Note: Descriptions are shown in the official language in which they were submitted.
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WO 98/01428 PCT/US97/11325
TITLE
AMIDINOTNDOLES, AM~D~NOAZOLES, AND ANALOGS T~EREOF AS INHlBllORS OF FACTOR
Xa AND OF THROMBIN
FIELD OF THE INVENTION
This invention relates generally to amidinoindoles,
amidinoazoles, and analogs which are inhibitors of trypsin-
like serine protease enzymes, especially thrombin and 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
EP 0, 540,051 and JP 06227971 describe a series of
15 compounds useful as factor Xa inhibitors or to treat influenza
based on the formula:
NH~ X--(CH2)n--Y
wherein A is an alkylene linker optionally substituted by
hydroxyalkyl, carboxyl, alkoxycarbonyl, alkoxycarbonylalkyl,
or carboxyalkyl, X is a bond, O, S, or carbonyl, n is 0-4, and
Y is an optionally substituted carbocycle or heterocycle. The
present invention does not involve compounds containing the
above noted combination of A, X, n, and Y.
Tidwell et al, Thrombosis Research 1981, 24, 73-83,
describe factor Xa inhibitory activity of a series of aromatic
mono- and di-amidines. The amidino aromatic moieties are
include indole, indoline, benzofuran and benzimidazole.
Tidwell et al, J. Med. Chem. 1983, 26, 294-298,
report a series of amidinoindoles of the formula:
R2
X
wherein one of Rl and R2 is amidine, X may be methyl or ethyl
when Y and Z are H, Y may be C(O)CH2CH3 when X and Z are H, and
. . .
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Z may be CHO, COCH3, COCF3, or C(O)Ph when X and Y are H.
Thrombin inhibition constants are given for these compounds.
EP 0,655,439 discuss IIb/IIIa antagonists of the formula:
~X7 X, (La)--A
R2
wherein the core ring is a heterocycle, B is a basic group, A
is an acidic group, Rl is an optional substituent, R2 is an
optional substituent, and La and Lb are linkers which may
optionally be substituted. The present invention does not
contain the La-A group.
Fairley et al, J. Med. Chem. 1993, 36, 1746-1753,
illustrate a series of bis(amidinobenzimidazoles) and
bis(amidinoindoles) of the formulae:
N N~ Nr N~1
wherein R is an amidine or derivative thereof and X is an
alkylene, alkenylene, phenylene or phenylenedimethylene
linker. The DNA binding capabilities of these compounds were
studied and reported, but inhibition of trypsin-like enzymes
was not discussed.
WO 95/08540 depicts bis(amidinobenzimidazolyl)alkanes of
the formula:
Z~H N3~ Z
wherein Z is an amidine derivative and R and Rl are selected
from a variety of substituents including hydroxyl, amino, and
alkoxy. These compounds are said to be useful in the
treatment of viruses, specifically HIV. No mention is made of
Xa or thrombin inhibition.
Trypsin-like enzymes are a group of proteases which
hydrolyzed peptide bonds at basic residues liberating either a
C-terminal arginyl or lysyl residue. Among these are enzymes
of the blood coagulation and fibrinolytic system required for
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hemostasis. They are Factors II, X, VII, IX, XII, kallikrein,
tissue plasminogen activators, urokinase-like plasminogen
activator, and plasmin. Elevated levels of proteolysis by
these proteases can result in disease states. For example,
consumptive coagulopathy, a condition marked by a decrease in
the blood levels of enzymes of both the coagulation system,
the fibrinolytic system and accompanying protease inhibitors
is often fatal. More specifically, proteolysis by thrombin is
required for blood clotting. Inhibition of thrombin results
in an effective inhibitor of blood clotting. The importance
of an effective inhibitor of thrombin is underscored by the
observation that conventional anticoagulants such as heparin
(and its complex with the protein inhibitor, antithrombin III)
are ineffective in blocking arterial thrombosis associated
with myocardial infarctions and other clotting disorders.
However, a low molecular weight thrombin inhibitor, containing
a different functionality, was effective in blocking arterial
thrombosis (Hanson and Harker, Proc. Natl. Acad. Sci. U.S.A.
85, 3184 (1988).
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 o blood coagulation. The generation of thrombin, the
final serine protease in the pathway to generate a fibrin
clot, from its precursor is amplified by formation of
prothrombinase complex (factor Xa, factor V, Ca2~ and
phospholipid). Since it is calculated that one molecule of
factor Xa can generate 138 molecules of thrombin ~Elodi, S.,
Varadi, K.: Optimization of conditions for the catalytic
effect of the factor IXa-factor VIII Complex: Probable role of
the complex in the amplification of blood coagulation.
Thromb. Res. 1979, 15, 6l7-629~, inhibition of factor Xa may
be more ef icient that inactivation of thrombin in
interrupting the blood coagulation system.
There-ore, efficacious and specific inhibitors of factor
Xa or thrombin are needed as potentially valuable therapeutic
agents for the treatment of thromboembolic disorders. It is
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thus desirable to discover new thrombin or factor Xa
inhibitors.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to
provide novel amidinoindoles and analogs thereof which are
useful as factor Xa or thrombin 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):
,W2~ 3 Jb
or pharmaceutically acceptable salt or prodrug forms thereof,
wherein D, Da, J, Ja, Jb, W, Wl, W2, and W3, are defined below,
are effective factor Xa or thrombin inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[l] Thus, in a first embodiment, the present invention
provides a novel compound of formula I:
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,W2~ Jb
Da W3
I
or stereoisomer or pharmaceutically acceptable salt form
thereof wherein:
W and W3 are selected from CH and N;
W1 and w2 are selected from C, CH, and N;
provided that from 0-2 of W, W1, W2, and W3 are N;
one of D and Da is selected from H, C1_4 alkoxy, CN,
C ( =NR7 ) NR8R9, NHC ( =NR7 ) NR8R9, NR8CH ( =NR7 ), C ( O ) NR8R9, and
(CH2 ) tNR8R9, and the other is absent;
provided that if one of D and Da is H, then at least one of W,
wl, w2, and W3 is N;
one Of Ja and Jb is substituted by -(CH2)n-Z-A-B;
J, Ja~ and Jb combine to form an aromatic heterocyclic system
containing from 1-2 heteroatoms selected from the group
consisting of N, O, and S substituted with 0-2 R1,
provided that Jb can only be C or N;
J, Ja, and Jb can, alternatively, combine to form a
heterocyclic ring wherein Jb is N and J and Ja are CH2
substituted with 0-1 Rl;
J, Ja, and Jb can, alternatively, combine to form a
heterocyclic ring wherein Jb is CH, J is NR1 and Ja is CH2
substituted with 0-1 Rl;
R1 is selected from H, Cl_4 alkyl, (CH2)roR3~ (CH2)rNR3R3 ,
- 35 (CH2)rC(=O)R2, (CH2) r (CH=CH)(CH2)rC(=O~R2,
(CH2)rNR3C(=o)R2~ (cH2)rso2R4~ (CH2)rNR3So2R4~ and (CH2) r~
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5-membered heterocyclic system having 1-4 heteroatoms
selected from N, O, and Si
R2 is selected from H, oR3 ~ Cl_4 alkyl, NR3R3 , CF3, and C3_10
carbocyclic residue substituted with 0-2 R6;
R3 and R3 are independently selected from H, Cl_4 alkyl, and
C3_l0 carbocyclic residue substituted with 0-2 R6;
10 R4 is selected from C1_4 alkyl, NR3R3 , and C3_10 carbocyclic
residue substituted with 0-2 R6;
Z is selected from CH=CH, CH~(CH2)mQ(CH2)mR5)~
CH((CH2)mQ(CH2)mR5)C(o)NR3~ CH((CH2)mC(o)(CH2)mR5a),
N((cH2)qQ(cH2)mR5)~ N(Q'(CH2)mR5)~
C(o)N((cH2)mQ~(cH2)mR5a)~ C(O)(CH2)r, C(O)O(CH2)r,
OC(O) (CH2)r, C(O) (CH2)rNR3(CH2)r, NR3C(o) (CH2)r,
oC(o)NR3(cH2)r~ NR3C(o)o(cH2)r~ NR3C(o)NR3(CH2)r,
S(O)p(CH2)r, S02CH2, SCH2C(o)NR3, So2NR3(CH2)r,
NR3S02(CH2)r, and NR3So2NR3(CH2)r;
Q is selected from a bond, O, NR3, C(O), C(o)NR3, NR3C(o), S02,
NR3So2, and S02NR3;
Q' is selected from a bond, C(O), C(O) NR3, S02, and So2NR3;
R5 is selected from H, Cl_4 alkyl, C3_10 carbocyclic residue
substituted with 0-2 R6, 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,
provided that when Q is SO2 or NR3So2~ R5 is other than H
and when Q' is S02, R5 is other than H;
RSa is selected from NHR5, oR5, and R5;
A is selected from:
benzyl substituted with 0-2 R6,
phenethyl substituted with 0-2 R6,
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phenyl-CH= substituted with 0-2 R6,
C3_l0 carbocyclic residue substituted with 0-2 R6, and
5-10 membered heterocyclic system containing from 1-3
heteroatoms selected from the group consistin~ of N, O, and S
substituted with 0-2 R6;
B is selected from:
X-Y, C3-6 alkyl, NR3R3 , C(=NR3)NR3R3 , NR3C(=NR3)NR3R3',
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;
~5 A and B can, alternatively, combine to form a Cg_l0 carbocyclic
residue substituted with 0-2 R6 or a 9-10 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), -S~O)p-, -S(o)pCR3R3 -, -CR3R3'S(o)p-,
-S(o)2NR3-, -NR3S(0)2-, -C(o)NR3-, -NR3C(o)-, -NR3-,
NR3CR3R3'- -CR3R3'NR3-, O, -CR3R3 O-, and -oCR3R3 -;
Y is selected from:
C3-1o 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, (cH2)noR3~ halo, Cl_4 alkyl, CN, NO2,
(CH2)rNR3R3 , (CH2)rC(O)R3, NR3C(O)R3 , NR3C(o)NR3R3',
CH(=NH)NH2, NHC(=NH)NH2, So2NR3R3 , CoNHSo2R4,
NR3So2NR3R3 , NR3So2-cl-4 alkyl, and (Cl-4 alkyl)-
tetrazolyl;
., . ~
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R7 is selected from H, OH, Ci-6 alkyl, C1 6 alkylcarbonyl, C1_O
alkoxy, Cl_4 alkoxycarbonyl, C6_l0 aryloxy, C6_l0
aryloxycarbonyl, C6_l0 arylmethylcarbonyl, Cl 4
alkylcarbonyloxy Cl_4 alkoxycarbonyl, C6_l0
arylcarbonyloxy Cl_4 alkoxycarbonyl, Cl_6
alkylaminocarbonyl, phenylaminocarbonyl, and phenyl Cl_~
alkoxycarbonyl;
R8 is selected from H, Cl-6 alkyl and (CH2)n-phenyl;
R9 is selected from H, Cl_6 alkyl and (CH2)n-phenyl;
n is selected from 0, l, 2, 3, and 4;
m is selected from 0, l, and 2;
p is selected from 0, l, and 2;
q is selected from l and 2; and,
r is selected from 0, l, 2, 3, and 4;
provided that:
(a) Z is other than CH2; and,
(b) if Z is CH((cH2)mQ(cH2)mR5) or CH((CH2)mC(o)(cH2)mR5a)~
then B is other than X-Y, a C3 l0 carbocyclic residue or a 5-l0
membered heterocyclic system.
[2] In a preferred embodiment, the present invention provides
compounds of formula II:
D_ Wl ~ J~
a_W2 ( ~ z B
n
wherein: from 0-l of W, Wl, W2, and W3 are N;
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Rl is selected from H, Cl 4 alkyl, (CH2)roR3/ (CH2)rNR3R3 ,
( CH2 ) rC ( =0 ) R2, ( CH2 ) rNR3C ( =0 ) R2, ( CH2 ) rSo2R4,
(CH2)rNR3So2R4~ and (cH2)r-5-membered heterocyclic system
having 1-4 heteroatoms selected from N, O, and S;
R2 is selected from H, GR3, Cl~4 alkyl, NR3R3 , and CF3;
R3 and R3 are independently selected from H, Cl 4 alkyl, and
phenyl;
R4 is selected from Cl 4 alkyl, phenyl and NR3R3 ;
Z is selected from CH=CH, CH((CH2) mQ (CH2 ) mR5 ),
CH((CH2) mQ (CH2 ) mR5 ) C (O) NR3, CH((CH2)mC(o)(cH2)mR5a)~
N((CH2)qQ(CH2)mR5)~ N(Q'(CH2)mR5)~
C(O)N((CH2)mQ'(CH2)mR5a), C(O), C(O)CH2, C(O)O, OC(O),
C ( O ) ( CH2 ) rNR3 ( CH2 ) r , NR3C(o), oC(o)NR3, NR3C(o)o,
NR3C(o)NR3, S(O)p, SO2CH2~ So2NR3/ NR3So2/ and NR3So2NR3;
B is selected from:
X-Y, C3-6 alkyl,
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;
A and B can, alternatively, combine to form a Cg_lo carbocyclic
residue substituted with 0-2 R6 or a 9-10 membered
heterocyclic system containing from 1-3 heteroatoms
selected from the group consisting of N, O, and S
substituted with 0-2 R6; and,
~5 R6 is selected from H, OH, (cH2)noR3~ halo, Cl_g alkyl, CN, NO2,
(CH2)rNR3R3 , (cH2)rc(o)R3~ NR3C(o)R3 , NR3C(o)NR3R3',
So2NR3R3 , CoNHso2R4~ NR3So2NR3R3 , NR3So2-cl-4 alkyl and
(Cl_4 alkyl)-tetrazolyl.
.. . .. . .
. .
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[3] In a more preferred embodiment, the present invention
provides compounds of formula II, wherein:
J, Ja, and Jb combine to form an aromatic heterocyclic system
containing from 1-2 nitrogen atoms, substituted with 0-l
Rl i
J, Ja, and Jb can, alternatively, combine to form a
heterocyclic ring wherein Jb is N and J and Ja are CH2
substituted with 0-l Rl;
J, Ja, and Jb can, alternatively, combine to form a
heterocyclic ring wherein Jb is CH, J is NRl and Ja is CH2
substituted with 0-l ~l;
Rl is selected from H, Cl_4 alkyl, (CH2)roR3t (CH2)rNR3R3 ,
(CH2)rC(=O)R2, (cH2)rNR3c(=o)R2~ (CH2)rSo2R4~ and
(CH2)rNR3So2R4;
Z is selected from CH((CH2) mQ ( CH2 ) mR5 ),
CH((CH2)mQ(CH2)mR5)C(O)NR3~ CH((CH2)mC(o)(cH2)mR5a)~
N( (CH2)C~Q(CH2)mRS) ~ N(Q' (CH2)mR5),
C(O)N( (CH2)mQ' (CH2)mR5a), C(O), C(O)CH2,
C(O) (CH2)rNR3(cH2)r~ NR3C(o), NR3C(o)NR3, S(0)2, S02CH2,
So2NR3, NR3So2, and NR3So2NR3;
A is selected from:
benzyl substituted with 0-2 R6,
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;
B is selected from:
X-Y, C3-6 alkyl,
benzyl substituted with 0-2 R6,
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C5-6 carbocyclic residue substituted with 0-2 R~, 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 R6;
X is selected from -C(O)-, -C(O) CR3R3 -, -S(0)2-, -S(o)pCR3R3 -,
-S(G)2NR3-, -C(o)NR3-, -NR3-, -NR3CR3R3 -, and O;
Y is selected from:
10Cs_6 carbocyclic residue substituted with 0-2 R6, 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 R6;
15R6 is selected from H, OH, (cH2)noR3~ halo, Cl_4 alkyl, CN, N02,
(CH2)~NR3R3 , (CH2)rC(o)R3~ NR3C(o)R3 , NR3C(o)NR3R3',
S02NR3R3 , CoNHso2R4~ NR3So2NR3R3 , NR3So2-cl-4 alkyl and
(Cl_4 alkyl)-tetrazolyl;
n is selected from 0, 1, and 2i and,
r is selected from 0, 1, and 2.
[4] In an even more preferred embodiment, the present
invention provides compounds of formula II:
D ~ J~
Da Jb
(\~Z'A'B
III
wherein:
J and Jb combine to form an aromatic heterocyclic system
containing from 1-2 nitrogen atoms, substituted with 0-1
Rl;
... . . .
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J and Jb can, alternatively, form a heterocyclic ring wnerein
Jb is N and J is CH2 substituted with 0-1 Rli
J and J~ can, alternatively, form a heterocyclic ring wherein
Jb is CH and J is NRl;
z is selected from C(o)N(Q'R5a), C(O), C(o)NR3, NR3C(o), and
So2NR3;
Q' is selected from C(O) and C(o)NR3;
R5 is selected from H and Cl 4 alkyl;
R5a is selected from NHR5, oR5, and R5;
A is selected from:
benzyl substituted with 0-1 R6,
phenyl substituted with 0-1 R6,
piperidinyl substituted with 0-1 R6,
piperazinyl substituted with 0-1 R6, and
pyridyl substituted with 0-1 R6;
B is selected from:
X-Y,
benzyl substituted with 0-1 R6,
phenyl substituted with 0-2 R6,
cyclohexyl substituted with 0-1 R6, and
pyridyl substituted with 0-1 R6;
30 X is selected from: -C(O)-, -S(O)2-, SO2CH2~ -S(0)2NR3-, -NR3-
and -C(O) NR3-;
Y is selected from:
phenyl substituted with 0-2 R6, and
pyridyl substituted with 0-1 R6;
R6 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 ,
12
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So2NR3R3 , CoNHso2R4~ NR3so2NR3R3 , NR3So2-cl-4 alkyl and
(Cl_4 alkyl)-tetrazolyl;
n is selected from 0, l, and 2.
[5] In a further preferred embodiment, the present invention
provides compounds of formula IV:
DJ~z,A~B
IV
wherein A, B, D, and Z are as defined above.
[6] In a still further preferred embodiment, the present
invention provides compounds selected from:
3-((4-cyclohexyl)phenylaminomethylcarbonyl)methyl-5-
amidinoindole
3-(4-p-toluenesulfonyl-piperazinecarbonyl~methyl-5-
amidinoindole
3-(4-(2-aminosulfonylphenyl)pyridine-2-aminocarbonyl)methyl-5-
amidinoindole;
3-(4-[2-tetrazole]phenyl)phenylaminocarbonyl)methyl-5-
amidinoindole;
3-(4-biphenylaminocarbonyl)methyl-5-amidinoindole;
3-(4-(phenylmethylsulfonyl)piperazinecarbonyl)methyl-5-
amidinoindole;
-
3-(4-cyclohexylphenylaminocarbonyl)methyl-5-amidinoindole;
. . .
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3-(4-benzylpiperazinecarbonyl)methyl-5-amidinoindole;
3-(3-amidinobenzylamino(methylcarbonylmethoxy)carbonyl)methyl-
5-amidinoindole;
3-(4-(2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-
amidinoindole;
3~ benzylpiperidine-4-aminocarbonyl)methyl-5-amidinoindole;
3-(4-phenylpiperazinecarbonyl)methyl-5-amidinoindole;
3-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole;
3-{2-bromo-4-(2-
aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-
cyanoindole;
3-{2-methyl-4-(2-
aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-
methylamino indole;
3-{2-fluoro-4-(2-
aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-
amidnoindole;
3-~2-chloro-4-(2-
aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-
cyanoindole;
3-{2-iodo-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-
5-cyanoindole;
3-{2-methyl-4-(2-
aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-
amidinoindole;
14
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3-{2-methyl-4-(2-(t-
butylaminosulfonyl))phenylphenylaminocarbonyl)methyl-5-
amidinoindole;
3-{4-~2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-a-
(methylcarboxy methyl ether)-5-amidinoindole;
3-{4-(2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl -a-
(benzyl)-5-amidinoindole;
3-{4-(2-trifluoromethyl)phenyl)pyrid-2-ylaminocarbonylmethyl
5-amidinoindole;
3-{4-(2-ethylaminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-
amidinoindole;
3-{4-(2-propylaminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-
5-amidinoindole;
20 2-methyl-3-~2-iodo-4-(2-
aminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-
amidinoindole;
2-methyl-3-{4-(2-
aminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-
amidinoindole;
3-{4-(2-aminosulfonyl)phenyl)phenyl}-N-
methylaminocarbonylmethyl-5-amidinoindole;
2-methyl-3-{4-(2-t-
butylaminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-
methoxyindole; and,
~ 35 3-{4-(2-N-methylaminosulfonyl)phenyl)phenyl}-N-
methylaminocarbonylmethyl-5-amidinoindole;
..... ........ . . . .. . ...
