR3R3 S(O)-Y A-CR3R3 S02-Y
3 A-SCR3R3 _y A-S(o)CR3R3 -Y A-So2CR3R3 -Y

The thioethers of Table 3 serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table 4. A combination of wet alumina and oxone provides a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone.

SUBSTITUTESHEET(RULE26) W097/38984 PCT~S97/064~1 Scheme VII: Preparation of analogs where Z = -C(O)- or -SO2.

~_NH2+ B---\ (CH2)n i)COupling T ~ CH ) ~0 ii) NH2NH2 ~--NH NH2 ,a (R2)~m L.G. L.G' F¦ ~\ (cH2)n ~ ~ O
B-A-C(O)CI /
¦ B-A-SO2CI

~_ f j--lCH~l n Q~' N' S'A B

A cyclic urea precursor of Formula 1 which is suitable for the preparation of analogs where Z = -C~O)- or -SO2- can be synthesized by an adaptation of the chemistry outlined in Scheme I. The approach in Scheme VII makes use of a N-hydrazino-alkylbromide as the alkylating agent for the aniline derivative. The alkylation product is then deprotected according to a method proscribed by Greene and Wutts and cyclized by treatment of the resulting diamine with phosgene or one of its e~uivilents. The resulting cyclic urea can be treated with a strong base such as sodium hydride or potassium t-butoxide in an aprotic solvent like dimethyl formamide, dimethylsulfoxide or toluene. This mixture is quenched with an acid chloride or sulfonyl chloride analog of A-B at a temperature ranging from -78 C to the reflux point of the solvent.

SUBSTITUTE SHEET(RULE26) . .

CA 022~1394 1998-10-0~

Scheme VIII: The Pinner method to transform the cyclic urea precursor where Z = -CN to Formula 1.

(R2)m (R2)m ~N" ,N\z A B ~ ~N\;~N\z A B

Formula 1 The final transformation of the cyclic urea precursor of Formula 1 prepared in Schemes I to VII to Formula 1 is outlined in Scheme VIII. The preferred method was first described by Pinner and Klein (Ber,, 10, 1889 (1877); for a more recent review see: Decrolx, J. Chem. Res., 134 (1978)).
By this method the nitrile is dissolved in an anhydrous alcohol or a mixture of 1 equivalent or greater of an alcohol and an anhydrous aprotic co-solvent such as a chlorohydrocarbon or an acetate ester of the selected alcohol (i.e., methyl acetate for methyl alcohol). Typically, this mixture is cooled below ambient temperature and dry hydrogen chloride gas is added slowly to the reaction mixture until the solvent is saturated. This saturated solution is sealed and stirred at ambient temperature or lower to form an imidate intermediate which is isolated and characterized. The imidate is then dissolved in a dry alcohol solvent and excess ammonia in the form of a gas, a standardized ammonia/alcohol solution, solid ammonium acetate or ammonium carbonate is added. The crude compound is conveniently purified by reverse phase HPLC
or recrystallization to give the cyclic urea defined by Formula 1.
Scheme IX outlines the general route for the preparation of 5-membered aryl- or heteroaryl-fused examples of Formula II. The preparation of the biaryl amine intermediate can be accomplished by the palladium catalyzed coupling of the substituted aniline to the triflate ester according to the method of Louie et. al., (J. Org. Chem. 1997, 62, 1268-1273).

SUBSTITUTE SHEET (RULE 26) CA 02251394 1sss-10-05 W097/38984 PCT~S97/06431 Scheme IX: Preparation of precursors to 5-membered heteroaryl-fused examples of Formula II

R~,~NH2 ~NO2 ~N~2 ~; NO2 ~ ~NH

D D

~NH2 ~ Scheme I
r~,N~pG + H~Z-A-B ~ H Formula 11 D D

The aniline nitrogen can then be protected as a carbamate, the nitro group reduced to the amine. This amine can be coupled with a Z-A-B group in which Z incorporates a carbonyl group, such as an aldehyde, which can be used as a reactive partner in a reductive alkylation of the newly generated amine. The resulting intermediate can then be processed according to the art described for Route B of Scheme I.

SUBSTITUTE SHEET(RULE26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 Schem~ X: Preparation of precursors to 6-membered aryl- or heteroaryl-fused examples of Formula II
Route A

NH2 ~CO2CI~ ~CH20H
~CO2C~ N'PG ~

D D \ Scheme I
Route E~
Formula ll Route B

'Co C~ + H2N-Z-A-B -- ~CO2CH3 - ~CH20H
OTf B-A-~ PG B~A-Z' PG ~ Scheme I
~ Route B

Formula ll The steps which can be used for the regiocontrolled preparation of both isomers of the 6-membered aryl- or heteroaryl-fused examples of Formula II is outlIne in Routes A
and B of Scheme X. One regioisomer is available by applying the chemistry developed by Louie et al. to the triflate of the salicylate ester in Route A. Following protection of the resulting biaryl amine, the ester can be reduced by lithium borohydride or some other compatible hydride reducing agent and then processed further as outline in Route B of Scheme I.
The alternative regioisomer of Formula II contemplated by this invention can be prepared according to Route B of Scheme X. To effect the palladium catalyzed coupling of the H2N-z-A-B group with the triflate salicylate ester the conditions reported by Wolfe and Buchwald (Pd(OAc)2, BiNAP, NaO-t-Bu, toluene; ~. Org. Chem. 1997, 62, 1264-1267) are optimal. The amine coupling product is then suitably N-protected and the ester functionality is reduce to the benzylic alcohol. This intermediate is then treated further according to the methods outlined in Scheme I, Route B.

SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 Scheme XI: Preparation of precursors to 7-membered aryl- or heteroaryl-fused examples of Formula II

+ o=~3--Z-A-B ' ~CH2~<3 Z-A-B
co2C~b CH20PG CH20PG

~ ~ O

Scheme XI describes the route used to prepare a precursor to one regioisomer of the 7-membered aryl- or heteroaryl-fused example of Formula II. The point of departure is usually the 2-cyano substituted aryl- or heteroaryl-ester. Lithium aluminum hydride reduction of these compounds leads to the corresponding amino alcohol which can then be selectively O-protected with a silyl protecting group, preferably the t-butyl dimethylsilyl group. This material is now ready for reductive alkylation by a Z-A-B group in which Z- contains a carbonyl compound such as an aldehyde, ketone or cyclic ketone. In our experience this transformation can best be performed using a mixture of sodium cyanoborohydride and zinc chloride in tetrahydrofuran solvent. Following reductive alkylation the resulting secondary amine is reacted with an aryl isocyanate in an inert solvent such as dimethylformamide.
The isocyanate addition product can then be O-deprotected, and the benzylic alcohol be transformed to the benzylic chloride with a mixture of methanesulfonyl chloride and triethylamine in chloroform or dichloromethane. The benzylic chloride is then cyclized to the 7-membered ring precursor to Formula II
with sodium hydride in dimethylformamide at 0 ~C.

SUBSTITUTE SHEET (RULE 26) CA 022~1394 1sss-1o-o~

W097t38984 PCT~S97/06431 Sch~me XII: Preparation of precursors to alternative regioisomers of 7-membered aryl- or heteroaryl-fused examples of Formula II
Route A

NH2 ¢ ~ CH2CH2NO2 , ~ CH2CH2NH
¢~CH2CH2NO2 + ~ ~ PG _ ~NPG

D D
~ Scheme I
A-B ~ ~N,Z-A-~ Route Ei Formula 11 Route B

~CH2CH20-PG + H2N-Z-A-B ~ Scheme I
OTf PGN'Z-A-B

Routes to alternative regioisomers for 7-membered aryl-or heteroaryl-fused examples of Formula II are demonstrated in Scheme XII. In Route A, the phenethylnitro triflate can undergo a palladium catalyzed coupling with the aniline analog according to the procedure of Louie et al. The coupled product is then N-protected, usually as a carbamate or amide, then the nitro group is reduced to the amine by catalytic hydrogenation or with tin(II) chloride in aqueous or alcohol solvent. A Z-A-B group in which Z- incorporates a carbonyl functionality can then be used as a partner in a reductive alkylation with the primary amine function under the conditions described previously. This intermediate can then be submitted to the chemistry described in Scheme I, Route B
to obtain a compound of Formula II. Route B describes the coupling of a protected phenethyl alcohol triflate with an amine containing Z-A-B group under the conditions recommended by Wolfe and Buchwald. This product is then N-protected as a suitable carbamate or amide and then processed by the chemistry described in Route B of Scheme I.

SU~S 111 UTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration fo the invention and are not intended to be limiting thereof.

Exam~les The synthesis of representative compounds according to the invention is described in further detail below with reference to the fo~lowing specific, but non-limiting examples.
Abbreviations used in the Examples are defined as follows: "~C" for degrees Celsius, "d" for doublet, "dd" for doublet of doublets, "DAST" for diethylaminosulfur trifluoride, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, "hr~
for hour or hours, "m" for multiplet, "M" for molar, "min" for minute or minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" for triplet, "TLC" for thin layer chromatography.

EXaMPLE 1 Pre~aration of N-(3-am;~; n~l~h~nYl ) -N ' - ( 1-benzYl~iPeridin-4-Yl)cYcloPentYlurea 4-(2-Hydroxyethyl)amino-1-benzylpiperidine: A mixture of 4-amino-1-benzylplperidine (1.0 g, 5.3mmol, 1.1 mL) and bromoethanol (0.662g, 5.3mmol, 0.375 mL) was stirred under a 30 N2 atmosphere for 18 h at ambient temperature. This material was used in directly in the next step (1.82 g). LRMS (M+H)+
m/z 235.

N-(3-Cyanophenyl)-N'-(2-l~y~J~yeLhyl)-N'-(l-benzylpiperidin-4-35 yl)urea: To a stirred solution of 4-(2-hydroxyethyl)-amino-1-benzylpiperidine (1.82 g), and triethylamine (0.789g, 7.8mmol) in DMF (50 mL) was added 3-cyanophenylisocyanate (1.12g, 7.8 mmol). This mixture was heated at 60~C for 18 under a N2 SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 atmosphere. The reaction was diluted with water and extracted with ethyl acetate, dried with MgS04, filtered and concentrated to give the desired product, N-(3-cyanophenyl)-N'-(2-hydroxyethyl)-N'-(l-benzylpiperidin-4-yl)urea (2.04g, 5.3 mmol). LRMS (M+H)+ m/z 379.

N-(3-Cyanophenyl)-N'-(l-benzylpiperidin-4-yl)cyclopentylurea:
To a stirred solution of N-(3-cyanophenyl)-N'-(2-hydroxyethyl)-N'-(l-benzylpiperidin-4-yl)urea (2.04g, 5.3 mmol) in chloroform at -10~C was added a few drops of pyridine followed by thionyl chloride (0.702g, 5.9mmol). This mixture was stirred for 2 h then heated at reflux for lh. It was concentrated in vacuo, dissolved in ethanol (50 ml) and a solution of potassium hydroxide (10 %) in ethanol (15 mL) was added and refluxed for 2h. The mixture was cooled then evaporated; it was dissoved in ethyl acetate, washed with water and brine then dried (MgS04). After removal of the solvent, the residue was purified by silica gel chromatography using ethyl acetate as the eluant. There was obtained 0.59 g of N-(3-cyanophenyl)-N'-(l-benzylpiperidin-4-yl)cyclopentylurea. LRMS (M+H)+ m/z 361.

N-(3-Amidinophenyl)-N'-(l-benzylpiperidin-4-yl)cyclopentyl-urea: A stirred solution of N-(3-cyanophenyl)-N'-(l-benzylpiperidin-4-yl)cyclopentylurea (56 mg) in anhydrous methanol (10 ml) was cooled to O C and saturated with dry hydrogen chloride gas. This mixture was tightly stoppered and stirred at ambient temperature for 18 h. The solution was evaporated to dryness and the residual hydrogen chloride gas removed by pumping on the imidate salt for 18 h. The imidate was dissolved in anhydrous methanol (10 ml) and ammonium acetate (100 mg) was added. The mixture was stirred at ambient temperature for 24 h, then evaporated to give 55 mg of crude product. Purification of this material by reverse phase HPLC gave 26 mg of N-(3-amidinophenyl)-N'-(l-benzylpiperidin-4-yl)cyclopentylurea as the bis-trifluoroacetic acid salt;
HRMS Calc. 378.229386, found 378.229774; lH NMR (CD30D) d:
2.05-2.21 (m, 4H), 3.18 (dd, 2H, J= 11 Hz, J=6.OHz), 3.58 (dd, SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 4H, J=11 Hz, J= 6.0 Hz), 3.98 (t, 2H, J= 7.5 Hz), 4.02 (m,lH), 4.32 (s, lH), 7.45 (m, 7H), 7.81 (d,lH, J= 7.5 Hz), 8.01 (s,lH).

Pre~aration of N-(3-am;~; nODh~nYl ) -N ~ - ( 1-benzYl~iperidin-4-Yl ) cYclohexYlurea 4-(3-Hydl~y~lo~yl)amino-1-benzylpiPeridine: This material was prepared in the same fashion as its lower homolog 4-(2-hydroxyethyl)amino-1-benzylpiperidine using 3-bromopropanol rather than 2-bromoethanol.

N-(3-Ami~; n~rh~nyl )-N'-(1-benzylpiperidin-4-yl)cyclohexyl-urea: This material was prepared from 4-(3-hydroxypropyl)-amino-1-benzylpiperidine by the same route employed in the synthesis of N-~3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea. There was obtained 26 mg of the desired product as the bis-tifluoroacetic acid salt after purification by reverse phase HPLC. LRMS (M+2H)2+ m/z 196.7, (M+H)+ m/z 392;1H NMR (CD30D): d 2.23 (m, 6H), 3.21 (bt, 2H), 3.58 (t, 2H, J= 5.12 Hz), 3.62 (m, 2H), 4.39 (m, 3H), 4.53 (t, 2H, J=
5.12Hz), 7.51 (m, 5H), 7.62-7.78 (m, 3H), 7.81 (s, lH).

Pre~aration of N-(3-amidinoPhenYl)-N'-(4-a~;~;n~PhenYl~cyclo-heDtvlurea N-(3-cyAn~rh~nyl)-N~-(4-cyAnorh~nyl)urea: m-Cyanoaniline (0.5 g, 3.38 mmol) and p-cyanophenylisocyanate (0.49 g, 3.38 mmol) were dissolved in dimethylformaide (8 ml) and triethylamine (1 ml). The reaction was stirred at ambient temperature under a nitrogen atmosphere for 24 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water (3x), brine, dried (MgSO4) and concentrated to give a amorphous solid.
This was triturated to a crystalline white solid with ethyl ether. This solid was filtered and washed with ether to give SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 N-(3-cyanophenyl)-N'-(4-cyanophenyl)urea as a white powder (0.92 g, mp 183-5 C)i LRMS (M+H)+ m/z 280, ~M+NH4)+ m/z 297;
lH NMR (DMSO-d6): 9.32(s, lH), 9.21(s, lH), 7.97(s, lH), 7.75-7.6(m, 5H), 7.55-7.4(m, 2H).

N-(3 -Cy~rh~nyl )-N'-(g-cyanophenyl)cycloheptylurea: N-(3-Cyanophenyl)-N'-(4-cyanophenyl)urea (0.25 g, 0.95 mmol) was dissolved in DMF (2 ml) and added to a cooled slurry of sodium hydride (0.80 g, 2.0 mmol, hexane washed to remove the mineral oil) in dimethylformamide (25 ml) under a nitrogen atmosphere.
After strirring for 15 min, 1,4-dibromobutane (0.25g, 0.95 mmol) was added slowly. The reaction was stirred at 0 C for lh and then allowed to warm to 75 C for 3 h. To the reaction additional sodium hydride was added and the reaction was heated to 75 C for an additional 6 h. The reaction was allowed to cool to ambient temperature, was poured into lN HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4) and concentrated to give a viscous oil. The oil was purified by flash chromatography on silica gel eluting with methylene chloride: ethyl acetate 95:5 to give N-(3-cyanophenyl)-N'-(4-cyanophenyl)cycloheptylurea as an oil (0.075 gm 0.24 mmol);
LRMS (M+H)+ m/z 317; lH NMR (CDC13): 7.7-7.45(m, 6H), 7.4(d, 2H), 3.82(m, 4H), 1.95(m, 4H).
N-(3-amidinophenyl)-N'-(4-am;~; norh~nyl )cycloheptylurea: Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N'-(4-cyanophenyl)cycloheptyl-urea (0.065 g, 0.21 mmol) in anhydrous ethanol ~5 ml) under a nitrogen atmosphere for 15 min. The reaction was stoppered and allowed to warm to ambient temperature and stir overnight.
The reaction was concentrated in vacuo to give a white amorphous solid. This was dissolved in anhydrous ethanol (5 ml) and ammonium carbonate (0.118 g, 1.23 mmol) was àdded.
The reaction was stirred under a nitrogen atmosphere at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give a white solid. The product was purfied by HPLC on a Vydec~ C-18 column eluting with solvent S~Jt~:j 111 UTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

mixture A (acetonitrile: water:TFA 80:20:0.3) and solvent mixture B (water: TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 20 minutes. The major fraction was concentrated to give N-(3-amidinophenyl)-N'-(4-amidinophenyl)cycloheptylurea as a white solid (mp204-206 C)i LRMS (M+H)+ m/z 351, (M+2H)+2 m/z 176.2; HRMS calc.
351.1933, found 351.1936; lH NMR (DMSO-d6): 9.4(bs, 2H), 9.2(broad s, 2H), 9.18 (broad s, 2H), 7.95 (broad s, 2H), 7.8-7.5(m, 6H), 7.47 (d, 2H), 3.9(bd, 4H), 1.83(m, 4H).
EXAMP~E 4 PreParation of N-(3-am;~;n~h~nYl~-N'-((4-amidino~henYl)meth~l)cYcloheDtYlurea N-(3-cyanophenyl)-N'-((4-cyanophenyl)methyl)urea: m-Cyano-phenyl isocyanate (2.0 g, 13.9 mmol) and triethylamine (3.09 g, 30.5 mmol) in dimethylformamide (30 ml) was cooled to O C
and p-cyanobenzylamine hydrogen chloride (2.3 g, 13.9 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction was thawed to ambient temperature and was stirred for 18 h.
The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with l_ HCl and brine, then dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on silica gel with 1:1 hexane:ethyl acetate as an eluenti there was obtained 0.54 g of pure N-(3-cyanophenyl)-N'-((4-cyanophenyl)methyl)urea; LRMS
~M+H)+ m/z 294.

N-(3-cyanophenyl~-N'-((4 -cy~orh~yl )methyl)cycloheptylurea:
To a suspension of sodium hydride (0.29 g of a 60 % suspension in mineral oil, 7.28 mmol) in dimethylformamide (45 ml) at ambient temperature was added a dimethylformamide solution (5 ml) of N-(3-cyanophenyl)-N'-((4-cyanophenyl)-methyl)urea (0.67 g, 2.43 mmol). This mixture was stirred for 30 min before 1,4-dibromobutane (1.05 g, 4.85 mmol) in dimethylformamide (10 ml) was added over 20 min. The reaction was then heated at 70 C for 1 h, after which analysis by thin layer chromatography (1:2 hexane:ethyl acetate) demonstrated that SUBSTITUTE SHEET (RULE 26) .

CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 all of the starting urea had been consumed. The cooled reaction mixture was poured into ice water and extracted with ethyl acetate (3x). The extract was washed with 1_ HCl and brine, then dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on a column of silica gel with 1:1 hexane:ethyl acetate as the eluent. There was obtained 0.47 g of pure N-(3-cyanophenyl)-N'-((4-cyanophenyl)methyl)cycloheptyl-urea; LRMS: (M+H)+ m/z 331.

N-(3-amidinophenYl)-N'-((4-am;~; n~rh~nyl )methyl)cycloheptyl-urea: N-(3-Cyanophenyl)-N'-((4-cyanophenyl)methyl)cyclo-heptylurea (0.47 g, 1.42 mmol) was dissolved in a mixture of anhydrous chlorform (25 ml) and anhydrous methanol (10 ml).
This solution was cooled to O C and slowly saturated with dry hydrogen chloride gas. The reaction vessel was securely stoppered and stored in a refrigerator for 18 h; the solvent was removed in vacuo and there was obtained 0.59 g of the imidate as the hydrogen chloride salt; LRMS: (M+H)+ m/z 396.

The imidate prepared above (0.59 g) was stirred in anhydrous methanol (25 ml) with ammonium carbonate (0.72 g, 7.49 mmol).
After 72 h the solvent was removed in vaCuo and the residue dissolved in water. The aqueous solution was washed with ethyl ether (3x), then the water removed by lyophillization.
The product was purified by HPLC on a vydec~ C-18 column eluting with solvent mixture A (water: TFA 99.5:0.5) and solvent mixture B (acetonitrile: TFA 99.5:0.5) using a gradient starting with A at 100 % and changing to B at 100 %
over 50 min. The fractions cont~;ning pure N-(3-amidinophenyl)-N'-((4-amidinophenyl)methyl)cycloheptylurea were collected and lyophillized to give 0.027 g of material;
HRMS (M+H)+ calc. 365.208985, found 365.209496.

SUBSTITUTE SHEET(RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 Pre~aration of N-(3-amidino~henYl)-N'-(1-A~;~;noDi~eridin-4-Yl ) CYC lohePtylurea N-(3-Cyanophenyl)-N'-(1-benzylpiperidin-4-yl)urea:
m-Cyanophenyl isocyanate (1.0 g, 6.94 mmol) was dissolved in dimethylformamide (15 ml) and triethylamine (2 ml) under a nitrogen atmosphere, then 4-amino-1-benzyl-piperidine (1.32 g, 6.94 mmol) was added slowly. The reaction was stirred at ambient temperature for 1 h and then at 70 C for 2h. The reaction was allowed to cool to ambient temperature and partioned between water and ethyl acetate. The organic layer was washed with water (2x) and brine then dried (MgSO4) and concentrated to give a white amorphous solid. The solid was triturated with ethyl ether to give a white powder. The solids was filtered, washed with ethyl ether and dried to give N-(3-cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cyclopentylurea as a white powder, (1.7 g, 74%, mp 165-6 C)i LRMS (M+H)+ m/z 335; 1H NMR (CDCl3): 7.62(s, lH), 7.57(d, lH), 7.15-7.2(M, 7H), 7.15(s, lH), 5.05(d, lH), 3.65(m, lH), 3.5(s, 2H), 2.85(m,2H), 2.1(m,2H), 1.95(m, 2H), 1.45(m,2H).

N-(3-Cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea:
N-(3-Cyanophenyl)-N'-(1-benzylpiperidin-4-yl)urea (0.5 g, 1.49 mmol) was dissolved in DMF (25 ml) and 1,4 dibromobutane (0.33 g, 1.49 mmol) was added under a nitrogen atmosphere. The reaction was heated to 70 C and sodium hydride (0.131 gm 3.3 mmol) was added portionwise over 20 minutes. The reaction was heated for 4 h then allowed to cool to ambient temperature.
When cool, it was poured into water and extracted with ethyl acetate. The organic layer was washed water (2x) and brine, then dried (MgSO4) and concentrated to give a viscous oil.
The crude oil was purified by flash chromatography on silica gel eluting with methylene chloride: ethyl acetate 40:60 to give N-(3-cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea as an oil (0.37 g, 64%); LRMS (M+H)+ m/z 389.4; 1H NMR (CDCl3): 7.4-7.25(m, 9H), 3.9(m, lH), 3.57(m, SU~ TE SHEET(RULE26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 2H), 3.42(s, 2H), 3.25(m, 2H), 2.87(m, 2H), 2.03(m, 2H), 1.8-1.5(m, 8H).

N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea: N-(3-Cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea (0.1 g 0.26 mmol) was dissolved in ethanol (10 ml) and cyclohexene (2 ml). Palladium hydroxide catalyst (0.05 g) was added and the reaction was heated at reflux under a nitrogen atmosphere.
After 30 min the reaction was allowed to cool to ambient temperature, filtered and concentrated to give a viscous oil.
The crude product was purified by flash chromatography on silica gel by eluting with methylene chloride:methanol 85:15 with 3 % triethylamine. The product, N-(3-cyanophenyl)-N~-(piperidin-4-yl)cycloheptylurea, was concentrated to give an oil which crystallized from ethyl ether (0.05 g, 48%, mp 157-8 C); LRMS (M+H)+ m/z 299; 1H NMR (CDCl3): 7.5-7.3(m, 4H), 4.05(m, lH), 3.60(m, 2H), 3.32(m, 2H), 3.17(m, 2H), 2.72(m, 2H), 2.0-1.6(m, 8H).

N-(3-Cyanophenyl)-N'-( l-r i ~; n~piperidin-4-yl)cycloheptylurea:
N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (0.05 g, 0.126 mmol) was dissolved in pyridine (2 ml) and 3,5-dimethylpyrazole-1-carboxamidine (0.037 g, 0.188 mmol) was added under a nitrogen atmosphere. The reaction was heated to 110 C for 6 h, then was allowed to cool and was concentrated to give a viscous amber oil. The product was purfied by HPLC
on a Vydec~ C-18 column eluting with solvent mixture A
(acetonitrile: water:TFA 80:20:0.3) and solvent mixture B
(water: TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The product eluted at 13.8 minutes was concentrated to give N-(3-cyanophenyl)-N'-(1-amidinopiperidin-4-yl)cyclo-heptylurea as an amorphous solid (0.036 g); LRMS (M+H)+ m/z 341.

N-(3-Amidinophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptyl-urea: Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N'-(1-amidinopiperidin-4-yl)cyclo-heptylurea (0.03 g, 0.075 mmol) in anhydrous ethanol SlJts~ ~ JTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 (5 ml) for 15 min. The reaction was stoppered, allowed to warm to ambient temperature and stirred for 24 h. The reaction was concentrated to give a viscous residue which was dissolved in anhydrous ethanol and ammonium carbonate (0.06 g, 0.63 mmol) was added. The reaction was stirred over night at ambient temperature and then concentrated in vacuo. The crude product appeared to be about 1:2 ratio of the desired product to starting material. Pure N-(3-amidinophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea was isolated by HPLC on a Vydec~ C-18 column eluting with solvent mixture A
(acetonitrile: water:TFA 80:20:0.3) and solvent mixture B
(water: TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 20 min, to give two major fractions: N-(3-amidinophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea, the desired product eluted at 13.3 minutes, (~.2 mg); LRMS (M+2H)+2 m/z 179.8i HRMS calc.
358.2355, found 358.2349; 1~ NMR (DMSO-d6): 9.25(s, 2H), 9.0(s, 2H), 7.55-7.4(m, 4H), 7.32(s, 4H), 3.95(m, 3H), 3.65~m, 2H), 3.25(m, 2H), 3.07(m, 2H), 1.8-1.6(m, 8H).
The second fraction, eluting at 18.1 min., was the starting material N-(3-cyanophenyl)-N'-(1-amidinopiperidin-4-yl)cyclo-heptylurea (16.6 mg); LRMS (M+H)+ m/z 341.1; HRMS calc.
341.20898, found 3341.2077; 1H NMR (DMSO-d6): 7.6(s, lH), 7.5-7.4(m, 3H), 7.3(s, 4H), 4.0-3.9(m, 3H), 3.6(m, 2H), 3.25(m, 2H), 3.05(m, 2H), 1.8-1.55(m, 8H).

PreParation of N-(3-amidinoPhenYl)-N'-(1-benzYlPiPeridin-4-Yl)c~clohePtYlurea N-(3-A~;~;nophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptyl-urea: Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N'-(1-benzylpipèridin-4-yl)cycloheptylurea (0.03 g, 0.077 mmol) in anhydrous ethanol(10 ml) under a nitrogen atmosphere for 15 min. The reaction was stoppered, allowed to warm to ambient temperature and stirred for 24 h. The reaction was concentrated to a solid SUBSTITUTE SHEET(RULE 26) .. . ... . ... . . ....

CA 022~l394 lsss-lo-o~

WO9713B984 PCT~S97/06431 and dissolved in anhydrous ethanol (5 ml) and ammoniu~
carbonate (O.023 g, 0.23 mmol) was added. The reaction mixture was stirred at ambient temperature overnight then was concentrated in vacuo. N-(3-Amidinophenyl)-N'-(1-benzylplperidin-4-yl)cycloheptylurea was purified by HPLC on a Vydec~ C-18 column eluting with solvent mixture A
(acetonitrile: water:TFA 80:20:0.3) and solvent mixture B
~water: TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The major fraction eluting at 15 minutes was concentrated to give N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea as an amorphous solid; LRMS (M+H)+ m/z 406, (M+2H)+2 m/z 203.8;
1H NMR (DMSO-d6): 9.52(broad s, lH), 9.27(s, 2H), 9.02(s, 2H), 7.5(m, 9H), 4.3(m,m, 2H), 3.95(m, lH), 3.67(m, 2H), 3.42(m, 2H), 3.2(m,2H), 3.1(m, 2H), 2.05-1.6(m, 8H).

PreParation of N-(3-a~;~;noPhenYl~-N'-(1-( a-phenethYl)piperidin-4-Yl)cYclohePtYlurea N-(3-am;~;n~ph~nyl)-N'-(l-(a-phenethyl)piperidin-4-yl)cycloheptylurea: N-(3-amidinophenyl)-N'-(1-(a-phenethyl)piperidin-4-yl)cycloheptylurea was prepared by a method ana7ogous to the preparation of N-(3-amidinophenyl)-N~-(1-benzylpiperidin-4-yl)cycloheptylurea starting with 4-amino-1-(a-phenethyl)piperidine rather than 4-amino-1-benzylpiperidinei HRMS: calc 420.276336, found 420.276129; lH
NMR (CD30D) d: 1.78 (d, 3H, J= 6.95 Hz), 1.79 (m, 4H), 2.05 (m, 4H), 2.89 (m,3H), 3.38 (m, 2H), 3.76 (m,2H), 3.82 (broad d,2H), 3.92 (m,lH)4.42 (q, lH, J= 6.95 Hz), 7.42 (broad s,5H), 7.52 (broad s, 3H), 7.60 (s, lH).

PreParation of N-(3-amidinoPhen~l)-N'-(l-((PhenYl)methane)sulfonYl)-Piperidin-4-yl)cyclohe~tylurea N-(3 -Cy~n~rh~nyl ) -N'-(1-(t-butoxycarbonyl)piperidin-4-yl)urea:
A mixture of 4-amino-N-(t-butoxycarbonyl)piperidine (0.133 SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 mol, 30.5 g, prepared by the method of Mach, R.H. et al., J.
Med. Chem. (1993) 36(23), 3707-20) and triethylamine (1.5 equivilents, 0.2 mol, 20.2 g, 27.8 ml) in dimethylformamide (230 ml) was cooled to 0 C and m-cyanophenylisocyanate (1.1 equivilents, 0.146 mmol, 21.1 g) in dimethylformamide (70 ml) was added dropwise. The reaction was stirred at ambient temperature for 18 h. It was poured into water and extracted with ethyl acetate (3x). The ethyl acetate extracts were washed with lN HCl and brine, then dried (Na2SO4) and evaporated to give 43.56 g of crude material. Pure N-(3-cyanophenyl)-N'-~1-(t-butoxycarbonyl)piperidin-4-yl)urea was isolated by flash chromatography on silica gel (1.2 kg) eluted with 2:1 hexane:ethyl acetate (6 L) then 1:1 heaxane ethyl acetate collected in 800 ml fractions. Fractions 9 thru 14 contained pure product, yield 21.69 g.

N-(3-Cyanophenyl)-N'-(1-(t-butoxycarbonyl)piperidin-4-yl)cycloheptylurea: A mixture of sodium hydride (2.44 g of a 60 % suspension in mineral oil, 60.9 mmol) and dimethylformamide (350 ml) was stirred at ambient temperature for 5 min, then N-(3-cyanophenyl)-N'-(1-(t-butoxycarbonyl)-piperidin-4-yl)urea (7.0 g, 20.3 mmol) in dimethylformamide (30 ml) was added dropwise. This mixture was stirred at ambient temperature for 30 min after which gas evolution ceased. 1,4-Dibromobutane (8.79 g, 40.6 mmol) in dimethylformamide (20 ml) was added slowly over 25 min.
Following the addition of the alkylating agent the reaction mixture was heated at 70 -80 C for 3 h then was stirred at ambient temperature for 18 h. The reaction mixture was poured into water (1 L) and extracted with ethyl acetate (4 x 250 ml). The ethyl acetate extracts were washed with brine (6x), dried (Na2SO4) and evaporated to give 10.58 g of crude product. Pure N-(3-cyanophenyl)-N'-(1-(t-butoxycarbonyl)-piperidin-4-yl)cycloheptylurea was isolated by medium pressure chromatography on a silica gel column (600 g) by eluting with 2:1 hexane:ethyl acetate to give 3.20 g of pure product.

SUBSTITUTE SHEET(RULE26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea: N-(3-Cyanophenyl)-N'~ (t-butoxycar~onyl~piperidin-4-yl)cycloheptylurea (3.2 g, 7.76 mmol) was stirred in dichloromethane (40 ml) and trifluoroacetic acid (40 ml) at ambient temperature for 1.5 h. The reaction mixture was evaporated and the residue taken up in water. The aqueous suspension was made basic (pH 11) by the dropwise addition of aqueous sodium hydroxide solution ~50 %). The basic aqueous suspension was extracted with ethyl acetate (2x); the ethyl acetate extracts were washed with brine, dried (Na2SO4), and evaporated to give N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (2.17 g, 7.28 mmol, 94 %). This sample was in all respects identical to the sample of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea prepared in Example 5.
N-(3-Cyanophenyl)-N'-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea: N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (2.07 g, 6.95 mmol) in tetrahydrofuran (100 ml) with triethylamine (7.64 mmol, 0.77 g, 1.1 ml) was cooled to 0 C and a-toluenesulfonyl chloride (1.46 g, 7.64 mmol) in tetrahydrofuran (60 ml) was added dropwise. The reaction was allowed to cool to ambient temperature and was stirred for 18 h. The solvent was removed in vacuo and the residue patitioned between water and 5:1 ethyl acetate:acetone. The organic layer was washed with 1_ HCl and lN NaOH, then brine.
It was dried (Na2SO4) and evaporated to give 2.63 g of crude product. Purification by medium pressure liquid chromatography on a silica gel column (350 g) gave N-(3-cyanophenyl)-N'-(1-((phenyl)methane)- sulfonyl)piperidin-4-yl)cycloheptylurea (1.81 g, 4.0 mmol, 58%, mp 203-204 C); HRMS
(M+H)+ calc. 453.196038, found 453.198085.

N- ( 3-am;~; n~ph~nyl ) -N '-(1-((phenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea: A solution of N-(3-cyanophenyl)-N'-(1-((phenyl)methane)-sulfonyl)piperidin-4-yl)cycloheptylurea (1.15 g, 2.54 mmol) in anhydrous methyl acetate (300ml) was cooled to 0 C and anhydrous methanol (0.81 g, 25.4 mmol, 1.02 ml) was added. The cooled solution was SlJ~::i 111 IJTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 saturated with dry hydrogen chloride gas then was stoppered tightly and was left to stir at ambient temperature for 18 h.
Analytical thin layer chromatography (5 % methanol in chloroform) showed complete consumption of the starting nitrile. The methyl acetate solution was diluted with ethyl ether ~1.7 L) then left to form crystals in the refrigerator over 18 h. After this time, precipitation of the imidate was complete and the intermediate product was isolated as the hydrogen chloride salt by filtration. The solid imidate was pumped on for several hours to remove any residual HCl and protect the product from moisture. This procedure gave 1.27 g of imidate hydrochloride (2.43 mmol, 96 %, mp 131-134 C).

The imidate prepared above (1.27 g, 2.43 mmol) was dissolved in dry methanol ~50 ml) and 2N ammonia in methanol solution (24.3 mmol, 12.15 ml) was added. This reaction was stoppered and stirred at ambient temperature for 24 h. After this time, the solvent was removed in vacuo and the 1.27 g of crude product was isolated. The major cont~m;n~nt (aproximately 50 %) was the corresponding amide. This mixture was separated by HPLC on a Vydec~ C-18 column eluting with solvent mixture A
(water: TFA 99.5:0.5) and solvent mixture B (acetonitrile: TFA
99.5:0.S) using a gradient starting with A at 100 % and changing to B at 100 % over 50 min. The desired product, N-(3-amidinophenyl)-N'-(1-((phenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea, was eluted at 30 min; after collection of the fractions and lyophylization, 0.30 g of pure product was obtained as the trifluoroacetic acid salt (O.S mmol, 20 %, mp 208-209 C); HRMS (M+H)+ calc. 470.222587, found 470.219813.
The following Example 9 to 12 were prepared by essentially the same preparative methods as described above for Example 8; the only changes involved the sulfonylation or acylation of the common intermediate N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea. In each case, however, the same procedureusing the appropriate sulfonylating or acylating agent in tetrahydrofuran with triethylamine was used.

SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 EXAMP~E 9 Pre~aration of N-(3-~m;~;ne~henYl)-N'-(l-benzoYlDi~eridin-4-yl ) cYclohe~tYlurea N-(3-amidinophenyl)-N'-(l-benzoylpiperidin-4-yl)cycloheptylurea: In this case the title compound was prepared by acylation of N-(3-cyanophenyl)-N'-(piperidin-4-In this case the title compound was prepared by acylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with benzoyl chloride folowed by amidine formation as described above; HRMS ~M+H)+ calc. 421.223966, found 421.222804.

PreDaration of N-(3-amidino~henYl)-N'-(1-15((phenYl)methane)carbonYlDi~eridin-4-Yl)cyclohe~t~lurea N-(3-~ ;n~phenyl)-N'-(l-((phenyl)methane)c~hnnylpiperidin-g-yl)cycloheptylurea: In this case the title compound was prepared by acylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with phenylacetyl chloride folowed by amidine formation as described above; HRMS (M+H)+ calc.
434.255601, found 434.255065.

25Pre~aration of N-(3-amidino~henYl)-N'-(1-(PhenYl)sulfonYlPiperidin-4-Yl)cYclohe~tylurea N-(3-amidinophenyl)-N'-(l-(phenyl)sulfonylpiperidin-4-yl)cycloheptylurea: In this case the title compound was prepared by acylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with benzoyl chloride folowed by amidine formation as described above; HRMS (M+H)+ calc. 456.206937, found 456.204189.

SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 Preparation of N-(3-~dinoPhen~l)-N'-(1-(4-acet~ oDhenYl)sulfon~lDiPeridin-4-yl)cyclohept~lurea N-(3-amidinophenyl)-N'-(1-(4-acetamidophenyl)sulfonyl-piperidin-4-yl)cycloheptylurea: In this case the title compound was prepared by sulfonylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with (4-acetamidophenyl)-sulfonyl chloride folowed by amidine formation as described above; HRMS (M+H)+ calc. 513.228401, found 513.226577.

Pre~aration of N-(3-amidino~hen~l)-N'-(1-(2-a~;norh~nyl)sulfonYlPiPeridin-4-~,rl)cYClohePtYlurea N-(3-cyanophenyl)-N'-(1-(2-nitrophenyl)sulfonylpiperidin-4-yl)cycloheptylurea: N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (1.5 g, 5.03 mmol) in tetrahydrofuran (30 ml) and triethylamine (1.02 g, 10.06 mmol) was cooled to O C.
A solution of (2-nitrophenyl)sulfonyl chloride (1.3 g, 5.86 mmol) in tetrahydrofuran (5 ml) was added dropwise and the reaction was stirred at ambient temperature for 18 h.The solvent was removed in vacuo and the residue dissolved in ehtylacetate. The ethyl acetate solution was washed with lN
HC1 and brine, then dried (Na2SO4) and evaporated. Pure N-(3-cyanophenyl)-N'-(1-(2-nitrophenyl)sulfonylpiperidin-4-yl)cycloheptylurea was isolated by flash chromatography on silica gel by first eluting with 2:1 hexane ehtyl acetate, then 1:1 hexane ethyl acetate. There was obtained 0.71 g of the title compoundi LRMS (M+H)+ m/z 484.

N-(3-cyanophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea: N-(3-cyanophenyl)-N'-(1-(2- ' nitrophenyl)sulfonylpiperidin-4-yl)cycloheptylurea (0.71 g, 1.47 mmol) in ethanol (90 ml) and water (10 ml) was stirred with zinc dust (3.2 g, 48.6 mmol) and calcium chloride (0.11 g, 0.95 mmol). This mixture was heated at reflux for SlJ~ UTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 3 h then filtered hot through a Celite~ pad and evaporated;
0.59 g of N-~3-cyanophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea was obtained; LRMS (M+H)+ m/z 454.

N-(3-amidinophenyl)-N'-(1-(2-amin~rh~yl)sulfonylpiperidin-4-yl)cycloheptylurea: N-(3-cyanophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea (0.20 g, 0.44 mmol) in anhydrous chloroform (25 ml) and anhydrous methanol (10 ml) was cooled to 0 C and saturated with dry hydrogen chloride gas. The reaction vessel was securely stoppered and was stirred at ambient temperature for 18 h.
The intermediate imidate was obtained as the hydrogen chloride salt (0.23 g) by removal of the solvent and residual hydrogen chloride in vacuo; LRMS (M+H)+ m/z 486.

The imidate prepared above (0.23 g) and a 2N solution of ammonia in methanol (1.5 ml) were stirred in a tightly stopper flask at ambient temperature for 18 h. A mixture of the desired amidine and the corresponding amide were obtained anfter removal of the solvent. This mixture was separated by HPLC on a Vydec~ C-18 column eluting with solvent mixture A
(water: TFA 99.5:0.5) and solvent mixture B (acetonitrile: TFA
99.5:0.5) using a gradient starting with A at 100 % and changing to B at 100 % over 50 min. There was obtained 38 mg of the desired product N-(3-amidinophenyl)-N'-(1-(2-aminophenyl)sulfonyl-piperidin-4-yl)cycloheptylurea; HRMS
(M+H)+ calc. 471.217836, found 471.218097.

The corresponding amide side product N-(3-amidophenyl)-N'-(1-(2-aminophenyl)sulfonyl-piperidin-4-yl)cycloheptylurea was also isolated (46 mg); HRMS (M+H)+ calc. 472.201852, found 472.202530.

The following Example 14 to 16 were prepared by essentially the same preparative methods as described above for Example 13; the only changes involved the sulfonylation of the common intermediate N-(3-cyanophenyl)-N'-(piperidin-4-SUBSTITUTE SHEET(RULE26) CA 022~l394 lsss-lo-o~

W097t38984 PCT~S97/06431 yl)cycloheptylurea. In each case, however, the same procedure using the appropriate sulfonylating agent in tetrahydrofuran with triethylamine was used.

Pre~aration of N-~3-amidino~henYl)-N~-(1-(3-aminoPhenYl)sulfonYlPiperidin-4-yl)cYclohe~tylurea N-(3-am;~; norh~nyl ) -N ' ~ ( 1- ( 3-am; n~ph~nyl ) sulfonylpiperidin-4-yl)cycloheptylurea: In this case the title compound wasprepared by sulfonylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with 3-nitrophenylsulfonyl chloride.
This product was reduced by a mixture of zinc dust and calcium chloride in aqueous ethanol followed by amidine formation as described above to give the title compoundi HRMS (M+H) + calc.
471.217836, found 471.219532.

Pre~aration of N- (3-am;~;no~h~nyl) -N' - (1- (4-aminoDhenyl) ~ulfonYl~i~eridin-4-Yl)cYclohePtylurea N- (3-am;~;norh~nyl) -N~ - (4-_minophenyl)sulfonylpiperidin-4-yl)cycloheptylurea: In this case the title compound was prepared by sulfonylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with 4-nitrophenylsulfonyl chloride.
This product was reduced by a mixture of zinc dust and calcium chloride in aqueous ethanol followed by amidine formation as described above to give the title compound; HRMS (M+H) + calc.
471.217836, found 471.217059.

Pre~aration of N-(3-amidino~henYl)-N~-(1-((2-Am;no~he~Yl) methane)sulfonYl)-~i~eridin-4-Yl)cYclohe~tYlurea N-(3-A~ ;nophenyl)-N'-(1-((2-aminophenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea: In this case the title compound was prepared by sulfonylation of N-(3-cyanophenyl)-SlJts~ 111 IJTE SHEET (RULE 26) .. .. ... . .

CA 022~1394 1998-10-0~

WO 97/38g84 PCTtUS97/06431 M'-(piperidin-4-yl)cycloheptylurea with ((2-nitrophenyl)methane)sulfonyl chloride. This product was reduced by a mixture of zinc dust and calcium chloride in aqueous ethanol followed by amidine formation as described above to give the title compound; HRMS (M+H)+ calc.
485.233486, found 485.235037.

PreDaration of N-(3-ami~ino~h~nyl~-N~ ((2-acet~m;~
Phen~l)methane)sulfon~lDi~eridin-4 -Yl ) cYcloheDt~lurea N-(3-~ya~o~henyl)-N~ -((2-am;nnrh~nyl)methane)sulfonyl-piperidin-4-yl)cycloheptylurea: This material was prepared by sulfonylation of N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea with ((2-nitrophenyl)methane)sulfonyl chloride in tetrahydrofuran and triethyl amine, as described for EXAMPLE 16. Reduction of the nitro group using zinc dust and calcium chloride in aqueous ethanol gave N-(3-cyanophenyl)-N'-(1-((2-aminophenyl)methane)sulfonyl-piperidin-4-yl)cycloheptylurea;
LRMS (M+H)+ m/z 468.

N-(3-cy~norh~nyl)-N'-(1-((2-acetam;~oph~nyl)methane)sulfonyl-piperidin-4-yl)cycloheptylurea: N-(3-cyanophenyl)-N'-(1-((2-aminophenyl)methane)sulfonylpiperidin-4-yl)cycloheptylurea (0.296 g, 0.63 mmol) in chloroform (30 ml) and triethylamine (0.13 g, 1.27 mmol) was cooled to 0 C and acetyl chloride (0.06 g, 0.76 mmol) was added. The reaction was allowed to warm to ambient temperature and was stirred for 6 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with lN HCl and brine, then dried ~Na2SO4) and evaporated. Purification by silica gel flash chromatography with 5~ methanol in chloroform gave 194 mg of N-(3-cyanophenyl)-N'-(1-((2-acetamidophenyl)methane)sulfonyl-piperidin-4-yl)cycloheptylurea; LRMS (M+H)+ m/z 510.

N-(3-ami~;n~phenyl)-N'-(1-((2-acetr-;~rhenyl)methane)-sulfonylpiperidin-4-yl)cycloheptylurea: N-(3-cyanophenyl)-N~-SlJ~ 111 UTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 ~ 2-acetamidophenyl)methane)sulfonyl-piperidin-4-yl)cycloheptylurea (0.194 g, 0.38 mmol) in anhydrous methyl acetate (25 ml) and anhydrous methanol (10 ml) was cooled to 0 C and saturated with dry hydrogen chloride gas. The reaction vessel was securely stoppered and was stirred at ambient temperature for 18 h. The intermediate imidate was obtained as the hydrogen chloride salt (0.174 g) by removal of the solvent and residual hydrogen chloride in vacuo; ~RMS
(M+H)+ m/z 542.
The imidate prepared above (0.174 g) and a solution of ammonium acetate (0.15 g) in methanol (10 ml) were stirred at ambient temperature for 18 h. A mixture of the desired amidine and the corresponding amide were obtained after removal of the solvent. This mixture was separated by HPLC on a Vydec~ C-18 column eluting with solvent mixture A (water:
TFA 99.5:0.5) and solvent mixture B (acetonitrile: TFA
99.5:0.5) using a gradient starting with A at 100 % and changing to B at 100 % over 50 min. There was obtained 9.6 mg of the desired product N-(3-amidinophenyl)-N'-(1-((2-acetamidophenyl)methane)-sulfonylpiperidin-4-yl)cyclo-heptylurea; HRMS (M+H)+ calc. 527.244051, found 527.246420.

The corresponding amide side product N-(3-amidophenyl)-N'-(1-((2-acetamidophenyl)methane)-sulfonylpiperidin-4-yl)cyclohepty urea was also isolated (8.5 mg); HRMS (M+H)+
calc. 528.228066, found 528.236184.

Pre~aration of 1-(1-benzoYlPiPeridin-4-Yl)-3-(3-amidino~henYl)-5-ethen~1-2-~midazoli~;no~e 1-(1-t-butoxyc~rhonylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazol;~;n~s: A mixture of N-(3-cyanophenyl)-N'-(1-(t-butoxycarbonyl)-piperidin-4-yl)urea (O.50 g, 1.45 mmol) and sodium hydride (0.20 g of a 60 % suspension in mineral oil, 8.3 mmol) in dimethylformamide was stirred at ambient temperature for 30 min. then cis-1,4-dichloro-2-butene (0.18 SUBSTITUTE SHEET(RULE26) ..

CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 g, 1.44 mmol) was added. This mixture was heated at 70 C for 4 h, after which an addition 0.2 g of 60 % sodium hydride and 0.04 g of cis-1,4-dichloro-2-butene was added. The mixture was heated at 70 C for an addition 2 h during which the remaining starting material was consumed. The reaction was diluted with brine (50 ml) and extracted with ethyl acetate (3x). The ethyl acetate extracts were washed with brine, then dried ~Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel, eluting with 2:1 hexane:ethyl acetate to give 0.20 g of l~ t-butoxycarbonylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone; LRMS (M+H)+ m/z 397.

l-(piperidin-4-yl)-3-(3-am;~;n~rh~nyl)-5-ethenyl-2-;~;dazoli~;no~e: 1-(1-t-Butoxycarbonylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone (1.32 g, 3.3 mmol) was stirred in 1:1 dichloromethane: trifluoroacetic acid (30 ml) for 4 h. This solvent was removed in vacuo, and 1.35 g of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone was obtained as the trifluoroacetic acid salt LRMS (M+H)+ m/z 297.

1-(1-benzoylpiperidin-4-yl)-3-(3-cyanophenyl)-5-ethenyl-2-; ;~A7~1;~;non~: The free base of l-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone (1.99 g, 6.72 mmol) in tetrahydrofuran (50 ml) and triethylamine (1.36 g, 13,44 mmol) was cooled to 0 C and benzoyl chloride in tetrahydrofuran (10 ml) was added. After 4 h the reaction was complete; the solvent was removed in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with l_ HCl and brine, then dried (Na2SO4) and evaporated. The desired product was isolated by flash chromatography using silica get and 2:1 ethyl acetate as eluent. There was obtained 0.63 g of pure 1-(1-benzoylpiperidin-4-yl)-3-(3-cyanophenyl)-5-ethenyl-2-imidazolidinone; LRMS (M+H)+ m/z 401.

SlJts:i 111 UTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 benzoylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-~ 701i~; none 1-(1-Benzoylpiperidin-4-yl)-3-(3-cyanophenyl)-5-ethenyl-2-imidazolidinone (0.30 g, 0.75 mmol) in anhydrous 4:1 chloroform:methanol (25 ml) was cooled to 0 C
and saturated with dry hydrogen chloride gas. The reaction vessel was stoppered securely then left to stand at 10 C for 72 h. The solvent was removed in vacuo to give 0.33 g of the imidate as the hydrogen chloride salt (0.75 mmol); LRMS (M+H)+
m/z 433.
The imidate prepared above (0.33 g, 0.75 mmol) was dissolved in anhydrous methanol (10 ml) and ammonium carbonate (0.36 g, 3.76 mmol) was added. This mixture was stirred at ambient temperature for 18 h, then the solvent was removed in vacuo.
The residue was dissolved in water (10 ml) and washed with diethyl ether (3x). The aqueous layer was lyophillized and the crude product was purified by HPLC on a Vydec~ C-18 column eluting with solvent mixture A (water: TFA 99.5:0.5) and solvent mixture B ~acetonitrile: TFA 99.5:0.5) using a gradient starting with A at 100 % and changing to B at 100 %
over 50 min. The fractions containing pure 1-(1-benzoylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone were collected and lyophillized to give 0.090 g of material; HRMS (M+H) + calc. 418.224300, found 418.223792.
The following Example 19 and 20 were prepared by essentailly the same preparative methods as described above for Example 18; the only changes involved the sulfonylation of the common intermediate 1-(piperidin-4-yl)-3-~3-amidinophenyl)-5-ethenyl-2-imidazolidinone. In each case, however, the same procedure using the appropriate acylating or sulfonylating agent in tetrahydrofuran with triethylamine was used.

S~J~S 111 UTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097l38984 PCT~S97/06431 PreParation of 1~ ((~henYl)methan~)sulfonYl~Pi~eridin-4-yl)-3-(3-ami~in~DhsnYl)-5-ethenyl-2-imidazoli~;n~ne In this case the title compound was prepared by sulfonylation of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone with ~-toluene sulfonyl chloride in tetrahydrofuran with triethylamine folowed by amidine formation as described above; HRMS (M+H)+ calc. 468.206937, found 468.204978.

PreParation of 1-(l-PhenYlsulfonYlpiPeridin-4-yl)-3-(3 amidinoPhenyl)-5-ethenyl-2-imidazol;~; none In this case the title compound was prepared by sulfonylation of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone with phenylsulfonyl chloride in tetrahydrofuran with triethylamine folowed by amidine formation as described above; HRMS (M+H)+ calc. 454.191287, found 454.191418.
EXAMP~E 21 Pre~aration of 1,2,4,5-tetrahYdro-2-((~henYl)methane)-sulfonYl)~iperidin-4-Yl)-4-(3 - A~; dinoPhenYl)-3H-2,4-benzodiazePin-3-one N-[methyl(2-((t-butyldimethylsilyloxy)methyl)Phenyl)]-N-~(N-carbo-t-butoxy)piperidin-4-yl]amine: A solution of methyl-2-cyanobenzoate (10 g, 62.11 mmol) in ethyl ether (300 mL) was added dropwise to a slurry of lithium aluminum hydride in ethyl ether (200 mL). After the addition was complete, more ether was added (200 mL) and the mixture heated at reflux for 2h. The cooled reaction mixture was quenched by careful addition of succesive amounts of water (7.1 mL), lN sodium hydroxide solution (7.1 mL) and water (21.3 mL). The reaction was filtered and evaporated to give 6.96 g (50.8 mmol) of 2-(aminomethyl)benzyl alcohol. This material was carried on without further purification.

SU~ JTE SHEET (RULE 26) CA 022~l394 Igss-lo-o~

W097/38984 PCT~S97106431 The material from above was dissolved in tetrahydrofuran (140 mL) and cooled to 0~C. To this mixture was added imidazole (1.3 equivilents, 4.5 g, 66.04 mmol) and t-butyldimethylsilyl chloride (1.05 equivilents, 8.04 g, 53.34 mmol). The reaction mixture was stirred at ambient temperature for 18 h then was diluted with water (500 mL) and extracted with ethyl ether (3 x 150 mL). The ether extract was dried (MgSO4) and evaporated to give 10.78 g (41 mmol) of the t-butyldimethyl-silyl ether of 2-(aminomethyl)benzyl alcohol.

To a mixture of the t-butyldimethylsilyl ether prepared above (7.77 g, 29.5 mmol) and N-(carbo-t-butoxy)piperidin-4-one (5.88 g, 29.5 mmol) in methanol at 0~C was added zinc chloride (4.02 g, 29.5 mmol) followed by sodium cyanoborohydride (2.04 g, 32.45 mmol). The reaction was thawed to ambient temperature and stirred for 18 h. After this time, the reaction was judged to be complete by TLC (20% methanol in chloroform); the solvent was removed by distillation in vaccuo and the residue partitioned between ethyl acetate and lN
hydrochloric acid solution. The ethyl acetate layer was washed with brine and dried (MgSO4) then evaporated to give 11.66 g (26.87 mmol) of N-[methyl(2-((t-butyldimethylsilyloxy)methyl)phenyl)]-N-[(N'-carbo-t-butoxy)piperidin-4-yl]amine.

N-[methyl(2-(chloromethyl)phenyl)~-N-[(N'-carbo-t-butoxy)piperidin-4-yl]-(3-cyano)benzamide: A mixture of 11.66 g (26.87 mmol) of N-[methyl(2-((t-butyldimethylsilyloxy)-methyl)phenyl)]-N-[(N-carbo-t-butoxy)piperidin-4-yl]amine and 3-cyanophenyl isocyanate (3.87 g, 26.87 mmol) in dimethyl-formamide (100 mL) was stirred at ambient temperature for 24 h. The reaction was judged to be complete by TLC (5% methanol in chloroform) and diluted with brine (500 mL). The suspension was extracted with ethyl acetate (150 mL) and the ethyl acetate extracts were washed with brine (5 x 100 mL) then dried (MgSO4) and evaporated to give 14.54 g of crude material. This material was purified further by elution from SU~a ~ JTE SHEET (RULE 26) , .. .. ~ . .... .. . . . .

CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 a 400 gram column of silica gel with a mixture of ethyl acetate and hexane; the material isolated from the eluent was 11.66 g (20.17 mmol) of the pure isocyanate addition product.

A tetrahydrofuran solution (200 mL) of the purified isocyanate addition product (11.5 g, 20 mmol) was treated with solid tetra-n-butylammonium fluoride (5.75 g, 22 mmol). The reaction was complete in 30 min (TLC, 1:1 hexane:ethyl acetate) whereupon the solvent was removed by distillation in vaccuo and the residue partioned between ethyl acetae and water. The ethyl acetate layer was dried (MgSO4) and evaporated to give 13.23 g of the desilylsted benzyl alcohol tainted with a silyl fluoro- or silyloxy- side product from the cleaved protecting group. This material was assumed to contain a quantitative yield of the desired benzyl alcohol (20 mmol) and dissolved in chloroform (300 mL). The cooled solution (0~C) was treated with triethylamine (2.23 g, 3.1 mL, 22 mmol) followed by the dropwise addition of methane- sulfonyl chloride (2.29 g, 1.55 mL, 20 mmol) in chloroform (50 mL). The reaction was allowed to thaw to ambient temperature and stirred for 18 h. The reaction was washed with 5% sodium hydrogensulfate solution ~2 x 150 mL) then dried and evaporated to give 10.25 g of crude product as the benzyl chloride. A portion of this material (ca. 5 g) was purified further by elution from a 400 g column of silica gel with 3:1 hexane:ethyl acetate. The pure N-[methyl(2-(chloromethyl)phenyl)]-N-[(N'-carbo-t-butoxy)piperidin-4-yl]-(3-cyano)benzamide (3.1 g, 6.43 mmol) was isolated from the eluent as a white solid mp: 165-170~C.
1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-h~n7o~;azepin-3-one: The pure N-[methyl(2-(chloro-methyl)phenyl)]-N-[(N'-carbo-t-butoxy)piperidin-4-yl]-(3-cyano)benzamide (3.1 g, 6.43 mmol) was dissolved in dimethylformamide (30 mL), cooled to 0~C and a 60% suspension of sodium hydride in mineral oil (0.52 g of suspension, 12.46 mmol) was added. The reaction was complete after 2h at 0~C;
it was diluted with water (150 mL) and extracted with ethyl SUBSTITUTE S~EET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 acetate (3 x 50 mL). The ethyl acetate solution was washed with brine (5 x 50 mL), t'nen was dried and evaporated. The yield of the cyclized product was 2.7 g (6.05 mmol); this material was cont~in~ted with a small amount of mineral oil but was carried on to th- next step without further purification.

The t-butoxycarbonyl protecting group on the product prepared above (2.7 g, 6.05 mmol) was removed by treatment with 4N
hydrogen chloride in dioxane (15 mL) at 0~C for 3 h. The reaction mixture was purged with nitrogen gas, then evaporated. The residue was dissolved in water (50 mL) and washed with ethyl ether (2 x 25 mL). The water solution was made basic (pH 12) with 10% sodium hydroxide solution and the product extracted wi~h ethyl acetate (3 x 50 mL). The ethyl acetate solution was washed with lN aqueous sodium hydroxide, then was dried (MgSO4) and evaporated to give 1.62 g (4.68 mmol) of 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-~3-cyanophenyl)-3H-2,4-benzodiazepin-3-one as a tan solid, mp 20 115.8 ~C; HRMS for C21H23N4O (M+H)+: calc. 347.187187, found 347.184824.

1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one:
25 A solution of 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one (0.805 g, 2.33 mmol) in tetrahydrofuran (50 mL) was cooled to 0~C and triethylamine (0.26 g, 0.36 mL 2.6 mmol) was added. To this mixture a tetrahydrofuran solution (25 mL) of benzylsulfonyl chloride (0.5 g, 2.6 mmol) was added dropwise. The reaction mixture was allowed to thaw to ambient temperature and stirred for 24 h.TLC indica~ed that the reaction was complete (10% methanol in chloroform). The mixture was evaporated and the residue suspended in a 3:1 mixture of water:lN hydrogen chloride solution. The product solidified, the suspension was filtered and the resulting powder air-dried, to give 0.89 g of crude product. This material was purified further by flash chromatography with a column of silica gel (80 g) and eluting SUBSTITUTE SHEET (RULE 26) .. .. .. ... ..

CA 022~l394 lsss-lo-o~

W097t38984 PCT~S97/06431 with 2:1 then 1:1 hexane:ethyl acetate. From the eluent there was isolated 0.41 g (0.82 mmol) of pure 1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one, mp: 205-207 ~C.

1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-~;dinophenyl)-3H-2,4 -~n 70~ i A 7epin-3-one:
A solution of 0.41 g (0.82 mmol) of pure 1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in chloroform (10 mL) was added to a saturated solution of dry, gaseous hydrogen chloride in dry methanol (10 mL) and chloroform (50 mL) at -78~C. The reaction vessel was stoppered tightly and allowed to thaw to ambient temperature; this mixture was maintained in this fashion for 18 h. After this time, excess hydrogen chloride gas was removed from the reaction mixture by purging with a stream of dry nitrogen gas; the solution was then evaporated and pumped on for several hours to remove traces of free hydrogen chloride gas. The resulting imidate was detected by LRMS:m/z (M+H)+ = 533. This material was dissolved in a solution of dry chloroform (20 mL) and 2.0 M ammonia in methanol (5 mL, 10 mmol), the reaction vessel was stoppered tightly and stirred at ambient temperature for 6 days. The reaction mixture was evaporated and there was obtained about 0.45 g of the amidine product contaiminated with the amide side product. This mixture was purified by HPLC, eluting with a an aqueous phase of 0.05% trifluoroacetic acid in water and an organic phase of 0.05% trifluoroacetic acid in acetonitrile. The product, 1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one (0.11 g, 0.17 mmol), was isolated as the trifluoroacetic acid salt by lyophylization of the appropriate fractions; mp: 210-211~C;
purity > 99.5% (HPLC); HRMS: (M+H)+ for C28H3lNsso3~ calc.
518.222587, found 518.221085.

SUBSTITUTE SHEET(RULE 26) . .

CA 022~1394 Isss-lo-o~

W097138984 PCT~S97/06431 PreParation of 1,2,4,5-tetrahydro-2-(thio~en-2-Yl~-sulfonYl)~iPeridin-4 -Yl ) - 4-(3-ami~; no~h9nyl ) - 3H-2,4-benzodiazeD~n-3-one The intermediate 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one was sulfonylated with (thiophen-2-yl)sulfonyl chloride according to the procedure outlined for the preparation of 1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-cy~lophenyl~-3H-2,4-benzodiazepin-3-one in EXAMPLE 21.

The title compound was obtained via the imidate according to the procedure for l,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one of EXAMPLE 21 by starting with the intermediate prepared above. LRMS: m/z = 509i mp = 119-120~C.

PreParation of 1, 2,4,~-tetrahYdro-2-((~henYl)methane)-sulfonYl)~i~eridin-4-Yl)-4-(3-am;~;n~henYl)-7,8-dlmethoxY-3H-2,4-benzodiazeDin-3-one The intermediate 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one was prepared from methyl 3,4-dimethoxy-6-cyanobenzoate according to the procedure for the preparation of l,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in EXAMPLE 21.
The intermediate 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one was sulfonylated with benzylsulfonyl chloride according to the procedure outlined for the preparation of l,2,4,5-tetrahydro-2-((phenyl)methane)sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in EXAMPLE 21.