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or a stereoisomer or pharmaceutically acceptable salt form
thereof.
[7] In another further preferred embodiment, the present
invention provides compounds of formula IVa:
D'~ ~ z~A~s
IVa
wherein A, B, D, and Z are as defined above.
[8] In another still further preferred embodiment, the
present invention provides compounds selected from:
3-{4-(2-(n-
butylaminosulfonyl)phenylphenylaminocarbonyl)methyl-5-
cyanoindoline
3-{4-(2-(n-
propylaminosulfonyl)phenylphenylaminocarbonyl)methyl-5-
amidinoindoline;
(-)-3-{4-(2-aminosulfonyl)phenyl)pyrid-2-
ylaminocarbonylmethyl-5-amidinoindoline;
3-{4-(2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-
amidinoindoline;
3-{4-(2-
dimethylaminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-
amidinoindoline;
(+)-3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-
ylaminocarbonylmethyl-5-amidinoindoline;
16
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-)-3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-
ylaminocarbonylmethyl-5-amidinoindoline;
3-{4-(2-aminosulfonyl)phenyl)pyrid-2-yl)aminocarbonylmethyl-5-
aminocarboxyindoline;
3-{4-(2-t-
butylaminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-
amidinoindoline; and,
3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-
yl}aminocarbonylmethyl-5-amidinoindoline;
~5 or a stereoisomer or pharmaceutically acceptable salt form
thereof.
[93 In another further preferred embodiment, the present
invention provides compounds of formula IVb:
,A
Z B
IVb
wherein A, B, D, and Z are as defined above.
[lO] In another still further preferred embodiment, the
present invention provides compounds selected from:
~0 3-{4-(2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-6-
amidinoindazole;
3-{4-(2-aminosulfonyl)phenyl)phenyl aminocarbonylmethyl-6-
amidinoindazole;
CA 022~9~73 1999-01-06
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3-{4-(2-t-butyl aminosulfonyl)phenyl)pyrid-2-
ylaminocarbonylmethyl-6-amidinoindazolei and,
3-{4-(2-t-butylaminosulfonyl)phenyl)phenyl
aminocarbonylmethyl-6-amidinoindazole;
or a stereoisomer or pharmaceutically acceptable salt form
thereof.
[ll] In another further preferred embodiment, the present
invention provides compounds of formula IVc:
D~ ~ (?~ A
IVc
wherein D, Da, Z, A, and B are as defined above.
~ 12] In another still further preferred embodiment, the
present invention provides compounds selected from:
[4-(phenyl)phenylcarbonyl~methyl-6-amidinobenzimidazole;
[4-(phenyl)phenylcarbonyl]methyl-5-amidinobenzimidazole;
[4-(3-aminophenyl)phenylcarbonyl]methyl-6-
amidinobenzimidazole;
[4-(3-aminophenyl)phenylcarbonyl]methyl-5-
amidinobenzimidazole;
[4-(4-fluorophenyl)phenylcarbonyl]methyl-6-
amidinobenzimidazole;
18
,_ . ~.
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[4-(4-formylphenyl)phenylcarbonyl]methyl-5-
amidinobenzimidazole;
[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-
amidinobenzimidazole;
[4-(2-tert-butylaminosulfonylphenYl)phenylcarbonyl]methyl-6
amidinobenzimidazole;
~0 {4-[(2-tetrazolyl)phenyl]phenylcarbonyl}methyl-6-
amidinobenzimidazole;
[4-(2-aminosulfonylphenyl)phenylaminocarbonyl]methyl-6-
amidinobenzimidazole;
[4-(2-aminosulfonylphenyl)phenylaminocarbonyl]methyl-5-
amidinobenzimidazole;
1-(4-benzylpiperidinecarbonyl)methyl-6-amidinobenzimidazole;
1-(4-benzylpiperidinecarbonyl)methyl-5-amidinobenzimidazole;
.,
1-(4-benzylpiperidinecarbonyl)methyl-6-amidinobenzimidazole;
2-[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-
amidinobenzimidazole;
2-[4-(2-tert-butylaminosulfonylphenyl)phenylcarbonyl]methyl-5-
azabenzimidazole;
2S-[4-(2-tert-aminosulfonylphenyl)phenylaminocarbonyl]methyl-
thio-lH-imidazo(4,5-C) pyridine; and,
2S-[4-(2-aminosulfonylphenyl)phenylaminocarbonyl]methyl-thio-
lH-imidazo(4,5-C) pyridine;
or a stereoisomer or pharmaceutically acceptable salt form
thereof.
19
.. . . .. .. . . . . ..
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[13] In a preferred embodiment, the present invention provides
compounds of formula V:
H2N
W 'W3
V
wherein one of R and Ra is -(cH2)n-z-A-B and the other H;
~O W, W2, and W3 are selected from CH and N, provided that at most
one of W, W2, and W3 can be N;
J is selected from N and C-Rl;
Rl is selected from H, O, (CH2)roR3~ (CH2)rC(=O)R2,
(CH=CH)C(=O)R2, (CH2)rNR3C(=o)R2~ (CH2)rSo2R4,
(CH2)rNR3So2R4~ and (cH2)r-5-membered heterocyclic system
having 1-4 heteroatoms selected from N, O, and Si
~0 R2 is selected from H, oR3, Cl_4 alkyl, NR3R3 , CF3, and C3_l0
carbocyclic residue substituted with 0-2 R6;
R3 and R3 are independently selected from H, Cl_4 alkyl, and
C3_l0 carbocyclic residue substituted with 0-2 R6;
R4 is selected from oR3, Cl_4 alkyl, NR3R3 , and C3_l0
carbocyclic residue substituted with 0-Z R6;
Z is selected from CH=CH, CH(CH2) mQ (CH2 ) mR5,
CH((CH2)mQ(CH2)mR5)C(o)NR3~ CH(cH2)mc(o)(cH2)mR5
N(CH2)qQ(CH2)mR5~ NQ~(cH2)mRs~ C(o)N((cH2)mQ~(cH2)mR5a)~
C(O), C(O)CH2, C(O)O, OC(O), C(o)NR3(cH2)r~ NR3C(o),
oC(o)NR3, NR3C(o)o, NR3C(o)NR3, S(O)p, SO2CH2, S02NR3,
NR3So2, and NR3So2NR3;
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PCT~S97/11325
~ WO98/01428
Q is selected from a bond, O, NR3, C(O), C(o)NR3, NR3C(o), SO2,
NR3So2, and So2NR3i
Q~ is selected from a bond, C(O), C(o)NR3, SO2, and So2NR3;
R5 is selected from H, C1_4 alkyl, C3-s 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,
provided that when Q is SO2 or NR3so2~ R5 is other than H
and when Q' is SO2, R5 is other than H;
R5a is selected from NHR5, oR5, and R5;
~5 A is se~ected from:
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~0 substituted with 0-2 R6;
B is selected from:
H, X-Y, NR3R3 , C(=NR3)NR3R3 , NR3C(=NR3)NR3R3 ,
benzyl su~stituted 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;
~0 X is selected from C1-4 alkylene, -C(O)-, -C(o)CR3R3 -,
-CR3R3 C(O), -S(O)p-, -S(o)pCR3R3 -, -CR3R3'S(o)p-,
-S(0)2NR3-, -NR3S(o)2-~ -C(o)NR3-, -NR3C(o)-, -NR3-,
-NR3CR3R3 -, -CR3R3 NR3-, O, -CR3R3 O-, and -oCR3R3'-;
Y is selected from:
C3_10 carbocyclic residue substituted with 0-2 R6, and
. .
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5-l0 membered heterocyclic system containing from l-3
heteroatoms selected from the group consisting of N, O, and S
substituted with 0-2 R6;
R6 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',
CH(=NH)NH2, NHC(=NH)NH2, C(=o)R3, S02NR3R3 , NR3So2NR3R3',
and NR3So2-Cl_4 alkyl;
n is selected from 0, l, 2, 3, and 4;
m is selected from 0, l, and 2;
p is selected from 0, l, and 2;
q is selected from l and 2; and,
r is selected from 0, l, 2, 3, and 4.
[14] In another more preferred embodiment, the present
invention provides compounds of formula VI:
H2N
~ ~ J
VI
wherein one of R and Ra is ~(CH2)n-Z-A-B and the other H;
W and w2 are selected from CH and N, provided that at most one
of W and w2 can be N;
J is selected from N and C-Rl;
Rl is selected from H, (CH2)roR3~ (CH2)rC(=O)R2,
(CH2)rNR3C(=o)R2, (CH=CH)C(=O)R2, (CH2)rSo2R4~ and
(CH2) rNR3So2R4;
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R2 is selected from H, oR3, C1_4 alkyl, NR3R3 , and CF3;
R3 and R3 are independently selected from H, C1_4 alkyl, and
phenyl;
R4 is selected from oR3, Cl_4 alkyl, NR3R3 , and phenyl;
Z is selected from C(O), C(o)cH2~ C(o)NR3, NR3C(o), S(O)2,
S02CH2, S32NR3~ NR3So2~ and NR3So2NR3;
A is selected from:
C3_10 car~ocyclic 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,
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 -C(O)-, -C(O) CR3R3 -, -CR3R3'C(o), -S(O)p-,
-S(o)pCR3R3 -, -CR3R3 S(O)p-, -S(0)2NR3-, -NR3S(0)2-,
-C(o)NR3- -NR3-, -NR3CR3R3'-, and -CR3R3 NR3-;
Y 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;
35 R6 is selected from H, OH, (cH2)noR3~ halo, C1_4 alkyl, CN, N02,
(CH2)rNR3R3 ,(CH2)rC(O)R3, NR3C(O)R3 , NR3C(O)NR3R3 ,
C(=o)R3, So2NR3R3 , NR3So2NR3R3 , and NR3So2-cl-4 alkyl;
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n is selected from 0, 1, 2, 3, and 4;
p is selected from 0, 1, and 2; and,
5 r is selected from 0, 1, 2, 3, and 4.
[15] In another even more preferred embodiment, the present
invention provides compounds of formula VII:
H2N R 1
HN w2~ A
~Z \B
VII
wherein, W and w2 are selected from CH and N, provided that at
most one of W and w2 can be N;
R 1 i s s elected from H, (CH2)roR3~ (CH2)rC(=O)R2,
( CH2 ) rNR3C ( =0 ) R2, (CH=CH) C ( =0 ) R2, ( CH2 ) rSo2R4, and
tCH2) rNR3 SO2 R4;
R2 is selected from H, oR3, Cl_4 alkyl, NR3R3 , and CF3;
R3 and R3 are independently selected from H, C1_4 alkyl, and
phenyli
R4 is selected from oR3, C1_4 alkyl, NR3R3 , and phenyl;
Z is selected from C(O), C(o)cH2~ C(o)NR3, S(O)2, SO2CH2,
So2NR3, and NR3So2NR3;
~0 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;
24
. ~
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B is selected from:
X-Y,
C3_l0 carbocyclic residue substituted with 0-2 R6, and
5-l0 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 -S(O)p-, -S(O) pCR3R3 -, -CR3R3 S (O) p-,
0 -S (O) 2NR3-, -NR3S (O) 2-, and -C(o)NR3-;
Y is selected from:
C3_l0 carbocyclic residue substituted with 0-2 R6, and
5-l0 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, (cH2)noR3~ halo, Cl_4 alkyl, CN, NO2,
(CH2)rNR3R3 ,(CH2)rC(O)R3/ NR3C(o)R3 , NR3C(o)NR3R3 ,
C (=O) R3, So2NR3R3 , NR3so2NR3R3 , and NR3So2-cl-4 alkyl;
n is selected from 0, l, 2, 3, and 4;
p is selected from 0, l, and 2; and,
r is selected from 0, l, 2, 3, and 4.
[16] In another further preferred embodiment, the present
invention provides compounds selected from:
l-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole;
l-(4-benzylpiperidinecarbonyl)ethyl-5-amidinoindole;
l-(4-(3-fluoro)benzylpiperidinecarbonyl)methyl-5-
amidinoindole;
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(4-amidino)benzyl-N-(methylacetate)aminocarbonyl)meth
5-amidinoindole;
methyl l-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole-3-
propanoate;
l-((4-benzylpiperidinecarbonyl)methyl-(3-ethanehydroxyl)-5
amidinoindole;
~O l-(4-benzylpiperidine-l-carbonyl)methyl-3-methylcarboxylic
acid-5-amidinoindole;
l-(l-benzylpiperidine-4-aminocarbonyl)methyl-5-amidinoindole;
l-(4-benzoylpiperidinecarbonyl)methyl-5-amidinoindole;
l-(4-(3-fluoro)benzylpiperazinecarbonyl)methyl-5-
amidinoindole;
l-(4-phenylbenzylaminocarbonyl)methyl-5-amidinoindole;
methyl l-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole-3-
propenoate; and,
~5 l-(4-(2-fluoro)benzylpiperidinecarbonyl)methyl-5-
amidinoindole;
or a stereoisomer or pharmaceutically acceptable salt form
thereof.
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.
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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.
DEFINITIONS
The compounds herein described may have asymmetric
centers. Compounds of the present invention con~i n ing 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.
When any variable (e.g., R6) occurs more than one time in
any constituent or formula for a compound, its definition on
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 and R6 at each occurrence is
selected independently from the defined list of possible R6.
Also, combinations of substituents and/or variables are
permissible only if such combinations result in stable
compounds.
As used herein, "Cl_4 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,
27
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WO98/01428 PCT~S97/11325
n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl;
~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
like.
IlHalo'' or "halogen" as used herein refers to fluoro,
chloro, bromo, and iodoi 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 residue" is
intended to mean any stable 3- to 7-membered monocyclic or
bicyclic or 7- to lO-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, 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 lO-membered bicyclic
heterocyclic ring which is saturated partially unsaturated or
unsaturated (aromatic), and which consists of carbon atoms and
from l to 4 heteroatoms independently selected from the group
consisting of N, O 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
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.
28
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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 ring which
consists of carbon 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 aromatic 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, benzothiophenyl, benztriazolyl,
benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalonyl, 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, isoindolinyl, isoindolyl,
isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,
morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxazolidinyl., oxazolyl, oxazolidinylperimidinyl,
phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, 4-piperidonyl,
pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,
pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,
pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,
quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,
carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, 6H-l,2,5-thiadiazinyl, thianthrenyl,
thiazolyl, thienyl, thienothiazole, thienooxazole,
thienoimidazole, thiophenyl, triazinyl, xanthenyl. Preferred
~ 35 heterocycles include, but are not limited to, pyridinyl,
furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl,
~ benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl,
benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also
29
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WO98/01428 - PCT~S97/11325
included are fused ring and spiro compounds containing, for
example, the above heterocycles.
When a bond to a substituent is shown to cross the 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
substituent. Combinations of substituents and/or variables
are permissible only if such combinations result in stable
compounds.
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.
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,
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.
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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.
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 animals without excessive toxicity,
irritation, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk
ratio.
"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
mAmm~lian 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
administered to a mAmm~lian subject, cleaves to form a free
hydroxyl, free amino, or free sulfhydryl group, respectively.
Examples of prodrugs include, but are not limited to, acetate,
~ 35 formate and benzoate derivatives of alcohol and amine
functional groups in the compounds of formula (I), and the
- like. Preferred prodrugs are amidine prodrugs wherein either
D or Da is C(=NH)N(H)Rl0, and Rl0 is selected from OH, Cl_4
31
~ . . ...... . . .
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alkoxy, C6_l0 aryloxy, Cl_4 alkoxycarbonyl, C6_l0
aryloxycarbonyl, C6_l0 arylmethylcarbonyl, Cl_ 4
alkylcarbonyloxY Cl_~ alkoxycarbonyl, and C6_l0 arylcarbonyloxy
Cl_4 alkoxycarbonyl. More preferred prodrugs are where R7 is
OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and
methylcarbonyloxymethoxycarbonyl.
I~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 I 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
32
CA 022~9~73 1999-01-06
~ WO98/01428 - PCT~S97/11325
present in the compounds described in this invention. An
authoritative account describing the many alternatives to the
trained practitioner is Greene and Wuts ( Protective Groups In
Organic Synthesis, Wiley and Sons, l99l).
The following descriptions detail general methods of
making benzimidazoles, indazoles and indoles through a variety
of intermediates. These methods are not intended to represent
all of the possible means of making the above compounds,
merely a broad representation. One of ordinary skill in the
art would readily understand what s~arting groups would be
necessary to make all of the present compounds.
Intermediate l which can be formed via acylation of 4-
amino-3-nitrobenzonitrile (Aldrich Chemical Co.) with an acyl
chloride (RlCHO) or an anhydride ((RlCO)2O) in the presence of
a base, followed by hydrogenation is shown below in Scheme l.
Reductive amination of an aldehyde (RCHO) in the presence of l
using borane-pyridine in acetic acid can afford N-alkylated
product 2. Alkylation of l with a halide (P3X) in the presence
of a base, such as Cs2CO3~ can provide compound 3. Compounds 2
and 3 can be subjected to the Pinner reaction to give 6-
amidino-benzimidazole derivative 4 and 5-amidino-benzimidazole
derivative 5, respectively (see ~h~nn~ et al ~. Org. Chem.
1995, 60, 960).
Scheme l: Amidino-benzlmidazole~ via 4-A~;no-3-
n~trn~n7o~itrile
~ .,
CA 02259573 1999-01-06
WO 98/01428 - PCT/US97/1132~i
NC~ NH2 o
NC~ ~ Rl-- H Rl
BH3-Pyr. \ K2CO3
1) HCl (gas), EtOH NC N
2) (NH4)2CO3, EtOH ~ Nl\~ R
H2N ~ N ~ R1 1) HCl (gas), EtOH
2 ) ( NH4 )2C03, EtOH
NH
R= (CH2)n 1-Z-A-B H2N
P3=(CH2)n-Z-A-B N
5 P3
Scheme 2 shows palladium (0) catalyzed coupling of 3-
amino-4-nitrophenyl halides with zinc cyanide in DMF under
reflux can provide compound 6 (see Lawton et al J. Org. Chem.
1959, 24, 26). Acylation of 6 with an acyl chloride or
anhydride in the presence of base, followed by hydrogenation
can form compound 7. Alkylation of 7 with a halide in the
presence of a base, such as Cs2CO3~ can provide compound 8.
Reductive amination of an aldehyde with 7 using borane-
pyridine in acetic acid can afford N-alkylated product 9.
Compounds 8 and 9 can be converted to either their 6-amidino-
benzimidazole or 5-amidino-benzimidazole derivatives,
respectively via the Pinner reaction.
~h~ - 2: Amidino-h~n7;mi~7oles via 3-amino-4-nitrophenyl
halides
CA 02259573 1999-01-06
WO98/01428 - ~ PCT~S97/1132S
zn(CN)2
X ~ NH2 Pd(0) NC ~ NH2
N02 DMF ~ NO2
reflux 6
X = Br, I
l) RlCOCl or
(RlCO) 2~~ NaH
2) H2, 10% Pd/C,
p3 ~ MeOH
NC ~ ~ Rl NC ~ N ~ R1 NC ~ N\~ R
N P3X NH2 ~ RCHo ~ N
K2CO3 BH3-Pyr
8 7 9 ~-R
Ullmann reaction of 4-chloro-3-nitrobenzonitrile with an
amine (P3NH2) in the presence of a base, such as NaHCO3, can
form compound l0 shown in Scheme 3. Hydrogenation of lO,
followed by cyclization with an acid, such as formic acid, can
give compound 5, which can be converted to its 5-amidino-
benzimidazole derivatives as described above. In addition,
compound 5 could be derivatized by addition of Br-(CH2)n-Z-A-B
and the resulting mixture subjected to the Pinner reaction and
separated by standard techniques.