SUBSTITUTE SHEET (RULE 26) .

CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97tO6431 The title compound was obtained via the imidate according to the procedure for l,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one of EXAMPLE 21 by starting with the intermediate prepared above. HRMS: (M+H)+ for C30H3sNsOsS, calc. 578.243716, found 578.245119.

PreParation of 1.2,4,5-tetrah~dro-2-(thio~hen-2-Yl)-sulfonYl)PiPeridin-4-Yl)-4-(3-amidino~henyl)-7~8-dimethoxv-3H
2,4 -h~n 70~i A 7eDin- 3-one The intermediate 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one was prepared from methyl 3,4-dimethoxy-6-cyanobenzoate according to the procedure for the preparation of l,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in EXAMPLE 21.

The intermediate 1,2,4,5-tetrahydro-2-(piperidin-4-yl)-4-(3-cyanophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one was sulfonylated with (thiophen-2-yl)sulfonyl chloride according to the procedure outlined for the preparation of 1,2,4,5-tetrahydro-2-((phenyl)methane)sulfonyl)piperidin-4-yl)-4-(3-cyanophenyl)-3H-2,4-benzodiazepin-3-one in EXAMPLE 21.

The title compound was obtained via the imidate according to the procedure for l,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one of EXAMPLE 21 by starting with the intermediate prepared above. HRMS: (M+H)+ for C27H31NsOsS2, calc. 570.184488, found 570.186900.

EXAMPLES 25 to 55 (shown in Table 7) Examples 25 to 55 were prepared by essentially the same preparative methods as described above for Example 8; the only changes involved the sulfonylation, alkylation or acylation of the common intermediate N-(3-cyanophenyl)-N'-(piperidin-4-SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 yl)cycloheptylurea. In each case, the same procedure using the appropriate sulfonyl chloride, sulfamoyl chloride, alkyl chloride or acyl chloride in tetrahydrofuran with triethylamine was used. Following imidate formation, the reaction with methanolic ammonia to give the amidine product was executed as described in Example 13.
An exceptional case was the preparation of Example 28;
this product was obtained as a by-product of the formation of the amidine Example 29. During the methanolic ammonia step competing deacylation of Example 29 led to the formation of Example 28. Both Examples 28 and 29 were obtained pure and homogeneous by HPLC purification of the mixture obtained during amidine formation under standard preparative HPLC
purification conditions.

PreParation of N-(3-amidinoPhen~l)-N'-((l-((DhenYl)-l,l-dimethYl)methane~sulfonYl)-~iDeridin-4-Yl)cycloheptylurea The title compound was prepared from N-(3-cyanophenyl)-N'-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea found in Example 8 N-(3-cyanophenyl)-N'-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea (1.94 g, 4.29 mmol) in dimethylformamide (25 mL) was cooled to -10~C and lM potassium t-butoxide solution in tetrahydrofuran (12.9 mL, 12.9 mmol) was added dropwise. The reaction was stirred for 15 min at -10~C then methyl iodide (1.83 g, 12.9 mmol) was added. After 2 h reaction was complete by TLC; the reaction micture was poured into water (200 mL), then was extracted with ethyl acetate (3 x 50 mL). The ethyl acetate extracts were washed with water (5 x 50 mL), dried ~MgSO4) and evaporated to give 0.55 g of N-(3-cyanophenyl)-N'-((1-((phenyl)-1,1-dimethyl)methane)-sulfonyl)-piperidin-4-yl)cycloheptylurea; LRMS (M + NH4)+ m/z = 498.

To 0.55 g of N-(3-cyanophenyl)-N'-((1-((phenyl)-1,1-dimethyl)methane)-sulfonyl)-piperidin-4-yl)cycloheptylurea SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 (1.14 mmol) in pyridine (20 mL) with triethylamine (1 mL) was passed a stream of gaseous hydrogen sulfide for 30 min. The reaction mixture was stoppered tightly and allowed to stand for 18 h. The solution was then poured into lN hydrochloric acid solution (250 mL) and extracted with ethyl acetate (3 x 50 mL). The ethyl acetate solution was dried and evaportated to give 0.53 g (1.03 mmol) of N-(3-thioamidophenyl)-N~-((1-((phenyl)-1,1-dimethyl)methane)-sulfonyl)-piperidin-4-yl)cycloheptylurea; LRMS (M + H)+ m/z = 515.
The product prepared above, 0.53 g (1.03 mmol) of N-(3-thioamidophenyl)-N'-((1-((phenyl)-1,1-dimethyl)methane)-sulfonyl)-piperidin-4-yl)cycloheptylurea, was stirred in methyl iodide (10 mL) for 2 h. The reaction was then evaporated to give 0.62 g (1.03 mmol) of the thioimidate.

The thioimidate (o.62 g, 1.03 mmol) was stirred with ammonium acetate (0.45g, 5.9 mmol) in methanol (20 mL) and heated at 60~C for 2 h. The reaction was then e~aporated, the residue stirred in dichloromethane, the insoluable material removed by filtration and the dichloromethane solution evaporated to give ca. 0.5 g of crude amidine. This material was purified by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.143 g of the title compo~nd following lyophylization of the appropriate fractionsi HRMS (M+H)+ calc.
489.253887, found 498.252412.

EXAMPLE ~7 Preparation of N-(3-amidinoPhenYl)-N'-(methvl((Phenyl-methane)carbamide)morPholin-3-Yl))cYclohePtYlurea N-benzyl 3-(aminomethyl)morpholine: N-benzyl 3-(chloro-methyl)morpholine (lOg, 44.3 mmol) in dimethylformamide (200 mL) with sodium azide (8.64 g, 133 mmol) and potassium iodide (0.73 g) was heated at 100~C for 72 h. The reaction was poured into water (1 L) and extracted with ethyl acetate (3 x 150 mL). The ethyl acetate layer was washed with water (5 x SUBSTITUTE SHEET (RULE 26) ~ ,, CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 150 mL), then dried (MgSO4) and evaporated to give 9.28 g of material. This was purified further by flash chromatography using 3:1 hexane:ethyl acetate as the eluent. There was obtained 7.89 g of the pure azide.

The material prepared above was dissolved in methanol (300 mL) and palladium hydroxide catalyst (1.0 g) was added. This mixture was stirred under an atmosphere of hydrogen gas at ambient pressure for 2 h, whereupon selective reduction of the azide group was complete. The reaction mixture was purged with nitrogen gas and the catalyst removed by filtration through a Celite pad.After removal of the solvent there was obtained 5.80 g of N-benzyl 3-(aminomethyl)morpholine (28.1 mmol); LRMS (M+H)+ m/z = 207.
N-(3-cyanophenyl)-N'-(methyl(N-methyl(phenyl))morpholin-3-yl))cycloheptylurea: A mixture of 5.80 g of N-benzyl 3-(aminomethyl)morpholine (28.1 mmol) and 3-cyanophenyl isocyanate (4.46 g, 31 mmol) in dimethylformamide (100 mL) was stirred at ambient temperature for 18 h. The reaction was diluted with water (500 mL) then extracted with ethyl acetate (3 x 100 mL). The ethyl acetate solution was washed with water (5 x 100 mL), dried (MgSO4) and evaporated to give 9.49 g of the urea (27.1 mmol); LRMS (M+H)+ m/z = 351.
To a mixture of sodium hydride (3.25 g of a 60% suspension in mineral oil, 81.3 mmol) in dimethylformamide (450 mL) was added dropwise 9.49 g of the urea (27.1 mmol) prepared above as a solution in dimethylformamide (50 mL). This mixture was stirred for 30 min, then 1,71 g of 1,4-dibromobutane (54.2 mmol) in dimethylformamide (40 mL) was added slowly. The reaction was heated to 70~C for 6 h then poured into water (2 L) and extracted with ethyl acetate (3 x 250 mL). The ethyl acetate extract was washed with water (5 x 250 mL) , was dried (MgSO4) and evaporated. The residue was purified by flash chromatography using 2:1 hexane:ethyl acetate as an eluent.
There was obtained 7.59 g of N-(3-cyanophenyl)-N'-(methyl(N-SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 methyl(phenyl))morpholin-3-yl))cycloheptylurea; LRMS (M+H~+
m/z = 405.

N-(3-cyanophenyl)-N'-(methyl(morpholin-3-yl))cycloheptylurea:
To N-(3-cyanophenyl)-N'-(methyl(N-methyl~phenyl))morpholin-3-yl))cycloheptylurea (4.66 g, 11.55 mmol) in dichloromethane (100 mL) was added 1-chloroethyl chloroformate (1.81 g, 12.7 mmol) in dichloromethane (10 mL). After 2 h the reaction was complete by TLC; the solvent was removed by evaporation in vaccuo and replaced by methanol (60 mL). The mixture was refluxed for 1 h then the solvent evaporated to give 3.53 g of N-(3-cyanophenyl)-N'-(methyl(morpholin-3-yl))cycloheptyl-urea;
LRMS (M+H)+ m/z = 315.

N-(3-cyanophenyl)-N'-(methyl((phenylmethane)carbamide)-morpholin-3-yl))cycloheptylurea: To 1.0 g of N-(3-cyanophenyl)-N'-(methyl(morpholin-3-yl))cycloheptylurea (3.18 mmol) in tetrahydrofuran (30 mL) with triethylamine (0.68 g, 6.7 mmol) at 0~C was added phenylacetyl chloride (0.54 g, 3.5 mmol) in tetrahydrofuran (10 mL). The mixture was allowed to thaw to ambient temperature and stirred for 18 h. After this time, the solvent was removed by evaporation in vaccuo and the residue purified by flash chromatography with lO~ methanol in chloroform used as the eluent. There was obtained 1.17 g (2.7 mmol) of N-(3-cyanophenyl)-N'-(methyl((phenyl-methane)carbamide)morpholin-3-yl))cycloheptylurea as product;
LRMS (M+H)+ m/z = 433.

N-(3-amidinophenyl)-N'-(methyl((phenyl-methane)carbamide)-morpholin-3-yl))cycloheptylurea: To a saturated solution of gaseous hydrogen chloride in dry chloroform (20 mL) and dry methanol (8 mL) at -78~C was added dropwise a chloroform (5 mL) solution of 1.17 g (2.7 mmol) of N-(3-cyanophenyl~-N'-(methyl((phenyl-methane)carbamide)morpholin-3-yl))cycloheptylurea. This mixture was stoppered tightly, wasallowed to thaw to ambient temperature and was stirred for 18 h. The solvent was removed in vaccuo to give 1.04 g of the corresponding imidate; LRMS (M+H)+ m/z = 465.

SUBSTITUTE SHEET(RULE 26) .. . .. ~ .

CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 The imidate prepared above was dissolved in 2M ammonia in methanol solution (6.72 mmol, 3.36 mL), the flask was stoppered securely and the mixture stirred at ambient temperature for 18 h. After this time the solvent was removed in vaccuo and the residue (ca. 1.2 g) was purified by HP~C
(gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.12 g of N-(3-amidinophenyl)-N'-(methyl((phenyl-methane)carbamide)-morpholin-3-yl))cycloheptylureai mp 49-53 ~C; HRMS (M+H)+: calc.
450.250515, found 450.251817.

EXAMPLE15 Pre~aration of N-(3-amidino~henYl~-N'-(methYl((thioDhen-2-Yl)sulfonYl)morDholin-3-Yl))cyclohe~tylurea This compound was prepared by the same methods used for Example 57. Starting with the common intermediate N-(3-cyanophenyl)-N'-(methyl(morpholin-3-yl))cycloheptylurea, this material was sulfonylated with (thiophen-2-yl)sulfonyl chloride using the same conditions for the acylation described above. There was obtained 0.75 g of the sulfonylation product following purification by flash chromatography using a gradient of 2:1 hexane:ethyl acetate to 1:2 hexane:ethyl acetate as a gradienti LRMS (M+H)+ m/z = 461.

The imidate and subsequently, the amidine N-(3-amidinophenyl)-N'-(methyl((thiophen-2-yl)sulfonyl)morpholin-3-yl))cycloheptylurea were obtained as described. Following HPLC purification 0.32 g of the title compound was isolated;
mp 78-83 ~Ci HRMS (M+H)+: calc. 478.158273, found 478.156983.

SUBSTITUTE SHEET(RULE26) CA 022~1394 1998-10-0~

EXI~LE 5 9 PreDaration of N- ( 3 -amidinoDhenYl ) -N ' - (methYl ( (Phen~rl-methane ) sulf onYl ) morPholin-3 -Yl ) ) cYcloheDtylurea This compound was prepared by the same methods used for Example 57. Starting with the common intermediate N-(3-cyanophenyl)-N'-(methyl(morpholin-3-yl))cycloheptylurea, this material was sulfonylated with (phenyl)methylsulfonyl chloride using the same conditions for the acylation described above.
There was obtained 0.68 g of the sulfonylation product following purification by flash chromatography using a gradient of 1:1 hexane:ethyl acetate to 1:3 hexane:ethyl acetate as a gradient; LRMS (M+H)+ m/z = 469.
The imidate and subsequently, the amidine N-(3-amidinophenyl)-N'-(methyl((phenylmethane)sulfonyl)morpholin-3-yl))cycloheptylurea were obtained as described above.
Following HPLC purification 0.102 g of the title compound was isolated; mp 45-53 ~C; HRMS (M+H)+: calc. 486.217502, found 486.217928.

PreParation of N-(3-amidino~henYl)-N'-((N-benzYl)~i~eridin-3-Yl)cYclohePtYlurea N-Benzyl 3-aminopiperidine: To 10.0 g of N-benzyl 3-hydroxypiperidine hydrogen chloride salt (44 mmol) in chloroform (200 mL) with triethylamine (9.34 g, 92.4 mmol) at 0~C was added dropwise methanesulfonyl chloride (5.54 g, 48.4 mmol) in chloroform (10 mL).The reaction mixture was allowed to thaw to ambient temperature and stirred 72 h. After this time, the solvent was removed in vaccuo, the residue was dissol~ed in ethyl acetate (200 mL) and washed with water (200 mL). The organic solution was dried (MgSO4) and evaporated to give 9.1 g (33.8 mmol) of the mesitylate.

SU~:j 111 UTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 The material prepared above was dissolved in dimethylformamide (200 mL) and stirred at 100 ~C with sodium azide (11 g, 170 mmol). After 48 h the reaction was complete by TLC; it was diluted with brine (200 mL) and extracted with ethyl acetate (3 x 100 mL). The ethyl acetate extracts were washed with - water (5 x 100 mL), then dried and evaporated to give 6.12 g of the azide; LRMS (M+H)+ m/z = 217.

The azide (6.12 g, 28.4 mmol) in methanol (250 mL) with palladium hydroxide catalyst (1.0 g) was stirred under an atmosphere of hydrogen gas at ambient pressure for 1 h 15 min.
After this time selective reduction of the azide was complete.
The react-on mixture was purged with nitrogen gas and the catalyst removed by filtration through a Celite pad. The solvent was removed by distillation in vaccuo to give 4.3 g of N-benzyl 3-aminopiperidinei LRMS (M+H)+ m/z = 191.

N-(3-cyanophenyl)-N'-((N-~enzyl)piperidin-3-yl)cycloheptyl-urea: A mixture of 4.3 g of N-benzyl 3-aminopiperidine (22.6 mmol) and 3-cyanophenyl isocyanate (3.58 g, 24.9 mmol) in dimethylformamide (100 mL) was stirred at ambient temperature for 18 h. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (3 x 150 mL). The organic solution was washed with water (5 x 100 mL), dried and evaporated. This material was purified further by flash chromatography on silica gel using a gradient of 1:1 to 3:1 ethyl acetate:hexane. There was obtained 3.18 g of the pure urea (9.52 mmol); LRMS (M+H)+ m/z = 335.

To 1.14 g of sodium hydride (60% suspension, 28.6 mmol) in dimethylformamide (160 mL) was added a dimethylformamide (20 mL) solution of the urea (3.18 g, 9.52 mmol). After 30 min, 1,4-dibromobutane (4.32 g, 20 mmol) in dimethylformamide (10 mL) was added dropwise, then the mixture was heated to 70 ~C
for 3 h. The reaction was diluted with water (700 mL) and extracted with ethyl acetate (3 x 100 mL). The organic solution was washed with water (5 x 100 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 on silica gel using an elution gradient of 5 to 10% methanol in chloroform. There was obtaine 3.17 g of N-~3-cyanophenyl~-N'-((N-benzyl)piperidin-3-yl)cycloheptyl-urea; LRMS (M+H)+ m/z = 389.

N-(3-am;~;noph~nyl)-NI-~(N-benzyl)piperidin-3-yl)cycloheptyl-urea: To a saturated solution of hydrogen chloride gas in dry methanol (8 mL) and dry chloroform (15 mL) at -78 ~C was added a chloroform (5 mL) solution of N-(3-cyanophenyl)-N~-((N-benzyl)piperidin-3-yl)cycloheptyl-urea (0.5 g, 1.29 mmol).
The reaction mixture was stoppered securely and allowed to stir at ambient temperature for 18 h. After this time the solvent was removed in vaccuo and 0.49 g of the imidate hydrochloride salt was obtained; LRMS (M+H) + m/z = 422.
The imidate obtained above was dissolved in 2M ammonia in methanol (1.75 mL, 3.5 mmol). The reaction vessel was stoppered securely and the mixture stirred at ambient temperature for 18 h. After this time the solvent was removed in vaccuo and the residue was purified by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.015 g of pure N-(3-amidinophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptylureai HRMS (M+H)+: calc.406.260686, found 406.259064.

EXAMPLE 61~reDaration of N-(3-amidino~henYl)-N'-((N-(benzYl~sulfonyl)-piPeridin-3-Yl)cYclohePtvlurea N-(3-cyanophenyl)-N'-(piperidin-3-yl)cycloheptylurea: A
mixture of N-(3-cyanophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptyl-urea (prepared in Example 60, 2.7 g, 6.98 mmol) and ~-chloroethyl chloroformate (1.09 g, 7.65 mmol) was stirred at ambient temperature for 2.5 h, whereupon the reaction was complete as judged by TLC.The solvent was removed by evaporation in vaccuo and was replaced with methanol (40 mL). The reaction was heated at reflux until all of the newly SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-05 W O 97/38984 PCT~US97/06431 formed intermediate was consumed as indicated by TLC.
Evaporation of the solvent gave 2.49 g of N-(3-cyanophenyl)-N'-(piperidin-3-yl)cycloheptylurea; LRMS (M+H)+ m/z = 299.

N-(3-cyanophenyl)-N'-((N-(benzyl) 8ul fonyl)piperidin-3-yl)cycloheptylurea: To N-(3-cyanophenyl)-N'-(piperidin-3-yl)cycloheptylurea (1.2 g, 4.03 mmol) and triethylamine (0.85 g, 8.46 mmol) in tetrahydrofuran (30 mL) at 0 ~C was added benzylsulfonyl chloride (0.92 g, 4.83 mmol) in tetrahydrofuran solution (10 mL). The reaction was allowed to thaw to ambient temperature then stirred for 18 h. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate (100 mL). The organic solution was washed with lN sodium hydroxide solution (100 mL), lN hydrochloric acid (100 mL) and saturated sodium hydrogen carbonate (100 mL). The solution was dried (MgSO4) and evaporated to give 0.99 g (2.19 mmol) of N-(3-cyanophenyl)-N'-((N-(benzyl)-sulfonyl)piperidin-3-yl)cycloheptylurea; LRMS (M+H)+ m/z = 453.

N-(3-am;~; n~rh~nyl) -N'-((N-(benzyl)sulfonyl)piperidin-3-yl)cycloheptylurea: To a -78 ~C saturated solution of hydrogen chloride gas in dry chloroform (20 mL) and methanol(10 mL) was added 0.99 g (2.19 mmol) of N-(3-cyanophenyl)-N'-((N-(benzyl)-sulfonyl)piperidin-3-yl)cyclo-heptylurea in chloroform (5 mL). The reaction vessel wasstoppered securely, was allowed to thaw to ambient temperature and was stirred 18 h. After this time the solvent was removed by evaporation in vaccuo and there was obtained 1.04 g of the imidate as the hydrogen chloride salt; LRMS (M+H)+ m/z = 485.
The imidate prepared above was dissolved in 2M ammonia in methanol solution (3.22 mL, 6.44 mmol). The reaction was stoppered securely and was stirred for 18 h. Following removal of the solvent and purification by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) there was obtained 0.316 g of N-(3-amidinophenyl)-N'-((N-(benzyl)-SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-lO-O~

WO 97/38g84 PCT/US97tO6431 sulfonyl)piperidin-3-yl)cycloheptylureai HRMS (M+H)+:
calc.470.225587, found 470.221857.

Additionally, there was isolated as a slower eluting peak 0.066 g of the amide side product, N-(3-amidophenyl)-N'-((N-(benzyl)sulfonyl)piperidin-3-yl)cycloheptylurea.

Pre~aration of N-(3-ami~;n~he~Yl)-N'-(~N-(thio~hsn-2-~rl) sulfonYl)Diperidin-3-yl)cyclohe~tylurea This compound was prepared by the same methods used for Example 61. Starting with the common intermediate N-(3-cyanophenyl)-N'-(piperidin-3-yl)cycloheptylurea, this material was sulfonylated with (thiophen-2-yl)sulfonyl chloride using the same conditions for the sulfonylation described above.
There was obtained 0.87 g of the sulfonylation product following purification by flash chromatography using a gradient of 2:1 hexane:ethyl acetate to 1:1 hexane:ethyl acetate as a gradient; LRMS (M+H) + m/z = 445.

The imidate and subsequently, the amidine N-(3-amidinophenyl)-N'-((N-(thiophen-2-yl)sulfonyl)piperidin-3-yl)cycloheptylurea were obtained as described above. Following HPLC purification 0.234 g of the title compound was isolatedi HRMS (M+H) +:
calc. 462.163359, found 462.164841.

Additionally, there was isolated as a slower eluting peak 0.045 g of the amide side product, N-(3-amidophenyl)-N'-((N-(thiophen-2-yl)sulfonyl)piperidin-3-yl)cycloheptylurea ; HRMS
(M+H) +: calc. 463.147374, found 463.146300.

SUBSTITUTE SHEET(RULE 26) ~ , .

CA 022~l394 Igss-lo-o~

W097/38984 PCT~S97/06431 PreParation of N-(3-ami~;no~henYl)-N'-(4-(2-sulfonamido-PhenYl ~ ~henYl ) c~rc lohe~tYlurea N-(3 -Cy~norh~nyl )-N'-(4-bromophenyl)cycloheptylurea: A
- mixture of 3-cyanophenyl isocyanate (3.76 g, 26.1 mmol) and 4-bromoaniline (4.5 g, 26.1 mmol) in 1:1 tetrahydrofuran:chloroform (100 mL). After 72 h at ambient temperature, product was isolated by filtration, the filtrate was washed with cold chloroform and air dried to give 6.6 g of N-(3-cyanophenyl)-N'-(4-bromophenyl)urea (21 mmol).

To 1.41 g of sodium hydride (60% suspension, 33.6 mmol) in dimethylformamide (300 mL) was added a dimethylformamide (20 mL) solution of 6.6 g of N-(3-cyanophenyl)-N'-(4-bromophenyl)urea (21 mmol). After 30 min, 1,4-dibromobutane (6.2 g, 28.6 mmol) in dimethylformamide (10 mL) was added dropwise, then the mixture was heated to 60 ~C for 2 h and then was stirred at ambient temperature for 18 h. The reaction was diluted with water (700 mL) and extracted with ethyl acetate (3 x 100 mL). The organic solution was washed with water (5 x 100 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel using an elution gradient of 5 to 10% methanol in chloroform.
There was obtained 3.68 g of N-(3-cyanophenyl)-N'-(4-bromophenyl)cycloheptylurea.

N-(3-cyanophenyl)-N'-(4-(2-((N-t-butyl)sulfonamido)phenyl)-phenyl)cycloheptylurea: A mixture of N-(3-cyanophenyl)-N~-(4-bromophenyl)cycloheptylurea (4.0 g, 10.81 mmol), 2-((N-t-butyl)sulfonamido)phenylboronic acid (3.9 g, 15.2 mmol), tetrabutylammonium bromide (0.203 g) and sodium carbonate (2.47 g) in benzene (170 mL) was thoroughly purged with dry nitrogen gas. Tetrakis(triphenylphosphine)palladium(0) catalyst (0.635 g) was added and the mixture was heated at reflux under a nitrogen atmosphere for 18 h. The benzene solution was washed with water (3 x 100 mL) and brine (100 mL), then dried (MgSO4) and evaporated. The crude product was SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 triturated with n-butylchloride, filtered and air dried to give 3.92 g of N-(3-cyanophenyl)-N'-(4-(2-((N-t-butyl)sulfon-amido)phenyl)-phenyl)cycloheptylurea.

N-(3-amidinophenyl)-N'-(4-(2-sUlfQn~ phenyl)phenyl)-cycloheptylurea: A solution of 3.0 g of N-(3-cyanophenyl)-N~-(4-(2-((N-t-butyl)sulfon-amido)phenyl)phenyl)cycloheptyl-urea (5.98 mmol) in dry methanol (40 mL) and dry chloroform (300 mL) was saturated with hydrogen chloride gas with ice cooling.
This solution was stoppered tightly and was stirred for 18 h at ambient temperature. The solvent was removed by evaporation and the residue dissolved in 2M ammonia in methanol (60 mmol, 30 mL). This solution was stirred in a securely stoppered reaction vessel for 48 h at ambient temperature. After this time the solvent was removed in vaccuo and 2.28 g of crude product was obtained. A portion (0.735 g) of this material was purified by HPLC (gradient elution with a mixture of 0.05% aqueous trifluoroacetic acid and 0.05% trifluoroacetic acid in acetonitrile) to give 0.396 g of pure N-(3-amidinophenyl)-N'-(4-(2-sulfonamidophenyl)-phenyl)cycloheptylurea ; mp 163-166 ~C HRMS ~M+H)+:
calc.464.175637, found 464.177525.

PreParation of N-(3-amidinoPhenYl)-N'-(5-(2-sulfonamido-Phenyl)PYridin-2-Yl)cYclohePtylurea Example 64 was prepared by a procedure similar to that used for Example 63 with the exception that 2-amino-5-bromopyridine was substituted for 4-bromoaniline in the intial step. There was obtained 0.043 g of N-(3-amidinophenyl)-N'-(5-(2-sulfonamido-phenyl)pyridin-2-yl)cycloheptylurea as a bis trifluoroacetate salti mp 75-79 ~C; HRMS ~M+H)+: calc.
465.170886, found 465.170759.

SIJI~:~ 111 UTE SHEET (RULE 26) , . . ... . . . . ....

CA 022~l394 Igss-lo-o~

W097/38984 PCT~S97/06431 Pre~aration of N-(3 -r ; ~; ns~henYl)-N'-(methYl(4-(2-sulfonamidoPhenYl)~hen~l))cYclohePtYlurea N-(3-cyanophenyl)-N'-(methyl(4-bromo)phenyl)urea: A mixture of 4-bromobenzyl amine (3.81 g, 20 mmol) and 3-cyanophenyl isocyanate (2.65 g, 18.4 mmol) in dimethylformamide (60 mL) was stirred at ambient temperature for 48 h. The reaction was partioned between lN hydrochloric acid solution (200 mL) and ethyl acetate (200 mL). The ethyl acetate solution was washed with water (5 x 100 mL), then dried (MgSO4) and evaporated to give 5.33 g of N-(3-cyanophenyl)-N'-(methyl(4-bromo)phenyl)urea.

N-(3-cyanophenyl)-N'-(methyl(4-bromophenyl))cycloheptyl-urea: To 1.82 g of sodium hydride (60% suspension, 45.3 mmol) in dimethylformamide (270 mL) was added a dimethylformamide (30 mL) solution of the N-(3-cyanophenyl)-N'-(methyl(4-bromo)phenyl)urea (4.98 g g, 15.1 mmol). After 30 min, 1,4-dibromobutane (6.52 g, 30.2 mmol) in dimethylformamide (10 mL)was added dropwise, This mixture was heated to 70 ~C for 3 h then cooled to ambient temperature and stirred for 48 h. The reaction was diluted with water (1 L) and extracted with ethyl acetate (4 x 250 mL). The organic solution was washed with water (5 x 150 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1% methanol in chloroform. There was obtained 2.3 g of N-(3-cyanophenyl)-N'-(methyl(4-bromophenyl))cycloheptylurea.

N-(3-cyanophenyl)-N'-(methyl(4-(2-(N-t-buty)sulfonamido-phenyl)phenyl))cycloheptylurea: A mixture of N-(3-cyanophenyl)-N'-(methyl(4-bromophenyl))cycloheptylurea (1.24 g, 3.2 mmol), 2-((N-t-butyl)sulfonamido)phenylboronic acid (1.17 g, 4.5 mmol), tetrabutylammonium bromide (0.06'g) and sodium carbonate (0.73 g) in benzene (50 mL) and water (5 mL) was thoroughly purged with dry nitrogen gas. Tetrakis(tri-phenylphosphine)palladium(0) catalyst (0.188 g) was added and the mixture was heated at reflux under a nitrogen atmosphere SIJ~S 111 IJTE SHEET (RULE 26) .

CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 for 18 h. The benzene solution was washed with water (3 x 100 mL) and brine (100 mL), then dried (MgSO4) and evaporated to give 2.0 g of crude product. Recrystallization from acetone gave 0.80 g of N-(3-cyanophenyl)-N'-(methyl(4-(2-(N-t-buty)sulfonamido-phenyl)phenyl))cycloheptylureai mp 177-179 ~C .

An additional 0.365 g of product was recovered from the mother liquors by silica gel chromatography using 1% methanol in chloroform as an eluent.

N-(3-cyanophenyl)-N'-(methyl(4-(2-sulfonamido-phenyl)phenyl))cycloheptylurea: A solution of 1.17 g of N-(3-cyano-phenyl)-N'-(methyl(4-(2-(N-t-buty)sulfonamido-phenyl)phenyl))cycloheptylurea (2.27 mmol) in trifluoroaceticacid (30 mL) was heated at reflux for 1 h. The reaction was evaporated and the residue suspended in 10% sodium hydroxide solution (30 mL). The suspension was extracted with ethyl acetate (50 mL), the extracts were washed with 10% sodium hydroxide solution (2 x 25 mL) and brine (25 mL). The solution was dried (MgSO4) and evaporated to give 0.72 g of crude product. This material was purified by column chromatography using a gradient of 1.5 to 2.5% methanol in chloroform. There was obtained 0.55 g of N-(3-cyanophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea.

N-(3-amidinophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)-phenyl))cycloheptylurea: A solution of 0.55 g of N-(3-cyanophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)-phenyl))cycloheptylurea (1.2 mmol) in dry methyl acetate (70mL) and dry methanol (0.192 g, 0.24 mL, 6.0 mmol) was cooled to 0 ~C and saturated with dry hydrogen chloride gas.The reaction was stoppered tightly and stirred at ambient temperature 18 h. Precipitation of the imidate product was initiated by the addition of ethyl ether (70 mL) to the cold solution. The solid was isolated by filtration and maintained in vaccuo for 18 h to remove the last traces of hydrogen SUBSTITUTE SHEET (RULE 26) ,, ~

CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 chloride gas; there was obtained 0.50 g of the imidate as the hydrogen chloride salt.

The imidate from above was stirred for 18 h in a methanol (20 mL) solution of ammonium acetate (0.462 g , 6 mmol). The reaction was evaporated and partioned between ethyl acetate (50 mL) and lN hydrochloric acid (50 mL). The ethyl acetate solution was dried and evaporated to give 0.16 g of the amide side-product. Lyophylization of the hydrochloric acid solution gave 0.39 g of the crude amidine. Purification of this material by HPLC (gradient elution with a mixture of 0.05% a~ueous trifluoroacetic acid and 0.05~ trifluoroacetic acid in acetonitrile) gave 0.258 g of N-(3-amidinophenyl)-NI-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea as the trifluoroacetic acid salt; mp 90-94 ~C; HRMS (M+H)+ calc.
478.191671, found 478.191287.

SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 Table 5 H2; ~ ~ ~ ) n ~ ~ ~ A

o Ex n R2 A B HRMS
(M+H)+
m/z 0 H 4-piperidinyl N-benzyl 378.229774 2 1 H 4-piperidinyl N-benzyl LRMS
(M+H) +
m/z 392 3 2 H pheny~ 4-am ~:no 351.1936 4 2 H benzy_ 4-am-~ no 365.209496 2 H 4-piperi~inyl N-(am_~_no) 358.2349 6 2 H 4-piperi~inyl N-benzyl LRMS
(M+H) +
m/z 406 7 2 H ~--p_per_~-ny~ N-(1-phenethyl)) 420.276129 '' H ~'-p per_~_ny_N-benzylsulfonyl 470.219813 '' H ~' -p~ per ~-ny N-benzoyl 421.222804 ' 0 ' H ~' -p per-~-ny N-benzylcarbonyl 434.255065 2 H ~' -p per-~-ny~ N-phenylsulfonyl 456.204189 -2 2 H 4-p per_~_ny_ N-(4-acetamido- 513.226577 phenylsulfonyl) 13 2 H 4-piperidinyl N-(2-amino- 471.218097 phenylsulfonyl) 14 2 H 4-piperidinyl N-(3-amino- 471.219532 phenylsulfonyl) 2 H 4-piperidinyl N-(4-amino- 471.217059 phenylsulfonyl) 16 2 H 4-piperidinyl N-(2-aminophenyl- 485.235037 methane-sulfonyl) 17 2 H 4-piperidinyl N-(2-acetamido- 527.246420 phenylmethane-sulfonyl~
18 0-CH=CH24-piperidinylN-phenylmethane- 418.223792 car~ony~
19 0 -CH-CH24-piperidinylN-benzy_sulzonyl 468.204978 0-CH=cH24-piperidinylN-pheny_sul-onyl 454.191418 SUBSTITUTE SHEET(RULE26) CA 0225l394 lsss-l0-05 W097/38984 PCT~S97/06431 Table 6 Rl~

HN

H2N/~ ~N~

Ex. Rl0 B HRMS
(M+H)+
m~z 21 H benzylsulfonyl 518.221085 22 H 2-thiophenylsulfonyl LRMS:
m/z = 509 23 7,8-di-OCH3benzylsulfonyl 578.245119 24 7,8-di-OCH32-thiophenylsulfonyl 570.186900 Table 7 HN ~
H2 ~ ~ N\Z _ A

Ex.Z-A B* HRMS
(M+H)+
m/z 2,~-p_per c_nyl2-fluorophenylsulfonyl474.198031 _~-p-per-c ny_isopropylsulfonyl 422.222957 ~,~-p_per c._ny8-quinolinylsulfonyl 507.217649 ~84-p_per_cr ny_1-(5-amino-4- 492.183742 methylthiazolyl)sulfonyl 294-piperidinyl1-~5-N-acetylamino-4- 534.193475 methylthiazolyl)sulfonyl 304-piperidinyl N N 514.168829 -SO
314-piperidinyl2-(5-chlorothiophenyl 497.124056 SUBSTITUTE SHEET (RULE 26) CA 022~1394 lsss-lo-o~

W097/38984 PCT~S97106431 32 4-piperidinyl3-(2-carbomethoxy) 520.168929 thiophenylsul-onyl 33 4-piperidinyl2-thiophenylsu_fonyl 462.163248 34 4-piperidinyl2-carbomethoxypnenyl- 514.212199 s~lfonyl ~-p_per-c_ny~ 2-pyr_dy~methy_ 407.258632 36 i-p-per-c ny 3-pyr-dy_methy. 407.255034 37 ~-p-per-c-ny_cyclohexy_am_nosul-onyl 477.2646 --8 ~-p-per-c_nylisopropylaminosul oryl 437.2339 ~-p_per_c-nypneny aminosulfony_ 471.2182 ~0 ~-p per-c-ny.pneny_aminocarbony_ 435.2519 ~1 ~-p-per_~-nycyclohexylaminocarbonyl 441.2968 ~2 ~-p_per-cs ny_ phenyl-N- 485.2340 methylaminosulfonyl ~: ~'-p_per-c_ny: 4-pyridylmethy 407.255561 ~- ~-p per-c.-ny3-pyridylrrethylsul onyl 471.218739 -p-per-c_ny 1-napntny_su: ony: 506.222676 -p_per-c.-ny 2-nap~tny_su_-ony 506.221512 ~, 4-p-per_c_ny_5-(2-pneny_su__ony_- 602.158636 thiophenyl)sulfonyl 48 4-piperidinyl3-pyridylsulfonyl 457.204869 49 4-piperidinyl2-(4-phenylsulfonyl- 602.157432 thiophenyl~sulfonyl 4-piperidinyl5-(N-methylimidazolyl) 460.213785 sulfonyl ~-p per-c_ny~2-pyridyl~.ethylsulfonyl 471.219270 2 ~-p per-c._ny_2-thiophenylmethyl 412.216008 3 i-p_per c ny4-fluoropnenylsul_onyl 474.199222 .,4 ~-p_per_c_ny_4-fluorophenylmetnyl- 488.210708 sulfonyl 53 4-piperidinyl3,5-bistrifluoromethyl- 592.181914 phenylsulfonyl 54 4-piperidinyl2-trifluoromethylphenyl- 524.193512 sulfonyl 4-piperidinyl2-pyridylsulfonyl 457.202166 56 4-piperidinyl (1,1-dimethyl-1- 498.252412 phenyl)methylsulfonyl 57 3-morpholinyl-N-(benzylcarbonyl) 450.251817 methyl 58 3-morpholinyl- N-(thiophen-2- 478.156983 methyl ylsulfonyl) 59 3-morpholinyl-N-(benzylsulfonyl) 486.217928 methyl -p_per_c-ny N-benzyl 406.259064 6: -p-per c.-ny. N-(benzylsulfonyl) 470.221857 62 3-p_per-c._ny_N- (thic?henylsu_fonyl) 462.164841 ~3 pheny_ 2-su _onam-c.opneny_ 464.177525 ~4 2-pyridyl 2-su.:onam_cop~eny 465.170759 benzyl 2-su_ionam-copneny_ 478.191287 *Unless otherwise indicated, group B is substituted on A para to Z, if present, and the cyclourea.

SUBSTITUTESHEET(RULE26) CA 022~1394 1998-10-0~

WO 97138g84 PCT/US97/06431 Table 8 ~ ~ ~ N ~ ,N ~ \ ~ g Ex. n R2 Z Al A2 B
101 0 Hbond CH CH amino 102 0 Hbond CH CH amidino 103 0 Hbond CH CH guanidlno 104 0 Hbond CH CH 2-sulfamidophenyl 105 0 H bond CH CH 2-trifluoromethylphenyl 106 0 OH bond CH CH amino 107 0 OH bond CH CH amldino 108 0 OH bond CH CH guanldino 109 0 OH bond CH CH 2-sulfamidophenyl 110 0 OH bond CH CH 2-trifluoromethylphenyl 111 0 NHC(O)CH3 bond CH CH amlno 112 0 NHC(O)CH3 bond CH CH amidlno 113 0 NHC(O)CH3 bond CH CH guanidino 114 0 NHC(O)CH3 bond CH CH 2-sulfamidophenyl 115 0 NHC(O)CH3 bond CH CH 2-trifluoromethylphenyl 116 0 NHSO2CH3 bond CH CH amlno 117 o NHS02CH3 bond CH CH amidino 118 0 NHSO2CH3 bond CH CH guanidino 119 0 NHSO2CH3 bond CH CH2-sulfamidophenyl 120 0 NHS02CH3 bond CH CH2-trifluoromethylphenyl 121 0 OCH3 bond CH CH amlno 122 0 OCH3 bond CH CH amldlno 123 0 OCH3 bond CH CH guanidlno 124 0 OCH3 bond CH CH2-sulfamidophenyl 125 0OCH3 bond CH CH 2-trifluoromethylphenyl 126 0 OCH2C6H5 bond CH CH amino 127 0 OCH2C6H5 bond CH CH amidino 128 0 OCH2C6H5 bond CH CH guanidino 129 0 OCH2C6H5 bond CH CH2-sulfamidophenyl 130 0 OCH2C6H5 bond CH CH2-trifluoromethylphenyl 131 0 H CH2 CH CH amino 132 0 H CH2 CH CH amidino 133 0 H CH2 CH CH guanidino 134 0 H CH2 CH CH2-sulfamidophenyl 135 0 H CH2 CH CH 2-trifluoromethylphenyl 136 0 OH CH2 CH CH amino 137 0 OH CH2 CH CH amidlno 138 0 OH CH2 CH CH guanidino 139 0 OH CH2 CH CH 2-sulfamidophenyl 140 0 OH CH2 CH CH 2-trifluoromethylphenyl 141 0 NHC(O)CH3 CH2 CH CH amlno SUBSTITUTE SHEET(RU~E 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 142 0 NHC(O)CH3 CH2 CH CH amidino 143 0 NHC(O)CH3 CH2 CH CHguanidino 144 0NHC(O)CH3 CH2 CH CH2-sulfamidophenyl 145 0NHC(O)CH3 CH2 CH CH2-trifluoromethylphenyl 146 0NHSO2CH3 CH2 CH CHamino 147 0NHSO2CH3 CH2 CH CHamidino 148 0NHSO2CH3 CH2 CH CHguanidino 149 0NHSO2CH3 CH2 CH CH2-sulfamidophenyl 150 0NHSO2CH3 CH2 CH CH2-trifluoromethylphenyl 151 0 OCH3 CH2 CH CH amino 152 0 OCH3 CH2 CH CH amidino 153 0 OCH3 CH2 CH CHguanid1no 154 0 OCH3 CH2 CH CH2-sulfamidophenyl 155 0 OCH3 CH2 CH CH2-trifluoromethylphenyl 156 0OCH2C6H5 CH2 CH CHamino 157 0OCH2c6H5 CH2 CH CHamldino 158 0OCH2C6H5 CH2 CH CHguanidino 159 0OCH2C6H5 CH2 CH CH2-sulfamidophenyl 160 0OCH2C6H5 CH2 CH CH2-trifluoromethylphenyl 161 0 H bond N CH amlno 162 0 H bond N CH amidlno 163 0 H bond N CH guanidino 164 0 H bond N CH2-sulfamidophenyl 165 0 H bond N CH 2-trifluoromethylphenyl 166 0 OH bond N CH amino 167 0 OH bond N CH amidlno 168 0 OH bond N CH guanldino 169 0 OH bond N CH 2-sulfamidophenyl 170 0 OH bond N CH 2-trifluoromethylphenyl 171 0 NHC(O)CH3 bond N CH amino 172 0 NHC(O)CH3 bond N CH amidino 173 0 NHC(O)CH3 bond N CH guanldino 174 0 NHC(O)CH3 bond N CH 2-sulfamidophenyl 175 0 NHC(O)CH3 bond N CH 2-trifluoromethylphenyl 176 0 NHSO2CH3 bond N CH amino 177 0 NHSO2CH3 bond N CH amldino 178 0 NHSO2CH3 bond N CH guanidino 179 0 NHSO2CH3 bond N CH2-sulfamidophenyl 180 0 NHSO2CH3 bond N CH2-trifluoromethylphenyl 181 0 OCH3 bond N CH amino 182 0 OCH3 bond N CH amidino 183 0 OCH3 bond N CH guanidino 184 0 OCH3 bond N CH2-sulfamidophenyl 185 0 OCH3 bond N CH 2-trifluoromethylphenyl 186 0OCH2C6H5 bond N CH amino 187 0OCH2C6H5 bond N CHamidino 188 0OCH2C6H5 bond N CHguanidlno 189 0OCH2C6H5 bond N CH2-sulfamidophenyl 190 0OCH2C6H5 bond N CH2-trifluoromethylphenyl 191 0 H CH2 N CH amino 192 0 H CH2 N CH amidino 193 0 H CH2 N CH guanidino 194 0 H CH2 N CH2-sulfamidophenyl SU~S 111 UTE SHEET (RULE 26) CA 022~1394 1998-10-0~

PCT~S97/06431 195 0 H CH2 N CH 2-trifluoromethylphenyl 196 0 OH CH2 N CH amino 197 0 OH CH2 N CH amldlno 198 0 OH CH2 N CH guanidino l99 0 OH CH2 N CH 2-sulfamidophenyl 200 0 OH CH2 N CH 2-trifluoromethylphenyl 201 0 NHC(O)CH3 CH2 N CH amino 202 0 NHC(O)CH3 CH2 N CH amidino 203 0 NHC(O)CH3 CH2 N CH guanidino 204 0 NHC(O)CH3 CH2 N CH2-sulfamidophenyl 205 0 NHC(O)CH3 CH2 N CH2-trifluoromethylphenyl 206 0 NHSO2CH3 CH2 N CH amino 207 0 NHS02CH3 CH2 N CH amidino 208 0 NHSO2CH3 CH2 N CHguanldino 209 0 NHSO2CH3 CH2 N CH2-sulfamidophenyl 210 0 NHSO2CH3 CH2 N CH2-trifluoromethylphenyl 211 0 OCH3 CH2 N CH amino 212 0 OCH3 CH2 N CH amldlno 213 0 OCH3 CH2 N CH guanidino 214 o OCH3 CH2 N CH2-sulfamidophenyl 215 0 OCH3 CH2 N CH2-trifluoromethylphenyl 216 0 OCH2C6H5 CH2 N CH amino 217 0 OCH2C6H5 CH2 N CH amidino 218 0 OCH2C6H5 CH2 N CHguanidino 219 0 OCH2C6H5 CH2 N CH2-sulfamidophenyl 220 0 OCH2C6H5 CH2 N CH2-trifluoromethylphenyl 221 0 H bond N N amlno 222 0 H bond N N amidino 223 0 H bond N N guanidino 224 0 H bond N N2-sulfamidophenyl 225 0 H bond N N 2-trifluoromethylphenyl 226 0 OH bond N N amlno 227 0 OH bond N N amidlno 228 0 OH bond N N guanidino 229 0 OH bond N N 2-sulfamidophenyl 230 0 OH bond N N 2-trifluoromethylphenyl 231 0 NHC(O)CH3 bond N N amlno 232 0 NHC(O)CH3 bond N N amidino 233 0 NHC(O)CH3 bond N N guanidino 234 0 NHC(O)CH3 bond N N 2-sulfamidophenyl 235 0 NHC(O)CH3 bond N N 2-trifluoromethylphenyl 236 0 NHSO2CH3 bond N N amino 237 0 NHSO2CH3 bond N N amidino 238 0 NHSO2CH3 bond N N guanldlno 239 0 NHSO2CH3 bond N N2-sulfamidophenyl 240 0 NHSO2CH3 bond N N2-trifluoromethylphenyl 241 0 OCH3 bond N N amino 242 0 OCH3 bond N N amidino 243 0 OCH3 bond N N guanidino 244 0 OCH3 bond N N2-sulfamidophenyl 245 0 OCH3 bond N N 2-trifluoromethylphenyl 246 o OCH2C6H5 bond N N amino 247 0 OCH2c6H5 bond N N amidino SUBSTITUTE SHEET ~RULE 26) CA 022~1394 1998-10-0~

WO 97/38984 PCT/USg7/06431 248 0CCH2C6H5 bond N Nguanidino 249 0OCH2C6H5 bond N N2-sulfamidophenyl 250 0OCH2C6H5 bond N N2-trifluoromethylphenyl 251 0 H CH2 N Namino 252 0 H CH2 N Namidino 253 0 H CH2 N Nguanidino 254 0 H CH2 N N2-sulfamidophenyl 255 0 H CH2 N N 2-trifluoromethylphenyl 256 0 OH CH2 N N amino 257 0 OH CH2 N N amidino 258 0 OH CH2 N N guanidino 259 0 OH CH2 N N 2-sulfamidophenyl 260 0 OH CH2 N N 2-trifluoromethylphenyl 261 0 NHC(O)CH3 CH2 N Namino 262 0 NHC(O)CH3 CH2 N Namldino 263 0 NHC(O)CH3 CH2 N Nguanidino 264 0 NHC(O)CH3 CH2 N N2-sulfamidophenyl 265 0 NHC(O)CH3 CH2 N N2-trifluoromethylphenyl 266 0 NHSO2CH3 CH2 N Namlno 26~ 0 NHSO2CH3 CH2 N Namidino 263 0NHSO2CH3 CH2 N Nguanidino 263 0NHSO2CH3 CH2 N N2-sulfamidophenyl 270 0NHSO2CH3 CH2 N N2-trifluoromethylphenyl 271 0 OCH3 CH2 N Namino 272 0 OCH3 CH2 N Namidino 273 0 OCH3 CH2 N Nguanidino 274 0 OCH3 CH2 N N2-sulfamidophenyl 275 0 OCH3 CH2 N N2-trifluoromethylphenyl 276 0OCH2C6H5 CH2 N Namino 277 0OCH2C6H5 CH2 N Namidino 278 0OCH2C6H5 CH2 N Nguanidino 279 0OCH2C6H5 CH2 N N2-sulfamidophenyl 280 0OCH2C6H5 CH2 N N2-trifluoromethylphenyl SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsgs-lo-o~

W097138984 PCT~S97/06431 Table 9 R~2 H2~ 1 ) n Al=~
~ ~ N ~ N ~ ~ B

Ex. n R2 Z A1 A2 B
301 1 Hbond CH CH amino 302 1 Hbond CH CH amidino 303 1 Hbond CH CH guanidino 304 1 Hbond CH CH 2-sulfamidophenyl 305 1 H bond CH CH 2-trifluoromethylphenyl 306 1 OH bond CH CH amino 307 1 OH bond CH CH amidino 308 1 OH bond CH CH guanidino 309 1 OH bond CH CH 2-sulfamidophenyl 310 1 OH bond CH CH 2-trifluoromethylphenyl 311 1 NHC(O)CH3 bond CH CH amino 312 1 NHC(O)CH3 bond CH CH amidino 313 1 NHC(O)CH3 bond CH CH guanidino 314 1 NHC(O)CH3 bond CH CH 2-sulfamidophenyl 315 1 NHC(O)CH3 bond CH CH 2-trifluoromethylphenyl 316 1 NHSO2CH3 bond CH CH amino 317 1 NHSO2CH3 bond CH CH amidino 318 1 NHSO2CH3 bond CH CH guanidino 319 1NHSO2CH3 bond CH CH 2-sulfamidophenyl 320 1NHS02CH3 bond CH CH2-trifluoromethylphenyl 321 1 OCH3 bond CH CH amino 322 1 OCH3 bond CH CH amidino 323 1 OCH3 bond CH CH guanidino 324 1 OCH3 bond CH CH 2-sulfamidophenyl 325 1OCH3 bond CH CH 2-trifluoromethylphenyl 326 1 OCH2C6Hs bond CH CH amino 327 1OCH2C6H5 bond CH CH amidino 328 1OcH2c6H5 bond CH CH guanidino 329 1OCH2C6Hs bond CH CH2-sulfamidophenyl 330 1OCH2C6H5 bond CH CH2-trifluoromethylphenyl 331 1 H CH2 CH CH amino 332 1 H CH2 CH CH amidino 333 1 H CH2 CH CH guanidino 334 1 H CH2 CH CH2-sulfamidophenyl 335 1 H CH2 CH CH 2-trifluoromethylphenyl 336 1 OH CH2 CH CH amino 337 1 OH CH2 CH CH amidino 338 1 OH CH2 CH CH guanidino 339 1 OH CH2 CH CH 2-sulfamidophenyl 340 1 OH CH2 CH CH 2-trifluoromethylphenyl 341 1 NHC(O)CH3 CH2 CH CH amino SUBSTITUTE SHEET (RULE 26) .. .... . . . .. .. .. . . . . .

CA 022~l394 lsss-lo-o~

W097l38984 PCT~S97/06431 342 1 NHC(O)CH3 CH2 CH CH amidino 343 1 NHC(O)CH3 CH2 CH CHguanidino 344 1NHC(O)CH3 CH2 CH CH2-sulfamidophenyl 345 1NHC(O)CH3 CH2 CH CH2-trifluoromethylphenyl 346 1NHSO2CH3 CH2 CH CH amino 347 1NHSO2CH3 CH2 CH CH amidino 348 1NHSO2CH3 CH2 CH CH guanidino 349 1NHSO2CH3 CH2 CH CH2-sulfamidophenyl 350 1NHSO2CH3 CH2 CH CH2-trifluoromethylphenyl 351 1OCH3 CH2 CH CH amino 352 1OCH3 CH2 CH CHamidino 353 1OCH3 CH2 CH CHguanidino 354 1OCH3 CH2 CH CH2-sulfamidophenyl 355 1OCH3 CH2 CH CH2-trifluoromethylphenyl 356 1OCH2C6H5 CH2 CH CH amino 357 1OcH2c6H5 CH2 CH CH amidino 358 1OCH2C6Hs CH2 CH CH guanidino 359 1oCH2C6H5 CH2 CH CH2-sulfamidophenyl 360 1OCH2C6Hs CH2 CH CH2-trifluoromethylphenyl 361 1 H bond N CH amino 362 1 H bond N CH amidino 363 1 H bond N CHguanidino 364 1 H bond N CH2-sulfamidophenyl 365 1 H bond N CH 2-trifluoromethylphenyl 366 1 OH bond N CH amino 367 1 OH bond N CH amidino 368 1 OH bond N CH guanidino 369 1 OH bond N CH 2-sulfamidophenyl 370 1 OH bond N CH 2-trifluoromethylphenyl 371 1 NHC(O)CH3 bond N CH amino 372 1 NHC(O)CH3 bond N CH amidino 373 1 NHC(O)CH3 bond N CH guanidino 374 1 NHC(O)CH3 bond N CH 2-sulfamidophenyl 375 1 NHC(O)CH3 bond N CH 2-trifluoromethylphenyl 376 1 NHSO2CH3 bond N CH amino 377 1 NHSO2CH3 bond N CH amidino 378 1 NHSO2CH3 bond N CHguanidino 379 1NHSO2CH3 bond N CH2-sulfamidophenyl 380 1NHSO2CH3 bond N CH2-trifluoromethylphenyl 381 1OCH3 bond N CH amino 382 1OCH3 bond N CH amidino 383 1OCH3 bond N CHguanidino 384 1OCH3 bond N CH2-sulfamidophenyl 385 1OCH3bond N CH 2-trifluoromethylphenyl 386 1 OCH2C6Hs bond N CH amino 387 1OCH2C6H5 bond N CH amidino 388 1OCH2C6H5 bond N CHguanidino 389 1OCH2C6H5 bond N CH2-sulfamidophenyl 390 1OCH2C6H5 bond N CH2-trifluoromethylphenyl 391 1 H CH2 N CH amino 392 1 H CH2 N CH amidino 393 1 H CH2 N CHguanidino 394 1 H CH2 N CH2-sulfamidophenyl SUBSTITUTE SHEET (RULE 26) CA 022~l394 Isss-lo-o~

W097/38984 PCT~S97/06431 395 1 H CH2 N CH 2-trifluoromethylphenyl 396 1 OH CH2 N CH amino 397 1 OH CH2 N CH amidino 398 1 OH CH2 N CH guanidino 399 1 OH CH2 N CH 2-sulfamidophenyl 400 1 OH CH2 N CH 2-trifluoromethylphenyl 401 1 NHC(O)CH3 CH2 N CH amino 402 1 NHC(O)CH3 CH2 N CH amidino 403 1 NHC(O)CH3 CH2 N CH guanidino 404 1NHC(O)CH3 CH2 N CH2-sulfamidophenyl - 405 1NHC~O)CH3 CH2 N CH2-trifluoromethylphenyl 406 1NHSO2CH3 CH2 N CH amino 407 1NHSO2CH3 CH2 N CH amidino 408 1NHSO2CH3 CH2 N CH guanidino 409 1NHSO2CH3 CH2 N CH2-sulfamidophenyl 410 1NHSO2CH3 CH2 N CH2-trifluoromethylphenyl 411 1 OCH3 CH2 N CH amino 412 1 OCH3 CH2 N CH amidino 413 1 OCH3 CH2 N CH guanidino 414 1OCH3 CH2 N CH2-sulfamidophenyl 415 1OCH3 CH2 N CH2-trifluoromethylphenyl 416 1OCH2C6Hs CH2 N CH amino 417 1OcH2c6H5 CH2 N CH amidino 418 1OCH2C6H5 CH2 N CH guanidino 419 1OCH2C6Hs CH2 N CH2-sulfamidophenyl 420 1OCH2C6Hs CH2 N CH2-trifluoromethylphenyl 421 1 H bond N N amino 422 1 H bond N N amidino 423 1 H bond N N guanidino 424 1 H bond N N 2-sulfamidophenyl 425 1 H bond N N 2-trifluoromethylphenyl 426 1 OH bond N N amino 427 1 OH bond N N amidino 428 1 OH bond N N guanidino 429 1 OH bond N N 2-sulfamidophenyl 430 1 OH bond N N 2-trifluoromethylphenyl 431 1 NHC(O)CH3 bond N N amino 432 1 NHC(O)CH3 bond N N amidino 433 1 NHC(O)CH3 bond N N guanidino 434 1 NHC(O)CH3 bond N N 2-sulfamidophenyl 435 1 NHC(O)CH3 bond N N 2-trifluoromethylphenyl 436 1 NHSO2CH3 bond N N amino 437 1 NHSO2CH3 bond N N amidino 438 1 NHSO2CH3 bond N N guanidino 439 1 NHS02CH3 bond N N 2-sulfamidophenyl 440 1 NHSO2CH3 bond N N2-trifluoromethylphenyl 441 1 OCH3 bond N N amino 442 1 OCH3 bond N N amidino 443 1 OCH3 bond N N guanidino 444 1 OCH3 bond N N 2-sulfamidophenyl 445 1 OCH3 bond N N 2-trifluoromethylphenyl 446 1 OCH2C6Hs bond N N amino 447 1 OcH2c6H5 bond N N amidino SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 448 1OCH2C6H5 bond N Nguanidino 449 1OCH2C6H5 bond N N2-sulfamidophenyl 450 1OCH2C6H5 bond N N2-trifluoromethylphenyl 451 1 H CH2 N N amino 452 1 H CH2 N Namidino 453 1 H CH2 N Nguanidino 454 1 H CH2 N N2-sulfamidophenyl 455 1 H CH2 N N 2-trifluoromethylphenyl 456 1 OH CH2 N N amino 457 1 OH CH2 N N amidino 458 1 OH CH2 N N guanidino 459 1 OH CH2 N N 2-sulfamidophenyl 460 1 OH CH2 N N 2-trifluoromethylphenyl 461 1 NHC(O)CH3 CH2 N Namino 462 1 NHC(O)CH3 CH2 N Namidino 463 1 NHC(O)CH3 CH2 N Nguanidino 464 1 NHC(O)CH3 CH2 N N2-sulfamidophenyl 465 1 NHC(O)CH3 CH2 N N2-trifluoromethylphenyl 466 1 NHSO2CH3 CH2 N Namino 467 1 NHSO2CH3 CH2 N Namidino 468 1 NHSO2CH3 CH2 N Nguanidino 469 1 NHSO2CH3 CH2 N N2-sulfamidophenyl 470 1 NHSO2CH3 CH2 N N2-trifluoromethylphenyl 471 1 OCH3 CH2 N Namino 472 1 OCH3 CH2 N Namidino 473 1 OCH3 CH2 N Nguanidino 474 1 OCH3 CH2 N N2-sulfamidophenyl 475 1 OCH3 CH2 N N2-trifluoromethylphenyl 476 1 OcH2c6H5 CH2 N Namino 477 1 OCH2C6H5 CH2 N Namidino 478 1 OCH2C6Hs CH2 N Nguanidino 479 1 OcH2c6H5 CH2 N N2-sulfamidophenyl 480 1 OCH2C6H5 CH2 N N2-trifluoromethylphenyl SIJ~ 11 I ~JTE SHEET (RULE 26) CA 022~l394 Isss-lo-o~

W097/38984 PCT~S97/06431 Table 10 H2r ~ N ~ ,N ~ \ ~ B
-Ex. n R2 Z Al A2 B
501 2 Hbond CH CH amino 502 2 Hbond CH CH guanidino 503 2 Hbond CH CH 2-sulfamidophenyl 504 2 H bond CH CH 2-trifluoromethylphenyl 505 2 OH bond CH CH amino 506 2 OH bond CH CH amidino 507 2 OH bond CH CH guanidino 508 2 OH bond CH CH 2-sulfamidophenyl 509 2 OH bond CH CH 2-trifluoromethylphenyl 510 2 NHC(O)CH3 bond CH CH amino 511 2 NHC(O)CH3 bond CH CH amidino 512 2 NHC(O)CH3 bond CH CH guanidino 513 2 NHC(O)CH3 bond CH CH 2-sulfamidophenyl 514 2 NHC(O)CH3 bond CH CH 2-trifluoromethylphenyl 515 2 NHSO2CH3 bond CH CH amino 516 2 NHSO2CH3 bond CH CH amidino 517 2 NHSO2CH3 bond CH CH guanidino 518 2NHSO2CH3 bond CH CH 2-sulfamidophenyl 519 2NHSO2CH3 bond CH CH2-trifluoromethylphenyl 520 2 OCH3 bond CH CH amino 521 2 OCH3 bond CH CH amidino 522 2 OCH3 bond CH CH guanidino 523 2 OCH3 bond CH CH 2-sulfamidophenyl 524 2OCH3 bond CH CH 2-trifluoromethylphenyl 525 2OCH2C6H5 bond CH CH amino 526 2OcH2c6H5 bond CH CH amidino 527 2OCH2C6H5 bond CH CH guanidino 528 2OcH2c6H5 bond CH CH 2-sulfamidophenyl 529 2OCH2C6H5 bond CH CH2-trifluoromethylphenyl 530 2 H CH2 CH CH amino 531 2 H CH2 CH CH guanidino 532 2 H CH2 CH CH 2-sulfamidophenyl 533 2 H CH2 CH CH 2-trifluoromethylphenyl 534 2 OH CH2 CH CH amino 535 2 OH CH2 CH CH amidino 536 2 OH CH2 CH CH guanidino 537 2 OH CH2 CH CH 2-sulfamidophenyl 538 2 OH CH2 CH CH 2-trifluoromethylphenyl 53g 2 NHC(O)CH3 CH2 CH CH amino 540 2 NHC(O)CH3 CH2 CH CH amidino 541 2 NHC(O)CH3 CH2 CH CH guanidino SUBSTITUTE SHEET(RULE 26) , .