Scheme 3: Amidino-benzimldazoleg via the Ullmann Reaction
H2
1O NHP3 RlCO2H or 5
RlCOCl 3
As described in Scheme 4, bromination of 4-amino-
benzonitrile with NBS, followed by treatment with NaNO2 and
Cu2O in conc. HCl can provide compound ll (see Tsuji et al
20 Chem. Pharm. Bull. 1992, 40, 2399). Ullmann reaction of ll
with an amine in the presence of a base, such as NaHCO3, can
- form compound 12. Hydrogenation of ll, followed by
cyclization with formic acid can give compound 8, which can be
CA 02259573 1999-01-06
WO98/01428 - PCT~S97/11325
converted to its 6-amidino-benzimidazole derivative as
described above.
Scheme 4: Amidino-benzimidazoles ~ia the Ullmann Reaction
NC ~ 1) NBS WC ~ P3-NH2
NH2 2) NaNO2 ~ N02
Cu2~ 11
conc. HCl
1 3 Pl 3
NC " ~ N 1) H2, 10% Pd/C NC NH
2) R1COOH ~ NO2
8 12
Scheme 5 details the synthesis of 2-substituted-amidino-
benzimidazoles from 3,4-diamino-benzonitrile and 3-amino-4-
hydroxybenzonitrile 13 which are obtained by hydrogenation of4-amino-3-nitro-benzonitrile or 4-hydroxy-3-nitrobenzonitrile.
Treatment of 13 with an acyl chloride or an acid in the
presence of PPA can form compound 14 (see Walker et al
Synthesis 1981, 303). Compound 14 can be converted to its
amidino derivative via the Pinner reaction. Alternatively,
when Y is NH, alkylation of 14 with a halide in the presence
of a base, such as K2CO3, can afford a mixture of two
regioisomers 15 and 16, which can, after being separated, be
subjected to the Pinner reaction to give 2-substituted-6-
amidino-benzimidazoles and 2-substituted-5-amidino-
benzimidazole derivatives, respectively.
Scheme 5: 2-Substituted-amidino-benz;~;dazolss
36
CA 022~9~73 l999-0l-06
~ WO98101428 - PCT~S97/11325
N_ , ~ NH2 ' [ ~ \ ~ P3
JH P3C02H or P3COCl J
13 PPA / 14
/ when J = NH
RlX, K2C03
Rl ~/ Rl
/ ~ + ~ N
16
Protection of 6-hydroxy-indazole with pivalic anhydride
in the presence of a base, followed by treatment with triflic
anhydride can give compound 17 as shown in Scheme 6.
Palladium (0) catalyzed coupling of 17 with zinc cyanide can
provide compound 18. Deprotection of compound 18 under acidic
conditions, followed by alkylation of with a halide in the
presence of a base can yield compound 19, which can be
converted to its 6-amidino-indazole derivative via the Pinner
reaction.
Scheme 6: Amidino-benz;nA~7~1es ~ia 6-llyd o~y-;n~7ole
HO ~ 1) (Boc)2O ~ ~ Zn(cN)2
Pd(0)
NC~ ~ N 2) P3X K2CO Nr ~ Boc
19 18
1-Substituted-amidino-indoles and -indazoles could be
made from 5-cyanoindole as outlined below in Scheme 7.
Intermediate 21 can easily be obtained via alkylation of 20
with Br(CH2)nZ. Peptide coupling with H-A-B using the BOP
37
CA 02259573 l999-0l-06
WO98/01428 - PCT~S97/11325
reagent or alkylation should afford intermediate 22 which is
can then be converted to amidine 23 under Pinner conditions.
Scheme 7: 1-Substituted-P~;dino-indole8 and -;~7Oles from
5-cyanoindole (Ja=CH or N)
~=\ l.NaH, DMF ~ \ Z-H
NC~ Br(CH2) nZ ~N~n
21
f~J\ ~Z--A-B ~=J\ ~A-B
peptide ~N~ n l.HCl , ~N~ n
coupling, ~ MeOH
acylation, NC 22 2.(NH4) 2C~3 HN 23
alkylation
H-A-B
Scheme 8 shows 3-substituted-amidino-indoles and
-indazoles are also derivable from 5-cyanoindole. Compound 26
may be obtained by substitution Of R1 on 24 to form 25 and
acylation of 25 in the presence of oxalyl chloride at r.t.
under nitrogen atmosphere. The compound can be subjected to
selective ketone reduction with triethylsilane in
trifluoroacetic acid for 3h and then coupled with H-A-B.
Scheme 8: 3-Substituted-amidino-indoles and indazoles from 5-
cyanoindole (Ja=CH or N)
38
CA 02259573 l999-0l-06
WO98tO1428 - PCT~S97/11325
l.NaH, ~ 1. (COCl)2 ~OMe
:~ XRl b~ CH2CL2 ~ ~
CN CN CN
24 25 26
l.TFA ~ ~A-B 1 . HCl, ~A-B
Et3SiH ~ ~ MeOH
2. KOH ~ 2.(NHs)2CO3 ~ ,
3. peptide CN ~ ~
coupling HN NH2
H-A-B 27 2 8
The piperazine phenylsulfonamide, 31, and various other
sulfonamide analogues can be prepared from commercially
available BOC-piperazine via sulfonation with phenylsulfonyl
chloride in CH2cl2 and triethylamine as indicated in Scheme 9.
Scheme 9: Phenylsulfonylpiperazines from Boc-piperazine
r~ R6-PhS02C1 BoCNAN--\\S~/ r E~ N-- ~,
29 CH2Cl2/Et3N 30 ~ R6 ~
Biphenyl compounds may be prepared by procedures known to
those of skill in the art. For example, Scheme 10 shows how
to obtain substituted biphenyls via a Suzuki coupling with BOC
protected 4-bromoaniline (or 1-bromo-4-nitrobenzene) to afford
compound 35.
Scheme 10: Biphenyls from bromoAn;l;ns
39
CA 02259573 1999-01-06
WO 98/01428 - PCT/US97/11325
B (OH) 2 NHBOC N~2
NH2 NHBOC
Oc) 20 ~ ~p6 ~., 3 TFA
Compound 38 can be obtained via deprotection of the t-
butyl group when R6=so2NH-t-Bul with TFA followed by alkylation
or acylation with R3X as outlined in Scheme 11.
gcheme 11: Preparation of 4~-~;no-biphenyl-2-sulfon~ides
NO2 NO2 NH2
TFA ~ R3X
~3,SO2NH-t-Bu ~3,SO2NH2 ~So2NH-R3
36 37 38
Scheme 12 shows how intermediates 43-45 may be obtained
via the same intermediate 39. Acylation with oxalyl chloride
followed by addition of methanol should yield ketoester 40 and
selective reduction with triethyl silane may afford methyl
acetate 42. Reduction with sodium borohydride can give the
alcohol which then can be converted to 45 with R3X.
Intermediate 43 may be obtained via formylation with POC13 in
DMF to yield aldehyde 41 which could then subjected to a
Wittig olefination to afford compound 43.
Scheme 12: Addition Of Rl substituent to l-substituted indoles
or ; n~ 701es
CA 02259573 l999-0l-06
WO 98/01428 PCT/US97/11325
B-A~ B-A~
2 MeOH
3CgN CN 4 0
TFA,
DMF, POC13 Et3SiH
B-A~ B~
~H C ~ ,D OMe
41 CN 42 CN
Ph3P=CH2R2 / l.NaBH4
THF / l.NaBH4 EtOH
~ EtOH 2.XR3, NaH
B-A
z 2.XR3, NaH
B -A~
\~ R2 ~ Z
~/ B~ oR3
43 1 \) oR3 CN
[~ 45
CN
Sulfonyl chloride 49 may be obtained via aldehyde 47.
The aldehyde can be reduced with sodium borohydride,
sulfonated with methane sulfonyl chloride, and displaced with
sodium sulfite in ethanol. Sulfonyl chloride 49 should then
be obtained via chlorination with sulfonyl chloride as
detailed in Scheme 13.
41
,
CA 02259573 l999-0l-06
WO98/01428 ~ PCT~S97/11325
Scheme 13: Addition of Rl to l-protQcted indole~ or in~7Oles
; POCl3 ~ ~ NaBH4 ~ _~OH
CN CN CN
~6 47 48
l.NaH, MsCl ~ so2c
2.Na2SO3
3.Socl2 CN
49
P is a protecting ~roup e.g. MEM-group.
Scheme 14 details how substitution at the 2-position of
the indole may be acomplished via lithiation with s-BuLi at
-78'C followed by addition of RlX to yield compound 51.
Compound 51 can then converted to compound 52 by the
previously mentioned methodology.
Scheme 14: Addition of two R1'B to l-protected indole
~ ~ l.s-BuLi 3~ ~ OH
2 . XR
CN CN CN
50 51 52
In Scheme 15, it is shown how the 5-cyanoindole compound
54 may be prepared via compound 53 by using sodium methoxide
in the presence of nitromethane, followed by Zn reduction and
condensation.
42
CA 022~9~73 1999-01-06
WO98/01428 - PCT~S97/11325
Scheme 15: Formation of indole~
w2~ ~ l.NaOMe NC~ W
w~ No2 CH3NO2 W2~w3 N
53 2. Zn/EtO~ 54 H
TFA
s
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 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, Sulfon~ide and
Sulf~ide l;n~A~es be~.re_" A ~nd B.
then the reactive to give the
Rxn. substituent of following product
No. if A contains : Y is : A-X-Y :
1 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
43
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WO9$/01428 PCT~S97/1132
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
10 A-NHR3 as a ClSO2-Y A-NR3-So2-Y
substituent
11 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
13 a secondary NH ClSO2-CR3R3 -Y A-So2-CR3R3 -Y
as part of a
rinq or chain
14 A-NHR3 as a ClSO2-NR3-Y A-NR3-So2-NR3-Y
substituent
15 a secondary NH ClSO2-NR3-Y A-So2-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)Cl 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
44
.. . . . .. ..
CA 022~9~73 1999-01-06
- WO98/01428 PCT~S97/1132
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 NH as A-S02-Y
part of a ring or
chain
24 A-CR3R3 S02Cl NHR3-Y as a A-CR3R3 So2-NR3-Y
substituent
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.
T~ble 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)Cl BrM~CR3R3 -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
, ,
CA 022~9~73 1999-0l-06
~ WO98/01428 - PCT~S97tll32
sulfide complex in dimethyl sulfide as a solvent or with a
variant 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 link~es 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-cR3R3lo-y
3 A-OH Br-cR3R3l-y A-oCR3R3 -Y
4 A-SH Br-Y A-S-Y
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.
46
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~ WO98/01428 - PCT~S97/11325
Table 4: Preparation of -SO- and -S02- link~es 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-SO2-Y
2 A-CR3R3 S-Y A-CR3R3 S(O)-Y A-CR3R3 SO2-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.
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.
ExamPles
The synthesis of representative compounds according to
the invention is described in further detail below with
reference to the following 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
47
CA 02259573 1999-01-06
WO98/01428 PCT~S97/11325
spectroSCOpy, "t~ for triplet, "TLC" for thin layer
chromatography.
Examples 1-15 were prepared by Michael addition of 5-
cyano-benzimidazole to the a,~-unsaturated esters by using
K2CO3 (2 mmol) as a base in DMF (10 mL) at 90-110~C for 16-24
hours, followed by the Pinner reaction. A mixture of meta-
and para-isomers was obtained by purification on TLC plates
with 10-20% MeOH in CH2cl2. The pure meta- or para-isomer was
separated by HPLC.
5--Cy~nr~hsn 7; ~ ~ 7~1e
N C~ MeOH \(~N N C~N?
reflux H
A solution of 4-amino-3-nitrobenzonitrile (20 mmol) in
MeOH ~300mL) in the presence of 5% of Pd/C (1 g) was treated
with hydrogen at room temperature for 16 hours. The reaction
mixture was filtered and concentrated to give 3,4-
diaminobenzonitrile (2.4 g, 90% of yield), which was directly
treated with formic acid (20 mL) under reflux for 4 hours.
After removal of the excess formic acid, the residue was
dissolved in EtOAc, washed with 10% sodium bicarbonate and
brine, and dried over MgSO4. Concentration gave 5-
cyanobenzimidazole (2.2 g, 85%). lH MMR (CD30D)~8.39 (s, lH),
8.05 (s, lH), 7.76 (d, J = 8.4 Hz, lH), 7.59 (dd, J = 8.4 Hz,
J = 1.1 Hz, lH)i MS: 144 (M+H)+.
Preparation of Ethyl 2-~3-cy~norh~nyl)ethacrylate and Ethyl
2-(4-cy~norh~nyl)ethacrylate
To a stirred suspension of zinc powder (22 mmol) in THF
(10 mL) was added 1,2-dibromoethylene (0.2 g) at room
temperature and the mixture was stirred for 30 minutes. A
solution of 3-cyanobenzylbromide or 4-cyanobenzylbromide (20
mmol) in THF (25 mL) was slowly added at a rate of one drop
48
CA 022~9~73 1999-0l-06
WO98101428 - PCT~S97/11325
per five seconds at 5-10~C. The mixture was stirred for 3
hours, and then transferred into a solution of copper (I)
cyanide (20 mmol) and lithium chloride (40 mmol) in THF (20
mL) at -78~C. The resulting mixture was warmed up and stirred
at -20~C for 20 minutes, and was then cooled to -78~C. After
ethyl 2-(bromomethyl)acrylate (20 mmol) was slowly added, the
mixture was stirred at -78~C for 2 hours, and then warmed to
room temperature overnight. Ether (100 mL) and aqueous
saturated ammonium chloride (50 mL) were added to the mixture
and the mixture filtered- The filtrate was washed with water
and brine, and dried over MgSO~. Concentration gave a residue,
which was purified by column chromatography with gradient
solvent system (cH2cl2-EtoAc) to give ethyl 2-(3-
cyanophenyl)ethacrylate (1.2 g, 26.2%) and ester ethyl 2-(4-
cyanophenyl)ethacrylate (3.6 g, 78.6%).
For ethyl 2-(4-cyanophenyl)ethacrylate: lH NMR (CDCl3)~
7.58 (dd, J = 8.4 Hz, J = 1.8 Hz, 2H), 7.28 (d, J = 8.4 Hz,
2H), 6.17 (d, J = 1.1 Hz, lH), 5.48 (dd, J = 2.6 Hz, J = 1.1
Hz, lH), 4.22 (q, J = 7.3 Hz, 2H), 2.86 (dd, J = 8.6 Hz, J =
7.1 Hz, 2H), 2.61 (dd, J = 8.6 Hz, J = 7.0 Hz, 2H),1.32 (t, J
= 7.0 Hz, 3H); MS: 247 (M+NH4)+.
For ethyl 2-(3-cyanophenyl)ethacrylate: lH NMR (CDC13)~
7.51-7.36 (m, 4H), 6.17 (s, lH), 5.48 (d, J = 1.1 Hz, lH),
4.22 (q, J = 7.3 Hz, 2H), 2.84 (dd, J = 8.4 Hz, J = 7.0 Hz,
2H), 2.61 (dd, J = 8.4 Hz, J = 7.0 Hz, 2H),1.32 (t, J = 7.0
Hz, 3H); 13C MMR (CDC13)~166.80, 142.85, 139.41, 133.14,
132.05, 129.85, 129.17, 118.94, 112.43, 60.79, 34.50, 33.57,
14.22; MS 247 (M+NH4)+.
Preparation of Ethyl t3-(4-cY~norhenyl)-2-bromomethyl~acrylate
To a solution of 4-cyanobenzylbromide (40 mmol) in xylene
(40 mL) was added triphenylphosphine (40 mmol) and the
resulting solution was heated at 110~C for 2 hours. After
removal of xylene, a white solid was obtained, which was
dissolved in a mixture of THF (40 mL) and EtOH (40 mL),
treated with DBU (40 mmol) at room temperature for one hour,
and then to it was added ethyl pyruvate (40 mmol). The
49
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~ WO98/01428 - PCT~S97/113~5
resulting mixture was stirred at room temperature overnight
and filtrated to remove Ph3PO. The filtrate was concentrated,
dissolved in EtOAc, washed with lN HCl, water and brine, and
dried over MgSO4. Concentration gave a mixture of cis and
trans olefins in almost quantitative yield. A solution of the
olefins (5 mmol), NBS (5 mmol), and AIBN (0.25 mmol) in CC14
(200 mL) was refluxed under nitrogen for 16 hours, filtered,
concentrated and purified by column chromatography with
gradient solvent system (cH2cl2-EtoAc) to give the title
10compound (1.25 g, 85 %) as a white solid. lH NMR (CDC13)~7.71
(d, J = 1.4 Hz, lH), 7.68 (d, J = 8-8 Hz, 2H), 7.58 (J = 8.5
Hz, 2H), 4.29 (q, J = 7.3 Hz, 2H), 4.23 (s, 2H), 1.32 (t, J =
7.3 Hz, 3H).
15Prepara~ion of Ethyl 2-(4-benzyloxyphenyl)methacrylate
A mixture of 4-bromophenol (40 mmol), benzylbromide (40
mmol) and Na2CO3 in DMF (200 mL) was stirred at room
temperature for 24 hours and was then poured into water. A
solid was collected and was further recrystallized from hexane
to give 4-benzyloxy~enzene bromide in almost quantitative
yield. A solution of the bromide in THF ( 100 mL) was treated
with BuLi (44 mmol) at -78~C over 30 minutes and then with a
solution of ZnI2 (40 mmol) in THF(40 mL) over 20 minutes.
After the resulting mixture was warmed to room temperature
over an hour, it was cooled to -78~C and a solution of copper
(I) cyanide (40 mmol) and lithium chloride (80 mmol) in THF
(50 mL) was slowly added. The resulting mixture was warmed
and stirred at -20~C for 20 minutes, cooled to -78~C, and to it
was added ethyl 2-(bromomethyl)acrylate (40 mmol). The
resulting mixture was stirred at -78~C for 2 hours and was then
warmed to room temperature overnight. Ether and aqueous
saturated ammonium chloride were added and filtered. The
filtrate was washed with water and brine, and dried over MgSO4.
Concentration gave a residue, which was purified by column
chromatography with gradient solvent system (CH2Cl2-EtOAc) to
give the title compound (3.6 g, 30.4%): lH NMR (CDC13) ~7.44-
7.26 (m, 5H),7.12 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 HZ,
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2H), 6.20 (s, lH), 5.92 (s, lH), 5.07 (s, 2H), 4.18 (q, J =
7.4 Hz, 2H), 3.57 (s, 2H), 1.27 (t, J = 7.4 Hz, 3H)i MS: 314
(M+NH4)+.
ExamPle 1
Pre~aration of EthYl 2-(3-ar;~; n~h~nYl )ethYl-3-(5-
am;~;n~n7;~;dazole)pro~ionate and Ethvl 2-(3-
amidino~henYl)ethYl-3-(6-am;~; n~h~n 7 imidazole)DroDionate
A mixture of 5-cyanobenzimidazole (2 mmol), ethyl 2-(3-
cyanophenyl)ethacrylate (2 mmol) and K2CO3 (2 mmol) in DMF (10
mL) was heated at 90~C under nitrogen for 16 hours. The
mixture was diluted with EtOAc (150 mL), washed with lN HCl,
water, and brine, and dried over MgSO4. After filtration and
concentration, a residue was purified by column chromatography
with gradient solvent system (cH2cl2-EtoAc) to give a mixture
of ethyl 2-(3-cyanophenyl)ethyl-3-(6-
cyanobenzimidazole)propionate and ethyl 2-(3-
cyanophenyl)methyl-3-(5-cyanobenzimidazole)propionate (0.57 g,
76.4%) as a colorless oil. lH NMR (CDCl3)~8.13-7.36 (m, 8H),
4.55 (dd, J = 14.3 Hz, J = 9.2 Hz, lH), 4.28 (dd, J = 14.3 Hz,
J = 5.5 Hz, lH), 4.07 (q, J = 7.0 Hz, 2H~, 3.00-2.91 (m, lH),
2.80-2.64 (m, 2H), 2.18-2.07 (m, lH), 1.92-1.82 (m, lH), 1.12
(t, J = 7.0, 3H).