CA 022~1394 1998-10-0~

542 2 NHC(O) CH3 CH2 CH CH2-sulfamidophenyl 543 2 NHC(O) CH3 CH2 CH CH2-trifluoromethylphenyl 544 2 NHSO2CH3 CH2 CH CHamino 545 2 NHSO2CH3 CH2 CH CHamidino 546 2 NHSO2CH3 CH2 CH CHguanidino 547 2 NHS02CH3 CH2 CH CH2-sulfamidophenyl 548 2 NHSO2CH3 CH2 CH CH2-trifluoromethylphenyl 549 2 OCH3 CH2 CH CH amino 550 2 OCH3 CH2 CH CHamidino 551 2 OCH3 CH2 CH CHguanidino 552 2 OCH3 CH2 CH CH2-sulfamidophenyl 553 2 OCH3 CH2 CH CH2-trifluoromethylphenyl 554 2 oCH2C6H5 CH2 CH CHamino 555 2 OcH2c6H5 CH2 CH CHamidino 556 2 OCH2C6H5 CH2 CH CHguanidino 557 2 oCH2C6H5 CH2 CH CH2-sulfamidophenyl 558 2 OCH2C6H5 CH2 CH CH2-trifluoromethylphenyl 559 2 H bond N CH amino 560 2 H bond N CH amidino 561 2 H bond N CHguanidino 562 2 H bond N CH2-sulfamidophenyl 563 2 H bond N CH 2-trifluoromethylphenyl 564 2 OH bond N CH amino 565 2 OH bond N CH amidino 566 2 OH bond N CH guanidino 567 2 OH bond N CH 2-sulfamidophenyl 568 2 OH bond N CH 2-trifluoromethylphenyl 569 2 NHC(O)CH3 bond N CH amino 570 2 NHC(O)CH3 bond N CH amidino 571 2 NHC(O)CH3 bond N CH guanidino 572 2 NHC(O)CH3 bond N CH 2-sulfamidophenyl 573 2 NHC(O)CH3 bond N CH 2-trifluoromethylphenyl 574 2 NHSO2CH3 bond N CH amino 575 2 NHSO2CH3 bond N CH amidino 576 2 NHSO2CH3 bond N CHguanidino 577 2NHSO2CH3 bond N CH2-sulfamidophenyl 578 2NHSO2CH3 bond N CH2-trifluoromethylphenyl 579 2 OCH3 bond N CH amino 580 2 OCH3 bond N CH amidino 581 2 OCH3 bond N CHguanidino 582 2 OCH3 bond N CH2-sulfamidophenyl 583 2 OCH3bond N CH 2-trifluoromethylphenyl 584 2OCH2C6H5 bond N CH amino 585 2OCH2C6H5 bond N CH amidino 586 2 OCH2C6Hs bond N CHguanidino 587 2OCH2C6H5 bond N CH2-sulfamidophenyl 588 2OCH2C6Hs bond N CH2-trifluoromethylphenyl 589 2 H CH2 N CH amino 590 2 H CH2 N CH amidino 591 2 H CH2 N CHguanidino 592 2 H CH2 N CH2-sulfamidophenyl 593 2 H CH2 N CH 2-trifluoromethylphenyl 594 2 OH CH2 N CH amino SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 595 2 OH CH2 N CH amidino 596 2 OH CH2 N CH guanidino 597 2 OH CH2 N CH2-sulfamidophenyl 598 2 OH CH2 N CH 2-trifluoromethylphenyl 599 2 NHC(O)CH3 CH2 N CH amino 600 2 NHC(O)CH3 CH2 N CH amidino 601 2 NHC(O)CH3 CH2 N CH guanidino 602 2 NHC(O)CH3 CH2 N CH2-sulfamidophenyl 603 2 NHC(O)CH3 CH2 N CH2-trifluoromethylphenyl 604 2 NHSO2CH3 CH2 N CH amino 605 2 NHSO2CH3 CH2 N CH amidino 606 2 NHSO2CH3 CH2 N CH guanidino 607 2 NHSO2CH3 CH2 N CH2-sulfamidophenyl 608 2 NHSO2CH3 CH2 N CH2-trifluoromethylphenyl 609 2 OCH3 CH2 N CH amino 610 2 OCH3 CH2 N CH amidino 611 2 OCH3 CH2 N CH guanidino 612 2 OCH3 CH2 N CH2-sulfamidophenyl 613 2 OCH3 CH2 N CH2-trifluoromethylphenyl 614 2 OCH2C6Hs CH2 N CH amino 615 2 OcH2c6H5 CH2 N CH amidino 516 2 OCH2C6Hs CH2 N CH guanidino 617 2 OCH2C6Hs CH2 N CH2-sulfamidophenyl 618 2 OcH2c6H5 CH2 N CH2-trifluoromethylphenyl 619 2 H bond N N amino 620 2 H bond N N amidino 621 2 H bond N N guanidino 622 2 H bond N N2-sulfamidophenyl 623 2 H bond N N 2-trifluoromethylphenyl 624 2 OH bond N N amino 625 2 OH bond N N amidino 626 2 OH bond N N guanidino 627 2 OH bond N N 2-sulfamidophenyl 628 2 OH bond N N 2-trifluoromethylphenyl 629 2 NHC(O~CH3 bond N N amino 630 2 NHC(O)CH3 bond N N amidino 631 2 NHC(O)CH3 bond N N guanidino 632 2 NHC(O)CH3 bond N N 2-sulfamidophenyl 633 2 NHC(O)CH3 bond N N 2-trifluoromethylphenyl 634 2 NHSO2CH3 bond N N amino 635 2 NHSO2CH3 bond N N amidino 636 2 NHSO2CH3 bond N N guanidino 637 2 NHSO2CH3 bond N N2-sulfamidophenyl 638 2 NHSO2CH3 bond N N2-trifluoromethylphenyl 639 2 OCH3 bond N N amino 640 2 OCH3 bond N N amidino 641 2 OCH3 bond N N guanidino 642 2 OCH3 bond N N2-sulfamidophenyl 643 2 OCH3 bond N N 2-trifluoromethylphenyl 644 2 OCH2C6Hs bond N N amino 645 2 OcH2c6H5 bond N N amidino 646 2 OcH2c6H5 bond N N guanidino 647 2 OCH2C6H5 bond N N2-sulfamidophenyl SUBSTITUTE SHEET (RUI_E 26) CA 022~l394 Igss-lo-o~

PCT~S97/06431 648 2OcH2c6Hs bond N N2-trifluoromethylphenyl 649 2 H CH2 N N amino 650 2 H CH2 N Namidino 651 2 H CH2 N Nguanidino 652 2 H CH2 N N2-sulfamidophenyl 653 2 H CH2 N N 2-trifluoromethylphenyl 654 2 OH CH2 N N amlno 655 2 OH CH2 N N amidino 656 2 OH CH2 N N guanidino 657 2 OH CH2 N N 2-sulfamidophenyl 658 2 OH CH2 N N 2-trifluoromethylphenyl 659 2 NHC(O)CH3 CH2 N N amlno 660 2 NHC(O~CH3 CH2 N Namidino 661 2 NHC(O)CH3 CH2 N Nguanidino 662 2NHC(O)CH3 CH2 N N2-sulfamidophenyl 663 2NHC(O)CH3 CH2 N N2-trifluoromethylphenyl 664 2NHSO2CH3 CH2 N N amino 665 2NHSO2CH3 CH2 N Namidino 666 2NHSO2CH3 CH2 N Nguanldino 667 2NHSO2CH3 CH2 N N2-sulfamidophenyl 668 2NHSO2CH3 CH2 N N2-trifluoromethylphenyl 669 2 OCH3 CH2 N N amlno 670 2 OCH3 CH2 N Namidino 671 2 OCH3 CH2 N Nguanidino 672 2 OCH3 CH2 N N2-sulfamidophenyl 673 2 OCH3 CH2 N N2-trifluoromethylphenyl 674 2OCH2C6H5 CH2 N N amino 675 2OCH2C6Hs CH2 N Namidlno 676 2OCH2C6Hs CH2 N Nguanidino 677 2OCH2C6H5 CH2 N N2-sulfamidophenyl 678 2OCH2C6H5 CH2 N N2-trifluoromethylphenyl SUBSTITUTE SHEET(RULE26) .. , . . . ..... ,.. ~
., ~, CA 022~l394 Igss-lo-o~

W097/38984 PCT~S97/06431 Table 11 ~ N~ ~ N

Ex. n R2 Z Al A2 B
701 0 H bond CH CHimidazol-1-yl 702 0 H bond CH CHmorpholin-1-yl 703 0 H bond CH CH2-methylimidazol-1-yl 704 0 H bond CH CHpyridin-3-yl 705 0 H bond CH CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 706 0 H bond CH CHpyrazol-1-yl 707 0 H bond CH CH phenyl 708 0 H bond CH CHcyclohexyl 709 0 H bond CH CHN,N-dimethylsulfamido 710 0 H bond CH CHN,N-dimethylamido 711 0 H bond N CHlmldazol-l-yl 712 0 H bond N CHmorpholin-1-yl 713 0 H bond N CH2-methylimidazol-1-yl 714 0 H bond N CHpyridin-3-yl 715 0 H bond N CH 2-(5~-trifluoromethyl~
tetrazol-1'-yl 716 0 H bond N CHpyrazol-1-yl 717 0 H bond N CH phenyl 718 0 H bond N CHcyc 1 ohexyl 719 0 H bond N CHN,N-dimethylsulfamido 720 0 H bond N CHN,N-dimethyla~ido 721 0 H bond N Nimidazol-1-yl 722 0 H bond N Nmorpholin-1-yl 723 0 H bond N N2-methylimidazol-1-yl 724 0 H bond N Npyridin-3-yl 725 0 H bond N N2-(5'-trifluoromethyl) tetrazol-1'-yl 726 0 H bond N Npyrazol-1-yl 727 0 H bond N N phenyl 728 0 H bond N Ncyclohexyl 729 0 H bond N NN,N-dimethylsulfamido 730 0 H bond N NN,N-dimethylamido 731 0 H bond F CHimidazol-1-yl 732 0 H bond F CHmorpholin-1-yl 733 0 H bond F CH2-methylimidazol-1-yl 734 0 H bond F CHpyridin-3-yl 735 0 H bond F CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 736 0 H bond F CHpyrazol-1-yl 737 0 H bond F CH phenyl 738 0 H bond F CHcyc 1 ohexyl 739 0 H bond F CHN,N-dimethylsulfamido 740 0 H bond F CHN,N-dimethylamido SUBSTITUTE SHEET (RULE 26) CA 022~l394 Isss-lo-o~

WO97/38984 PCT~S97/06431 741 0 H bond Cl CHimidazol-1-yl 742 0 H bond Cl CHmorpholin-1-yl 743 0 H bond Cl CH2-methylimidazol-1-yl 744 0 H bond Cl CHpyrld1n-3-yl 745 0 H bond Cl CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 746 0 H bond Cl CHpyrazol-1-yl 747 0 H bond Cl CH phenyl 748 0 H bond Cl CHcyclohexyl 749 0 H bond C1 CHN,N-dimethylsulfamido 750 0 H bond C1 CHN,N-dimethylamido 751 0 H bond Br CHimidazol-1-yl 752 0 H bond Br CHmorpholln-1-yl 753 0 H bond Br CH2-methylimidazol-1-yl 754 0 H bond Br CHpyridin-3-yl 755 0 H bond Br CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 756 0 H bond Br CHpyrazol-1-yl 757 0 H bond Br CH phenyl 758 0 H bond Br CHcyclohexyl 759 0 H bond Br CHN,N-dimethylsulfamido 760 0 H bond Br CHN,N-dimethylamido 761 0 H CH2 CH CHimidazol-1-yl 762 0 H CH2 CH CHmorpholln-1-yl 763 0 H CH2 CH CH2-methylimidazol-1-yl 764 0 H CH2 CH CHpyrld1n-3-yl 765 0 H CH2 CH CH2-(5'-trifluoromethyl) tetrazol~ yl 766 0 H CH2 CH CHpyrazol-1-yl 767 0 H CH2 CH CH phenyl 768 0 H CH2 CH CHcyclohexyl 769 0 H CH2 CH CHN,N-dimethylsulfamido 770 0 H CH2 CH CHN,N-dimethylamido 771 0 H CH2 N CH imidazol-1-yl 772 0 H CH2 N CHmorpholin-1-yl 773 0 H CH2 N CH2-methylimidazol-1-yl 774 0 H CH2 N CH pyridin-3-yl 775 0 H CH2 N CH2-(5'-trifluoromethyl) tetrazol-1'-yl 776 0 H CH2 N CH pyrazol-1-yl 777 0 H CH2 N CH phenyl 778 0 H CH2 N CH cyclohexyl 779 0 H CH2 N CHN, N-dimethylsulfamido 780 0 H CH2 N CHN,N-dimethylamido 781 0 H CH2 N Nimidazol-1-yl 782 0 H CH2 N Nmorpholin-1-yl 783 0 H CH2 N N2-methylimidazol-1-yl 784 0 H CH2 N Npyridin-3-yl 785 0 H CH2 N N2-(5'-trifluoromethyl) tetrazol-1'-yl 786 0 H CH2 N Npyrazol-1-yl 787 0 H CH2 N N phenyl 788 0 H CH2 N Ncyclohexyl 789 0 H CH2 N NN, N-dimethylsulfamido SUBSTITUTE SHEET (RULE 26) CA 022~l394 Isss-lo-o~

PCT~S97/06431 790 0 H CH2 N NN,N-dimethylamido 791 0 H CH2 F CHimidazol-1-yl 792 0 H CH2 F CHmorpholin-1-yl 793 0 H CH2 F CH2-methylimidazol-1-yl 794 0 H CH2 F CHpyridin-3-yl 795 0 H CH2 F CH2-(5'-trifluoromethyl) tetrazol-1'-yl 796 0 H CH2 F CHpyrazol-1-yl 797 0 H CH2 F CH phenyl 798 0 H CH2 F CHcyclohexyl - 799 0 H CH2 F CHN,N-dimethylsulfamido 800 0 H CH2 F CHN,N-dimethylamido 801 0 H CH2 C1 CHimidazol-1-yl 802 0 H CH2 C1 CHmorpholin-1-yl 803 0 H CH2 Cl CH2-methylimidazol-1-yl 804 0 H CH2 C1 CHpyridin-3-yl 805 0 H CH2 C1 CH2-(5'-trifluoromethyl) te~razol-1'-yl 806 0 H CH2 Cl CHpyrazol-1-yl 807 0 H CH2 Cl CH phenyl 808 0 H CH2 Cl CHcyclohexyl 809 0 H CH2 Cl CHN,N-dimethylsulfamido 810 0 H CH2 Cl CHN,N-dimethylamido 811 0 H CH2 Br CHimidazol-1-yl 812 0 H CH2 Br CHmorpholin-1-yl 813 0 H CH2 Br CH2-methylimidazol-1-yl 814 0 H CH2 Br CHpyridin-3-yl 815 0 H CH2 Br CH2-(5'-trifluoromethyl) tetrazol-1'-yl 816 0 H CH2 Br CHpyrazol-1-yl 817 0 H CH2 Br CH phenyl 818 0 H CH2 Br CHcyclohexyl 819 0 H CH2 Br CHN,N-dimethylsulfamido 820 0 H CH2 Br CHN,N-dimethylamido 821 0 OH bond F CHpyrazol-1-yl 822 0 OH bond F CH phenyl 823 0 OH bond F CHcyclohexyl 824 0 OH bond F CHN,N-dimethylsulfamido 825 0 OH bond F CHN,N-dimethylamido 826 0 NHC(O)CH3 bond Cl CH imidazol-l-yl 827 0 NHC(O)CH3 bond Cl CH morpholin-1-yl 828 0 NHC(O)CH3 bond Cl CH 2-methylimidazol-1-yl 829 0 NHC(O)CH3 bond Cl CH pyridin-3-yl 830 0 NHC(O)CH3 bond Cl CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 831 0 NHSO2CH3 bond Cl CH pyrazol-1-yl 832 0 NHSO2CH3 bond Cl CH phenyl 833 0 NHSO2CH3 bond Cl CH cyclohexyl 834 0 NHSO2CH3 bond Cl CH N,N-dimethylsulfamido 835 0 NHSO2CH3 bond Cl CH N,~-dimethylamido 836 0 OCH3 bond Br CHimidazol-1-yl 837 0 OCH3 bond Br CHmorpholin-1-yl 838 0 OCH3 bond Br CH2-methylimidazol-1-yl SUBSTITUTE SHEET (RULE 26) . . , ~ . .

CA 022~1394 1998-10-0~

W097/38984 PCT~S97106431 839 0 OCH3 bond Br CHpyridin-3-yl 840 0 OCH3 bond Br CH2-(5~-trifluoromethyl) tetrazol-l'-yl 841 0 OCH2C6H5 bond Br CHpyrazol-l-yl 842 0 OcH2c6H5 bond Br CHphenyl 843 0 OCH2C6H5 bond Br CHcyclohexyl 844 0 OCH2C6H5 bond Br CHN,N-dimethylsulfamido 845 0 OCH2C6H5 bond Br CHN,N-dimethylamido 846 0 OH CH2 CH CHpyrazol-l-yl 847 0 OH CH2 CH CH phenyl 848 0 OH CH2 CH CHcyclohexyl 849 0 OH CH2 CH CHN,N-dimethylsulfamido 850 0 OH CH2 CH CHN,N-dimethylamido 851 0 NHC(O)CH3 CH2 N CHimidazol-l-yl 852 0 NHC(O)CH3 CH2 N CHmorpholin-l-yl 853 0 NHC(O)CH3 CH2 N CH2-methylimidazol-1-yl 854 0 NHC(O)CH3 CH2 N CHpyridin-3-yl 855 0 NHC(O)CH3 CH2 N CH2-(5~-trifluoromethyl) tetrazol-l'-yl 856 0 NHSO2CH3 CH2 N CHpyrazol-l-yl 857 0 NHSO2CH3 CH2 N CH phenyl 858 0 NHSO2CH3 CH2 N CHcyclohexyl 859 0 NHSO2CH3 CH2 N CHN,N-dimethylsulfamido 860 0 NHSO2CH3 CH2 N CHN,N-dimethylamido 861 0 OCH3 CH2 N Nimidazol-l-yl 862 0 OCH3 CH2 N Nmorpholin-l-yl 863 0 OCH3 CH2 N N2-methylimidazol-1-yl 864 0 OCH3 CH2 N Npyridin-3-yl 865 0 OCH3 CH2 N N2-(5'-trifluoromethyl) tetrazol-l'-yl 866 0 OCH2C6H5 CH2 N Npyrazol-l-yl 867 0 OCH2C6H5 CH2 N N phenyl 868 0 OCH2C6H5 CH2 N Ncyclohexyl 869 0 OCH2C6H5 CH2 N NN,N-dimethylsulfamido 870 0 OCH2C6H5 CH2 N NN,N-dimethylamido SUBSTITUTE SHEET (RULE 26) CA 022~l394 Isss-lo-o~

W097/38984 PCT~S97/06431 Table 12 )n A
~ ~ N ~ N ~ ~ s Ex. n R2Z A1 A2 B
901 1 Hbond CH CH imidazol-1-yl 902 1 Hbond CH CH morpholin-1-yl 903 1 Hbond CH CH 2-methylimidazol-1-yl 904 1 Hbond CH CH pyridin-3-yl 905 1 H bond CH CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 906 1 Hbond CH CH pyrazol-1-yl 9 0 7 1 Hbond CH CH phenyl 908 1 Hbond CH CH cyc lohexyl 909 1 Hbond CH CH N,N-dimethylsulfamido 910 1 H bond CH CHN,N-dimethylamido 911 1 H bond N CHimidazol-1-yl 912 1 H bond N CHmorpholin-1-yl 913 1 H bond N CH2-methylimidazol-1-yl 914 1 H bond N CHpyridin-3-yl 915 1 H bond N CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 916 1 H bond N CHpyrazol-1-yl 917 1 H bond N CH phenyl 918 1 H bond N CHcyclohexyl 919 1 H bond N CHN,N-dimethylsulfamido 920 1 H bond N CHN,N-dimethylamido 921 1 H bond N Nimidazol-1-yl 922 1 H bond N Nmorpholin-1-yl 923 1 H bond N N2-methylimidazol-1-yl 924 1 H bond N Npyridin-3-yl 925 1 H bond N N2-(5'-trifluoromethyl) tetrazol-1'-yl 926 1 H bond N Npyrazol-1-yl 927 1 H bond N N phenyl 928 1 H bond N Ncyclohexyl 929 1 H bond N NN,N-dimethylsulfamido 930 1 H bond N NN,N-dimethylamido 931 1 H bond F CHimidazol-1-yl 932 1 H bond F CHmorpholin-1-yl 933 1 H bond F CH2-methylimidazol-1-yl 934 1 H bond F CHpyridin-3-yl 935 1 H bond F CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 936 1 H bond F CHpyrazol-1-yl 937 1 H bond F CH phenyl 938 1 H bond F CHcyclohexyl 939 1 H bond F CHN,N-dimethylsulfamido 940 1 H bond F CHN,N-dimethylamido SU~S 111 UTE SHEET (RULE 26) CA 022~l394 Igss-lo-o~

W097/38984 PCT~S97/06431 941 1 H bond Cl CHimidazol-1-yl 942 1 H bond Cl CHmorpholin-1-yl 943 1 H bond Cl CH2-methylimidazol-1-yl 944 1 H bond Cl CHpyrldln-3-yl 945 1 H bond C1 CH2-(5'-trifluoromèthyl) tetrazol-1'-yl 946 1 H bond Cl CHpyrazol-1-yl 947 1 H bond Cl CH phenyl 948 1 H bond Cl CHcyclohexyl 949 1 H bond Cl CHN, N-dimethylsulfamido 950 1 H bond Cl CHN,N-dimethylamido 951 1 H bond Br CHimidazol-1-yl 952 1 H bond Br CHmorpholin-1-yl 953 1 H bond Br CH2-methylimidazol-1-yl 954 1 H bond Br CHpyridin-3-yl 955 1 H bond Br CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 956 1 H bond Br CHpyrazol-1-yl 957 1 H bond Br CH phenyl 958 1 H bond Br CHcyclohexyl 959 1 H bond Br CHN, N-dimethylsulfamido 960 1 H bond Br CHN,N-dimethylamido 961 1 H CH2 CH CHimidazol-1-yl 962 1 H CH2 CH CHmorpholin-1-yl 963 1 H CH2 CH CH2-methylimidazol-1-yl 964 1 H CH2 CH CHpyridin-3-yl 965 1 H CH2 CH CH2-(5~-trifluoromethyl) tetrazol-1'-yl 966 1 H CH2 CH CHpyrazol-l-yl 967 1 H CH2 CH CH phenyl 968 1 H CH2 CH CHcyclohexyl 969 1 H CH2 CH CHN, N-dimethylsulfamido 970 1 H CH2 CH CHN,N-dimethylamido 971 1 H CH2 N CH imidazol-1-yl 972 1 H CH2 N CHmorpholin-1-yl 973 1 H CH2 N CH2-methylimidazol-1-yl 974 1 H CH2 N CH pyridin-3-yl 975 1 H CH2 N CH2-(5'-trifluoromethyl) tetrazol-1'-yl 976 1 H CH2 N CH pyrazol-1-yl 977 1 H CH2 N CH phenyl 978 1 H CH2 N CH cyclohexyl 979 1 H CH2 N CHN,N-dimethylsulfamido 980 1 H CH2 N CHN,N-dimethylamido 981 1 H CH2 N Nimidazol-1-yl 982 1 H CH2 N Nmorpholin-1-yl 983 1 H CH2 N N2-methylimidazol-1-yl 984 1 H CH2 N Npyridin-3-yl 985 1 H CH2 N N2-(5~-trifluoromethyl) tetrazol-1'-yl 986 1 H CH2 N Npyrazol-1-yl 987 1 H CHz N N phenyl 988 1 H CH2 N Ncyclohexyl 989 1 H CH2 N NN,N-dimethylsulfamido SUBSTITUTE SHEET (RULE 26) CA 022~l394 Iggs-lo-o~

W097/38984 PCT~S97/06431 990 1 H CH2 N NN,N-dimethylamido 991 1 H CH2 F CHimidazol-l-yl 992 1 H CH2 F CHmorpholin-l-yl 993 1 H CH2 F CH2-methylimidazol-1-yl 994 1 H CH2 F CHpyridin-3-yl 995 1 H CH2 F CH2-(5'-trifluoromethyl) tetrazol-l'-yl 996 1 H CH2 F CH pyrazol-l-yl 997 1 H CH2 F CH phenyl 998 1 H CH2 F CH cyclohexyl - 999 1 H CH2 F CHN,N-dimethylsulfamido 1000 1 H CH2 F CHN,N-dimethylamido 1001 1 H CH2 Cl CHimidazol-l-yl 1002 1 H CH2 Cl CHmorpholin-l-yl 1003 1 H CH2 Cl CH2-methylimidazol-1-yl 1004 1 H CH2 Cl CHpyridin-3-yl 1005 1 H CH2 Cl CH2-(5'-trifluoromethyl) tetrazol-l'-yl 1006 1 H CH2 Cl CHpyrazol-l-yl 1007 1 H CH2 Cl CH phenyl 1008 1 H CH2 Cl CHcyclohexyl 100g 1 H CH2 Cl CHN,N-dimethylsulfamido 1010 1 H CH2 Cl CHN,N-dimethylamido 1011 1 H CH2 Br CHimidazol-l-yl 1012 1 H CH2 Br CHmorpholin-l-yl 1013 1 H CH2 Br CH2-methylimidazol-1-yl 1014 1 H CH2 Br CHpyridin-3-yl 1015 1 H CH2 Br CH2-(5'-trifluoromethyl~
tetrazol-l'-yl 1016 1 H CH2 Br CHpyrazol-l-yl 1017 1 H CH2 Br CH phenyl 1018 1 H CH2 Br CHcyclohexyl 1019 1 H CH2 Br CHN,N-dimethylsulfamido 1020 1 H CH2 Br CHN,N-dimethylamido 1021 1 OH bond F CH pyrazol-l-yl 1022 1 OH bond F CH phenyl 1023 1 OH bond F CH cyclohexyl 1024 1 OH bond F CHN,N-dimethylsulfamido 1025 1 OH bond F CHN,N-dimethylamido 1026 1 NHC(O)CH3 bond Cl CH imidazol-l-yl 1027 1 NHC(O)CH3 bond Cl CH morpholin-l-yl 1028 1 NHC(O)CH3 bond Cl CH2-methylimidazol-1-yl 1029 1 NHC(O)CH3 bond Cl CHpyridin-3-yl 1030 1 NHC(O)CH3 bond Cl CH2-(5'-trifluoromethyl) tetrazol-l'-yl 1031 1 NHSO2CH3 bond Cl CHpyrazol-l-yl 1032 1 NHSO2CH3 bond Cl CH phenyl 1033 1 NHSO2CH3 bond Cl CHcyclohexyl 1034 1 NHSO2CH3 bond Cl CHN,N-dimethylsulfamido 1035 1 NHSO2CH3 bond Cl CHN,N-dimethylamido 1036 1 OCH3 bond Br CH imidazol-l-yl 1037 1 OCH3 bond Br CHmorpholin-l-yl 1038 1 OCH3 bond Br CH2-methylimidazol-1-yl SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097l38984 PCT~S97/06431 1039 1 OCH3 bond Br CHpyridin-3-yl 1040 1 OCH3 bond Br CH2-(5~-trifluoromethyl) tetrazol-1'-yl 1041 1 OCH2C6H~ bond Br CHpyrazol-1-yl 1042 1 OcH2c6H5 bond Br CHphenyl 1043 1 OcH2c6H5 bond Br CHcyclohexyl 1044 1 OcH2c6H5 ~ond Br CHN,N-dimethylsulfamido 1045 1 OCH2C6H5 bond Br CHN,N-dimethylamido 1046 1 OH CH2 CH CHpyrazol-1-yl 1047 1 OH CH2 CH CHphenyl 1048 1 OH CH2 CH CHcyclohexyl 1049 1 OH CH2 CH CHN,N-dimethylsulfamido 1050 1 OH CH2 CH CHN,N-dimethylamido 1051 1 NHC(O)CH3 CH2 N CHimidazol-1-yl 1052 1 NHC(O)CH3 CH2 N CHmorpholin-1-yl 1053 1 NHC(O)CH3 CH2 N CH2-methylimidazol-1-yl 1054 1 NHC(O)CH3 CH2 N CHpyridin-3-yl 1055 1 NHC(O)CH3 CH2 N CH2-(5'-trifluoromethyl) tetrazol-1'-yl 1056 1 NHSO2CH3 CH2 N CHpyrazol-1-yl 1057 1 NHSO2CH3 CH2 N CHphenyl 1058 1 NHSO2CH3 CH2 N CHcyclohexyl 1059 1 NHSO2CH3 CH2 N CHN,N-dimethylsulfamido 1060 1 NHSO2CH3 CH2 N CHN,N-dimethylamido 1061 1 OCH3 CH2 N Nimidazol-1-yl 1062 1 OCH3 CH2 N Nmorpholin-1-yl 1063 1 OCH3 CH2 N N2-methylimidazol-1-yl 1064 1 OCH3 CH2 N Npyridin-3-yl 1065 1 OCH3 CH2 N N2-(5'-trifluoromethyl) tetrazol-1'-yl 1066 1 OcH2c6H5 CH2 N Npyrazol-1-yl 1067 1 oCH2C6H5 CH2 N Nphenyl 1068 1 OcH2c6H5 CH2 N Ncyclohexyl 1069 1 OcH2c6H5 CH2 N NN,N-dimethylsulfamido 1070 1 OCH2C6Hs CH2 N NN,N-dimethylamido SlJtl~ 111 UTE SHEET (RULE 26) CA 022~l394 lsgs-lo-o~

W097/38984 PCT~S97/06431 Table 13 ~21 ~ N~ N

Ex. n R2Z Al A2 B
1101 2 Hbond CH CH imidazol-l-yl 1102 2 Hbond CH CH morpholin-l-yl 1103 2 Hbond CH CH 2-methylimidazol-1-yl 1104 2 Hbond CH CH pyridin-3-yl 1105 2 Hbond CH CH 2-(5'-trifluoromethyl) tetrazol-l'-yl 1106 2 Hbond CH CH pyrazol-l-yl 1107 2 Hbond CH CH phenyl 1108 2 Hbond CH CH cyclohexyl 1109 2 H bond CH CHN,N-dimethylsulfamido 1110 2 H bond CH CHN,N-dimethylamido 1111 2 H bond N CHimidazol-l-yl 1112 2 H bond N CHmorpholin-l-yl 1113 2 H bond N CH2-methylimidazol-1-yl 1114 2 H bond N CHpyridin-3-yl 1115 2 H bond N CH2-(5'-trifluoromethyl) tetrazol-l'-yl 1116 2 H bond N CHpyrazol-l-yl 1117 2 H bond N CH phenyl 1118 2 H bond N CHcyclohexyl 1119 2 H bond N CHN,N-dimethylsulfamido 1120 2 H bond N CHN,N-dimethylamido 1121 2 H bond N Nimidazol-l-yl 1122 2 H bond N Nmorpholin-l-yl 1123 2 H bond N N2-methylimidazol-1-yl 1124 2 H bond N Npyridin-3-yl 1125 2 H bond N N2-(5'-trifluoromethyl) tetrazol-l'-yl 1126 2 H bond N Npyrazol-l-yl 1127 2 H bond N Nphenyl 1128 2 H bond N Ncyclohexyl 1129 2 H bond N NN,N-dimethylsulfamido 1130 2 H bond N NN,N-dimethylamido 1131 2 H bond F CHimidazol-l-yl 1132 2 H bond F CHmorpholin-l-yl 1133 2 H bond F CH2-methylimidazol-1-yl 1134 2 H bond F CHpyridin-3-yl 1135 2 H bond F CH2-(5'-trifluoromethyl) tetrazol-l'-yl 1136 2 H bond F CHpyrazol-l-yl 1137 2 H bond F CH phenyl 1138 2 H bond F CHcyclohexyl 1139 2 H bond F CHN,N-dimethylsulfamido 1140 2 H bond F CHN,N-dimethylamido SUBSTITUTE SHEET (RULE 26) , . . . . .
, . . .