ExamPles 2 and 3
PreDaration of EthYl 2-(3-amidinoDhenYl)ethYl-3-(5-
am;~;n~h~n~imidazole)~ro~ionate and EthYl 2-(3-
Pm;dino~henYl)ethY1-3-(6-ami~i nnh~n7; midazole)Dro~ionate
The mixture of esters o~tained in Example 1 was treated
with HCl (gas) in anhydrous ethanol (10 mL) for 15 minutes at
0~C and then stirred for 16 hours. After removal of excess HCl
(gas) and ethanol, the residue was treated with (NH4)2CO3 (5
equivalents) in anhydrous ethanol (10 mL) at room temperature
for 24 hours. Concentration gave a residue, which was
purified on TLC plates with 10% MeOH in CH2C12 to give a
mixture of the title compounds (400 mg, 65.4%): mp 160-165~C;
51
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WO98/01428 PCT/US97/1132S
ESMS: 204.2 (M+2H)2+ The mixture was further separated by
HPLC on chiral OJ column with CO2/MeOH/TEA (80/20/0.1) to give
Example 2, ethyl 2-(3-amidinophenyl)ethyl-3-(5-
amidinobenzimidazole)propionate~ and Example 3, ethyl 2-(3-
amidinophenYl)ethyl-3-(6-amidinobenzimidazole)propionate~
Example 2: 1H NMR (CD30D) ~8.36 (s, lH), 8.17 (s, lH)
,7.75-7.72 (m, 2H), 7.63 (bs, 2H), 7.50-7.48 (m, 2H), .4.66
(dd, J = 9.5 Hz, J = 14-3 Hz, lH), 4.55 (dd, J = 5.5 Hz, J =
1014.2 Hz, lH), 4.02-3-92 (m, 2H), 3 14-3 08 (m, lH), 2.81 (t, J
= 7.0 Hz, 2H), 2.19-1.93 (m, 2H), 1.04 (t, J = 7.0 Hz, 3H);
ESMS: 204.2 (M+2H)2+.
Example 3: lH NMR (CD30D) ~8.37 (s, lH), 8.10 (s, lH)
15,7.84 (d, J = 8.4 Hz, lH), 7.72 (d, J = 8.4 Hz, lH), 7.65-7.62
(m, 2H), 7.55-7.46 (m, 2H), 4.68 (dd, J = 9.5 Hz, J = 14.3 Hz,
lH), 4.56 (dd, J = 5.5 Hz, J = 14.2 Hz, ~H), 4.04-3.94 (m,
2H), 3.24-3.18 (m, lH), 2.83 (t, J = 7.0 Hz, 2H), 2.19-1.95
(m, 2H), 1.05 (t, J = 7.0 Hz, 3H); ESMS: 204.2 (M+2H)2+.
ExamDle 4
PreDaration of EthYl 2-(4-amidinoDhenyl)ethyl-3-(5-
a~;~;nnh~n7;m;A~ole)~ro~ionate and EthYl 2-(4-
amidino~henYl)ethYl-3-(6-am;~; n~h~n 7; ~; ~A 701e)~ro~ionate
Example 4 was made using the same method as described for
Example 1, except ethyl 2-(4-cyanophenyl)ethacrylate (2 mmol)
was used (100 mg, 13~ for two steps): mp 230~C (Dec.); ESMS:
407 (M+H)+; HRMS: 407.2200 (obs.), 407.2195 (calcd.) for
30C22~26N6O2. Example 4 was further separated to gi~e Examples 5
and 6.
Exam~les 5 and 6
Pre~aration of EthYl 2-(4-amidinoPhenyl)ethyl-3-(5_
35ami~;nnhen7;m;dazole)Propionate and EthYl 2-(4-
;no~henyl)ethyl-3-(6-am;~;noh~n7imidazole)Dro~ionate
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The mixture of compounds obtained in Example 4 were
further separated to give Examples 5 and 6.
Example 5, ethyl 2-(4-amidinophenyl)ethyl-3-(5-
amidinobenzimidazole)propionate: lH NMR (DMso-d6):~9~43-9.o8
(m, 6H), 7.74-7.65 (m, 2H), 7.40-7.38 (m, 2H), 7.35-7.00 (m,
4H), 4.67-4.55 (m, 2H), 4.06 (bs, 2H), 3.48 (bs, 2H), 3.20
~bs, lH), 2.70 (bs, 2H), 1.00 (bs, 3H); ESMS: 407 (M+H)+.
Example 6, ethyl 2-(4-amidinophenyl)ethyl-3-(6-
amidinobenzimidazole)propionate: lH NMR (DMSO-d6):~9.23-9.12
(m, 6H), 8.41 (s, lH), 8.21 (s, lH), 7.84-7.82 (m, lH), 7.74
(d, J = 8.1 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 7.24 (bs, lH),
4.58-4.56 (m, 2H), 3.95-3.89 (m, 2H), 3.10-3.00 (m, lH), 2.73-
2.71 (m, 2H), 1.90-1.88 (m, 2H), 0.98-0.96 (m, 3H); ESMS: 407
(M+H)+.
Exam~le 7
PreDaration of Ethvl [3-(4-am;~;n~Dh~nvl)-2-(5-
ami~;nQhqn7imidazole)methYl]acrvlate
A mixture of 5-cyanobenzimidazole (2 mmol), ethyl [3-(4-
cyanophenyl)-2-bromomethyl]acrylate (2 mmol) and K2CO3 (2 mmol)
in DMF (10 mL) was heated at 90~C under nitrogen for 24 hours.
The mixture was diluted with EtOAc (150 mL), washed with lN
HCl, water, and brine, and dried over MgSO4. After filtration
and concentration, the residue was purified by column
chromatography ~cH2cl2-EtoAc) to give ethyl [3-(4-cyanophenyl)-
2-(5-cyanobenzimidazole)methyl]acrylate (0.401 g, 56.3 %) as a
colorless oil. lH NMR (CDCl3)~8.10-8.00 (m, 4H), 7.83-7.77
(m,, 2H), 7.52-7.44 (m, 2H), 7.01-6.98 (m, lH), 5.20 (s, 2H),
4.24 (q, J = 7.3 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H); MS: 357
(M+H)+.
The Pinner reaction converted ethyl [3-(4-cyanophenyl)-2-
(5-cyanobenzimidazole)methyl]acrylate (0.42 mmol) to the title
compound (400 mg, 65.4%): lH NMR (CD30D)~8.19-8.12 (m, 2H),
7.92-7.88 (m, 3H), 7.74-7.69 (m, 4H), 4.22-4.19 (m, 2H), 1.24-
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~ WO98/01428 PCT~S97/11325
1.20 (m, 3H); ESMS: 196.2 (M+2H)2+; HRMS: 391.1889 (obs.),
391.1882 (calcd.).
Exam~le 8
Pre~aration of EthYl 2-(4~ dino~henvl)methyl-3-(6_
am; ~; n~h~n 7; ~; ~ ~ 7ole)Dro~ionate and Ethvl 2-(4-
n~r~h~nYl)methyl-3-(5-am;~;n~h~n7imidazole)~roDionate
Ethyl [3-(4-cyanophenyl)-2-(5-
cyanobenzimidazole)methYl]aCrYlate was hydrogenated in MeOH in
the presence of 10% palladium on active carbon to give ethyl
2-(4-cyanophenyl)methYl-3-(6-cyanobenzimidazole)propionate and
ethyl 2-(4-cyanophenyl)methyl-3-(5-
cyanobenzimidazole)proPionate: lH NMR (CDC13) ~8.24-8.02 (m,
2H), 7.87-7.50 (m,, 4H), 7.34-7-28 (m, 2H), 4.58-4.55 (m, lH),
4.32-4.27 (m, lH), 4.12-3.93 (m, 2H), 3.20-2.91 (m, 2H), 2.79-
2.72 (m, lH), 1.10-0.95 (m, 3H).
The mixture obtained (1.5 mmol) was subjected to the
Pinner reaction to obtain the title compound (300 mg, 48%): 1H
NMR (CD30D):~8.63 (bs, lH), 8.27-7.96 (m, 7H), 4.98-4.54 (m,
2H), 3.98-3.80 (m, 2H), 3.53-3.45 (m, lH), 3.37-3.09 (m, 2H),
1.00-0.96 (m, 3H); ESMS: 197 (M+2H)2+.
Examples 51-63 were prepared by Method A, B, or C. All
compounds were finally purified by HPLC (CH3CN/H2/0.05% TFA).
Method A: Examples 51-59 were made by Suzuki coupling
reactions of [(4-bromophenyl)carbonyl]methyl-6-
cyanobenzimidazole or [(4-bromophenyl)carbonyl]methyl-5-
cyanobenzimidazole with a variety of boronic acids by using
Na2CO3 (2-4 equivalents) and Pd(PPh3)4 (5-10% mmol~1) as
catalyst in THF (80% in H2O, 10 mL/mmol), followed by Pinner
reactions.
A mixture of [(4-bromophenyl)carbonyl]methyl-6-
cyanobenzimidazole and [(4-bromophenyl)carbonyl]methyl-5-
cyanobenzimidazole was made in over 90% yield by alkylation of
5-cyano-benzimidazole (36 mmol) with 2, 4'-dibromoacetophenone
(36 mmol) by using NaH (48 mmol) as a base in THF (80 mL).
54
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The mixture were isolated by HPLC on chiralcel OJ column with
MeOH/CO2 (20/80) to give pure individual compounds.
[(4-Bromophenyl)carbonyl]methyl-6-cyanobenzimidazole: lH
NMR (CDCl3)~8.35 (s, lH), 8.11 (dd, J = 1.1 Hz, J = 0.7 Hz,
lH), 8.08 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.56
(dd, J = 8.4 Hz, J = 1.8 Hz, lH), 6.16 (s, lH); ESMS:
340/342 (M+H)+.
[(4-Bromophenyl)carbonyl]methyl-5-cyanobenzimidazole: lH
NMR (CDCl3)~8.31 (s, lH), 8.13 (t, J = 0.7 Hz, lH), 8.07 (d, J
= 8.8 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.75 (dd, J = 8.4
Hz, J = 0.7 Hz, lH), 7.57 (dd, J = 8.4 Hz, J = 1.1 Hz, lH),
6.15 (s, lH)i ESMS: 340/342 (M+H)+.
ExamDle 51
PreParation of [4-(Phenyl)phenylc~rhonyl]methyl-6
am; ~; n~h9n7i~; dazole
MP: 155-157~Ci lH NMR (CD30D)~8.44 (s, lH), 8.23 (d, J =
8.4 Hz, lH), 8.07 (d, J = 1.1 Hz, lH), 7.91 (d, J = 8.8 Hz,
lH), 7.88 (dd, J = 8.4, 2H), 7.72 (dd, J = 8.4 Hz, J = 1.1 Hz,
3H), 7.52-7.41 (m, 3H), 6.10 (s, 2H); MS: 355 (M+H)+, HRMS:
3S5.1554 (obs.), 355.1559 (calcd-)i Anal : (C22Hl8N4Ol +
0.9TFA + 1.2HCl + 0.5H20) C, H, N, F, Cl.
ExamDle 52
PreParation of [4-(DhenYl)~henYlcarbonyl]methyl-5
ami~;nohsn7imidazole
MP: 260-261~C; lH NMR (CD30D)~8.41 (s, lH), 8.22 (s,
lH), 8.20 (d, J = 8.8 Hz, 2H~, 7.87 (d, J = 8.4 Hz, 2H), 7.73-
7.70 (m, 4H), 7.51-7.41 (m, 3H), 6.10 (s, 2H); MS: 355.2
(M+H)+; HRMS: 355.1538 (obs.), 355.1559 (calcd.); Anal.:
(C22HlgN~Ol + 1.5TFA + 0.08HCl + lH2O) C, H, N, Cl.
Exa ~ le 53
preDaration of ~4-(3-aminoPhenYl)~henYlc~rho~yl]methyl-6-
am;~;nohenzimidazole
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WO98/01428 - PCT~S97/11325
H NMR (DMSO-d6)~9.22 (s, 1.5 H), 9.04 (s, 1.5 H), 8.48
~s, lH), 8.22 (d, J = 1.4 Hz, lH), 8.18 (d, J = 8.3 Hz, 2H),
7.91 (d, J = 8.5 Hz, lH), 7.84 (d, J = 8.5 Hz, 2H), 7.69 (dd,
J = 8.6 Hz, 1.7 Hz, lH), 7.21 (t, J = 1 8 Hz, lH), 7.04 (s,
lH), 7.00 (d, J = 8.4 Hz, lH), 6 73 (d, J = 8.1 Hz, lH), 6.14
(s, 2H); 13C NMR (DMso-d6) ~ 192-4, 165.9, 148.6, 147.6,
146.7, 146.2, 139.3, 134-3, 132-9, 129 7, 128.8, 126.8, 121.8,
121.3, 119.7, 115.6, 115.1, 113.0, 111.8, 51.0; MS: 370
(M+H)+; HRMS: 370.1664 (obs.), 370.1668 (calcd.)
ExamPle 54
PreParation of ~4-(3-am;noPh~nyl)~henylcarbonyl]methyl-5
ami~in~hsn 7 imidazole
lH NMR (CD30D)~8.48 (s, lH), 8.32 (d, J = 8.4 Hz, 2H),
7.87 (d, J = 845 Hz, 2H), 7.74 (s, 2H), 7.62-7.56 (m, 2H),
7.53 (d , J = 8.4 Hz, 2H), 7.25 (d, J = 7.4 Hz, lH), 6.12 (s,
2H); MS: 370 (M+H)+, HRMS: 370.1664 (obs.), 370.1668 (calcd.)
ExamDle 55
PreDaration of [4-(4-fluoroDhenyl)Dhenylcarbonyl]methyl-6
am;~;n~henzimidazole
MP: 102-105~C; lH NMR (CD30D) ~ 8.54 (bs, lH), 8.23 (d, J
= 8.8 Hz, 2H), 8.10 (bs, lH), 7.92 (bs, lH), 7.86 (d, J = 8.4
Hz, 2H); 19F NMR~-116.3, -77.65 (TFA); 13C NMR (CD30D) ~
192.9, 168.6, 165.0, 163.5, 147.2, 137.1, 134.3, 130.3, 130.2,
130.1, 128.5, 124.7, 123.4, 120.8, 117.1, 116.9, 112.9, 52.5;
MS: 373.2 [(M+H)+; HRMS: 373.1481 (obs.), 373.1465 (calcd.);
Anal.: (C22H17N4OlFl + l.9TFA + O.lHCl + 2H2o) C, H, N, F, Cl.
ExamDle 56
Pre~aration of [4-(4-formYlPhenyl)phenylcar-h~onyl]methyl-6
am;~;n~hsn7imidazole
MP: 125-128~C; lH NMR (CD30D) ~10.05 (s, lH), 8.48 (s,
lH), 8.27 (d, J = 8.4 Hz, lH), 8.07 (bs, lH), 8.05 (d, J = 8.4
Hz, 2H), 7.97 (d, J = 8.1 Hz, 2H), 7.95 (d, J = 8.1 Hz, 2H),
56
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- W0 98/01428
7.93 (d, J = 8.4 Hz , 2H), 7.73 (dd, J = 8.4 Hz, J = 1.8 Hz,
lH), 6.12 (s, 2H); 13C NMR (CD30D) ~192.99, 168.67, 147.86,
140.90, 140.15, 134.44, 130.10, 128.64, 128.57, 128.09,
124.63, 123.41, 120.75, 112.87, 104.26, 54.45i MS: 192.2
(M+2H)2+iHRMS: 383.1531 (obs.), 383.1508 (calcd.).
Exam~le 57
Pre~aration of [4-(2-
al in9~1l1 fonYlDhenY~ henylc~h~rtyl]methyl-6
am~A; nnh9n7imidazole
MP: 126-128~C; lH NMR (CD30D) ~ 8.55 (bs, lH), 8.18 (d,
J = 8.4 Hz, 2H), 8.13 (dd, J = 7.7 Hz, J = 1.4 Hz, lH), 8.09
(s, lH), 7.94 (d, J = 8.8 Hz, lH), 7.71 (dd, J = 8.4 Hz, J =
151.4 Hz, lH), 7.67 (d, J - 7.8 Hz, lH), 7.65 (d, J = 8.1 Hz,
2H), 7.60 (dd, J = 7.8 Hz, J = 1.4 Hz, lH), 7.36 (dd, J = 7.3
Hz, J = 1.4 Hz, lH), 6.13 (s, 2H); MS: 217.7 (M+2H)2+; HRMS:
434.1303 (obs.), 434.1287 (calcd.)
20ExamDle 58
PreDaration of ~4-(2-tert-
butYlaminosulfonYlDhenYl)~henYlC~rh~nYl]methYl-6-
a~n; A; n~he~n7imidazole
25MP: 118-120~C; lH NMR (CD30D) ~ 8.60 (bs, lH), 8.19 (d,
J = 8.4 Hz, 2H), 8.13 (dd, J = 7.7 Hz, J = 1.4 Hz, lH), 8.09
(s, lH), 7.95 (d, J = 8.8 Hz, lH), 7.76 (dd, J = 8.4 Hz, J =
1.4 Hz, lH), 7.67 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 7.7 Hz, J
= 1.5 Hz, lH), 7.60 (dd, J = 7.7 Hz, J = 1.4 Hz, lH), 7.34
(dd, J = 7.7 Hz, J = 1.4 Hz, lH), 6.14 (s, 2H), 1.09 (s, 9H)
3C NMR (CD30D) ~ 193.25, 168.78, 149.52, 147.86,
143.50,140.87, 134.76, 133.27, 133.07, 132.83, 131.58, 130.45,
129.77, 129.49, 128.76, 127.34, 124.45, 123.22, 120.99,
112.68, 55.30, 52.38, 30.22; Anal.: (c26H27N5o3sl + l.9TFA +
- 35 lH2O) C, H, N, F, S, Cl.
,
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ExamDle 59
Pre~aration of {4-~(2-tetrazolYl)Dhenyl]~henylcarbonyl}meth
6-am;~;n~h~n7lmldazole
MP: 144-145~Ci lH NMR (CD30D)~ 8.56 (bs, lH), 8.11-8.09
( m, 3H), 7.93 (d, J = 8.5 Hz, lH), 7.76 (dd, J = 8.5 Hz, J =
1.7 Hz, lH), 7.73 (d, J = 7.3 Hz, 2H), 7.67-7.62 (m, 2H), 7.38
(d, J = 8.8 Hz, 2H), 6.09 (s, 2H); 13C NMR (CD30D) ~ 192.97,
168.66, 156.91,149.40, 147.07, 146.51,142.32, 135.60, 134.66,
132.64, 131.79, 131.71, 130.90, 129.88, 129.47, 124.56,
123.43, 120.75, 112.87, 52.45i MS: 212.2 (M+2H)2+; HRMS:
423.1686 (obs.), 423.1682(calcd.)i Anal.: (c23HlgNgol+ 1.9TFA
+ 1 HCl +0.5H20) C, H, N, F, S, Cl.
Method B: Examples 60, 61 and 62 were made by alkylation
of 5-cyanobenzimidazole with ~4-(2-tert-
butylaminosulfonylphenyl)phenylaminocarbonyl]methylene
chloride, or (4-benzylpiperidinecarbonyl)methylene chloride,
followed by Pinner reactions.
Exam~les 60 and 61
PreDaration of r4-(2-
aminosulfonYl~henYl1Dhem~laminocarbonyl]methYl-6-
am;~;n~h~n7;m;~7ole (ExamDle 60) and ~4-(2-
aminosulfon~l~hen~l)DhenYlam;n~bonYl]methYl-5-
am;~;noh~n~;m; ~A701 e (Exam~le 61)
[4-(2-tert-Butylaminosulfonylphenyl)phenyl-
aminocarbonyl]methylene chloride was prepared by acylation of
4-[(o-SO2NHtBu)phenyl]aniline (3 mmol) with a-chloroacetyl
chloride (4 mmol) in CH3CN (100 mL) and K2CO3 (4 mmol).
Alkylation of 5-cyanobenzimidazole (2 mmol) with [4-(2-
tert-butylaminosulfonylphenyl)phenyl-aminocarbonyl]methylene
chloride (2 mmol) in DMF (10 mL) and K2CO3 (4 mmol) at r.t.
over 16 hours, followed by purification on thin layer TLC
plates, and further isolation by HPLC gave [4-(2-tert-
butylaminosulfonylphenyl)phenylaminocarbonyl]methyl-6-
cyanobenzimidazole (240 mg, 56%) and [4-(2-tert-
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WO98/01428 ~ PCT~S97/11325
butylaminosulfonylphenyl)phenylaminocarbonyl]methyl-5-
cyanobenzimidazole (160 mg, 37%).
[4-(2-tert-Butylaminosulfonylphenyl)phenyl-
aminocarbonyl]methyl-6-cYanobenzimidazole was converted to
Example 60 via ~he Pinner reaction and purified by HPLC: MP:
134-136~C; lH NMR (CD30D)~ 8.73 (bs, lH), 8.15 (s, lH), 8.10
(dd, J = 8.6 Hz, J = 1.2 Hz, lH), 7.93 (d, J = 8.3 Hz, lH),
7.75 (d, J = 7.4 Hz, lH), 7.64 (d, J = 8.4 Hz, 2H), 7.60 (dd,
J = 7.6 Hz, J = 1.2 Hz, lH), 7.52 (td, J = 7.6, J = 1.4 Hz,
lH), 7.40 (d, J = 8.8 Hz, 2H), 7.32 (dd, J = 7.6 Hz, J = 1.2
Hz, lH), 5.36 (s, 2H); 13C NMR (CD30D) ~168.79, 166.75,
143.05, 141.48, 138.93, 137.50, 133.63, 132.92, 131.28,
128.75, 128.59, 124.63, 123.35, 120.96, 120.53, 112.80, 47.51;
MS: 449.3 (M+H)+; HRMS: 449.1401 (obs.), 449.1396 (Calcd.);
Anal.: (C22H20N6o3sl+ 1.8TFA + 0.25 HCl +lH2O) C, H, N, F, S,
Cl.
[4-(2-tert-Butylaminosulfonylphenyl)phenyl-
aminocarbonyl]methyl-5-cyanobenzimidazole was converted to
Example 61 via the Pinner reaction and purified by HPLC: MP:
254~C (Dec.); lH NMR (CD30D) ~8.55 (s, lH), 8.22 (s, lH),
8.08 (d, J = 6.6 Hz, lH), 7.83-7.75 (m, 2H), 7.62 (d, J = 8.8,
2H), 7.59-7.52 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.31 (d, J =
7.4 Hz, lH), 5.33 (s, 2H); 13C NMR (DMSO-d6) ~165.73,
164.97, 147.72, 142.58, 142.19, 139.43, 138.17, 137.63,
135.23, 132.31, 131.35, 129.69, 127.39, 127.23, 122.20,
121.03, 120.96, 120.17, 118.21, 118.12, 111.24, 47.51; MS:
449.3 (M+H)+; HRMS: 449.1414 (obs.), 449.1396 (calcd.);
Anal.: (C22H20N6o3sl+ 2TFA + 0.15 HCl +l.5H2o) C, H, N, F, S,
Cl.
ExamPle 62
Pre~aration of 1-(4-benzYlDiPer;~;nec~ho~yl)methyl-6
am;~;n~h~n7Lmidazole and 1-(4-benzYl~iDer;~;ne~honyl)meth
5-a~;~;n~hAn7imidazole
(4-Benzylpiperidinecarbonyl)methylene chloride was
prepared by acylation of 4-benzylpiperidine (100 mmol) with a-
chloroacetyl chloride (100 mmol) in THF (250 mL) and K2CO3 (100
59
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mL. Alkylation of 5-cyanobenzimidazole (2 mmol) with (4-
benzylpiperidinecarbOnyl)methylene chloride (2 mmol) in DMF (5
mL) in the presence of NaH (3 I~unol) at from 0~C to room
temperature over 16 hours, followed by purification on TLC
5 plates gave 1-(4-benzylpiperidinecarbonyl)methyl-6-
cyanobenzimidazole and 1-(4-benzylpiperidinecarbonyl)methyl-5
cyanobenzimidazole (0.4 g, 56% of yield) This mixture (1.11
mmol) was then carried through the Pinner reaction, followed
by purification on TLC plates with 10% MeOH in CH2Cl2, and
10 further purification by HPLC to give the title compounds: MP:
54-56~C; MS: 376.4 (M+H)+; HRMS:376.2118 (obs.), 376.2137
(calcd.); Anal.: (c22H2sNsol+ 1.8TFA + 0.1 HCl).
Method C: Example 63 was made by Ulmann coupling
15 reaction of 4-chloro-3-nitrobenzenitrile with (4-
benzylpiperidinecarbonYl)methylamine~ followed by reduction of
4-[(4-benzylpiperidinecarbonyl)methylJamino-3-
nitrobenzonitrile, cyclization with formic acid, and finally
the Pinner reaction.
Exa~le 63
PreParation of 1-(4-benz~,rlPiDer;~;n~c~ nYl)methyl-6-
ami ~ i n-~hqn ~ imidazole
(4-BenzylpiperidineCarbonyl)methylamine was made by
treatment of (4-benzylpiperidinecarbonyl)methylene chloride
with NaN3 in aqueous acetone, followed by hydrogenation with 5%
Pd/C. Reaction of (4-benzylpiperidinecarbonyl)methylamine
(8.6 mmol) with 4-chloro-3-nitro-benzonitrile ~10 mmol) in DMF
(10 mL) in the presence of NaHCO3 (10 mmol) at 100~C for 16
hours gave 4-[(4-benzylpiperidinecarbonyl)methyl]amino-3-
nitrobenzonitrile (1.6 g, 49.2% of yield), which was then
hydrogenated in MeOH in the presence of 5% of Pd/C (10% w/w)
to produce 1-(4-benzylpiperidinecarbonyl)methyl-6-
cyanobenzimidazole (1.3 g, 90% of yield). 1-(4-
BenzylpiperidinecarbOnYl)methyl-6-cyanobenzimidazole (0.57
mmol) was then carried through the Pinner reaction, followed
by purification on TLC plates with 10% MeOH in CH2Cl2, and
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~ WO98/01428 - PCT~S97/11325
further purification by HPLC to give the title compound: mp:
68-70~Ci lH NMR (CD3OD)~ 8.52 (s, lH), 8.20 (s, lH), 7.75 (s,
2H), 7.29-7.24 (m, 2H), 7.18-7.16 (m, 3H), 5.43 (dd, J = 17.2
Hz, J = 24.5 Hz, 2H), 4.40 (d, J = 12.8 Hz, lH), 4.00 (d, J =
12.8 Hz, lH), 3.18 (t, J = 12.8 Hz, lH), 2.68 (t, J = 12.8 Hz,
lH), 2.59 (d, J = 7.00 Hz, 2H), 1-87-1 78 (m, 2H), 1.72-1.68
(m, lH, 1.42-1.35 (m, lH), 1-22-1-15 (m, lH); 13C NMR (CD30D)
168.76, 166.06, 148.73, 141.23, 139.50, 130.17, 129.45,
129.33, 127.35, 127.11, 124.04, 120.40, 113.19, 47.38, 46.36,
43.93, 43.73, 39.15, 33.35, 32.73i MS: 188.8 (M+2H)2+;
HRMS:376.2130 (obs.), 376.2137 (calcd ); Anal.: (C22H2sNsOl+
1.85TFA + 0.18HCl+ 0.5H20).
ExamDle 64
PreDaration of 2- r4- (2-
~;no~ulfonvlDhenYl)PhenYlcarbonyl]methyl-6
am; ~i nl~h~n7; i ~5~ 701e
N-ethylmalonyl-4'-amin~h;~l ~yl-2-tert-butyl~ulfonamide. To a
solution of 1.01 g of 4'-aminobiphenyl-2-tert-butylsulfonamide
in 30 mL anhydrous methylene chloride and 0.93 mL
triethylamine was added 0.43 mL of ethylmalonyl chloride by
dropwise addition. Let reaction mixture stir overnight at
ambient temperature. Concentrated in vaCuo to give a residue
which was taked up in 50mL ethyl acetate. The organics were
washed 3x20 mL water. The resulting organics were dried over
magnesium sulfate and concentrated under reduced pressure to
give the crude product. The crude product was purified via
st~n~rd chromatographic technique to give 0.70 g of N-
ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide.
LRMS(NH3-CI): 436(M+NH4). H NMR(CDC13, 300MHz): ~ 9.42 (s,
lH), 8.18 (d, lH), 7.79 ~d, 2H), 7.52 (m, 3H), 7.49 (d, lH),
7.30 (d, lH), 4.30 (q, 2H), 3.60 (s, lH), 3.50 (s, 2H), 1.35
(t, 3H), 1.0 (s, 9H).
2-~4-(2-aminosulfonylphenyl)phenylc~rhonyl]methyl-6-
cy~noben7im;~7ole. A mixture of 0.32 g of 3,4-
diaminobenzonitrile and 0.70 g of N-ethylmalonyl-4~-
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aminobiphenyl-2-tert-butylsulfonamide was heated to 180~C for
2Oh. Let mixture cool to ambient temperature. Concentration
and high vacuum gave 0.09 g of crude 2-[4-(2-
aminosulfonylphenyl)phenylcarbonyl]methyl-6-
cyanobenzimidazole. The crude material was carried through tothe next reaction sequence. LRMS(ES+): 431(M+H).
2-t4-(2-aminosulfonylPh~nyl)phenyl~Arhonyl~methyl-6-
am;~;n~h~n7imidazole. A solution of the crude 2-[4-(2-
aminosulfonylphenyl) phenylcarbonyl]methyl-6-
cyanobenzimidazole in 10 mL 1:1 anhydrous chloroform to
anhydrous ethanol was stirred in an ice bath. Hydrogen
choride gas was bubbled into the reaction vessel for 20
minutes. Then the reaction mixture was allowed to warm to
ambient temperature over l5h. Concentrated the reaction
mixture under reduced pressure and placed the crude product on
high vacuum. The resultant ethylimidate was treated directly
with 0.30 g of ammonium carbonate in anhydrous ethanol. The
reaction mixture was stirred at ambient temperature for 24h.
Concentrated reaction mixture under reduced pressure and
purified crude product via standard HPLC technique to give
purified 2-[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-
amidinobenzimid-azole. LRMS(ES+): 449(m+H). HRMS(FAB): calcd
449.139586 mass 449.139273. H NMR (DMSO,d6,300MHz~: ~ 10.50
(s, lH), 9.20 (bs, 2H), 8.67 (bs, 2H), 7.79 (d, 2H), 7.55 (m,
4H), 7.25 (m, 4H), 4.05 (s, 2H).
ExamDle 65
Pre~aration of 2-~4-(2-tert-
butYl_minoQulfonYl~hen~l)~henYlcA~h~Yl~methYl-5-
A 7:~h~n 7im:Ldazole
N-ethylmalonyl-4'-am; n~h~ ph~nyl - 2-tort-hutylsulf onA~; ~9 . To a
solution of 1.01 g of 4'-aminobiphenyl-2-tert-butylsùlfonamide
in 30 mL anhydrous THF and 0.93 mL of triethylamine was added
0.43 mL of ethylmalonyl chloride by dropwise addition. Let
reaction mixture stir for 24h. Concentrated in vacuo to give
a residue which was taked up in 50mL ethyl acetate. The
62
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organics were washed 3x20mL water. The resultant organics
were dried over magnesium sulfate and concentrated under
reduced pressure. The crude product was purified via standard
chromatographic technique to give 0.63g of N-ethylmalonyl-4/-
aminobiphenyl-2-tert-butylsulfonamide. LRMS(NH3-CI):
436(M+NH4). H NMR(CDC13, 300MHz): ~ 9.42 (s,lH), 8.18 (d,lH),
7.79 (d,2H), 7.52 (m,3H), 7.49 (d,lH), 7.30 (d,lH).
2-~4-(2-t~rt-butYlam; n~ l fonylphenyl)phenylc~h~nyl]methyl-5-
0 A~ h~n7Lmidazole. A mixture of 0.026 g of 3,4-diaminopyridine
and 0.10 g of N-ethylmalonyl-4~-aminobiphenyl-2-tert-
butylsulfonamide was heated to 165 C for 20h. Let mixture
cool to ambient temperature. Purified crude material by
standard chromatographic technique to give the 2-[4-(2-tert-
butylaminosulfonylphenyl)phenylcarbonyl]methyl-6-azabenzimid-
azole. LRMS(ES+): 464(M+H). HRMS(NH4-CI): Mass 464.175637
Calcd 464.175630. H NMR(CDC13,300MHz): ~ 9.49 (s,lH), 8.40
(s,lH), 8.15 (d,lH), 7.98 (s,lH), 7.47 (m,3H), 7.31 (d,2H),
7.25 (d,2H), 4.30 (s,2H), 1.0 (s,9H).
Exam~le 66
preDaration of 2S- [4- (2-tert-
am; n~ fonvlDhen~l)phenylam;n~c~he~l]methyl-thio-lH
i~idazo( 4, 5 -C ) PYridine
To a solution of lH-imidazo(4,5-C) pyridine-2-thiol (37
mg, 0.245 mmol) in DMF (2.5 mL) was added 4-(2-tert-
butylaminosulfonylphenyl)phenylaminocarbonyl]methyl chloride
(75 mg, 0.197 mmol) and then K2CO3 (58 mg, 0.42 mmol), and the
resulting mixture was heated at 120~C for 1 hour. To the
mixture at room temperature was added HCl (lN in Et2O, 1 mL)
and then MeOH (6 mL), a clear solution was obtained. To it
was then slowly added Et2O (200 ml), and a white suspension
was observed, which was filtered and a white solid (120 mg)
was collected. The solid was soluble in DMSO (8 mL), and the
resulting solution was purified by HPLC with H2O-CH3CN-TFA to
give the title compound (60 mg). HRMS (M+H)+ calc. m/z:
496.1477, obs: 496.1492.
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ExamDle 67
PreParation of 2S- [4- (2-
aminosulfonYlDhenYl)DhenYlaminOCarbOnvl]meth~ -thio-lH
5imidazo(4,5-C) DYridine
A solution of Example 66 (26 mg) in TFA (0.5 mL) was
heated for 16 hours. Removed all of the solvent and purified
by HPLC with H2o-cH3cN-TFA to give the title compound (13 mg).
HRMS (M+H)+ calc. m/z : 440.0851, obs : 440.0831.
ExamDle Pre~aration of 1-(4-benz~lPiDeri~inecA-bonyl)meth~l-5
amidinoindole
5-Cyanoindole-1-methylaCetate. To a stirred solution of 5-
cyanoindole (5.0 g, 35.2 mmol) in 10 mL of dry DMF at O C
under N2 atmosphere was added NaH (l.lg, 42.2mmol). The
reaction was stirred for 30 min. and then ~-bromomethyl-
acetate (5.4g, 35.2mmol) was added and stirred at roomtemperature for 2h. It was then quenched with H2O, extracted
with ethyl acetate ~3x), dried with Na2SO4, filtered and
concentrated in vacuo to afford a light yellow solid (7.5g,
35.2 mmol). lH NMR (CDC13) ~ppm 3.2 (s, 2H), 3.8 (s, 3H),
7.03 (s, lH), 7.32 (d, lH, J= 7.5Hz), 7.41 (d, lH, ~=7.5Hz),
7.61 (s, lH), 7.81 (s, lH). LRMS NH3-CI m/z (M+H)+ 229,
(M+NH4)+ 246.
3-(5-Cyanoindole) acetic acid. Methyl-5-cyanoindole-1-acetate
was saponified in MeOH, KOH (3.3eq) at rt for 18h. The
mixture was concentrated in vacuo, dissolved in water,
extracted with diethylether (2x) and the acidic aqueous layer
was acidified with 2N HCl. The resulting white solid was
filtered and dried in a vacuum oven to afford 6.2 g of the
title compound. LRMS ESI (M+H)+ 201.
1-(4-Benzylpiper;~; n9rA ~bonyl)methyl-5-cyano; nAol e. To a
stirred complex of 3-acetic acid-5-cyanoindole (2.0g,
64
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~ WO98/01428 - PCT~S9711132
0.1mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (DEC) in dry CH2cl2 was added 4-benzylpiperidine
(1.8g, 0.01mmol). The mixture was stirred under N2 atmosphere
for 18h, then concentrated in vacuo, dissolved in ethyl
acetate, washed with lN HCl (3x), NaHCO3 (3x), brine (2x),
dried with Na2SO4, filtered and concentrated in vacuo to
afford a white solid (2.8g). HRMS for C23H24N3o (M+H)+ calc.
358.191938, found 358.193278.
1-(4-Benzylpiper;~;n9cA~ho~yl)methyl-5-amidinoindole. N-l-
Acetyl-l-N'-PiPeridinYl-4-benZyl-5-cyanoindole (500mg), was
dissolved in dry MeOH (30 mL) cooled to O C and saturated with
HCl(g). The resulting solution was allowed to warm up to rt
over 18h. The mixture was concentrated in vacuo, re-dissolved
in dry MeOH and (NH4)2co3 (672.0 mg) was added, flask sealed
and stirred for 18 at rt. The resulting suspension was
filtered through Celite~, rinsed with dry MeOH, concentrated
in vacuo to afford 997mg of product (89~ by HPLC); 100 mg of
which was further purified via prep HPLC to afford 29 mg (100%
purity by HPLC). M.p. 214-21S C HRMS (NH3-CI) for C23H26N40
(M+H)+ calc. 375.217601, found 375.218487. lH NMR (CD30D) ~
ppm 1.05 (qd, lH, J= 7.5 Hz, J= 2.5 Hz), 1.25 (qd, lH, J=7.5,
J=2.5 Hz), 1.65 (bd, lH, J=7.5 Hz), 1.76 (bd, lH, J=7.5 Hz),
1.83 (m, lH), 2.58 (d, 2H, J=6.0 Hz0, 2.63 (t, lH, J= 75 Hz),
3.07 (t, lH, J=7.5 Hz), 4.03 (bd, lH, J=7.5 Hz), 4.2 (bd, lH,
J=7.5 Hz), 5.21 (qd, 2H, J= 7.5 Hz), 6.63 (s, lH), 7.18 (m,
3H), 7.23 (m, 2H), 7.38 (s, lH), 7.51 (d, lH, J= 5.0 Hz), 7.58
(d, lH, J=5.0 Hz), 8.05 (s, lH).
ExamDle 102
PreParation of 1-(4-benzYl~i~er;~; ne~A~ho~l )eth~1-5-
amidinoindole
Methyl-5-cyAnn;n~ole-3-ProPionate. To a stirred solution of
5-cyanoindole (1.0g, 7.Ommol), K2CO3 (0.966 g, 7.Ommol) in
acetonitrile was added 3-bromomethylpropionate (1.17 g,
7.Ommol). The mixture was stirred at reflux for 18h under a
nitrogen atmosphere, cooled, diluted with H2O, extracted with
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ethyl acetate, dried with Na2so4~ filtered and concentrated in
vacuo to afford 1.59 g of product. lH NMR (CD30D) ~ppm 2.85
(t, 2H, J= 6.6 Hz), 3.61 (s, 3H), 4.58 (t, 2H, J= 6.6 Hz),
6.61 (s, lH), 7.42, (m, 3H), 7-62 (d, lH, J= 8.4 Hz), 7.99 (s,
lH).