W097l38984 PCT~S97/06431 1141 2 H bond Cl CHimidazol-1-yl 1142 2 H bond C1 CHmorpholin-1-yl 1143 2 H bond Cl CH2-methylimidazol-1-yl 1144 2 H bond Cl CHpyridin-3-yl 1145 2 H bond Cl CH2-(5'-trifluoromethyl) tetrazol-1'-yl 1146 2 H bond Cl CHpyrazol-1-yl 1147 2 H bond Cl CH phenyl 1148 2 H bond Cl CHcyclohexyl 1149 2 H bond C1 CHN,N-dimethylsulfamido 1150 2 H bond Cl CHN,N-dimethylamido 1151 2 H bond Br CHimidazol-1-yl 1152 2 H bond Br CHmorpholin-1-yl 1153 2 H bond Br CH2-methylimidazol-1-yl 1154 2 H bond Br CHpyridin-3-yl 1155 2 H ~ond Br CH2-(5'-trifluoromethyl) tetrazol-1'-yl 1156 2 H bond Br CHpyrazol-1-yl 1157 2 H bond Br CH phenyl 1158 2 H bond Br CHcyclohexyl 1159 2 H bond Br CHN,N-dimethylsulfarnido 1160 2 H bond Br CHN,N-dimethylamido 1161 2 H CH2 CH CHimidazol-1-yl 1162 2 H CH2 CH CHmorpholin-1-yl 1163 2 H CH2 CH CH2-methylimidazol-1-yl 1164 2 H CH2 CH CHpyridin-3-yl 1165 2 H CH2 CH CH2-(5'-trifluoromethyl) tetrazol-1'-yl 1166 2 H CH2 CH CHpyrazol-1-yl 1167 2 H CH2 CH CHphenyl 1168 2 H CH2 CH CHcyclohexyl 1169 2 H CH2 CH CHN,N-dimethylsulfamido 1170 2 H CH2 CH CHN,N-dimethylamido 1171 2 H CH2 N CHimidazol-1-yl 1172 2 H CH2 N CHmorpholin-1-yl 1173 2 H CH2 N CH2-methylimidazol-1-yl 1174 2 H CH2 N CHpyridin-3-yl 1175 2 H CH2 N CH2-(5'-trifluoromethyl) tetrazol-1'-yl 1176 2 H CH2 N CHpyrazol-1-yl 1177 2 H CH2 N CH phenyl 1178 2 H CH2 N CHcyclohexyl 1179 2 H CH2 N CHN,N-dimethylsulfamido 1180 2 H CH2 N CHN,N-dimethylamido 1181 2 H CH2 N Nimidazol-1-yl 1182 2 H CH2 N Nmorpholin-1-yl 1183 2 H CH2 N N2-methylimidazol-1-yl 1184 2 H CH2 N Npyridin-3-yl 1185 2 H CH2 N N2-(5~-trifluoromethyl) tetrazol-1'-yl 1186 2 H CH2 N Npyrazol-1-yl 1187 2 H CH2 N N phenyl 1188 2 H CH2 N Ncyclohexyl 1189 2 H CH2 N NN,N-dimethylsulfamido SU~S 1 1 1 UTE SHEET (RULE 26) CA 0225l394 l998-lO-0~

WO 97138984 PCT/I~S97/06431 1190 2 H CH2 N NN,N-dimethylamido 1191 2 H CH2 F CH lmldazol-l-yl 1192 2 H CH2 F CHmorpholin-l-yl 1193 2 H CH2 F CH2-methylimidazol-1-yl 1194 2 H CH2 F CH pyridin-3-yl 1195 2 H CH2 F CH2-(5'-trifluoromethyl) tetrazol-l'-yl 1196 2 H CH2 F CH pyrazol-l-yl 1197 2 H CH2 F CH phenyl 119 8 2 H CH2 F CH cyclohexyl 1199 2 H CH2 F CHN,N-dimethylsulfamido 1200 2 H CH2 F CHN,N-dimethylamido 1201 2 H CH2 Cl CHimidazol-l-yl 1202 2 H CH2 Cl CHmorpholin-l-yl 1203 2 H CH2 Cl CH2-methylimidazol-1-yl 1204 2 H CH2 Cl CHpyridin-3-yl 1205 2 H CH2 Cl CH2- (5'-trifluoromethyl) tetrazol-l'-yl 1206 2 H CH2 Cl CHpyrazol-l-yl 1207 2 H CH2 Cl CHphenyl 1208 2 H CH2 Cl CHcyclohexyl 1209 2 H CH2 Cl CHN,N-dimethylsulfamido 1210 2 H CH2 Cl CHN,N-dimethylalTsido 1211 2 H CH2 Br CH imidazol-l-yl 1212 2 H CH2 Br CHmorpholin-l-yl 1213 2 H CH2 Br CH2-methylimidazol-1-yl 1214 2 H CH2 Br CHpyridin-3-yl 1215 2 H CH2 Br CH2-(5'-trifluoromethyl~
tetrazol-l'-yl 1216 2 H CH2 Br CH pyrazol-l-yl 1217 2 H CH2 Br CH phenyl 1218 2 H CH2 Br CH cyclohexyl 1219 2 H CH2 Br CHN,N-dimethylsulfamido 1220 2 H CH2 Br CHN,N-dimethylamido 1221 2 OH bond F CH pyrazol-l-yl 1222 2 OH bond F CH phenyl 1223 2 OH bond F CH cyclohexyl 1224 2 OH bond F CHN,N-dimethylsulfamido 1225 2 OH bond F CHN,N-dimethylamido 1226 2 NHC(O)CH3 bond Cl CH imidazol-l-yl 1227 2 NHC(O)CH3 bond Cl CH morpholin-l-yl 1228 2NHC(O)CH3 bond Cl CH2-methylimidazol-1-yl 1229 2NHC(O)CH3 bond Cl CHpyridin-3-yl 1230 2NHC(O)CH3 bond Cl CH2-~'-trifluoromethyl) tetrazol-l'-yl 1231 2NHSO2CH3 bond Cl CHpyrazol-l-yl 1232 2NHSO2CH3 bond Cl CHphenyl 1233 2NHSO2CH3 bond Cl CHcyclohexyl 1234 2NHSO2CH3 bond Cl CHN,N-dimethylsulfamido ~ 1235 2NHSO2CH3 bond Cl CHN,N-dimethylamido 1236 2 OCH3 bond Br CHimidazol-l-yl 1237 2 OCH3 bond Br CHmorpholin-l-yl - 1238 2 OCH3 bond Br CH2-methylimidazol-1-yl SUBSTITUTE SHEET(RULE 26) CA 022~l394 Igss-lo-o~

W097/38984 PCT~S97tO6431 1239 2 OCH3 bond Br CHpyridin-3-yl 1240 2 OCH3 bond Br CH2-(5'-trifluoromethyl) tetrazol-l'-yl 1241 2 OCH2C6H5 bond Br CHpyrazol-l-yl 1242 2 OCH2C6Hs bond Br CHphenyl 1243 2 OcH2c6H5 bond Br CHcyclohexyl 1244 2 OCH2C6H5 bond Br CHN,N-dimethylsulfamido 1245 2 OCH2C6H5 bond Br CHN,N-dimethylamido 1246 2 OH CH2 CH CHpyrazol-l-yl 1247 2 OH CH2 CH CH phenyl 1248 2 OH CH2 CH CHcyclohexyl 1249 2 OH CH2 CH CHN,N-dimethylsulfamido 1250 2 OH CH2 CH CHN,N-dimethylamido 1251 2 NHC(O)CH3 CH2 N CHimidazol-l-yl 1252 2 NHC(O)CH3 CH2 N CHmorpholin-l-yl 1253 2 NHC(O)CH3 CH2 N CH2-methylimidazol-1-yl 1254 2 NHC(O)CH3 CH2 N CHpyridin-3-yl 1255 2 NHC(O)CH3 CH2 N CH2-(5'-trifluoromethyl) tetrazol-l'-yl 1256 2 NHSO2CH3 CH2 N CHpyrazol-l-yl 1257 2 NHSO2CH3 CH2 N CHphenyl 1258 2 NHS02CH3 CH2 N CHcyclohexyl 1259 2 NHSO2CH3 CH2 N CHN,N-dimethylsulfamido 1260 2 NHSO2CH3 CH2 N CHN,N-dimethylamido 1261 2 OCH3 CH2 N Nimidazol-l-yl 1262 2 OCH3 CH2 N Nmorpholin-l-yl 1263 2 OCH3 CH2 N N2-methylimidazol-1-yl 1264 2 OCH3 CH2 N Npyridin-3-yl 1265 2 OCH3 CH2 N N2-(5'-trifluoromethyl) tetrazol-l'-yl 1266 2 OcH2c6H5 CH2 N Npyrazol-l-yl 1267 2 OCH2C6Hs CH2 N N phenyl 1268 2 OcH2c6H5 CH2 N Ncyclohexyl 1269 2 OcH2c6H5 CH2 N NN,N-dimethylsulfamido 1270 2 OcH2c6H5 CH2 N NN,N-dimethylamido SUBSTITUTE SHEET (RULE 26) , .. .. .

CA 022~l394 lsgs-lo-o~

W097/38984 PCT~S97/06431 Table 14 H~ B

Ex. n R2 B
1301 2 H benzoyl 1302 2 H phenylacetyl 1303 2 H phenylsulfonyl 1304 2 H benzylsulfonyl 1305 2 Hpicolin-2-ylsulfonyl 1306 2 Hpyridin-2-ylsulfonyl 1307 2 H picolin-2-yl 1308 2 H (phenyl-N-methylamino)sulfonyl 1309 2 H (1,1-dimethyl-1-phenyl)methylsulfonyl 1310 2 H thiophen-2-ylmethyl 1311 2 OH benzoyl 1312 2 OH phenylacetyl 1313 2 OH (phenyl-N-methylamino)sulfonyl 1314 2 OH (1,1-dimethyl-1-phenyl)methylsulfonyl 1315 2 OHpicolin-2-ylsulfonyl 1316 2 OHpyridin-2-ylsulfonyl 1317 2 OH picolin-2-yl 1318 2 OHthiophen-2-ylsulfonyl 1319 2 OHthiophen-2-ylmethylsulfonyl 1320 2 OH thiophen-2-ylmethyl 1321 2NHC(O)CH3 (phenyl-N-methylamino)sulfonyl 1322 2NHC(O)CH3(1,1-dimethyl-1-phenyl)methylsulfonyl 1323 2NHC(O)CH3phenylsulfonyl 1324 2NHC(O)CH3benzylsulfonyl 1325 2NHC(O)CH3picolin-2-ylsulfonyl 1326 2NHC(O)CH3pyridin-2-ylsulfonyl 1327 2NHC(O)CH3picolin-2-yl 1328 2NHC(O)CH3thiophen-2-ylsulfonyl 1329 2 NHC(O)CH3 thiophen-2-ylmethylsulfonyl 1330 2 NHC(O)CH3thiophen-2-ylmethyl 1331 2 NHSO2CH3 benzoyl 1332 2 NHSO2CH3phenylacetyl 1333 2 NHSO2CH3phenylsulfonyl 1334 2 NHSO2CH3benzylsulfonyl 1335 2 NHSO2CH3 (phenyl-N-methylamino)sulfonyl SUBSTITUTE SHEET (RULE 26) CA 0225l394 lggs-l0-05 W097/38984 PCT~S97/06431 1336 2 NHSO~CH3 (l,l-dimethyl-l-phenyl)methylsulfonyl 1337 2 NHSO2CH3 picolin-2-yl 1338 2 NHSO2CH3 thiophen-2-ylsulfonyl 1339 2 NHSO2CH3 thiophen-2-ylmethylsulfonyl 1340 2 NHSO2CH3 thiophen-2-ylmethyl SUBSTITUTE SHEET(RULE 26) W097/38984 PCT~S97/06431 Table 15 HN
o Ex. n R2 z B
1401 2 H bond benzoyl 1402 2 H bond phenylacetyl 1403 2 H bondphenylsulfonyl 1404 2 H bondbenzylsulfonyl 1405 2 H bondpicolin-2-ylsulfonyl 1406 2 H bondpyridin-2-ylsulfonyl 1407 2 H bond picolin-2-yl 1408 2 H bond ~phenyl-N-methylamino)sulfonyl 1409 2 H bond (1,1-dimethyl-1-phenyl)methylsulfonyl 1410 2 H bondthiophen-2-ylmethyl 1411 2 OH bond benzoyl 1412 2 QH bond phenylacetyl 1413 2 OH bond (phenyl-N-methylamino~sulfonyl 1414 2 OH bond (1,1-dimethyl-1-phenyl)methylsulfonyl 1415 2 OH bondpicolin-2-ylsulfonyl 1416 2 OH bondpyridin-2-ylsulfonyl 1417 2 OH bond picolin-2-yl 1418 2 OH bondthiophen-2-ylsulfonyl 1419 2 OH bond thiophen-2-ylmethylsulfonyl 1420 2 OH bondthiophen-2-ylmethyl 1421 2 NHC(O)CH3 bond (phenyl-N-methylamino)sulfonyl 1422 2 NHC(O) CH3 bond(1,1-dimethyl-1-phenyl)methylsulfonyl 1423 2 NHC(O) CH3 bondphenylsulfonyl 1424 2 NHC(O)CH3 bondbenzylsulfonyl 1425 2NHC(O)CH3 bondpicolin-2-ylsulfonyl 1426 2NHC(O)CH3 bondpyridin-2-ylsulfonyl 1427 2NHC(O)CH3 bond picolin-2-yl 1428 2NHC(O)CH3 bondthiophen-2-ylsulfonyl 1429 2NHC(O)CH3 bondthiophen-2-ylmethylsulfonyl 1430 2NHC(O~CH3 bondthiophen-2-ylmethyl 1431 2NHSO2CH3 bond benzoyl 1432 2NHSO2CH3 bond phenylacetyl 1433 2NHSO2CH3 bondphenylsulfonyl 1434 2NHSO2CH3 bondbenzylsulfonyl 1435 2NHS02CH3 bond (phenyl -N-methylamino)sulfonyl SUBSTITUTE SHEET(RULE 26) , . , ~ . .

CA 0225l394 lsss-l0-05 W097/38984 PCT~S97/06431 1436 2 NHSO2CH3 bond(1,1-dimethy~
phenyl)methylsulfonyl 1437 2 NHSO2CH3 bondpicolin-2-yl 1438 2 NHSO2CH3 bondthiophen-2-ylsulfonyl 1439 2 NHSO2CH3 bondthiophen-2-ylmethylsulfonyl 1440 2 NHSO2CH3 bondthiophen-2-ylmethyl SUts:i 111 IJTE SHEET (RULE 26) CA 022sl394 1998-lo-o~

W O 97/38984 PCTrUS97/06431 Table 16 ~ H
H2~ 1 ) n ~\
~ ~ ~ N ~ N ~ - B

Ex. n R2 z B
1501 2 H bond benzoyl 1502 2 H bondphenylacetyl 1503 2 H bondphenylsulfonyl 1504 2 H bondbenzylsulfonyl 1505 2 H bondpicolin-2-ylsulfonyl 1506 2 H bondpyridin-2-ylsulfonyl 1507 2 H bond picolin-2-yl 1508 2 H bond (phenyl-N-methylamino)sulfonyl 1509 2 H bond~1,1-dimethyl-1-phenyl)methylsulfonyl 1510 2 H bondthiophen-2-ylmethyl 1511 2 OH bond benzoyl 1512 2 OH bondphenylacetyl 1513 2 OH bond (phenyl-N-methylamino~sulfonyl 1514 2 OH bond(1,1-dimethyl-1-phenyl)methylsulfonyl 1515 2 OH bondpicolin-2-ylsulfonyl 1516 2 OH bondpyridin-2-ylsulfonyl 1517 2 OH bond picolin-2-yl 1518 2 OH bondthiophen-2-ylsulfonyl 1519 2 OH bond thiophen-2-ylmethylsulfonyl 1520 2 OH bondthiophen-2-ylmethyl 1521 2 NHC(O)CH3 bond(phenyl-N-methylamino)sulfonyl 1522 2 NHC(O)CH3 bond(1,1-dimethyl-1-phenyl)methylsulfonyl 1523 2 NHC(O)CH3 bondphenylsulfonyl 1524 2 NHC(O)CH3 bondbenzylsulfonyl 1525 2 NHC(O)CH3 bondpicolin-2-ylsulfonyl 1526 2 NHC(O)CH3 bondpyridin-2-ylsulfonyl 1527 2 NHC(O)CH3 bond picolin-2-yl 1528 2 NHC(O)CH3 bondthiophen-2-ylsulfonyl 1529 2 NHC(O)CH3 bondthiophen-2-ylmethylsulfonyl 1530 2 NHC(O)CH3 bondthiophen-2-ylmethyl 1531 2 NHSO2CH3 bond benzoyl 1532 2 NHS02CH3 bondphenylacetyl 1533 2 NHSO2CH3 bondphenylsulfonyl 1534 2 NHSO2CH3 bondbenzylsulfonyl 1535 2 NHSO2CH3 bond (phenyl-N-methylamino)sulfonyl SU~ UTE SHEET(RULE26) .. ..... . . ..

CA 0225l394 lsgs-l0-05 W097t38984 PCT~S97/06431 1536 2 NHS02CH3 bond(1,1-dimethyl-1-phenyl)methylsulfonyl 1537 2 NHSO2CH3 bondpicolin-2-yl 1538 2 NHSO2CH3 bondthiophen-2-ylsulfonyl 1539 2 NHS02CH3 bondthiophen-2-ylmethylsulfonyl 1540 2 NHSO2CH3 bondthiophen-2-ylmethyl S~ TE SHEET(RULE 26) CA 022~1394 1998-l0-0~

W097/38984 PCT~S97/06431 Table 17 H2~ ~ ~ ~ )n N N ~ N - s HN I
o Ex. n R2 z B
1601 2 H bondpicolin-2-ylsulfonyl 1602 2 H bondpyridin-2-ylsulfonyl 1603 2 H bondpicolin-2-yl 1604 2 H bondthiophen-2-ylsulfonyl 1605 2 H bond thiophen-2-ylmethylsulfonyl 1606 2 H bondthiophen-2-ylmethyl 1607 2 H bond4-fluorophenylsulfonyl 1608 2 H bond4-fluorobenzylsulfonyl 1609 2 H bondphenylsulfonyl 1610 2 H bondbenzylsulfonyl 1611 2 H bond (phenyl-N-methylamino)sulfonyl 1612 2 H bond(1,1-dimethyl-1-phenyl)methylsulfonyl 1613 2 OH bondpicolin-2-ylsulfonyl 1614 2 OH bondpyridin-2-ylsulfonyl 1615 2 OH bondpicolin-2-yl 1616 2 OH bondthiophen-2-ylsulfonyl 1617 2 OH bond thiophen-2-ylmethylsulfonyl 1618 2 OH bondthiophen-2-ylmethyl 1619 2 OH bond4-fluorophenylsulfonyl 1620 2 OH bond4-fluorobenzylsulfonyl 1621 2 OH bond (phenyl-N-methylamino)sulfonyl 1622 2 OH bond(1,1-dimethyl-1-phenyl)methylsulfonyl 1623 2 OCH3 bondpicolin-2-ylsulfonyl 1624 2 OC~3 bondpyridin-2-ylsulfonyl 1625 2 OCH3 bondpicolin-2-yl 1626 2 OCH3 bondthiophen-2-ylsulfonyl 1627 2 OCH3 bondthiophen-2-ylmethylsulfonyl 1628 2 OCH3 bondthiophen-2-ylmethyl 1629 2 OCH3 bond (phenyl-N-methylamino)sulfonyl 1630 2 OCH3 bond(1,1-dimethyl-1-phenyl)methylsulfonyl 1631 2 OCH3 bondphenylsulfonyl 1632 2 OCH3 bondbenzylsulfonyl 1633 2OCH2C6Hs bondpicolin-2-ylsulfonyl 1634 2OCH2C6Hs bondpyridin-2-ylsulfonyl 1635 2Oc~2c6Hs bondpicolin-2-yl 1636 2OCH2C6Hs bondthiophen-2-ylsulfonyl S~SIlIUTE SHEET(RULE26) CA 022~l394 l998-l0-0~

WO971389B4 PCT~S97/06431 1637 2OcH2c6H5 bond(phenyl-N-methylamino)sulfonyl 1638 2OCH2C6~5 bond(l,l-dimethyl-l-phenyl~methylsulfonyl 1639 2OCH2C6H5 bond4-fluorophenylsulfonyl 1640 2OcH2c6Hs bond4-fluorobenzylsulfonyl 1641 2OCH2C6Hs bondphenylsulfonyl 1642 2OCH2C6Hs bondbenzylsulfonyl 1643 2NHC(O)CH3 bondpicolin-2-ylsulfonyl 1644 2NHC(O)CH3 bondpyridin-2-ylsulfonyl 1645 2NHC(O)CH3 bond(phenyl-N-methylamino)sulfonyl 1646 2NHC(O)CH3 bond(l,l-dimethyl-l-phenyl)methylsulfonyl 1647 2NHC(O)CH3 bondthiophen-2-ylmethylsulfonyl 1648 2NHC(O)CH3 bond~hiophen-2-ylmethyl 1649 2NHC(O)CH3 bond4-fluorophenylsulfonyl 1650 2NHC(O)CH3 bond4-fluorobenzylsulfonyl 1651 2NHC(O)CH3 bondphenylsulfonyl 1652 2NHC(O)CH3 bondbenzylsulfonyl 1653 2 NHC(O)OCH3 bond (phenyl-N-methylamino)sulfonyl 1654 2 NHC(O)OCH3 bond(l,l-dimethyl-l-phenyl)methylsulfonyl 1655 2NHC(O)OCH3 bondpicolin-2-yl 1656 2NHC(O)OCH3 bondthiophen-2-ylsulfonyl 1657 2NHC(O)OCH3 bondthiophen-2-ylmethylsulfonyl 1658 2NHC(O)OCH3 bondthiophen-2-ylmethyl 1659 2NHC(O)OCH3 bond4-fluorophenylsulfonyl 1660 2NHC(O)OCH3 bond4-fluorobenzylsulfonyl 1661 2 NHC(O)OCH3 bondphenylsulfonyl 1662 2 NHC(O)OCH3 bondbenzylsulfonyl 1663 2NHC(O)NHCH3 bondpicolin-2-ylsulfonyl 1664 2NHC(O)NHCH3 bondpyridin-2-ylsulfonyl 1665 2NHC(O)NHCH3 bondpicolin-2-yl 1666 2NHC(O)NHCH3 bondthiophen-2-ylsulfonyl 1667 2NHC(O)NHCH3 bondthiophen-2-ylmethylsulfonyl 1668 2NHC(O)NHCH3 bondthiophen-2-ylmethyl 1669 2NHC(O)NHCH3 bond4-fluorophenylsulfonyl 1670 2NHC(O)NHCH3 bond4-fluorobenzylsulfonyl 1671 2 NHC(O)NHCH3 bond (phenyl-N-methylamino)sulfonyl 1672 2 NHC(O)NHCH3 bond(l,l-dimethyl-l-phenyl)methylsulfonyl 1673 2NHC(O)C6Hs bondpicolin-2-ylsulfonyl 1674 2NHC(O)C6Hs bondpyridin-2-ylsulfonyl 1675 2NHC(O)C6Hs bondpicolin-2-yl 1676 2NHC(O)C6H5 bondthiophen-2-ylsulfonyl 1677 2NHC(O)C6Hs bondthiophen-2-ylmethylsulfonyl 1678 2NHC(O)C6Hs bondthiophen-2-ylmethyl 1679 2 NHC(O)C6Hs bond(phenyl-N-methylamino)sulfonyl 1680 2 NHC(O)C6Hs bond(l,l-dimethyl-l-phenyl)methylsulfonyl SUBSTITUTE SHEET (RULE 26) ., " . .

CA 022~l394 Isgs-lo-o~

W097/38984 PCT~S97/06431 1681 2 NHC(O)C6Hs bondphenylsulfonyl 1682 2 NHc(o)c6Hs bondbenzylsulfonyl 1683 2NHSO2CH3 bondpicolin-2-ylsulfonyl 1684 2NHSO2CH3 bondpyridin-2-ylsulfonyl 1685 2NHSO2CH3 bond picolin-2-yl 1686 2NHSO2CH3 bondthiophen-2-ylsulfonyl 1687 2NHSO2CH3 bond (phenyl-N-methylamino)sulfonyl 1688 2NHSO2CH3 bond(1,1-dimethyl-1-phenyl)methylsulfonyl 1689 2NHSO2CH3 bond4-fluorophenylsulfonyl 1690 2NHSO2CH3 bond4-fluorobenzylsulfonyl 1691 2NHSO2CH3 bondphenylsulfonyl 1692 2NHS02CH3 bondbenzylsulfonyl 1693 2NHSO2NHCH3 bondpicolin-2-ylsulfonyl 1694 2NHSO2NHCH3 bondpyridin-2-ylsulfonyl 1695 2NHSO2NHCH3 bond (phenyl-N-methylamino)sulfonyl 1696 2NHSO2NHCH3 bond(1,1-dimethyl-1-phenyl)methylsulfonyl 1697 2NHSO2NHCH3 bondthiophen-2-ylmethylsulfonyl 1698 2NHSO2NHCH3 bondthiophen-2-ylmethyl 1699 2NHSO2NHCH3 bond4-fluorophenylsulfonyl 1700 2NHS02NHCH3 bond4-fluorobenzylsulfonyl 1701 2NHSO2NHCH3 bondphenylsulfonyl 1702 2NHSO2NHCH3 bondbenzylsulfonyl 1703 2NHSO2C6Hs bond (phenyl-N-methylamino)sulfonyl 1704 2NHSO2C6Hs bond(1,1-dimethyl-1-phenyl)methylsulfonyl 1705 2NHSO2C6Hs bond picolin-2-yl 1706 2NHSO2C6Hs bondthiophen-2-ylsulfonyl 1707 2NHSO2C6Hs bondthiophen-2-ylmethylsulfonyl 1708 2NHSO2C6Hs bondthiophen-2-ylmethyl 1709 2NHSO2C6Hs bond4-fluorophenylsulfonyl 1710 2NHSO2C6Hs bond4-fluorobenzylsulfonyl 1711 2NHSO2C6Hs bondphenylsulfonyl 1712 2NHSO2C6H5 bondbenzylsulfonyl SU~:i 111 UTE SHEET (RULE 26) ... . ...

CA 022~l394 Isss-lo-o~

W097/38984 PCT~S97/06431 Table 18 H2~ )n N~ N __-CN--B

Ex. n R2 z B
1801 2 H CH2 picolin-2-ylsulfonyl 1802 2 H CH2 pyridin-2-ylsulfonyl 1803 2 H CH2 picolin-2-yl 1804 2 H CH2 thiophen-2-ylsulfonyl 1805 2 H CH2thiophen-2-ylmethylsulfonyl 1806 2 H CH2thiophen-2-ylmethyl 1807 2 H CH24-fluorophenylsulfonyl 1808 2 H CH24-fluorobenzylsulfonyl 1809 2 H CH2(phenyl-N-methylamino)sulfonyl 1810 2 H CH2(1,1-dimethyl-1-phenyl)methylsulfonyl 1811 2 OH CH2picolin-2-ylsulfonyl 1812 2 OH CH2pyridin-2-ylsulfonyl 1813 2 OH CH2picolin-2-yl 1814 2 OH CH2thiophen-2-ylsulfonyl 1815 2 OH CH2thiophen-2-ylmethylsulfonyl 1816 2 OH CH2thiophen-2-ylmethyl 1817 2 OH CH24-fluorophenylsulfonyl 1818 2 OH CH24-fluorobenzylsulfonyl 1819 2 OH CH2(phenyl-N-methylamino)sulfonyl 1820 2 OH CH2(1,1-dimethyl-1-phenyl)methylsulfonyl 1821 2 OCH3 CH2picolin-2-ylsulfonyl 1822 2 OCH3 CH2pyridin-2-ylsulfonyl 1823 2 OCH3 CH2picolin-2-yl 1824 2 OCH3 CH2thiophen-2-ylsulfonyl 1825 2 OCH3 CH2thiophen-2-ylmethy~sulfonyl 1826 2 OCH3 CH2thiophen-2-ylmethyl 1827- 2 OCH3 CH2(phenyl-N-methylamino)sulfonyl 1828 2 OCH3 CH2(1,1-dimethyl-1-phenyl)methylsulfonyl 1829 2 OCH3 CH2phenylsulfonyl 1830 2 OCH3 CH2benzylsulfonyl 1831 2 OcH2c6H5 CH2picolin-2-ylsulfonyl 1832 2 OCH2C6Hs CH2pyridin-2-ylsulfonyl 1833 2 OCH2C6Hs CH2picolin-2-yl 1834 2 OCH2C6Hs CH2thiophen-2-ylsulfonyl SUBSTITUTE SHEET (RULE 26) CA 02251394 1998-lO-0~

PCT~US97/06431 1835 2OCH2C6H5 CH2(phenyl-N-methylamino)sulfonyl 1836 2OCH2C6Hs CH2(l,l-dimethyl-l-phenyl)methylsulfonyl 1837 2OCH2C6~s CH24-fluorophenylsulfonyl 1838 2OCH2C6Hs CH24-fluorobenzylsulfonyl 1839 2OCH2C6Hs CH2phenylsulfonyl 1840 2OCH2C6Hs CH2benzylsulfonyl 1841 2NHC~O)CH3 CH2picolin-2-ylsulfonyl 1842 2NHC(O)CH3 CH2pyridin-2-ylsulfonyl 1843 2NHC~O)CH3 CH2(phenyl-N-methylamino)sulfonyl 1844 2NHC(O)CH3 CH2~l,l-dimethyl-l-phenyl)methylsulfonyl 1845 2NHC(O)CH3 CH2thiophen-2-ylmethylsulfonyl 1846 2NHC(O)CH3 CH2thiophen-2-ylmethyl 1847 2NHC~O)CH3 CH24-fluorophenylsulfonyl 1848 2NHC(O)CH3 CH24-fluorobenzylsulfonyl 1849 2NHC(O)CH3 CH2phenylsulfonyl 1850 2NHC(O)CH3 CH2benzylsulfonyl 1851 2NHC(O)OCH3 CH2(phenyl-N-methylamino)sulfonyl 1852 2NHC(O)OCH3 CH2(l,l-dimethyl-l-phenyl)methylsulfonyl 1853 2NHC~O)OCH3 CH2picolin-2-yl 1854 2NHC(O)OCH3 CH2thiophen-2-ylsulfonyl 1855 2NHC(O)OCH3 CH2thiophen-2-ylmethylsulfonyl 1856 2NHC(O)OCH3 CH2thiophen-2-ylmethyl 1857 2NHC(O)OCH3 CH24-fluorophenylsulfonyl 1858 2NHC(O)OCH3 CH24-fluorobenzylsulfonyl 1859 2NHC(O)OCH3 CH2phenylsulfonyl 1860 2NHC(O)OCH3 CH2benzylsulfonyl 1861 2NHC(O)NHCH3 CH2picolin-2-ylsulfonyl 1862 2NHC(O)NHCH3 CH2pyridin-2-ylsulfonyl 1863 2NHC(O)NHCH3 CH2picolin-2-yl 1864 2NHC(O)NHCH3 CH2thiophen-2-ylsulfonyl 1865 2NHC(O)NHCH3 CH2thiophen-2-ylmethylsulfonyl 1866 2NHC(O)NHCH3 CH2thiophen-2-ylmethyl 1867 2NHC(O)NHCH3 CH24-fluorophenylsulfonyl 1868 2NHC(O)NHCH3 CH24-fluorobenzylsulfonyl 1869 2NHC(O)NHCH3 CH2(phenyl-N-methylamino)sulfonyl 1870 2NHC(O)NHCH3 CH2(l,l-dimethyl-l-phenyl)methylsulfonyl 1871 2NHC(O)C6H5 CH2picolin-2-ylsulfonyl 1872 2NHC(O)C6Hs CH2pyridin-2-ylsulfonyl 1873 2NHC(O)C6Hs CH2picolin-2-yl 1874 2NHC(O)C6Hs CH2thiophen-2-ylsuIfonyl 1875 2NHC(O)C6Hs CH2thiophen-2-ylmethylsulfonyl 1876 2NHC(O)C6Hs CH2thiophen-2-ylmethyl 1877 2NHC(O)C6Hs CH2(phenyl-N-methylamino)sulfonyl 1878 2NHC(O)C6Hs CH2(l,l-dimethyl-l-phenyl)methylsulfonyl SUt~ 111 UTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097/38g84 PCT~S97106431 1879 2NHC~O)C6Hs CH2phenylsulfonyl 1880 2NHC(O)C6H5 CH2benzylsulfonyl 1881 2NHSO2CH3 CH2picolin-2-ylsulfonyl 1882 2NHSO2CH3 CH2pyridin-2-ylsulfonyl 1883 2NHSO2CH3 CH2picolin-2-yl 1884 2NHSO2CH3 CH2thiophen-2-ylsulfonyl 1885 2NHSO2CH3 CH2(phenyl-N-methylamino)sulfonyl 1886 2NHSO2CH3 CH2(l,l-dimethyl-l-phenyl)methylsulfonyl 1887 2NHSO2CH3 CH24-fluorophenylsulfonyl 1888 2NHSO2CH3 CH24-fluorobenzylsulfonyl 1889 2NHSO2CH3 CH2phenylsulfonyl 1890 2NHS02CH3 CH2benzylsulfonyl 1891 2NHSO2NHCH3 CH2picolin-2-ylsulfonyl 1892 2NHSO2NHCH3 CH2pyridin-2-ylsulfonyl 1893 2NHS02NHCH3 CH2(phenyl-N-methylamino)sulfonyl 1894 2NHSO2NHCH3 CH2(l,l-dimethyl-l-phenyl)methylsulfonyl 1895 2NHSO2NHCH3 CH2thiophen-2-ylmethylsulfonyl 1896 2NHSO2NHCH3 CH2thiophen-2-ylmethyl 1897 2NHSO2NHCH3 CH24-fluorophenylsulfonyl 1898 2NHS02NHCH3 CH24-fluorobenzylsulfonyl 1899 2NHSO2NHCH3 CH2phenylsulfonyl 1900 2NHSO2NHCH3 CH2benzylsulfonyl 1901 2NHSO2C6Hs CH2(phenyl-N-methylamino)sulfonyl 1902 2NHSO2C6Hs CH2(l,l-dimethyl-l-phenyl)methylsulfonyl 1903 2NHSO2C6Hs CH2picolin-2-yl 1904 2NHSO2C6Hs CH2thiophen-2-ylsulfonyl 1905 2NHSO2C6Hs CH2thiophen-2-ylmethylsulfonyl 1906 2NHSO2C6Hs CH2thiophen-2-ylmethyl 1907 2NHSO2C6Hs CH24-fluorophenylsulfonyl 1908 2NHSO2C6Hs CH24-fluorobenzylsulfonyl 1909 2NHSO2C6Hs CH2phenylsulfonyl 1910 2NHSO2C6Hs CH2benzylsulfonyl SLI~ JTE SHEET (RULE 26) CA 0225l394 Isss-lo-os W O 97/38984 PCTrUS97/06431 ~able 19 R,2 H2 ~ ~¦ ) n ~ N ~ N A B

Ex. n R2 Z A B
2001 0 H (CH2)2O phenylamino 2002 0 H (CH2)2O phenylamidino 2003 0 H (CH2)2O phenylguanidino 2004 0 H ~CH2)2O phenylbenzyl 2005 0 H (CH2)2C(O) phenylphenyl 2006 0 H (CH2)2C(O) phenylcyclohexyl 2007 0 H (CH2)2C(O) phenyl4-pyridyl 2008 0 H (CH2)2C(O) phenyl2-furanyl 2009 0 H (CH2)2C(O)O phenylpiperidinyl 2010 0 H (CH2)2C(O)O phenylphenethyl 2011 0 H (CH2)2C(O)O phenylphenylcarbonyl 2012 0 H (CH2)2C(O)O phenyl2-aminophenyl-carbonyl 2013 0 H(CH2)2C(O)NH phenylbenzylcarbonyl 2014 0 H(CH2)2C(O)NH phenyl4-acetamidophenyl-methanecarbonyl 2015 0 H(CH2)2C(O)NH phenylphenylsulfonyl 2016 0 H(CH2)2C(O)NH phenyl4-amidinophenyl-sulfonyl 2017 0 H(CH2)2NHC(O)NH phenylbenzylsulfonyl 2018 0 H(CH2)2NHC(O)NH phenyl4~methoxycarbonyl-phenylmethane-sulfonyl 2019 0 H(CH2)2NHC(O) NH phenylphenylsulfonamide 2020 0 H(CH2)2NHC(O)NH phenyl4-acetamidophenyl-sulfonamide 2021 0 H(CH2)2S(O)2NH phenylphenylcarbamide 2022 0 H(CH2)2S(O)2NH phenyl2-aminophenyl-carba~ide 2023 0 H(CH2)2S(O)2NH phenylbenzylamine 2024 0 H(CH2)2S(O)2NH phenyl4-amidinophenyl-methaneamine 2025 0 H (cH2)2ocH2 phenylamino 2026 0 H (CH2)2OCH2 phenylamidino 2027 0 H (cH2)2ocH2 phenylguanidino 2028 0 H (cH2)2ocH2 phenylbenzyl 2029 0 H(cH2)2c(o)cH2 phenylphenyl 2030 0 H(cH2)2c(o)cH2 phenylcyclohexyl 2031 0 H(CH2)2C(O)CH2 phenyl4-pyridyl 2032 0 H~cH2)2c(o)cH2 phenyl2-furanyl 2033 0 H(cH2)2c(o)ocH2 phenylpiperidinyl SUBSTITUTE SHEET (RULE 26) .... _, , CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 2034 ~ H(CH2) 2C (O) OCH2 phenylphenethyl 2035 0 H(CH2 ) 2C (O) OCH2 phenylphenylcarbonyl 2036 0 H(cH2)2c(o)ocH2 phenyl2-aminophenyl-carbonyl 2037 0 H(CH2)2C(O)NHCH2 phenylbenzylcarbonyl 2038 0 H(cH2)2c(o)NHcH2 phenyl4-acetamidophenyl-methanecarbonyl 2039 0 H(cH2)2c(o)NHcH2 phenylphenylsulfonyl 2040 0 H(cH2)2c(o)NHcH2 phenyl4-amidinophenyl-sulfonyl 2041 0 H( CH2 ) 2NHC ( O ) NHCH2 phenyl benzylsulfonyl 2042 0 H(CH2)2NHC(O)NHCH2 phenyl4-methoxycarbonyl-phenylmethane-sulfonyl 2043 0 H(CH2)2NHC(O)NHCH2 phenylphenylsulfonamide 2044 ~ H(CH2)2NHC(O)NHCH2 phenyl4- acetamidophenyl-sulfonamide 2045 ~ H(cH2)2s(o)2NHcH2 phenylphenylcarbamide 2046 0 H(cH2)2s(o)2NHcH2 phenyl2-aminophenyl-carbamide 2047 0 H(CH2)2s(O)2NHcH2 phenylbenzylamine 2048 0 H(cH2)2s(o)2NHcH2 phenyl4-amidinophenyl-methaneamine ~B is substituted para to Z on A.

SUBSTITUTE SltEET (RULE 26) CA 022~l394 lsgs-lo-o~

W097l38984 PCT~S97/06431 Table 20 H2~ )n N ~ M A ~ s HN
o Ex. n R2 z A B
2101 1 H( CH2 ) 2~ phenylamino 2102 1 H(CH2 ) 2~ phenylamidino 2103 1 H(CH2 ) 2~ phenylguanidino 2104 1 H(CH2 ) 2~ phenylbenzyl 2105 1 H(CH2 ) 2C (O) phenylphenyl 2106 1 H( CH~ ) 2 C ( O ) phenylcyclohexyl 2107 1 H(CH2) ~C(O) phenyl4-pyridyl 2108 1 H(CH~ ) 2C (O) phenyl2-furanyl 2109 1 H(CH~ ) ~C (O) O phenylpiperidinyl 2110 1 H(CH~ ) 2C (O~ O phenylphenethyl 2111 1 H(CH2 ) 2C (O) O phenylphenylcarbonyl 2112 1 H(CH2 ) 2C (O) O phenyl2-aminophenyl-carbonyl 2113 1 H(CH2)2C(O) NH phenylbenzylcarbonyl 2114 1 H(CH2 ) 2C (O) NH phenyl4-acetamidophenyl-methanecarbonyl 2115 1 H(CH~ ) 2C (O)NH phenylphenylsulfonyl 2116 1 H( CH2 ) 2 C ( O ) NH phenyl4-amidinophenyl-sulfonyl 2117 1 H(CH~ ) 2NHC (O)NH phenylbenzylsulfonyl 2118 1 H( CH 7 ) 2NHC ( O ) NH phenyl4-methoxycarbonyl-phenylmethane-sulfonyl 2119 1 H(CH2)2NHC(O)NH phenylphenylsulfonamide 2120 1 H(CH2)2NHC(O)NH phenyl4-acetamidophenyl-sulfonamide 2121 1 H( CH2 ) 2 S ( ~ ) 2NH phenylphenylcarbamide 2122 1 H(CH2)2S(O)2NH phenyl2-aminophenyl-carbamide 2123 1 H(CH2)2S(O)2NH phenylbenzylamine 2124 1 H(CH2 ) 2S (O) 2NH phenyl4-amidinophenyl-methaneamine 2125 1 H(cH2)2ocH2 phenylamino 2126 1 H(cH2)2ocH2 phenylamidino 2127 1 H(cH2)2ocH2 phenylguanidino 2128 1 H(cH2)2ocH2 phenylbenzyl 2129 1 H(CH2 ) 2C (O) CH2 phenylphenyl 2130 1 H(CH2 ) 2C (O) CH2 phenylcyclohexyl 2131 1 H(CH2) 2C (O) CH2 phenyl4-pyridyl 2132 1 H(CH2 ) 2C (O) CH2 phenyl2-furanyl 2133 1 H(cH2)2c(o)ocH2 phenylpiperidinyl SUBSTITUTE SHEET(RULE26) CA 022~1394 1998-10-0~

WO9713B984 PCT~S97/06431 2134 1 H(CH2)2C(O)OcH2 pheny~ phenethyl 2135 1 H(cH2)2c(o)ocH2 phenylphenylcarbonyl 2136 1 H(CH2)2C(O)OCH2 phenyl2-aminophenyl-carbonyl 2137 1 H(cH2)2c(o)NHcH2 phenylbenzylcarbonyl 2138 1 H(CH2)2C(O)NHCH2 phenyl4-acetamidophenyl-methanecarbonyl 2139 1 H(CH2 ) 2C (O) NHCH2 phenylphenylsulfonyl 2140 1 H(cH2)2c(o)NHcH2 phenyl4-amidinophenyl-sulfonyl 2141 1 H(cH2)2NHc(o)NHcH2 phenylbenzylsulfonyl 2142 1 H(CH2)2NHC(O)NHCH2 phenyl4-methoxycarbonyl-phenylmethane-sulfonyl 2143 1 H(cH2)2NHc(o)NHcH2 phenylphenylsulfonamide 2144 1 H(cH2)2NHc(o)NHcH2 phenyl4-acetamidophenyl-sulfonamide 2145 1 H(CH2 ) 2S (~) 2NHcH2 phenylphenylcarbamide 2146 1 H(CH2)2S(O)2NHCH2 phenyl2-aminophenyl-carbamide 2147 1 H(cH2)2s(o)2NHcH2 phenylbenzylamine 2148 1 H(CH2 ) 2S (O) 2NHCH2 phenyl4-amidinophenyl-methaneamlne B is substituted para to Z on A.

SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 Table 21 H2. ~ ~ ) n ~,~N~N A B
HN
o Ex. n R2 z A B
2201 2 H (cH2)2o phenylamino 2202 2 H (cH2)2o phenylamidino 2203 2 H (CH2)2O phenylguanidino 2204 2 H (CH2)2O phenylbenzyl 2205 2 H (CH2)2C(O) phenylphenyl 2206 2 H (CH2)2C(O) phenylcyclohexyl 2207 2 H (CH2)2C(O) phenyl4-pyridyl 2208 2 H (CH2)2C(O) phenyl2-furanyl 2209 2 H (CH2)2C(O)O phenylpiperidinyl 2210 2 H (CH2)2C(O)O phenylphenethyl 2211 2 H (CH2)2C(O)O phenylphenylcarbonyl 2212 2 H (CH2)2C(O)O phenyl2-aminophenyl-carbonyl 2213 2 H (CH2)2C(O)NH phenylbenzylcarbonyl 2214 2 H (CH2)2C(O~NH phenyl4-acetamidophenyl-methanecarbonyl 2215 2 H (CH2)2C(O)NH phenylphenylsulfonyl 2216 2 H (CH2)2C(O)NH phenyl4-amidinophenyl-sulfonyl 2217 2 H (CH2)2NHC(O)NH phenylbenzylsulfonyl 2218 2 H (CH2)2NHC(O)NH phenyl4-methoxycarbonyl-phenylmethane-sulfonyl 2219 2 H (CH2)2NHC(O)NH phenylphenylsulfonamide 2220 2 H (CH2)2NHC(O)NH phenyl4-acetamidophenyl-sulfona~ide 2221 2 H (CH2)2S(O)2NH phenylphenylcarbamide 2222 2 H (CH2)2S(O)2NH phenyl2-aminophenyl-carbamide 2223 2 H (CH2)2S(O)2NH phenylbenzylamine 2224 2 H (CH2)2S(O)2NH phenyl4-amidinophenyl-methaneamine 2225 2 H (cH2)2ocH2 phenylamino 2226 2 H (cH2)2ocH2 phenylamidino 2227 2 H (cH2)2ocH2 phenylguanidino 2228 2 H (cH2)2ocH2 phenylbenzyl 2229 2 H (cH2)2c(o)cH2 phenylphenyl 2230 2 H (cH2)2c(o)cH2 phenylcyclohexyl 2231 2 H (cH2)2c(o)cH2 phenyl4-pyridyl 2232 2 H (cH2)2c(o)cH2 phenyl2-furanyl 2233 2 H (cH2)2c(o)ocH2 phenylpiperidinyl SUBSTITUTE SHEET(RULE26) .. . .

CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 2234 2 H(cH2)2c(o)ocH2 phenyl phenethyl 2235 2 H(cH2)2c(o)ocH2 phenyl phenylcarbonyl 2236 2 H(cH2)2c(o)ocH2 phenyl 2-aminophenyl-carbonyl 2237 2 H(cH2)2c(o)NHcH2 phenyl benzylcarbonyl 2238 2 H(cH2)2c(o)NHcH2 phenyl4-acetamidophenyl-methanecarbonyl 2239 2 H(cH2)2c(o)NHcH2 phenyl phenylsulfonyl 2240 2 H(cH2)2c(o)NHcH2 phenyl 4-amidinophenyl-sulfonyl 2241 2 H(CH2)2NHc(O)NHcH2 phenyl benzylsulfonyl 2242 2 H(cH2)2NHc(o)NHcH2 phenyl4-methoxycarbonyl-phenylmethane-sulfonyl 2243 2 H(CH2)2NHC(O)NHCH2 phenylphenylsulfonamide 2244 2 H(cH2)2NHc(o)NHcH2 phenyl4-acetamidophenyl-sulfonamide 2245 2 H(cH2)2s(o)2NHcH2 phenyl phenylcarbamide 2246 2 H(cH2)2s(o)2NHcH2 phenyl 2-aminophenyl-carbamide 2247 2 H(cH2)2s(o)2NHcH2 phenyl benzylamine 2248 2 H~cH2)2s(o)2NHcH2 phenyl 4-amidinophenyl-methaneamine B is substituted para to Z on A.

SUBSTITUTE S~EET (RULE 26) CA 022~l394 Isss-lo-o~

WO97t38984 PCT~S97/06431 Table 22 H2~
~ ~ N ~ N A _ B
HN ll O
Ex. n Z A B*
- 2301 0(CH2)20 2-fluorophenylimidazol~1-yl 2302 0(CH2)20 2-chlorophenylN,N-dimethylamido 2303 0[CH2)2O 2-bromophenyl morpholin-1-yl 2304 0(CH2)20 2-pyridyl 2-methylindazol-1-yl 2305 0(CH2)20 2-pyrimidinylN,N-dimethylsulfamido 2306 0(CH2)2C(O)2-fluorophenylpyridin-3-yl 2307 0(CH2)2C(O)2-chlorophenyl2-((5'-trifluormethyl) tetrazol-1'-yl~phenyl 2308 0(CH2)2C(O)2-bromophenyl pyrazol-1-yl 2309 0(CH2)2C(O) 2-pyridyl cyclohexyl 2310 0(CH2)2C(O)O2-pyrimidinylimidazol-1-yl 2311 0(CH2)2C(O)O2-fluorophenylN,N-dimethylamido 2312 0(CH2)2C(O)O2-chlorophenylmorpholin-l-yl 2313 0(CH2)2C(O)O2-bromophenyl2-methylindazol-1-yl 2314 0(CH2)2C(O)NH2-pyridylN,N-dimethylsulfamido 2315 0(CH2)2C(O)NH2-pyrimidinylpyridin-3-yl 2316 0(CH2)2C(O)NH2-fluorophenyl2-((5'-trifluormethyl) tetrazol-1'-yl)phenyl 2317 0(CH2)2C(O)NH2-chlorophenylpyrazol-1-yl 2318 0(CH2)2C(O)NH2-bromophenylcyclohexyl 2319 0(CH2)2NHC(O)NH2-pyridyl imidazol-1-yl 2320 0(CH2)2NHC(O)NH2-pyrimidinylN,N-dimethylamido 2321 0 (CH2)2NHC(O)NH 2-fluorophenyl morpholin-1-yl 2322 0 (CH2)2NHC(O)NH 2-chlorophenyl 2-methylindazol-1-yl 2323 0(CH2)2S(O)2NH2-bromophenylN,N-dimethylsulfamido 2324 0(CH2)2S(O)2NH2-pyridyl pyridin-3-yl 2325 0(CH2)2S(O)2NH2-pyrimidinyl2-((5'-trifluormethyl) tetrazol-1'-yl~phenyl 2326 0(CH2)2S(O)2NH2-fluorophenylpyrazol-1-yl 2327 0(CH2)2S(O)2NH2-chlorophenylcyclohexyl 2328 0(CH2)2OCH22-bromophenyl imidazol-1-yl 2329 0(CH2)2OcH2 2-pyridyl N,N-dimethylamido 2330 0(CH2)2OcH22-pyrimidinylmorpholin-1-yl 2331 0(CH2)2OCH22-fluorophenyl2-methylindazol-1-yl 2332 0(CH2)2OCH22-chlorophenylN,N-dimethylsulfamido 2333 0(CH2)2C(O)CH22-bromophenylpyridin-3-yl 2334 0(CH2)2C(O)CH22-pyridyl2-((5'-trifluormethyl) tetrazol-1'-yl)phenyl 2335 0(CH2)2C(O)CH22-pyrimidinylpyrazol-1-yl 2336 0(CH2)2C(O)CH22-fluorophenylcyclohexyl 2337 0(CH2)2C(O)OCH22-chlorophenylimidazol-1-yl 2338 0(CH2)2C(O)OCH22-bromophenylN,N-dimethylamido 2339 0(CH2)2C(O)OCH22-pyridylmorpholin-1-yl SUBSTITUTE SHEET (RULE 26) .. .. .

CA 022~l394 lsss-lo-o~

W097/38984 PCT~S97/06431 2340 0(CH2)2C~O)OCH22-pyrimidinyl 2-methylindazol-1-yl 2341 0(CH2)2C(O)OCH22-fluorophenylN,N-d_methylsulfamido 2342 0(CH2)2C(O)-2-chlorophenyl pyridin-3-yl 2343 0(CH2)2C(O)-2-bromophenyl 2-((5~-trifluormethyl) NHCH2 tetrazol-l'-yl)phenyl 2344 0(CH2)2C(O)- 2-pyridyl pyrazol-l-yl 2345 0(CH2)2C(O)-2-pyrimidinyl cyclohexyl 2346 0(CH2)2NHC(O)-2-fluorophenyl imidazol-l-yl 2347 0(CH2)2NHC(O)-2-chlorophenyl N,N-dimethylamido 2348 0(CH2)2NHC(O)-2-bromophenyl morpholin-l-yl 2349 0(CH2)2NHC(O)-2-pyridyl 2-methylindazol-1-yl 2350 0(CH2)2NHC(O)-2-fluorophenyl N,N-dimethylsulfamido 2351 0(CH2)2s(O)2-2-chlorophenyl pyridin-3-yl 2352 0(CH2)2S(O)2-2-bromophenyl 2-((5'-trifluormethyl) NHCH2 tetrazol-l'-yl)phenyl 2353 0(CH2)2S(O)2- 2-pyridyl pyrazol-l-yl 2354 0(CH2)2S(O)2-2-pyrimidinyl cyclohexyl *B is substituted para to Z on A.

SUBSTITUTE SHEET (RULE 26) ... . .. ... ......... .

CA 022~1394 1998-lO-0~

Table 23 H2~ ~ ~ )n ~ N~N ~A--B
o Ex. n Z A B
2401 1(CH2)2O 2-fluorophenyl imidazol-1-yl 2402 1(CH2)20 2-chlorophenylN,N-di~ethylamido 2403 1(CH2)2O 2-bromophenyl morpholin-1-yl 2404 1(CH2)2O 2-pyridyl 2-methylindazol-1-yl 2405 1(CH2)2O 2-pyrimidinylN,N-dimethylsulfamido 2406 1(CH2)2C(O)2-fluorophenylpyridin-3-yl 2407 1(CH2)2C(O)2-chlorophenyl2-((5'-trifluormethyl) tetrazol-1'-yl)phenyl 2408 1(CH2)2C(O)2-bromophenyl pyrazol-1-yl 2409 1(CH2)2C(O) 2-pyridyl cyclohexyl 2410 l(CH2)2C(O)O2-pyrimidinylimidazol-l-yl 2411 1(CH2)2C(O)O2-fluorophenylN,N-dimethylamido 2412 1(CH2)2C(O)O2-chlorophenylmorpholin-1-yl 2413 1(CH2)2C(O)O2-bromophenyl2-methylindazol-1-yl 2414 1(CH2)2C(O)NH2-pyridylN,N-dimethylsulfamido 2415 1(CH2)2C(O)NH2-pyrimidinylpyridin-3-yl 2416 1(CH2)2C(O)NH2-fluorophenyl2-((5'-trifluormethyl) tetrazol-1'-yl)phenyl 2417 1(CH2)2C(O)NH2-chlorophenylpyrazol-1-yl 2418 1(CH2)2C(O)NH2-bromophenylcyclohexyl 2419 1(CH2)2NHC(O)NH2-pyridyl imidazol-1-yl 2420 1(CH2)2NHC(O)NH2-pyrimidinylN,N-dimethylamido 2421 1 (CH2)2NHC(O)NH 2-fluorophenyl morpholin-1-yl 2422 1 (CH2)2NHC(O)NH 2-chlorophenyl 2-methylindazol-1-yl 2423 1(CH2)2S(O)2NH2-bromophenylN,N-dimethylsulfamido 2424 1(CH2)2S(O)2NH2-pyridyl pyridin-3-yl 2425 1(CH2)2S(O)2NH2-pyrimidinyl2-((5'-trifluormethyl) tetrazol-1'-yl)phenyl 2426 1(CH2)2S(O)2NH2-fluorophenylpyrazol-1-yl 2427 1(CH2)2S(O)2NH2-chlorophenylcyclohexyl 2428 1(CH2)2OCH22-bromophenyl imidazol-1-yl 2429 1(CH2)2OCH2 2-pyridyl N,N-dimethylamido 2430 1(CH2)2OCH22-pyrimidinylmorpholin-1-yl 2431 1(CH2)2OCH22-fluorophenyl2-methylindazol-1-yl 2432 1(CH2)2OCH22-chlorophenylN,N-dimethylsulfamido 2433 1(CH2)2C(O)CH22-bromophenylpyridin-3-yl 2434 1(CH2)2C(O)CH22-pyridyl2-((5~-trifluormethyl) tetrazol-1'-yl)phenyl ~ 2435 1(CH2)2C(O)CH22-pyrimidinylpyrazol-1-yl 2436 1(CH2)2C(O)CH22-fluorophenylcyclohexyl 2437 1(CH2)2C(O)OCH22-chlorophenylimidazol-1-yl 2438 1(CH2)2C(O)OCH22-bromophenylN,N-dimethylamido 2439 1(CH2)2C(O)OCH22-pyridylmorpholin-1-yl SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 2440 1(CH2)2C(O)OCH22-pyrimidinyl 2-methylindazol-1-yl 2441 1(CH2)2C(O~OCH22-fluorophenylN,N-dimethylsulfamido 2442 1(CH2)2CtO)-2-chlorophenyl pyridin-3-yl NHcH2 2443 1(CH2)2C(O)-2-bromophenyl 2-((5'-trifluormethyl) NHCH2 tetrazol~ yl)phenyl 2444 1(CH2)2C(O)- 2-pyridyl pyrazol-1-yl 2445 1(CH2)2C(O)-2-pyrimidinyl cyclohexyl 2446 1(CH2)2NHC(O)-2-fluorophenyl imidazol-1-yl 2447 1(CH2)2NHC(O)-2-chlorophenyl N,N-dimethylamido 2448 1(CH2)2NHC(O)-2-bromophenyl morpholin-1-yl 2449 1(CH2)2NHC(O)-2-pyridyl 2-methylindazol-1-yl 2450 1(CH2)2NHC(O)-2-fluorophenylN,N-dimethylsulfamido NHcH2 2451 1(CH2)2S(O)2-2-chlorophenyl pyridin-3-yl 2452 1(CH2)2S(O)2-2-bromophenyl 2-((5~-trifluormethyl) NHCH2 tetrazol-1'-yl)phenyl 2453 1(CH2)2S(O)2- 2-pyridyl pyrazol-1-yl 2454 1tCH2)2S(O)2-2-pyrimidinyl cyclohexyl ~B is substituted para to Z on A.

SUBSTITUTE SHEET(RULE 26) CA 022~1394 1998-10-0~

Table 24 H2~ ) n N~ N A B
o Ex. n Z A B
2501 2 (CH2)20 2-fluorophenyl imidazol-1-yl 2502 2 (CH2)2O 2-chlorophenylN,N-dimethylamido 2503 2 (CH2)2O 2-bromophenyl morpholin-1-yl 2504 2 (CH2)2O 2-pyridyl 2-methylindazol-1-yl 2505 2 (CH2)2O 2-pyrimidinylN,N-dimethylsulfamido 2506 2 (CH2)2C(O) 2-fluorophenyl pyridin-3-yl 2507 2 (CH2)2C(O) 2-chlorophenyl2-((5'-trifluormethyl) tetrazol-1'-yl)phenyl 2508 2 (CH2)2C(O) 2-bromophenyl pyrazol-1-yl 2509 2 (CH2)2C(O) 2-pyridyl cyclohexyl 2510 2 (CH2)2C(O)O 2-pyrimidinyl imidazol-1-yl 2511 2 (CH2)2C(0)0 2-fluorophenylN,N-dimethylamido 2512 2 (CH2)2C(O)O 2-chlorophenyl morpholin-1-yl 2513 2 (CH2)2C(O)O 2-bromophenyl2-methylindazol-1-yl 2514 2 (CH2)2C(O)NH 2-pyridylN,N-dimethylsulfamido 2515 2 (CH2)2C(O)NH 2-pyrimidinyl pyridin-3-yl 2516 2 (CH2)2C(O)NH 2-fluorophenyl2-((5'-trifluormethyl) tetrazol-1'-yl)phenyl 2517 2 (CH2)2C(O)NH 2-chlorophenyl pyrazol-1-yl 2518 2 (CH2)2C(O)NH 2-bromophenyl cyclohexyl 2519 2(CH2)2NHC(O)NH 2-pyridyl imidazol-1-yl 2520 2(CH2)2NHC(O)NH2-pyrimidinylN,N-dimethylamido 2521 2 (CH2)2NHC(O)NH 2-fluorophenylmorpholin-1-yl 2522 2 (CH2)2NHC(O)NH 2-chlorophenyl2-methylindazol-1-yl 2523 2 (CH2)2S(O)2NH2-bromophenylN,N-dimethylsulfamido 2524 2 (CH2)2S(O)2NH 2-pyridyl pyridin-3-yl 2525 2 (CH2)2S(O)2NH2-pyrimidinyl2-((5'-trifluormethyl) tetrazol-1'-yl)phenyl 2526 2 (CH2)2S(O)2NH2-fluorophenyl pyrazol-1-yl 2527 2 (CH2)2S(O)2NH2-chlorophenyl cyclohexyl 2528 2 (CH2)2OCH2 2-bromophenyl imidazol-1-yl 2529 2 (CH2)2OCH2 2-pyridyl N,N-dimethylamido 2530 2 (CH2)2OCH2 2-pyrimidinyl morpholin-1-yl 2531 2 (CH2)2OCH2 2-fluorophenyl2-methylindazol-1-yl 2532 2 (CH2)2OCH2 2-chlorophenylN,N-dimethylsulfamido 2533 2 (CH2)2C(O)CH22-bromophenyl pyridin-3-yl 2534 2 (CH2)2C(O)CH2 2-pyridyl2-((5~-trifluormethyl) tetrazol-1'-yl)phenyl 2535 2 (CH2)2C(O)CH22-pyrimidinyl pyrazol-1-yl 2536 2 (CH2)2C(O)CH22-fluorophenyl cyclohexyl 2537 2(CH2)2C(O)OCH22-chlorophenyl imidazol-1-yl 2538 2(CH2)2C(O)OCH22-bromophenylN,N-dimethylamido 253g 2(CH2)2C(O)OCH2 2-pyridyl morpholin-1-yl SUBSTITUTE SHEET(RULE26) .. . . . . ........... ....... ....... .

CA 022~1394 1998-10-0~

W097l38984 PCT~S97/06431 2540 2(CH2)2C(0)0CH22-pyrimidinyl 2-methylindazol-1-yl 2541 2(CH2)2C(O)OCH22-fluorophenylN,N-dimethylsulfamido 2542 2(CH2)2C(0)-2-chlorophenyl pyridin-3-yl 2543 2(CH2)2C(0)-2-bromophenyl 2-((5~-trifluormethyl) NHCH2 tetrazol-1'-yl)phenyl 2544 2(CH2)2C(0)- 2-pyridyl pyrazol-1-yl 2545 2(CH2)2C(0)-2-pyrimidinyl cyclohexyl 2546 2(CH2)2NHC(0)-2-fluorophenyl imidazol-1-yl 2547 2(CH2)2NHC(0)-2-chlorophenyl N,N-dimethylamido 2548 2(CH2)2NHC(0)-2-bromophenyl morpholin-1-yl 2549 2(CH2)2NHC(0)-2-pyridyl 2-me~hylindazol-1-yl 2550 2(CH2)2NHC(0)-2-fluorophenyl N,N-dimethylsulfamido 2551 2(CH2)2S(0)2-2-chlorophenyl pyridin-3-yl 2552 2(CH2)2S(0)2-2-bromophenyl 2-((5'-trifluormethyl) NHCH2 tetrazol-1'-yl)phenyl 2553 2(CH2)2S(0)2- 2-pyridyl pyrazol-l-yl 2554 2(CH2)2S(0)2-2-pyrimidinyl cyclohexyl B is substituted para to Z on A.