5-cYanoinaole-3-propionic acid. Methy-5-cyanoindole-3-
propionate (200 mg) was saponified in MeOH (lOmL)/KOH (150 mg,
0.88mmol) at rt for 18h. The solution was concentrated in
vacuo, dissolved in water and washed with chloroform. The
acidic layer was acidified and extracted with ethyl acetate,
dried with Na2so4~ filtered and concentrated in vacuo to
afford 188 mg of product. lH NMR (CD30D) ~ppm 2.83 (t, 2H,
J=6.6Hz), 4.43 (t, 2H, J=6.6 Hz), 6.6 (nd,lH, J3.2 Hz), 7.42
(d, 2H, J= 7.3 Hz), 7.43 (s, lH), 7.61 (d, lH, J=7.3 Hz), 7.99
(s, lH); LRMS ESI (M+H)+ 215.
1-(4-Benzylpiperi~; n9C~ ~hQnyl )ethyl-5-~;dinoindole.
Preparation follows the same last two steps of example 101.
Afforded 156 mg of the TFA salt lH NMR (DMSO-d6) ~ppm 2.42
(m, 4H), 2.89 (m, 4H), 3.21 (d, 2H, J= 5.0 Hz), 3.72 (bd, lH,
J=10.0 Hz), 4.12 (m,lH), 4.38 (bd, lH, J= 10 Hz), 4.51 (m,
2H), 6.62 ~s, lH), 7.1-7.31 (m, 5H), 7.62 (m,2H), 7.72 (d, lH,
J=6.0 Hz), 8.21 (bs, lH); HRMS (M+H)+ for C24H2gN40 calc.
389.234137, found 389.231258.
Exam~le 103
Pre~aration of 1-(4-(3-fluoro)benzYlDi~er;~;n~c~bonYl)methyl-
5-amidinoindole
4-(3-F1UG o~e"zyl)piperidine. To a stirred solution of 1-
benzylpiperidin-4-one (O.99mL, 5.34mmol) in THF was added
Ph3P=CH-(3-fluoro)phenyl (2.4lg, 5.34mmol) at O C under a
nitrogen atmosphere. After stirring for 4h at rt, the
reaction was quenched with H20, concentrated in vacuo and the
residue was chromatographed on silica gel using 1:1
hexanes:ethyl acetate as the eluant to afford 313mg of
product. LRMS NH3-CI (M+H)+ 282. The product (330 mg) was
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hydrogenated in MeOH, 10% Pd/C (300mg) and conc. HCl (5mL) in
a parr shaker at 50psi for 18h. The reaction was filtered
through Celite~ and the filtrate was concentrated in vacuo to
afford 250 mg of the title compound. LRMS NH3-CI (M+H)+ 194.
1-(4-(3-Fluoro)benzyl~ep;~;~;n~hQnyl)methyl-5-cyanoindole.
Prepared as in example 101. LRMS ESI (M+H)+ 376.
1-(4-(3-Fluoro)benzylpepirill;nocA~hQnyl)methyl-5-
a~;~; n~ n~l e. Example 103 was prepared via the same method
as example 101. HRMS FAB glycerol matrix for C23H26N4FO
(M+H)+ calc. 393.209065, found 393.208858.
Exam~le 104
Pre~aration of 1-(1-(4-a~;~;n~)benzYl-N-
(methYlacetate)a~in~c~r~onyl)methyl-5-amidinoindole
(4-Cyano)benzyl-N-(methylacetate)amine. ~-Bromo-tolunitrile
(2.0g, 10.5mmol) was dissolved in CHC13 and glycine methyl
ester (2.64g, 21.0mmol) and triethyl amine (2.92mL, 10.5mmol)
was added. The mixture was stirred for 18h under nitrogen
atmosphere, concentrated in vacuo and purified via silica gel
column using 1:1 hexanes:ethyl acetate as the eluant to afford
1.07g of the title compound (5.25mmol). LRMS ESI (M+H)+ 205.
lH NMR (C~Cl3) ~ppm 3.42 (s, 2H), 3.78 (s, 3H), 3.91 (s, 2H),
7.42 (d, 2H, J=8.0 Hz), 7.62 (d, 2H, J=8.0 Hz).
1-(l-(4-cyano)benzyl-N-(methylacetate)am;no~a~hQ~yl)methyl-5
cyAno;n~sle. Compound was prepared using the same coupling
procedure as in example 101. HRMS NH3-CI for C23H20N4o3
(M+H)+ calc. 401.161366, found 401.159527.
1-(l-(4-Amidino)benzyl-N-(methylacetate)am;no~A~bonyl)meth
5-amidinoindole. Prepared by the same Pinner conditions as
example 101. LRMS ESI (M+2H)+2 218.
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WO98/01428 - PCT~S97/11325
ExamDle 105
Pre~aration of Methvl 1-(4-benzYl~iDeridino-~-carbonyl)meth~
5-a~;~;noindole-3-~ro~anoate
Methyl 1-(4-~enzylpiperidine-1-C~hQ~yl)methyl-5-cyanoindole-
3-prspAn~te. 1-( 4-Benzylpiperidine-1-carbonyl)-5-cyanoindole
(l.Og, 2.8mmol) was dissolved in 2OmL of dry CH2cl2~ cooled to
O C and oxalyl chloride (1.07g, 8.4 mmol) was added. The
reaction stirred for 3h at rt- It was then concentrated in
vacuo and dissolved in dry MeOH (20mL) and stirred for 18h.
The resulting yellow solution was concentrated in vacuo and
l.Og (2.3mmol) was taken up in TFA (20mL) at O C and
triethylsilane (535 mg, 4.6mmol) was slowly added. The
reaction stirred at O C for 3h and then it was concentrated in
vacuo, dissolved in CH2cl2 and washed with sat. NaHC03, dried
with sodium sulfate, filtered and concentrated. The resulting
residue was chromatographed via silica gel using 7% MeOH/CHCl3
as the eluant to afford 840 mg of the title compound. LRMS ESI
(M+H)+ 430.
1-(4-Benzylpiperidine-1-~A ~hQnyl)methyl-3-methylacetate-5-
A~; dinoindole. The amidine was prepared as in example 101.
HRMS NH3-CI for C26H34N4o3 (M+H)+ calc. 447.239616, found
447.241907.
Exam~le 106
Pre~aration of 1-((4-benzvl~i~er;~ine~arbonYl)meth~1-(3-
ethAnel-Y~o~1)-5-amidinoindole
1-(~-Benzylpiperidine-l-cA~ho~yl)methyl-3-e~h~n~hydroxyl-5-
cy~ne~n~ole. Methyl 1-acetyl-(4-benzylpiperidin-1-yl)-3-
acetate-5-cyanoindole (lOOmg, 0.233 mmol) was dissolved in
ethanol and sodium borohydride (20mg, 0.51mmol) was added and
the solution stirred at rt for 18h. The reaction was
concentrated in vacuo diluted with water and extracted with
methylene chloride (3x), dried over sodium sulfate, filtered
and concentrated in vacuo to afford 93.0 mg of the title
compound. LRMS DCI-NH3 (M+NH4)+ 419.
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~ WO98/01428 PCT~S97/11325
1-(4-Benzylpiperidine-l-r~ho~yl)methyl-3-e~h~n~hydroxyl_5_
ami~inoindole. The amidine was prepared as in example 101.
HRMS NH3-CI for C25H3lN4o2 (M+H)+ calc. 419.244702, found
419.245383.
Exam~le 107
PreDaratiOn of 1-(4-benzYl~iDeridine-1-c~honyl)methyl-3-
methY~ hnYYlic acid-5-amidinoindole
Methyl 1-acetyl-(4-benzylpiperidin-1-yl)-3-acetate-5-
amidinoindole was hydrolyzed in TFA/H2O for 18h. Purified via
prep HPLC to afford the title compound. LRMS (M+H)+ 433.
ExamPle 108
PreParation of 1-~1-8enzYl~iDeridine-4-r ino~rbonYl)meth~1-5-
amidinoindole
1-(l-Benzylpiperidine-g-am;noç~bonyl)methyl-5-cyanoindole.
To a stirred complex of N-1-methylenecarbohydroxy-5-
cyanoindole (300mg, 1.5mmol) and DEC was added 4-amino-1
benzylpiperidine and triethylamine (0.209 mL, 1.5mmol). The
reaction was stirred at rt for 18h. The volatiles were
removed in vacuo and the residue was purified via silica gel
using 1%MeOH/CH2C12 as the eluant to afford 160 mg of product.
HRMS NH3-CI for C23H24N4o (M+H) + calc 373.204.204739, found
373.202837.
l-(l-Benzylpiperidine-4-am;nnrA~hnnYl)methYl-5-amidinoindole.
The amidine was prepared as in example 101 to afford 96mg of
the title compound. HRMS NH3-CI calc. 390.229386, found
390.229386.
ExamDle 109
PreParation of 1-(4-benzoYlDiDer;~;ne~arbonyl)methyl-5
amidinoindole
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1-(4-Benzoylpiper;~in0~A~ho~yl)methyl-5-cyanoindole. Prepared
as in example 108 except using 4-benzoylpiperidine. HRMS NH3-
CI ~M+H)+ for C23H2lN3o2 calc.372.171702, found 372.171620.
1-(4-Benzoylpiper;~;ne~A~bonyl)methyl-5-~mi~;no;n~QlQ, The
amidine was prepared using the same method as in example 101.
HRMS ~M+H)+ for C23H24N4o3 calc. 389-197751, found 389.198109.
Exam~le 110
Pre~aration of 1-(4-(3-fluoro)benzyl~i~erA7;
5-A~;dinoindole
1-(4-(3-Fluoro)benzylPiPerA 7; necA ~ho~yl )methyl-5-cyanoindole.
To a stirred solution of l-acetyl-(l-piperazine)-5-cyanoindole
(400mg, 1.31mmol), triethylamine (0Ø36 mL, 2.62mmol) in
diethyl ether was added 3-fluorobenzyl bromide (0.161 mL, 1.31
mmol) and stirred at room temperature under N2 atmosphere for
18h. The reaction quenced with water, extracted with ethyl
acetate, dried with sodium sulfate, filtered and concentrated
in vacuo to afford 438mg product. LRMS ~M+H)+ 377.
l-(4-(3-Fluoro)benzylpiperA7;ne~A-honyl)methyl-5-
amidinoindole. Prepared as in example 101. HRMS (M+H)+ for
C22H24NsOF calc. 394.204314, found 394.204917.
ExamDle 111
Pre~aration of 1-(4-~henYlbenzYlam;ne~hQ~Yl)meth~l-5
am; ~; n-~; n~ole
1-~-Phenylbenzylam;no~A~hQ~yl)methyl-5-cyAnoindole. To a
stirred complex of l-acetic acid 5-cyanoindole (250mg,
1.25mmol) and DEC (239mg,1.25mmol) in methylene chloride was
added 4-phenybenzylamine (228mg,1.25mmol). After stirring at
rt for 18h under a nitrogen atmosphere, the reaction was
concentrated in vacuo, dissolved in ethyl acetate, washed with
lN HCl, sodium bicarbonate, and brine, dried with sodium
sulfate, filtered and concentrated in vacuo to afford 215mg of
product. HRMS (M+H)+ calc. 366.260637, found 366.160323.
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1-(4-Phenylbenzyl_m;nO~A~honYl)methyl-5-amidinoindole.
Prepared as in example 101- HRMS calc. 383.187187 found
383.189667.
ExamDle 112
Pre~artion of methYl 1-(4-benzvl~i~eri~; neCA rho~yl ) methYl-5-
a~;~;noindole-3-~L~v6,,oate
Methyl 1-(4-benzylpiper;~;necArh~nyl)methyl-5-cyanoindole-3-
prop~noAte. To a stirred solution of DMF (15mL) and POCl3
(256mg 1 7mmol) at O C was added 1-(4-benzylpiperidine-
carbonyl)methyl-5-cyanoindole (199mg, 0.56mmol). After
stirring 3h, the reaction was quenched with 2N sodium
hydroxide and stirred for 30 min. It was then extracted with
chloroform, dried with sodium sulfate, filtered and
concentrated in vacuo to afford product. LRMS (M+H)+ 386. The
product was then refluxed in the presence of triphenyl
phosphonium~methylenecarbomethoxy)ylide in THF under a
nitrogen atmosphere for 18h. The reaction was concentrated in
vacuo and the residue purified via silica gel chromatography
using 7% MeOH/CHCl3 as the eluant to afford 140mg of product.
Methyl 1-(4-benzylpiper;~;nec~rbonYl)methyl-5-amidinoindole-3-
~ v~ oAte. Prepared as in example 101. LRMS (M+H)+ 459.
ExamDle 113
Pre~aration of 1-(4-(2-fluoro)benzYl~i~er;~nec~honYl)meth
5-Amidinoindole
4-(2-Fluoro)benzylpiperidine. To a stirred solution of
triphenylphosphonium-2-fluorobenzylbromide in dry THF at -78 C
was added n-buLi (2.5M, 2.13mL) and stirred for 30 min. To it
was then added 1-benzyl-4-piperidinene (0.99mL) and the
mixture stirred at rt for 4h- The reaction was quenched with
water and concentrated in vacuo. The resulting residue was
purified via silica gel chromatrography using 1:1
hexanes:ethyl acetate as the eluant to afford 313mg. LRMS
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(M+~)+ 282. The product was hydrogenated in a parr shaker at
50psi in MeOH (lOmL), 5-OmL conc. HCl and 10%Pd/C (300mg~ for
18h. The mixture was filterd through celite~ and concentrated
in vacuo to afford 250mg of product. LRMS (M+H)+ 194.
1-(4-(2-Fluoro)benzylpiper;~i~er~bonyl)methyl-5
Prepared by coupling 3-acetic acid-5-cyanoindole with 4-(2-
fluoro)benzylpiperidine using the method described in example
101. LRMS ~M+H)+ 376.
1-(4-(2-Fluoro)benzylpiper;~;nec~bonyl)methyl-5-
a~;~ooindole. Prepared as in example 101. HRMS (M+H)+
calc. 393.209065, found 393.208858.
ExamDle 201
Pre~aration of 3-((g-
cYclohexvl)~henYlaminomethY1carbOnyl)methyl-5-amidinoindole
Methyl 5-cy~n~;n~ole-3-acetate. To a stirred solution of 5-
cyanoindole (10.0g) in dry methylene chloride was added
(3.0eq, 61.43mL) of oxalyl chloride. After stirring for lh
under a nitrogen atmosphere at rt, the resulting precipitate
was filtered and rinsed with diethyl ether. The solids were
then taken up in dry MeOH and stirred for lh. At this time
the solids were filtered and rinsed with MeOH and diethyl
ether to afford 5.93g of methyl a-ketoacetate 5-cyanoindole.
LRMS (M+H)+ 229. Methyl a-ketoacetate (4.90g) was dissolved
in 50 mL trifluoro acetic acid at O~C and triethyl silane
(5.0g) was slowly added via a drop funnel (20 min.) . It was
then stirred at O~C for 3h. The resulting yellow solution was
concentrated in vacuo, neutralized with sodium bicarbonate,
extracted with diethyl acetate, dried with magnesium sulfate
filtered and concentrated in vacuo. Purification was
accomplished via silica gel chromatography using 1%
MeOH/CH2C12 as the eluant to afford 2.48g of product. LRMS
(M+H)+ 232.
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3-(5-Cy~no~n~o1e) acetic acid. The above ester was saponified
in KOH/MeOH at rt for 18h. The solution 3 was then
concentrated in vacuo, dissolved in water, extracted with
ethylacetate and the acidic layer was then acidified with lN
HCl at O~C. The resulting white solids were filtered and
further dried under high vacuum to afford the product. M.p.
196.5-198.5; Calc. C66.00 H4.04 N13.99, found C65.71 H4.24
N13.94. lH NMR (CD30D) ~ ppm 3-78 (s, 2H), 7.28 (s, lH), 7.38
(d, lH, J= 8.6 Hz), 7.45 (d, lH, J= 8.6 Hz), 7.89 (s, lH);
LRMS (M+)~ 199.
3-(4-CyclohexylphenYlaminomethYlCarbOnyl)methyl-5-cy~noin~Qle.
To a stirred complex of the 5-cyanoindole acetic acid (312mg,
1.5mmol) and BOP reagent (1.03g) in DMF was added 4-
cyclohexylphenylaminomethyl. After heating at 50 C under anitrogen atmosphere for 18h, the reaction was cooled to rt
diluted with water and extracted with ethyl acetate, washed
with lN HCl, sat. sodium bicarbonate, and brine, dried with
sodium sulfate, filtered and concentrated in vacuo. The
residue was purified via chromatography using 100% ethyl
acetate as the eluant to afford 210mg of product. LRMS (M+H)+
372.
3-((4-Cyclohexyl)phenYlaminomethylcarbonyl)methyl-5-
amidinoindole. Prepared as in example 101. HRMS (M+H)+ for
C24H2gN4O calc. 389.234137, found 389.232086.
ExamDle 202
PreDaration of 3-(4-D-toluenesulfonyl-
Di~er~7;~ec~rho~Yl)meth~1-5-am;~;nQindole
3-(4-Paratol~e~c~lfonylpiper~ 7; n9C~ ~ho~yl )methyl-5-
cyanoindole. To a stirred solution of 3-
(piperazinecarbonyl)methyl-5-cyanoindole hydrochloride (20Omg,
0.66mmol) and triethylamine (134mg, 185~L) in chloroform was
added toluenesulfonylchloride (126mg, 0.66mmol). After
stirring for 18h at rt under a nitrogen atmosphere, the
reaction was quenched with water, extracted with chloroform,
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washed with lN HCl, sat sodium bicarbonate, and brine, dried
with sodium sulfate, filtered and concentrated in vacuo to
afford 237mg of product. LRMS (M+H)+ 423.
3-(4-Paratol~sna~llfOnylpip~7;n9C~h~nyl)methyl-5-
amidinoindole. Prepared as in example 101. HRMS (M+H)+ for
C22H26N503S, calc. 440.174611, found 440.175637.
Exam~le 203
Pre~aration of 3-(4-(2-aminosulfonvlDhenYl)~yridine-2-
am;nocA~bonYl~methYl-5-amidinoindole
3-(4-(2-Aminosulfonylphenyl)pyridine-2-am;no~rhonyl)methyl-5-
cyanoindole. To a stirred solution of 5-cyano-3-acetic acid
15indole (400mg, 2.0mmol), BOP (884mg, 3.0mmol) in DMF (15mL)
was added 4-(2-aminosulfonyl)phenyl-2-aminopyridine (912mg,
3.0mmol) and heated at 50 C for 3h. The reaction was diluted
with water, extracted with ethyl acetate, washed with 10% HCl,
sodium bicarbonate, brine, and water, dried with magnesium
sulfate, filtered and concentrated in vacuo to afford 420mg of
product. LRMS 488. The t-butyl group was removed in TFA
reflux for lh and the product purified via silica gel using
100% ethyl acetate as the eluant to afford 101 mg of product.
LRMS 432.
3-(4-(2-Aminosulfonylphenyl)pyridine-2-aminocar~onyl)methyl-5-
~dinoindole. Prepared as in example 101. HRMS (M+H)+ for
C22H22NsO3S calc. 449.139586, found 449.139058.
30ExamDle 204
PreParation of 3-(4-~2-
tetrazole]~henYl)~henvlam;nec~ho~Yl)methYl-5-amidinoindole
3-(4-~2-Tetrazole]phenyl)phenylam;noc~honyl)methyl-5-
cyanoindole. 5-cyanoindole-3-acetic acid was dissolved in
DMF/CH2C12, DEC (382mg), and DMAP (lOmg) and the reaction
mixture stirred for 15 min. 4-((2-Tetrazole)phenyl)aniline
was added and the reactin mixture stirred for 2h. The
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reaction was concentra~ed in vacuo, dissolved in ethylacetate
and washed with water and brine, dried with magnesium sulfate,
filtered and concentrated in vacuo. Purification was done via
silical gel using 1:1 hexanes:ethylacetate to afford 660mg of
product. The trityl group was cleaved in THF (30mL) and 4M
HCl dioxane (0.988mL) at rt for 18h. It was then basified
with NaOH to pH 11, washed with ether, acidified to pH 3 with
10% HCl and the precipitate was collected and dried under high
vacuum to afford 250mg of product. LRMS (M+H)+ 420.
3-~4-[2-Tetrazole]phenyl)phenylam;noc~hsnyl)methyl-5-
amidinoindole. Prepared as in example 101. HRMS for
C23H20N8o (M+H)+ calc. 437.183833, ~ound 437.186710.
15ExamDle 205
PreDaration of 3-(4-biDhenYlam;n~c~bonyl)methyl-5-
am; ~ i nn; n~ole
The title compound was prepared as in example 101. HRMS
20(M+H)+ for C23H20N4o calc. 369.172173, found 369.171537.
ExamDle 206
PreDaration of 3-(4-
(PhenYlmethYlsulfonYl~DiPeraZ;nscA~bonyl)methYl-5-
25amidinoindole
The title compound was prepared as in example 101. HRMS
(M+H)+ C22H2sNsO3S calc. 440.176204, found 440.175637.
30ExamDle 207
Pre~aration of 3-(4-cYclohexYlDhenYlam;n~c~bonyl)methyl-5
amidinoindole
The title compound was prepared as in example 101. HRMS
35(M+H)+ C23H26N4O calc. 375.218732. found 375.218487.
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Exam~le 208
Pre~aration of 3-(4-benzYlDi~eraz;ne~A~bonyl)methyl-5-
amidinoindole
The title compound was prepared as in example 101. HRMS
(M+H~+ for C22H25N5o calc. 376-213722, found 376.213736.
Exam~le 209
Pre~aration of 3-(3-
10a~;~;nohen7ylp~;no(methylcarbonylmethoxy)carbonyl)methyl-5
am; dinoindole
The title compound was prepared as in example 101. HRMS cal.
435.214464, found 435.216822.
ExamDle 210
Pre~aration of l-methYl-3-(4-
ami~inob~n7Ylamino(methylcarbonylmethoxy)carbonyl)methyl-5
~;dinoindole
The title compound was prepared as in example 101. HRMS
calc.435.214464, found 435.213247.
ExamDle 211
25Pre~aration of 1-methYl-3-(4-~2-
aminosulfonYl]~henYlbenzYlamin~c~bonyl)methyl-5-ami~;nQindole
The title compound was prepared as in example 201. LRMS 476,
m.p. 231-C.
ExamDle 212
Pre~aration of l-methYl-3-(4-~henYlbenzylam;no~ho~yl)meth
5-amidinoindole
The title compound was prepared as in example 201. HRMS calc.
397.202837, found 397.204520.
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ExamPle 213
PreDaration of 1-methYl-3-(4-PhenYlPiperazinec~honyl)meth
5- d dinoindole
The title compound was prepared as in example 201. HRMS calc.
389.234137, found 389.234635.
ExamDle 214
PreParation of 3-(4-12-
aminosulfonyl)DhenylDhenylam; noc~ ~bonyl)methyl-5-amidinoindole
The title compound was prepared as in example 203. HRMS
calc.448.144337 found 448.143656.
15Exam~le 215
PreDaration of 3-(1-benzYlPiPeridine-4-aminoc~bonyl)methyl-5-
amidinoindole
The title compound was prepared as in example 201. HRMS calc.
20390.229386, found 390.230305.
ExamDle 216
PreParation of 3-(4-DhenYlPiPeraz; n~ho~Yl )methYl-5-
~m; dinoindole
The title compound was prepared as in example 201. HRMS calc.
362.198086, found 362.197315.
ExamPle 217
30PreParation of 3-(4-benzYlDiPer;~;nec~ho~Yl)methyl-5
amidinoindole
The title compound was prepared as in example 201. HRMS calc.
374.210662 found 374.210386.
ExamDle 2 18
PreParation of 1-methYl-3-(5-(2-aminosulfonYl)~henylpyridine-
2-aminocs~bonYl)methYl-5-amidinoindole
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The title compound was prepared as in example 201. HRMS calc.
463.155236, found 463.155236.
Exam~le 219
Preparation of 3-{2-bromo-4-(2-
~m; nogulfonyl)phenylphenylam;no~Arbonyl~methyl-5-cyanoindole
A solution of 3-{2-bromo-4-(2-
10 aminosulfonyl)phenylphenylaminocarbonYl)methyl-5-cyanoindoline
(1.2378 mmol, 0.7 g) in anhydrous methyl acetate (15 mL) and
anhydrous methanol (0.5 mL, 10.0 eq) was saturated with dry
hydrogen chloride gas at -20 C for 20 min. The reaction
mixture was stoppered tightly and left at ambient temperature
for 18 h. This reaction mixture was evaporated and pumped on
for several hours to remove any residual HCl. To this imidate
in anhydrous methanol (15 mL) was added ammonium carbonate
(1.189 g, 10.0 e~.). This reaction mixture was allowed to
stir at ambient temperature for 24 h. This final reaction
mixture was evaporated and purified by HPLC on a C-18 column
eluted with solvent mixture A (water:TFA 99.95:0.05) and
solvent mixture B (acetonitrile:TFA 99.95:0.05) using a
gradient starting with A at 80 % and changing to B at 100 %
over 60 min. After lyophylization, 0.122 g of pure product
(15%) was obtained; HRMS (M+H) calc. 526.054848, found
526.053791 for o-Br compound.
ExamDle 220
Preparation of 3-~2-methyl-4-(2-
~;nosulfonyl)phenylphenylam;nocArh~nyl)methyl-5-methylamino
indole
To the solution of 3-{2-methyl-4-(2-
aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyano indole
(0.5992 mmol, 0.3 g) in absolute ethanol:TFA 4:6 was added
palladium hydroxide on carbon (0.06 g, 20 % weight equivalent
of starting material used). This reaction mixture was stirred
under house ~acuum for 10 minutes at ambient temperature to
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remove oxygen. Then subjected to 1 atm H2 via balloon method
for 3 h. The reaction mixture was filtered through celite to
remove catalyst and washed with ethanol (20 mL). The filtrate
was evaporated to give the desired product with t-butyl
sulfonamide. This product was treated with trifluoroacetic
acid at 55~C for 2 h for deprotection of sulfonamide. The
reaction mixture was evaporated and purified by HPLC on a C-18
column eluted with solvent mixture A (water:TFA 99.95:0.05)
and solvent mixture B (acetonitrile:TFA 99.95:0.05) using a
gradient starting with A at 80 % and changing to B at 100 %
over 60 min. to give 10.0 mg of pure product (3 %, poor yield
due to poor solubility); HRMS ~M+H) calc. 449.164738, found
449.165207.
ExamPle 221
Preparation of 3-{2-fluoro-4-(2-
aminosulfonyl)phenYlphenylam;norA~bonyl)methyl-5-~;dinoindole
The titled compound was prepared as in Example 203. HRMS
(NH3-CI/DEP) (M+H)+ for C23H2lNsso3F calculated 466.134915;
found 466.133832.
Exam~le 222
Preparation of 3-{2-chloro-4-(2-
aminosulfonyl)phenylPhenylam;nocA~bonyl)methyl-5-cyanoindole
The titled compound was prepared as in Example 203. HRMS for
C2sH21NsSO3Cl (M+H)+ calc. 482.105364; found 482.103835.
ExamDle 223
Preparation of 3-{2-iodo-4-(2-
aminosulfonyl)phenylphenYlam;nocA~bonyl)methyl-5-cy-noindole
The titled compound was prepared as in Example 203. HRMS for
C23H21INsO3S (M+H)+ calc. 574.040989; found 574.042800.
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Examole 224
Preparation of 3-{2-methyl-4-~2-
ar-; no~-l 1 fonyl)phenylphenYlam;~o~bonyl)methyl-5-amidinoindole
The titled compound was prepared as in Examp~e 203. HRMS for
C24H24NsO3S (M+H)+ calc. 462.159987; found 462.158553.
Exam~le 225
Preparation of 3-{2-methyl-4-(2-(t-
10butylaminosulfonYl))phenylphenylam;n~c~honyl)methyl-5
amidinoindole
The titled compound was prepared as in Example 203. HRMS for
C2gH32NsO3S ~M+H)+ calc.518.222587; found 518.221998.
Exam~le 226
Preparation of 3-{4-(2-
Am;nosulfonyl)phenyl)phenylam;n~r~-honylmeth
(methylc~hQYy methyl ether)-5-amidinoindole
The titled compound (racemic) was prepared as in Example 203.
HRMS for C26H2sNsOsS (M+H)+ calc 520.166599; found 520.165466.
ExamDle 227
25Preparation of 3-{4-(2-
aminosulfonyl)phenyl)phenylaminocarbonYlmethyl-a-(benzyl)
am;~;n~;nAole
The titled compound (racemic) was prepared as in Example 203.
30HRMS for C3oH29N5o3s ~M+H) + calc. 538.191287; found 538.191263.
Exam~le 228
Preparation of 3-~4-(2-trifluoromethyl)phenyl)pyrid-2-
ylar;nnc~honylmethyl-5-P~;dinoindole
The titled compound was prepared as in Example 203. HRMS for
C23H20N5olF3 (M+H)+ 438.154170; found 438.152166.
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ExamDle 229
Preparation of 3-{4-(2-
ethylaminosulfonYl)phenyl)phenylamin~c~honylmethyl-5
amidinoindole
The tltled compound was prepared as in Example 203. HRMS for
C26H27NsO3S1 (M+H)+ calc. 476.175637; found 476.175892.
ExamDle 230
10 Preparation of 3-{4-(2-
propylam;no~ fonyl)phenyl)phenyl~am;nor~bonylmethyl-5-
amidinoindole
The titled compound was prepared as in Example 203. HRMS for
15C26H27NsO3S (M+H)+ calc. 490.191287; found 490.190996.
ExamDle 231
Preparation of 2-methyl-3-{2-iodo-4-(2-
am; n~--l 1 fonyl)phenyl)phenyl~ami noe~ ~honylmethyl ~ 5 -
20~;dinoindole
The titled compound was prepared as in Example 203. HRMS for
C24H23INsO3S1 (M+H)+ calc. 558.056639; found 558.057057.
25Exam~le 232
Preparation of 2-methyl-3-{4-(2-
am;~q~lfonyl)phenyl)phenyl~am~noe~ho~ylmethyl- 5 -
am;~;no;n~ole
The titled compound was prepared as in Example 203. LRMS for
C24H23NsO3S1 (M+H)+ 462.
ExamDle 233
Preparation of 3-{4-(2-am;n~ fonyl)phenyl)phenyl~-N
35methylam;noc~honylmethyl-5-~;dinoindole
The titled compound was prepared as in Example 203. LRMS for
C24H24NsO3S1 (M+H)+ 462.
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ExamDle 234
Preparation of 2-methyl-3-{4-(2-t-
butylaminosulfonyl)phenyl)phenyl}am;n~r~rbonylmethyl-5
methoxyindole
The titled compound was prepared as in Example 203. LRMS for
C2gH3lN3O4S1 (M+H)+ 506.
Exam~le 235
Preparation of 3-~4-(2-N-methylam;n~ fonyl)phenyl)phenyl}-N
methylam;no~-A~h~rylmethyl-5 -~m; dino, n~
The titled compound was prepared as in Example 203. HRMS for
C2~H23NsO3S (M+H)+ cacl. 462.159987i found 462.159054.
ExamDle 236
Preparation of 3-{4-(2-(n-
butylaminosulfonyl)phenylPhenylam;n~rA~ yl)methyl-5
cyAn~;n~line
To a solution of 3-acetic acid indoline (0.001 mol, 0.2 g) [or
indoline acid (0.001 mol, 0.202 g)] in anhydrous acetonitrile
(10 mL) was added thionyl chloride (0.3 mL, 4.0 eq.) [for
indoline, 1.0 M HCl in ethyl ether (0.05 mL, 1.0 eq.) was
added before thionyl chloride]. This reaction mixture was
warmed up at 50~C for 10 min. then allowed to cool to ambient
temperature and stirred for 2 h. The solvent and extra
thionyl chloride were removed in vacuo and the residue was
pumped on for several hours for further dry. To this dried
residue was added a mixture of A-B (0.338 g, 1.0 e~.~ and
triethyl amine (0.14 mL, 1.0 eq.; 2.0 eq. for HCl salt) in
anhydrous methylene chloride (10 mL). This reaction mixture
was allowed to stir at ambient temperature for 2 h. The
reaction mixture was evaporated and purified by flash
chromatography on a silica gel column (50 g) eluted with 3:1
hexane:ethyl acetate to give 0.4 g of pure product with n-
butyl sulfonamide (51 %).
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Exam~le 237
Preparation of 3-{4-(2-(n-
propylam;n~ fonyl)phenylphenylam;n~ bonyl)methyl-5-
amidinoindoline
The titled compound was prepared as in Example 203. HRMS for
C26H30N5S03 (M+H~ + calc. 492.206937; found 492.207667.
ExamDle 238
Preparation of (-)-3-{4-(2-aminosulfonyl)phenyl)pyrid-2-
ylaminocarbonylmQthyl-5-amidinoindoline
The titled compound was prepared as in Example 203. HRMS for
15 C22H24N603Sl (M+H) + calc.451.155236; found 451.154317.
Exa~ le 239
Preparation of 3-{4-(2-aminosulfonyl)phenyl)pyrid-2-
yl; ;n~c~hQnylmethyl-5-P~;dinoindoline
The titled compound (racemic) was prepared as in Example 203.
HRMS for C22H24N603Sl (M+H)+ calc. 451.155236; found
451.lS4317.
25ExamDle 240
Preparation of 3-{4-(2-
dimethylaminosulfonyl)phenyl)phenylam;no~hQnylmethyl-5-
am;~;n~indoline
The titled compound (racemic) was prepared as in Example 203.
HRMS for C25H26N503Sl (M+H) + calc. 450.159987; found
450.159435.
ExamDle 241
Preparation of (+)-3-t4-(2-t-butylaminosulfonyl)phenyl)pyrid-
2-ylam;n~h~nylmethyl-5-ami~;no;n~line
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The titled compound was prepared as in Example 203. HRMS for
C26H30N6o3sl (M+H)+ calc- 507.217836; found 507.217901. 98%ee;
rotation (+) 19.23.
5ExamDle 242
Preparation of (-)-3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-
2-ylam;nocArbony~methyl-5-amidinoindoline
The titled compound was prepared as in Example 203. HRMS for
10C26H30N603Sl (M+H)+ calc 507-217836; found 507.217678. 98%ee;
rotaion -16.28.
ExamPle 243
Preparation of 3-{4-(2-aminosulfonyl)phenyl)pyrid-2-
15yl)am; no~ rbonylmethyl-5- Am; no~arboxyindoline
The titled compound (racemic) was prepared as in Example 203.
HRMS for C22H23N603Sl (M+H) + calc. 451.1552036; found
451.154691.
ExamDle 244
Preparation of 3-{4-(2-t-
butylaminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-
amidinoindoline
The titled compound was prepared as in Example 203. LRMS for
C27H31N503Sl (M+H) + calc.506.3; found 506.4.
Exam~l30 Preparation of 3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-
yl}am;no~Arbonylmethyl-5-amidinoindoline
The titled compound (racemic) was prepared as in Example 203.
LRMS for C26H30N6o3sl (M+H) + calc.507.3; found 507.4.
ExamDle 246
Preparation of 3-{4-(2-aminosulfonyl)phenyl)pyrid-2-
yl r ; nr ~arhonylmethyl-6--amidino; n~lA701e
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The titled compound was prepared as in Example 203. HRMS for
C21H21N703Sl (M+H)+ calc. 450.134835; found 450.134725.
ExamDle 247
Preparation of 3-{4-(2-aminosulfonyl)phenyl)phenyl
am;no~:A~bonylmethyl-6-amidino;nAA7Ole
The titled compound was prepared as in Example 203. HRMS for
C22H22N603Sl (M+H)+ calc. 449.139586; found 449.138515.
ExamDle 248
Preparation of 3-{4-(2-t-butyl Am;nosulfonyl)phenyl)pyrid-2-
ylam;no~A~hor~ylmethyl-6-~n;dino;nAA7ole
The titled compound was prepared as in Example 203. HRMS for
C25H29N703Sl (M+H)+ calc.450.134835; 450.134725
ExamD20 Preparation of 3-~4-(2-t-butylaminosulfonyl)phenyl)phenyl
am;no~A~hnnylmethyl-6-a~;A;noindazole
The titled compound was prepared as in Example 203. HRMS for
C26H30N6o3sl (M+H)+ calc.505.202186; found 505.202631.
_
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Table 5
o
OEt
~ A-B
2 b N
Ex A~. A B MS (100%) or
Pos. HRMS
1 a+b phenethyl 3-amidino 204 (M+2H)2+
2 b phenethyl 3-amidino 204.2 (M+2H)2+
3 a phenethyl 3-amidino 204.2 (M+2H)2+
4 a+b phenethyl 4-amidino 407.2200
b phenethyl 4-amidino 204 (M+2H)2+
6 a phenethyl 4-amidino 204 (M+2H)2+
7 a+b phenyl-CH= 4-amidino 196.2 (M+2H)2+
8 a+b phenyl 4-amidino 197 (M+2H)2+
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Table 6a
~Z_A-B
HN a ~ N
EX Am. Z A B MS (100%)
pO5 or HRMS
51 a C(O) phenyl 4-phenyl 355.1554
52 b C(O) phenyl 4-phenyl 355.1559
53 a C(O) phenyl 4-(3-NH2)phenyl 370
(M+H~+
54 b C(O) phenyl 4-(3-NH2)phenyl 370
(M+H)+
a C(O) phenyl 4-(4-F)phenyl 373.1481
56 a C(O) phenyl 4-(4-CHO)phenyl 383.1531
57 a C(O) phenyl 4-(2-NH2SO2)phenyl 434.1303
58 a C(O) phenyl 4-(2-tBuNHSO2)
phenyl
59 a C(O) phenyl 4-(2-tetrazolyl) 423.1686
phenyl
a C(O)NH phenyl 4-(2-NH2SO2)phenyl 449.1414
61 b C(O)NH phenyl 4-(2-NH2SO2)phenyl 449.1401
62 a+b C(O) l-piperidine 4-benzyl 376.2118
63 b C(O) l-piperidine 4-benzyl 376.2130
64 a C(O) phenyl 4-(2-NH2SO2)phenyl 449.1393
65* 6- C(O) phenyl 4-(2-tBuNHs02) 436
aza phenyl
Ex. 65 contains the CH2-z-A-B group at the 2-position.