S(Jt~ 111 i.JTE SHEET (RULE 26) CA 02251394 lgss-l0-05 Table 25*

Z-A-B ~ Z A-B
-A-B ~--Z-A-B ~ o N~ N~ C~
N--Z-A-B _~Z-A-B ~--Z-A-B

~Z-A-B ~ ~
~$ D~3,N~N~Z A-B B-A-Z'N~ ~D

D i j k Z-A-B

D I m EX. D Z Al A2 B
2601 C(=NH)NH2 bond CH CH amino 2602 C(=NH)NH2 bond CH CH amidino 2603 C(=NH)NH2 bond CH CH guanidino 2604 C(=NH)NH2 bond CH CH 2-sulfamidophenyl 2605 C(=NH)NH2 bond CH CH2-trifluoromethylphenyl 2606 C(=NH)NH2 CH2 CH CH amino 2607 C(=NH)NH2 CH2 CH CH amidino 2608 C(=NH)NH2 CH2 CH CH guanidino 2609 C(=NH)NH2 CH2 CH CH 2-sulfamidophenyl 2610 C(=NH)NH2 CH2 CH CH2-trifluoromethylphenyl 2611 C(=NH)NH2 bond N CH amino 2612 C(=NH)NH2 bond N CH amidino 2613 C(=NH)NH2 bond N CH guanidino 2614 C(=NH)NH2 bond N CH 2-sulfamidophenyl 2615 C(=NH)NH2 bond N CH2-trifluoromethylphenyl 2616 C(=NH)NH2 CH2 N CH amino SUBSTITUTE SHEET(RULE 26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 2617 C(=NH)NH2 CH2 N CH amidino 2618 C(=NH)NH2 CH2 N CH guanidino 2619 C(=NH)NH2 CH2 N CH 2-sulfamidophenyl 2620 C(=NH)NH2 CH2 N CH2-trifluoromethylphenyl 2621 C(=NH)NH2 bond N N amino 2622 C(=NH)NH2 bond N N amidino 2623 C(=NH)NH2 bond N N guanidino 2624 C(=NH)NH2 bond N N 2-sulfamidophenyl 2625 C(=NH)NH2 bond N N2-trifluoromethylphenyl 2626 C(=NH)NH2 CH2 N N amino 2627 C(=NH)NH2 CH2 N N amidino 2628 C(=NH)NH2 CH2 N N guanidino 2629 C(=NH)NH2 CH2 N N 2-sulfamidophenyl 2630 C(=NH)NH2 CH2 N N2-trifluoromethylphenyl 2631 C(=NH)NH2 bond CH CH imidazol-1-yl 2632 C(=NH)NH2 bond CH CH morpholin-1-yl 2633 C(=NH)NH2 bond CH CH 2-methylimidazol-1-yl 2634 C(=NH)NH2 bond CH CH pyridin-3-yl 2635 C(=NH)NH2 bond CH CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 2636 C(=NH)NH2 bond CH CH pyrazol-1-yl 2637 C(=NH)NH2 bond CH CH phenyl 2638 C(=NH)NH2 bond CH CH cyclohexyl 2639 C(=NH)NH2 bond CH CH N,N-dimethylsulfamido 2640 C(=NH)NH2 bond CH CH N,N-dimethylamido 2641 C(=NH)NH2 bond N CH imidazol-1-yl 2642 C(=NH)NH2 bond N CH morpholin-1-yl 2643 C(=NH)NH2 bond N CH 2-methylimidazol-1-yl 2644 C(=NH)NH2 bond N CH pyridin-3-yl 2645 C(=NH)NH2 bond N CH 2-(5'-trifluoromethyl) tetrazol-1'-yl 2646 C(=NH)NH2 bond N CH pyrazol-1-yl 2647 C(=NH)NH2 bond N CH phenyl 2648 C(=NH)NH2 bond N CH cyclohexyl 2649 C~=NH)NH2 bond N CH N,N-dimethylsulfamido 2650 C(=NH)NH2 bond N CH N,N-dimethylamido 2651 C(=NH)NH2 bond N N imidazol-1-yl 2652 C(=NH)NH2 bond N N morpholin-1-yl 2653 C(=NH)NH2 bond N N 2-methylimidazol-1-yl 2654 C(=NH)NH2 bond N N pyridin-3-yl 2655 C(=NH)NH2 bond N N2-(5'-trifluoromethyl) tetrazol-1'-yl 2656 C(=NH)NH2 bond N N pyrazol-1-yl 2657 C(=NH)NH2 bond N N phenyl 2658 C(=NH)NH2 bond N N cyclohexyl 2659 C(=NH)NH2 bond N NN,N-dimethylsulfamido 2660 C(=NH)NH2 bond N N N,N-dimethylamido 2661 C(=NH)NH2 bond F CH imidazol-1-yl 2662 C(=NH)NH2 bond F CH morpholin-1-yl 2663 C(=NH)NH2 bond F CH 2-methylimidazol-1-yl 2664 C(=NH)NH2 bond F CH pyridin-3-yl 2665 C(=NH)NH2 bond F CH 2-(5'-trifluoromethyl) tetrazol-1'-yl SUBSTITUTE SHEET (RUEE 26) CA 022~l394 Isss-lo-o~

W097/38984 PCT~S97/06431 2666 C(=NH)NH2 bond F CHpyrazol-l-yl 2667 C(=NH)NH2 bond F CH phenyl 2668 C~=NH)MH2 bond F CHcyclohexyl 2669 C(=NH)NH2 bond F CHN,N-dimethylsulfamido 2670 C(=NH)NH2 bond F CHN,N-dimethylamido 2671 C(=NH)NH2 bond Cl CH imidazol-l-yl 2672 C(=NH)NH2 bond Cl CH morpholin-l-yl 2673 C(=NH)NH2 bond Cl CH2-methylimidazol-1-yl 2674 C(=NH)NH2 bond Cl CH pyridin-3-yl 2675 C(=NH)NH2 bond Cl CH2-(5'-trifluoromethyl) tetrazol-l'-yl 2676 C(=NH)NH2 bond Cl CH pyrazol-l-yl 2677 C(=NH)NH2 bond Cl CH phenyl 2678 C(=NH)NH2 bond Cl CH cyclohexyl 2679 C(=NH)NH2 bond Cl CHN,N-dimethylsulfamido 2680 C(=NH)NH2 bond Cl CH N,N-dimethylamido 2681 C(=NH)NH2 bond Br CH imidazol-l-yl 2682 C(=NH)NH2 bond Br CH morpholin-l-yl 2683 C(=NH)NH2 bond Br CH2-methylimidazol-1-yl 2684 C(=NH)NH2 bond Br CH pyridin-3-yl 2685 C(=NH)NH2 bond Br CH2-(5'-trifluoromethyl) tetrazol-l'-yl 2686 C(=NH)NH2 bond Br CH pyrazol-l-yl 2687 C(=NH)NH2 bond Br CH phenyl 2688 C(=NH)NH2 bond Br CH cyclohexyl 2689 C(=NH)NH2 bond Br CHN,N-dimethylsulfamido 2690 C(=NH)NH2 bond Br CH N,N-dimethylamido 2691 C(=NH)NH2 CH2 CH CH imidazol-l-yl 2692 C(=NH)NH2 CH2 CH CH morpholin-l-yl 2693 C(=NH)NH2 CH2 CH CH 2-methylimidazol-1-yl 2694 C(=NH~NH2 CH2 CH CH pyridin-3-yl 2695 C(=NH)NH2 CH2 CH CH2-(5'-trifluoromethyl) tetrazol-l'-yl 2696 C(=NH)NH2 CH2 CH CH pyrazol-l-yl 2697 C(=NH)NH2 CH2 CH CH phenyl 2698 C(=NH)NH2 CH2 CH CH cyclohexyl 2699 C(=NH)NH2 CH2 CH CHN,N-dimethylsulfamido 2700 C(=NH)NH2 CH2 CH CH N,N-dimethylamido 2701 C(=NH)NH2 CH2 N CH imidazol-l-yl 2702 C(=NH)NH2 CH2 N CH morpholin-l-yl 2703 C(=NH)NH2 CH2 N CH 2-methylimidazol-1-yl 2704 C(=NH)NH2 CH2 N CH pyridin-3-yl 2705 C(=NH)NH2 CH2 N CH2-(5~-trifluoromethyl) tetrazol-l'-yl 2706 C(=NH)NH2 CH2 N CH pyrazol-l-yl 2707 C(=NH)NH2 CH2 N CH phenyl 2708 C(=NH)NH2 CH2 N CH cyclohexyl 2709 C(=NH)NH2 CH2 N CHN,N-dimethylsulfamido 2710 C(=NH)NH2 CH2 N CH N,N-dimethylamido 2711 C(=NHJNH2 CH2 N N imidazol-l-yl 2712 C(=NH)NH2 CH2 N N morpholin-l-yl 2713 C(=NH)NH2 CH2 N N2-methylimidazol-1-yl 2714 C(=NH)NH2 CH2 N N pyridin-3-yl SUBSTITUTE SHEET (RUEE 26) .. . ...

CA 022~l394 Isss-lo-o~

WO97/38984 PCT~S97/06431 2715 C(=NH)NH2 CH2 N N2-(5'-trifluoromethyl) tetrazol-1'-yl 2716 C(=NH)NH2 CH2 N Npyrazol-1-yl 2717 C(=NH)NH2 CH2 N N phenyl 2718 C(=NH)NH2 CH2 N N cyclohexyl 2719 C(=NH)NH2 CH2 N NN,N-dimethylsulfamido 2720 C(=NH)NH2 CH2 N NN,N-dimethylamido 2721 C(=NH)NH2 CH2 F CHimidazol-1-yl 2722 C(=NH)NH2 CH2 F CHmorpholin-1-yl 2723 C(=NH)NH2 CH2 F CH2-methylimidazol-1-yl 2724 C(=NH)NH2 CH2 F CHpyridin-3-yl 2725 C(=NH)NH2 CH2 F CH2-(5'-trifluoromethyl) tetrazol-1'-yl 2726 C(=NH)NH2 CH2 F CHpyrazol-1-yl 2727 C(=NH)NH2 CH2 F CH phenyl 2728 C(=NH)NH2 CH2 F CH cyclohexyl 2729 C(=NH)NH2 CH2 F CH N,N-dimethylsulfamido 2730 C(=NH)NH2 CH2 F CH N,N-dimethylamido 2731 C(=NH)NH2 CH2 Cl CHimidazol-1-yl 2732 C(=NH)NH2 CH2 Cl CHmorpholin-1-yl 2733 C(=NH)NH2 CH2 Cl CH2-methylimidazol-1-yl 2734 C(=NH)NH2 CH2 C1 CHpyridin-3-yl 2735 C~=NH)NH2 CH2 Cl CH2-(5'-trifluoromethyl) tetrazol-1'-yl 2736 C(=NH)NH2 CH2 Cl CHpyrazol-1-yl 2737 C(=NH)NH2 CH2 Cl CH phenyl 2738 C(=NH)NH2 CH2 Cl CH cyclohexyl 2739 C(=NH)NH2 CH2 Cl CH N,N-dimethylsulfamido 2740 C(=NH)NH2 CH2 Cl CH N,N-dimethylamido 2741 C(=NH)NH2 CH2 Br CHimidazol-1-yl 2742 C(=NH)NH2 CH2 Br CHmorpholin-1-yl 2743 C(=NH)NH2 CH2 Br CH2-methylimidazol-1-yl 2744 C(=NH)NH2 CH2 Br CHpyridin-3-yl 2745 C(=NH)NH2 CH2 Br CH2-(5'-trifluoromethyl) tetrazol-1'-yl 2746 C(=NH)NH2 CH2 Br CHpyrazol-1-yl 2747 C(=NH)NH2 CH2 Br CH phenyl 2748 C(=NH)NH2 CH2 Br CH cyclohexyl 2749 C(=NH)NH2 CH2 Br CH N,N-dimethylsulfamido 2750 C(=NH)NH2 CH2 Br CH N,N-dimethylamido *Each entry in Table 25 is intended to correspond individually to each of formulae a-m.

SUBSTITUTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097138984 PCT~S97/06431 Utility The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in m~m~l s . 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, and pulmonary embolisms.
The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa.
The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, Ki Factor Xa determinations were made in 0.l0 M sodium phosphate buffer, pH 7.5, cont~inlng 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 (O.20 mM-l 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-vS)/vS = I/(Ki (l + S~Km)) S~J~S 111 IJTE SHEET (RULE 26) CA 022~1394 1998-10-0~

W097l38984 PCT~S97tO6431 where:
vO 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.
Using the methodology described above, a number of compounds of the present invention were found to exhibit a Ki of <1 ~m, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.
The antithrombotic effect of the compounds of the present 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 abdo~i n~l 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 formula (I) are also considered to be useful as inhibitors of serine proteases, notably human SUBSTITUTE SHEET (RULE 26) CA 022~l394 lsss-lo-o~

WO 97l38984 PCT/US97/06431 thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes.
Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in .J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, TX) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, ~N) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a Ki Of less than 5 ~n, thereby confirming the utility of the compounds of the invention as effective thrombin inhibitors.
The compounds of the present 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.

SUBSTITUTE SHEET (RULE 26) . .

CA 022~l394 Igss-lo-o~

W097/38984 PCT~S97/06431 The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" it 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"
it 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, but are not limited to, 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 are preferred. 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 IIb/IIIa antagonists, thromboxane-A2-receptor SU~ JTE SHEET (RULE 26) CA 022~l394 lsgs-lo-o~

W097/38984 PCT~S97tO6431 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. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, 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.
The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents'include 3~ 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 SUBSTITUTE SHEET(RULE 26) ~ .. ~ . , .. ~ , . . ...

CA 022~1394 1sss-1o-o~

W097/38984 PCT~S97/06431 complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. 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.
A~mi nl stration 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. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.
The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions cont~;n'ng test sample, but no compound of the present invention, then one would conclude factor Xa was present.

SUBSTITUTE SHEET (RULE 26) CA 022~1394 1ggs-1o-o~

W097/38984 PCT~S97/06431 Dosaae 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 st~n~rd 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 of concurrent treatment; the frequency of treatment; the route of ~mln; stration, 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 O.OOl to lO00 mg/kg of body weight, preferably between about O.Ol to lO0 mg/kg of body weight per day, and most preferably between about l.0 to 20 mg/kg/day.
Intravenously, the most preferred doses will range from about l to about lO mg/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 SU~:~ 111 UTE SHEET (RULE 26) ~ . .... . .

CA 022~1394 lsss-lo-o~

W097/38984 PCT~S97/06431 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 reglmen.
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 ~m; n; stered 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.

SU~S~ TE SHEET(RULE 26) CA 022~1394 1sss-1o-o~

W097/38984 PCT~S97/06431 Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, 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 of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about l milligram to about lO0 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 SUBSTITUTE SHEET(RULE26) , . . .

CA 022~1394 1sss-1o-o~

W097138984 PCT~S97/06431 necessary, buffer substances. Antioxidizlng agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, 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 Reminqton'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:
Ca~sules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with lO0 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Ca~sules 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 cont~ln'ng lO0 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 lO0 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, ll milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Iniectable A parenteral composition suitable for administration by injection is prepared by stirring l.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

SU~i 111 UTE SHEET (RULE 26) . .

CA 022~l394 Igss-lo-o~

W097l38984 PCT~S97/06431 Sus~ension An aqueous suspension is prepared for oral administration so that each 5 mL contain lO0 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, l.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 O.l to lO0 milligrams of the compound of Formula I and about l 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 lO milligrams per dosage unit, and the second anti-coagulant in an amount of about l 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 O.Ol to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about O.l to l milligrams of the compound of Formula I and about l 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 O.l to l 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.

SUBSTITUTE SHEET(RULE26) CA 022~1394 1998-10-0~

W097/38984 PCT~S97/06431 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 m; n; mlze 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 m;n;m;ze 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. The polymer coating serves to form an additional barrier to interaction with the other component.
These as well as other ways of min'm;zing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skillèd in the art, once armed with the present disclosure.
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the SUBSTITUTE SHEET (RULE 26) CA 0225l394 lsss-l0-05 W097/38984 PCT~S97/06431 scope of the appended claims, the invention may be practiced otherwise that as specifically described herein.

SUBSTITUTE S~EET(RULE26) .. .. . , , .. .. .. . ~ . . ~ ..

Claims (20)

WHAT IS CLAIMED AS NEW AND DESIRED TO BE SECURED BY LETTER
PATENT OF UNITED STATES IS:

1. A compound of formula I:

or stereoisomer or pharmaceutically acceptable salt form thereof, wherein;

one of D and D' is selected from CN, C(=NR11)NR12R13, NHC(=NR11) NR12R13, NR12CH(=NR11), C(O)NR12R13, and (CH2)t NR12R13 and the other is H;

R1 is selected from H, (CH2)r OR3, halo, C1-4 alkyl, (CH2)r NR4R4, (CH2)r CO2H, (CH2)r C(=O)R4, (CH2)r NR4C(=O)R4, (CH2)r SO2R5, and (CH2)r NR4SO2R5;

R2 is selected from H, =O, C1-4 alkyl substituted with 0, 1, or 2 R7, C2-6 alkenyl substituted with 0, 1, or 2 R7, (CH2)r OR3, (CH2)r C(O)R4, (CH2)r OC(O)R4, (CH2)r NR3R3', (CH2)r NR3C(O)R4, (CH2)r SO2R5, (CH2)r NR3SO2R5, C3-10 carbocyclic residue substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;

R2a is absent;

alternatively, R2 and R2a may be present on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R10 or a 5-6 membered aromatic heterocycle containing 0-2 heteratoms selected from the group consisting of N, O, and S and substituted with 0-2 R10a;

R3 and R3' are independently selected from H, C1-4 alkyl, benzyl and phenyl;

R3 and R3' may be taken together to form a 5 or 6 membered ring substituted with 0-2 R6;

R4 and R4' are independently selected from H, OR3, C1-4 alkyl, phenyl and NR3R3';

R5 is selected from C1-4 alkyl, phenyl and NR3R3';

Z is selected from a bond, C1-4 alkylene, (CH2)r O(CH2)r, (CH2)2NR3(CH2)r, (CH2)r C(O)(CH2)r, (CH2)r C(O)O(CH2)r, (CH2)2OC(O)(CH2)r, (CH2)r C(O)NR3(CH2)r, (CH2)2NR3C(O)(CH2)r, (CH2)2OC(O)O(CH2)r, (CH2)2OC(O)NR3(CH2)r, (CH2)2NR3C(O)O(CH2)r, (CH2)2NR3C(O)NR3(CH2)r, (CH2)r S(O)p(CH2)r, (CH2)r SO2NR3(CH2)r, (CH2)2NR3SO2(CH2)r, and (CH2)2NR3SO2NR3(CH2)r;

A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R6;

B is selected from:
X-Y, NR3R3', C(O)NR3R3', SO2NR3R3', benzyl substituted with 0-2 R6, C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R6;

X is selected from C1-4 alkylene, -C(O)-, -C(O)CR3R3'-, -CR3R3'C(O)-, -C(O)O-, -C(O)OCR3R3'-, -CR3R3'C(O)O-, -OC(O)-, -OC(O)CR3R3'-, -CR3R3'OC(O)-, -S(O)p-, -S(O)p CR3R3'-, -CR3R3'S(O)p-, -S(O)2NR3-, -NR3S(O)2-, -NR3S(O)2CR3R3 -, -CR3R3'S(O)2NR3-, -NR3S(O)2NR3-, -C(O)NR3-, -NR3C(O)-, -C(O)NR3CR3R3'-, -NR3C(O)CR3R3'-, -CR3R3'C(O)NR3-, -CR3R3'NR3C(O)-, -NR3C(C)O-, -OC(O)NR3-, -NR3C(O)NR3-, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, O, -CR3R3'O-, -OCR3R3'-, S, -CR3R3'S-, and -SCR3R3'-;

Y is selected from:
C1-4 alkyl substituted with 0-2 R6 C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R6;

R6 is selected from H, OH, CF3, (CH2)n OR3, halo, C1-4 alkyl, CN, NO2, (CH2)r NR3R3',(CH2)r C(O)R3, NR3C(O)R3', NR3C(O)NR3R3', SO2NR3R3', NR3SO2NR3R3', NR3SO2-C1-4 alkyl, SO2-phenyl, and NR3SO2R8;

R7 is selected from:
C3-10 carbocyclic residue substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R6;

R8 is selected from:
C3-10 carbocyclic residue substituted with 0-2 R9; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R9;

R9 is selected from H, OH, (CH2)n OR3, halo, C1-4 alkyl, CN, NO2, (CH2)r NR3R3', (CH2)r C(O)R3, NR3C(O)R3', NR3C(O)NR3R3', SO2NR3R3', NR3SO2NR3R3', and NR3SO2-C1-4 alkyl;

R10 is selected from H, OR3, halo, C1-4 alkyl, CN, NO2, NR3R3', NR3C(O)R3', NR3C(O)OR3', NR3SO2-phenyl, and NR3SO2-C1-4 alkyl;

R10a if a substituent on nitrogen is selected from H and C1-4 alkyl;

R10a if a substituent on carbon is selected from H, C1-4 alkyl, NR3R3', NR3C(O)R3 , NR3C(O)OR3', NR3SO2-phenyl, and NR3SO2-C1-4 alkyl;

R11 is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;

R12 is selected from H, C1-6 alkyl and (CH2)n-phenyl;

R13 is selected from H, C1-6 alkyl and (CH2)n-phenyl;

n is selected from 0, 1, 2, and 3;

m is selected from 0 and 1;

p is selected from 0, 1, and 2;

q is selected from 1, 2, 3, 4, and 5; and, r is selected from 0, 1, and 2.

2. A compound according to Claim 1, wherein:

D is C(=NH)NH2;

D' is H;

R1 is selected from H, (CH2)r OR3, halo, (CH2)r NR4R4', (CH2)r CO2H, (CH2)r C(=O)R4, (CH2)r NR4C(=O)R4, (CH2)r SO2R5, and (CH2)r NHSO2R5;

R2 is selected from H, =O, (CH2)r OR3, (CH2)r C(O)R4, (CH2)r OC(O)R4, (CH2)r NR3R3', (CH2)r NR3C(O)R4, (CH2)r SO2R5, (CH2)r NR3SO2R5, C3-10 carbocyclic residue substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;

R4 and R4' are independently selected from H, OR3, C1-4 alkyl, and NR3R3';

R5 is selected from C1-4 alkyl and NR3R3';

Z is selected from a bond, C1-4 alkylene, (CH2)r C(O)(CH2)r, (CH2)r C(O)NR3(CH2)r, (CH2)2NR3C(O)(CH2)r, (CH2)2OC(O)NR3(CH2)r, (CH2)2NR3C(O)O(CH2)r, (CH2)2NR3C(O)NR3(CH2)r, (CH2)r S(O)p(CH2)r, (CH2)r SO2NR3(CH2)r, (CH2)2NR3SO2(CH2)r, and (CH2)2NR3SO2NR3(CH2)r; and, X is selected from C1-4 alkylene, -C(O)-, -C(O)CR3R3'-, -CR3R3'C(O)-, -C(O)O-, -C(O)OCR3R3'-, -CR3R3'C(O)O-, -OC(O)-, -OC(O)CR3R3'-, -CR3R3'OC(O)-, -S(O)p-, -S(O)p CR3R3'-, -CR3R3'S(O)p-, -S(O)2NR3-, -C(O)NR3-, -NR3C(O)-, -NR3C(O)O-, -OC(O)NR3-, -NR3C(O)NR3-, -NR3-, -NR3CR3R3'-, -CR3R3'NR3-, O, -CR3R3'O-, and -OCR3R3'-.

3. A compound according to Claim 2, wherein:

R1 is selected from H, OR3, (CH2)OR3, halo, NR4R4', (CH2)NR4R4', C(=O)R4, (CH2)C(=O)R4, NHC(=O)R4, (CH2)NHC(=O)R4, SO2R5, (CH2)SO2R5, NHSO2R5, and (CH2)NHSO2R5;

R2 is selected from H, =O, OR3, C(O)R4, (CH2)C(O)R4, OC(O)R4, NR4R4', NR3C(O)R4, and NR4SO2R5;

A is selected from:
C5-6 carbocyclic residue substituted with 0-1 R6, and 5-6 membered heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N and O
substituted with 0-1 R6;

B is selected from: Y, X-Y, and NR2R2a;

Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, isoindazole, and benzothiadiazole;

Y may also be selected from the following bicyclic heteroaryl ring systems:

, , , , , , and ;

K is selected from O, S, NH, and N;

X is selected from -CH2-, -C(O)-, -C(O)CHR3-, -CHR3C(O)-, -S(O)p-, -S(O)p CR3R3 -, -CHR3S(O)p-, -S(O)2NR3-, -C(O)NR3-, -NR3C(O)-, -NR3-, -NR3CHR3-, and -CHR3NR3;

R6 is selected from H, OH, CF3, (CH2)nOR3, halo, C1-4 alkyl, CN, NO2, (CH2)r NR3R3 ,(CH2)rC(O)R3, NR3C(O)R3 , SO2NR3R3 , SO2-phenyl, NR3SO2-C1-4 alkyl, and NR3SO2R8;

R8 is selected from:
C5-6 carbocyclic residue substituted with 0-2 R9; and, 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R9;

R9 is selected from H, OH, (CH2)nOR3, halo, C1-4 alkyl, CN, NO2, (CH2)rNR3R3 ,(CH2)rC(O)R3, NR3C(O)R3 , NR3C(O)NR3R3 , SO2NR3R3 , NR3SO2NR3R3 , and NR3SO2-C1-4 alkyl; and, p is 2.

4. A compound according to Claim 3, wherein:

Z is selected from a bond, C1-4 alkylene, (CH2)rC(O)(CH2)r (CH2)rC(O)NR3(CH2)r, (CH2)2NR3C(O) (CH2)r;
(CH2)2NR3C(O)NR3(CH2)r, and (CH2)rS(CH2)r;

X is selected from -CH2-, -C(O)-, -C(o)CHR3-, -CHR3C(O)-, -S(O)p-, -S(O)pCR3R3 -, -CHR3S(O)p-, -S(O)2NR3-, -C(O)NR3-, and -NR3C(O)-;

R6 is selected from H, OH, CF3, (CH2)nOR3, halo, Cl-4 alkyl, CN, NO2, (CH2)rNR3R3 ,(CH2)rC(O)R3, NR3C(O)R3 , SO2NR3R3 , SO2-phenyl, and NR3SO2-C1-4 alkyl;

m is 1; and, r is selected from 0 and 1.

5. A compound according to Claim 4, wherein:

R3 and R3 are independently selected from H and C1-4 alkyl;

Z is selected from a bond, C1-4 alkylene, (CH2)rC(O)NR3(CH2) (CH2) 2NR3C (O) (CH2) r, and (CH2)2NR3C(O)NR3(CH2) r, A is selected from phenyl substituted with 0-1 R6 and a 6 membered heterocyclic system containing 1 N and 0-1 O
atoms and substituted with 0-1 R6;

X is selected from -CH2-, -S(O)p-, -S(O) pCR3R3 -, -S (O) 2NR3-, -C (O)NR3-, and ;

Y is selected from phenyl, i-propyl, quinolynyl, thiadizolyl, benzothiadiazolyl, thiophenyl, pyridyl, cyclohexyl, and naphthyl, each of which is substituted with 0-2 R6; and, n is selected from 0, 1, and 2.

6. A compound according to Claim 5, wherein:

R3 and R3' are independently selected from H and methyl;

Z is selected from a bond, CH2, -CH2CH2-, -CH2CH2CH2- and -CH2CH2CH2CH2-;

A is selected from phenyl substituted with 0-1 R6, and piperidinyl substituted with 0-l R6; and, n is 2.

7. A compound according to Claim 6, wherein the compound is selected from:

N-(3-amidinophenyl)-N'-((4-((2-sulphonamido)phenyl)phenyl)-methyl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-benzylpiperidin-4-yl) cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-(picolin-2-yl)piperidin-4-yl) cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-(picolin-3-yl)piperidin-4-yl) cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-(picolin-4-yl)piperidin-4-yl) cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-(a-phenethyl)piperidin-4-yl)cyclo-heptylurea;

N-(3-amidinophenyl)-N'-(1-((phenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-(phenyl)sulfonylpiperidin-4-yl)-cycloheptylurea;
N-(3-amidinophenyl)-N'-(l-(quinolin-8-yl)sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(1-(2-fluorophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(1-(4-acetamidophenyl)sulfonyl-piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(3-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(1-(4-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(1-((2-aminophenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(1-((2-acetamido-phenyl)methane)-sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(l-((thiophen-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(1-((5-chlorothiophen-2-yl)sulfonyl)-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(1-((5-carbomethoxythiophen-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(l-((benzo-2,1,3-thiadiazo-4-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(l-((cyclohexyl)sulfamido)piperidin-4-yl)cycloheptylureai N-(3-amidinophenyl)-N'-(l-((isopropyl)sulfamido)piperidin-4-yl)cycloheptylureai N-(3-amidinophenyl)-N'-(l-((phenyl)sulfamido)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(l-((isopropyl)sulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(1-((5-amino-4-methylthiazol-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-((5-acetamido-4-methylthiazol-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(1-(6-carbomethoxyphenyl-sulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(2-pyridylmethyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(3-pyridylmethyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(4-pyridylmethyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(phenyl-N''-methylsulfamido)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-((4-phenylsulfonylthiophen-2-yl)sulfonyl)-piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(4-pyridylmethylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(thiophen-2-ylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(4-fluorobenzylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(2-pyridylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(2-trifluormethyl-phenylsulfonyl)piperidin-4-yl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(2-phenylisopropylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-((l-((phenyl)-l,l-dimethyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(methyl((phenyl-methane)carbamide)morpholin-3-yl))cycloheptylurea;

N-(3-amidinophenyl)-N'-(methyl((thiophen-2-yl)sulfonyl)morpholin-3-yl))cycloheptylurea;

N-(3-amidinophenyl)-N'-(methyl((phenyl-methane)sulfonyl)morpholin-3-yl))cycloheptylurea;

N-(3-amidinophenyl)-N'-((N-benzyl)piperidin-3-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-((N-(benzyl)sulfonyl)-piperidin-3-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-((N-(thiophen-2-yl)sulfonyl)piperidin-3-yl)cycloheptylurea;
N-(3-amidinophenyl)-N'-(4-(2-sulfonamido-phenyl)phenyl)cycloheptylurea;

N-(3-amidinophenyl)-N'-(5-(2-sulfonamido-phenyl)pyridin-2-yl)cycloheptylurea;
and, N-(3-amidinophenyl)-N'-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea;

or stereoisomers or pharmaceutically acceptable salt forms thereof.

8. A compound according to Claim 1, wherein:

n is 2; and, R2 and R2a are on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R10 or a 5-6 membered aromatic heterocycle containing 0-2 heteratoms selected from the group consisting of N, O, and S and substituted with 0-2 R10a

9. A compound according to Claim 8, wherein the compound is of formula II:

wherein;

ring N contains 0-2 N atoms and is substituted with 0-2 R10;
and, D is selected from CN, C(=NR11)NRl2R13, NHC(=NR11)NR12R13 NR12CH(=NR11) C(O)NR12R13, and (CH2)tNR12R13.

10. A compound according to Claim 9, wherein:

D is C(=NH)NH2;

R1 is selected from H, (CH2)rOR3, halo, (CH2)rNR4R4 , ( CH2 ) rCO2H, ( CH2 ) rC (=O) R4, ( CH2 ) rNR4C (=O) R4, ( CH2 ) rSO2 R5, and ( CH2 ) rNHSO2R5;

R4 and R4 are independently selected from H, oR3, C1-4 alkyl, and NR3R3 R5 is selected from C1-4 alkyl and NR3R3 ;

Z is selected from a bond, C1-4 alkylene, (CH2)rC(O)(CH2)r, (CH2)rC(O)NR3 (CH2)r, (CH2)2NR3C(O) (CH2)r, (CH2)2OC(O)NR3(CH2)r, (CH2)2NR3C(O)O(CH2)r, (CH2)2NR3C(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, and (CH2)rSO2NR3(CH2)r; and, X is selected from C1-4 alkylene, -C(O)-, -C(O) CR3R3 -, -CR3R3 C(O)-, -C(O)O-, -C(O)OCR3R3 -, -CR3R3 C(O)O-, -OC(O)-, -OC(O)CR3R3 -, -CR3R3 OC(O)-, -S(O)p-, -S(O)pCR3R3 -, -CR3R3 S(O)p-, -C(O)NR3-, -NR3C(O)-, -NR3C(O)O-, -OC(O)NR3-, -NR3C(O)NR3-, -NR3-, -NR3CR3R3'-, -CR3R3 NR3-, O, -CR3R3 O-, and -OCR3R3 -.

11. A compound according to Claim 10, wherein:

Z is selected from a bond, C1-4 alkylene, C(o)NR3(cH2)r; S(0)2, S(O)2CH2, and (CH2)rSO2NR3(CH2)r;

A is selected from phenyl substituted with 0-1 R6 and 6 membered heterocyclic system containing 1 N and substituted with 0-1 R6; and, X is selected from C1-4 alkylene, -C(O)-, -C(O) CR3R3'-, -CR3R3 C(O)-, -S(O)p-, -S(O)pCR3R3 -, -C(O)NR3-, and, -NR3-

12. A compound according to Claim 11, wherein thecompound is selected from:

1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;

1,2,4,5-tetrahydro-2-(thiopen-2-yl)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;

1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one; and, 1,2,4,5-tetrahydro-2-(thiophen-2-yl)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one.

13. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to Claim 2 or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to Claim 3 or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to Claim 9 or a pharmaceutically acceptable salt thereof.

17. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

18. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to Claim 2 or a pharmaceutically acceptable salt thereof.

19. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to Claim 3 or a pharmaceutically acceptable salt thereof.

20. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to Claim 9 or a pharmaceutically acceptable salt thereof.