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Table 6b
H
N ~ '~ A
Ex Z' A B ~RMS
65* CH2C(O) phenyl 4-(2-tBuNHSO2)phenyl 464.1756
66 SCH2C(~)NH phenyl 4-(2-tBuNHS02)phenyl 496.1477
67 ScH2c(o)NH phenyl 4-(2-NH2SO2)phenyl 440.0831
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Table 7
~\ Z '--A- B
~/
H2 ~J
HN
E~ Rl Z ' A B MS or
~MS
101 H C(O) l-piperidine 4-benzyl 375.218
102 H CH2C (O) l-piperidine 4-benzyl 389.231
103 H C (O) l-piperidine4-(3-F)benzyl 393.209
104 HC ( O ) N ( CH2benzyl 4-amidino 218
C02CH3 )
105 CH2- C(O) l-piperidine 4-benzyl 447.242
C02Me
106 CH2- C(O) l-piperidine 4-benzyl 419.245
CH20H
107 CH2- C(O) l-piperidine 4-benzyl 433
C02H
108 HC ( O ) NH 4-piperidine l-benzyl 390.229
109 H C (O) l-piperidine 4-benzoyl 389.198
110 H C(O) l-piperazinyl 4-(3-F)benzyl 394.205
111 H C (O) NH benzyl 4-phenyl 383.190
112CH=CH- C(O) piperidine 4-benzyl 459
C02Me
113 H C ( O ) p iperidine 4-(2-F)benzyl 393.209
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Table 8a*
D Z-A-B
Ex D Rl Z A B NS or
HRMS
201 Am H C(O)- phenyl 4-cyclohexyl 389.232
CH2NH
202 Am H C(O) 1- 4-p- 440.176
piperazinyl toluenesulfonyl
203 Am H C(O)NH2-pyridyl 4-(2- 449.139
aminosulfonyl)
phenyl
204 Am H C(O)NH l-phenyl 4-(2-tetrazol-5- 437.187
yl)phenyl
205 Am H C(O)NH l-phenyl 4-phenyl 369.171
206 Am H C(O) 1- 4-phenyl- 440.176
piperazinyl methylsulfonyl
207 Am H C~O)NH l-phenyl 4-cyclohexyl 375.218
208 Am H C(O) 1- 4-benzyl 376.214
piperazinyl
209 Am Me C(O)N- benzyl 3-amidino 435.217
( CH2C02
CH3)
210 Am MeC(O) N-benzyl 4-amidino 435,213
(CH2C02
CH3)
211 Am MeC(O)NHbenzyl 4- (2- 476
aminosulfonyl)
phenyl
212 Am MeC(O) NHbenzyl 4-phenyl 397.205
213 Am MeC(O)CH2 1- 4-benzyl 389.235
piperazinyl
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214Am HC(O)NH phenyl 4-(2- 448.144
aminosulfonyl)
phenyl
215Am HC(O) 4- 1-benzyl 390.230
piperidinyl
216Am HC (0) 1- 4-phenyl 362.197
- piperazinyl
217Am HC~O) 1- 4-benzyl 374.210
piperidinyl
218Am MeC(O) NH2-pyridyl 5-(2- 463.155
aminosulfonyl)
phenyl
219CN HC(O)NH 2-Br-phenyl 4-(2- 526.054
aminosulfonyl)
phenyl
220CH3- HC (O)NH2-Me-phenyl 4-(2- 449.164
NH aminosulfonyl)
phenyl
221Am HC (O)NH2-F-phenyl 4-(2- 466.134
aminosulfonyl)
phenyl
222CN HC(O)NH 2-Cl-phenyl 4-(2- 482.104
aminosulfonyl)
phenyl
223CN HC (0) NH2-I-phenyl 4-(2- 574.043
aminosulfonyl)
phenyl
224Am HC(O)NH 2-Me-phenyl 4-(2- 462.156
aminosulfonyl)
phenyl
225Am HC (0) NH2-Me-phenyl 4-(2-t-Bu- 518.222
aminosulfonyl)
phenyl
226Am H(CH30- phenyl 4-(2- 520.165
C(O)- aminosulfonyl)
CH2 ) CH phenyl
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~ WO98/0142X
227Am H(phenylphenyl 4-(2- 538.191
-CH2)CH aminosulfonyl)
phenyl
228Am HC(O)NH2-pyridyl4-(2-CF3-phenyl) 43~3.152
229Am HC(O)NHphenyl 4-(2- 476.176
ethylaminosulfon
yl)phenyl
230Am HC(O)NHphenyl 4-(2- 490.191
propylamino-
sulfonyl)phenyl
231Am HC(O)NH2-I-phenyl 4-(2- 558.057
(R1=2- aminosulfonyl)
methyl) phenyl
232Am HC(O)NHphenyl 4-(2- 462
(Rl=2- aminosulfonyl)
methyl) phenyl
233Am HC(0)- phenyl 4-(2- 462
NCH3 aminosulfonyl)
phenyl
234CH30 HC(O)NHphenyl 4-(2-t-Bu- 506
(R1=2_ aminosulfonyl)
methyl) phenyl
235Am HC(0)- phenyl 4-~2- 462.160
NCH3 methylamino-
sulfonyl)phenyl
*For all Examples, but 226 and 277, n=1. For Examples 226 and
227, n=0.
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Table 8b
D Z-A-~
Ex D Rl z A B MS or
HRMS
236 CN H C(O)NH phenyl 4-(2-n-Bu-
aminosulfonyl)
phenyl
237 Am H C(O)NH phenyl4-(2-propylamino- 492.208
sulfonyl)phenyl
238 Am H C(O)NH 2-pyridyl 4-(2-aminosulfonyl)451.154
(_) phenyl
239 Am H C(O)NH 2-pyridyl 4-(2-aminosulfonyl)451.155
phenyl
240 Am H C(O)NH phenyl 4-(2-N,N- 450.160
dimethylamino-
sulfonyl)phenyl
241 Am H C(O)NH 2-pyridyl4-(2-t-Bu-amino- 507.218
(+) sulfonyl)phenyl
242 Am H C(O)NH 2-pyridyl4-(2-t-Bu-amino- 507.218
(_) sulfonyl)phenyl
243 NH2- H C(O)NH 2-pyridyl 4-(2-aminosulfonyl) 451.154
C(O) phenyl
244 Am H C(O)NH phenyl4-(2-t-Bu-amino- 506.4
sulfonyl)phenyl
245 Am H C(O)NH 2-pyridyl4-(2-t-Bu-amino- 507.4
sulfonyl)phenyl
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Tab~e 8c
~N- N Z-A-B
D/~/
E:x D Rl Z A B MS or
HRMS
246 Am H C(O)NH 2-pyridyl4-(2- 450.135
aminosulfonyl)
phenyl
247 Am H C (O)NH phenyl 4-(Z- 449.139
aminosulfonyl)
phenyl
248 Am H C(O)NH 2-pyridyl 4-(2-t-Bu-amino- 450.135
sulfonyl)phenyl
249 Am H C(O)NH phenyl 4-(2-t-Bu-amino- 505.203
sulfonyl)phenyl
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Table 9
HN~ ~
H2N (\-~ Z_A_B
Ex n Z A-B
301 1 C(O) 4-(2-
aminosulfonylphenyl)phenyl
302 1 C(O)4-(2-aminosulfonylphenyl)-2-
pyridyl
303 1 C(O)4-(2-methylaminosulfonyl-
phenyl)phenyl
304 1 C(O)4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
305 1 C(O) 2-aminosulfonyl-4-
cyclohexylphenyl
306 1 C(O)3-aminosulfonyl-4-t-butyl-2-
pyridyl
307 1 C(O)2-(5-indazol-5-yl)furanyl
308 1 C(O)2-(5-indazol-6-yl)thienyl
309 1 C(O)4-(2-tetrazolylphenyl)phenyl
310 1 C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
311 1 C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
312 1 C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
313 1 C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
314 1 C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
315 1 C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
316 1 C(O)NH2-(5-indazol-5-yl)furanyl
317 1 C(O)NH2-(5-indazol-6-vl~thienyl
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W098tO1428
318 1 C(O)NH4-(2-tetrazolylphenyl)phenyl
319 1 NHC(O) 4-(2-
aminosulfonylphenyl)phenyl
320 1 NHC(O) 4-(2~aminosulfonylphenyl)-2-
pyridyl
321 1 NHC(O) 4-(2-methylaminosulfonyl-
phenyl)phenyl
322 1 NHC(O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
323 1 NHC(O) 2-aminosulfonyl-4-
cyclohexylphenyl
324 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-
pyridyl
325 1 NHC(O) 2-(5-indazol-5-yl)furanyl
326 1 NHC(O) 2-(5-indazol-6-yl)thienyl
327 1 NHC(O)4- (2-tetrazolylphenyl)phenyl
328 1 SO2NH 4-(2-
aminosulfonylphenyl)phenyl
329 1 SO2NH 4-(2-aminosulfonylphenyl)-2-
pyridyl
330 ; SO2NH 4-(2-methylaminosulfonyl-
phenyl)phenyl
331 1 SO2NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
332 1 S02NH 2-aminosulfonyl-4-
cyclohexylphenyl
333 1 SO2NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
334 1 S02NH 2-(5-indazol-5-yl)furanyl
335 1 S02NH 2-(5-indazol-6-yl)thienyl
336 1 SO2NH4-(2-tetrazolylphenyl)phenyl
337 0CH(CH2CH20H)C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
338 0CH(CH2CH2OH)C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
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339 oCH(CH2CH2OH)C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
340 0CH(CH2CH2OH)C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
341 0CH(CH2CH2OH)C(O)NH2-aminosulfonyl-4-
cyclohexylphenyl
342 0CH(CH2CH2OH)C(O) NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
343 CCH(CH2CH2OH)C(O)NH2-(5-indazol-5-yl)furanyl
344 oCH(CH2CH20H)C(O)NH2-(5-indazol-6-yl)thienyl
345 oCH(CH2CH2OH)C(O) NH4-(2-tetrazoly~phenyl)phenyl
346 0 CH(CH2- 4-(2-
tetrazolyl)C(O) NHaminosulfonylphenyl)phenyl
347 0 CH(CH2- 4-(2-aminosulfonylphenyl)-2-
tetrazolyl)C(O) NH pyridyl
348 0 CH(CH2- 4-(2-methylaminosulfonyl-
tetrazolyl)C(O)NH phenyl)phenyl
349 o CH(CH2- 4-(2-ethylaminosulfonyl-
tetrazolyl)C(O)NH phenyl)-2-pyridyl
350 0 CH(CH2- 2-aminosulfonyl-4-
tetrazolyl)C(O) NHcyclohexylphenyl
351 0 CH(CH2- 3-aminosulfonyl-4-t-butyl-2-
tetrazolyl)C(O) NH pyridyl
352 0 CH(CH2- 2-(5-indazol-5-yl)furanyl
tetrazolyl)C(O) NH
353 0 CH(CH2- 2-(5-indazol-6-yl)thienyl
tetrazolyl)C(O)NH
354 0 CH(CH2- 4-(2-tetrazolylphenyl)phenyl
tetrazolyl)C(O) NH
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Table 10
HN~
H2N (\~ Z--A--B
EX n Z A-B
401 1 C(O) 4-(2-
aminosulfonylphenyl)phenyl
402 1 C(O)4-(2-aminosulfonylphenyl)-2-
pyridyl
403 1 C(O)4-(2-methylaminosulfonyl-
phenyl)phenyl
404 1 C(O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
405 1 C(O) 2-aminosulfonyl-4-
cyclohexylphenyl
406 1 C~O)3-aminosulfonyl-4-t-butyl-2-
pyridyl
407 1 C(O) 2-(5-indazol-5-yl)furanyl
408 1 C(O) 2-(5-indazol-6-yl)thienyl
409 1 C(O)4-(2-tetrazolylphenyl)phenyl
410 1 C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
411 1 C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
412 1 C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
413 1 C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
414 1 C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
415 1 C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
416 1 C(O)NH2-(5-indazol-5-yl)furanyl
417 1 C(O)NH2-(5-indazol-6-yl)thienyl
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418 1 C(O) NH 4-(2-tetrazolvlphenyl)phenyl
419 1 NHC(O) 4-(2-
aminosulfonylphenyl)phenyl
420 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-
pyridyl
421 1 NHC(O) 4-(2-methylaminosulfonyl-
phenyl)phenyl
422 1 NHC(O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
423 1 NHC(O) 2-aminosulfonyl-4-
cyclohexylphenyl
424 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-
pyridyl
425 1 NHC(O) 2-(5-indazol-5-yl)furanyl
426 1 NHC(O) 2-(5-indazol-6-yl)thienyl
427 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl
428 1 SO2NH 4-(2-
aminosulfonylphenyl)phenyl
429 1 SO2NH 4-(2-aminosulfonylphenyl)-2-
pyridyl
430 1 SO2NH 4-(2-methylaminosulfonyl-
phenyl)phenyl
431 1 S02NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
432 1 S02NH 2-aminosulfonyl-4-
cyclohexylphenyl
433 1 SO2NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
434 1 SO2NH 2-(5-indazol-5-yl)furanyl
435 1 SO2NH 2-(5-indazol-6-yl)thienyl
436 1 SO2NH 4-(2-tetrazolylphenyl)phenyl
437 0CH(CH2CH2OH)C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
438 0CH(CH2CH2OH)C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
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439 o CH(CH2CH2OH)C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
440 0 CH(CH2CH2OH)C(O) NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
441 0 CH(CH2CH2OH)C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
442 0 CH(CH2CH2OH)C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
443 0 CH(CH2CH2OH)C(O) NH2-(5-indazol-5-yl)furanyl
444 o CH(CH2CH2OH)C(O) NH2-(5-indazol-6-yl)thienyl
445 o CH(CH2CH2OH)C(O)NH4-(2-tetrazolylphenyl)phenyl
446 0 CH(CH2- 4-(2-
tetrazolyl)C(O) NHaminosulfonylphenyl)phenyl
447 0 CH(CH2- 4-(2-aminosulfonylphenyl)-2-
tetrazolyl)C(O)NH pyridyl
448 0 CH(CH2- 4-(2-methylaminosulfonyl-
tetrazolyl)C(O) NH phenyl)phenyl
449 0 CH (CH2- 4-(2-ethylaminosulfonyl-
tetrazolyl)C(O) NH phenyl)-2-pyridyl
450 0 CH (CH2- 2-aminosulfonyl-4-
tetrazolyl)C(O) NH cyc lohexylphenyl
451 0 CH(CH2- 3-aminosulfonyl-4-t-butyl-2-
tetrazolyl)C(O) NH pyridyl
452 0 CH(CH2- 2-(5-indazol-5-yl)furanyl
tetrazolyl)C(O) NH
453 0 CH(CH2- 2-(5-indazol-6-yl)thienyl
tetrazolyl)C(O) NH
454 0 CH(CH2- 4-(2-tetrazolylphenyl)phenyl
tetrazolyl)C(O) NH
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Table 11
HN~ ,~N>
H2N (~Z--A--B
Ex n Z A-B
501 1 C(O)4-(2-aminosulfonylphenyl)-2-
pyridyl
502 1 C(O)4-(2-methylaminosulfonyl-
phenyl)phenyl
503 1 C(O)4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
504 1 C(O) 2-aminosulfonyl-4-
cyclohexylphenyl
505 1 C(O)3-aminosulfonyl-4-t-butyl-2-
pyridyl
506 1 C(O)2-(5-indazol-5-yl)furanyl
507 1 C(O)2-(5-indazol-6-yl)thienyl
508 1 C(O)4-(2-tetrazolylphenyl)phenyl
509 1 C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
510 1 C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
511 1 C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
512 1 C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
513 1 C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
514 1 C(O)NH2-(5-indazol-5-yl)furanyl
515 1 C(O)NH2-(5-indazol-6-yl)thienyl
516 1 C(O)NH4-(2-tetrazolylphenyl)phenyl
517 1 NHC(O) 4-(2-
aminosulfonylphenyl)phenyl
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518 1 NHC ( O ) 4 - ( 2-aminosulfonylphenyl)-2-
pyridyl
519 1 NHC(O) 4-(2-methylaminosulfonyl-
phenyl)phenyl
520 1 NHC(O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
521 1 NHC(O) 2-aminosulfonyl-4-
cyclohexylphenyl
522 1 NHC (O) 3-aminosulfonyl-4-t-butyl-2-
pyridyl
523 1 NHC (O) 2-(5-indazol-5-yl)furanyl
524 1 NHC(O) 2-(5-indazol-6-yl)thienyl
525 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl
526 1 S02NH 4-(2-
aminosulfonylphenyl)phenyl
527 1 SO2NH 4-(2-aminosulfonylphenyl)-2-
pyridyl
528 1 S02NH 4-(2-methylaminosulfonyl-
phenyl)phenyl
529 1 SO2NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
530 1 S02NH 2-aminosulfonyl-4-
cyclohexylphenyl
531 1 SO2NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
532 1 SO2NH 2-(5-indazol-5-yl)furanyl
533 1 S02NH 2-(5-indazol-6-yl)thienyl
534 1 S02NH 4-(2-tetrazolylphenyl)phenyl
535 0CH(CH2CH2OH)C(O) NH 4-(2-
aminosulfonylphenyl)phenyl
536 0CH(CH2CH2OH)C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
537 0CH(CH2CH2OH)C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
538 0CH(CH2CH2OH)C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
102
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539 oCH(CH2CH2OH)C(O)NH2-aminosulfonyl-4-
cyclohexylphenyl
540 0CH(CH2CH2OH)C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
541 0CH(CH2CH~OH)C(O)NH2-(5-indazol-5-yl)furanyl
542 0CH(CH2CH2OH)C(O)NH2-(5-indazol-6-yl)thienyl
- 543 oCH(CH2CH2OH)C(O)NH4-(2-tetrazolylphenyl)phenyl
544 0CH(CH2- 4-(2-
tetrazolyl)C(O)NHaminosulfonylphenyl)phenyl
545 0CH(CH2- 4-(2-aminosulfonylphenyl)-2-
tetrazolyl)C(O)NHpyridyl
546 0CH(CH2- 4-(2-methylaminosulfonyl-
tetrazolyl)C(O)NHphenyl)phenyl
547 0CH(CH2- 4-(2-ethylaminosulfonyl-
tetrazolyl)C(O)NHphenyl)-2-pyridyl
548 0CH(CH2- 2-aminosulfonyl-4-
tetrazolyl)C(O)NHcyclohexylphenyl
549 0CH(CH2- 3-aminosulfonyl-4-t-butyl-2-
tetrazolyl)C(O)NHpyridyl
550 0CH(CH2- 2-(5-indazol-5-yl)furanyl
tetrazolyl)C(O)NH
551 0CH(CH2- 2-(5-indazol-6-yl)thienyl
tetrazolyl)C(O)NH
552 0CH(CH2-4-(2-tetrazolylphenyl)phenyl
tetrazolyl)C(O)NH
103
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Table 12
HN~ ~N
H2N (\'~ Z_A_B
EX n Z A-B
601 1 C(O) 4-(2-
aminosulfonylphenyl)phenyl
602 1 C(O)4-(2-aminosulfonylphenyl)-2-
pyridyl
603 1 C(O)4-(2-methylaminosulfonyl-
phenyl)phenyl
604 1 C(O)4-(2-ethylaminosulfonyl-
phenyl~-2-pyridyl
605 1 C(O) 2-aminosulfonyl-4-
cyclohexylphenyl
606 1 C(O)3-aminosulfonyl-4-t-butyl-2-
pyridyl
607 1 C(O)2-(5-indazol-5-yl)furanyl
608 1 C(O)2-(5-indazol-6-yl)thienyl
609 1 C(O)4-(2-tetrazolylphenyl)phenyl
610 1 C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
611 1 C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
612 1 C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
613 1 C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
614 1 C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
615 1 C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
616 1 C(O)NH2-(5-indazol-5-yl)furanyl
617 1 C(O)NH2-(5-indazol-6-yl)thienyl
104
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618 1 C~O)NH4-(2-tetrazolylphenyl)phenyl
619 1 NHC(O) 4-(2-
aminosulfonylphenyl)phenyl
620 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-
pyridyl
621 1 NHC(O) 4-(2-methylaminosulfonyl-
phenyl)phenyl
622 1 NHC(O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
623 1 NHC(O) 2-aminosulfonyl-4-
cyclohexylphenyl
624 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-
pyridyl
625 1 NHC(O) 2-(5-indazol-5-yl)furanyl
626 1 NHC(O) 2-(5-indazol-6-yl)thienyl
627 1 NHC(O)4-(2-tetrazolylphenyl)phenyl
628 1 SO2NH 4-(2-
aminosulfonylphenyl)phenyl
629 1 SO2NH 4-(2-aminosulfonylphenyl)-2-
pyridyl
630 1 SO2NH 4-(2-methylaminosulfonyl-
phenyl)phenyl
631 1 SO2NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
632 1 SO2NH 2-aminosulfonyl-4-
cyclohexylphenyl
633 1 SO2NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
634 1 SO2NH 2-(5-indazol-5-yl)furanyl
635 1 SO2NH 2-(5-indazol-6-yl~thienyl
636 1 SO2NH4-(2-tetrazolylphenyl~phenyl
637 0CH(CH2CH2OH)C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
638 0CH(CH2CH2OH)C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
105
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639 0CH(CH2CH2OH)C(O)NH 4-(2-methylaminosulfonyl-
phenyl)phenyl
640 0CH(CH2CH2OH)C(O)NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
641 0CH(CH2CH2OH)C(O) NH 2-aminosulfonyl-4-
cyclohexylphenyl
642 0CH(CH2CH2OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
643 0CH(CH2CH2OH)C(O)NH 2-(5-indazol-5-yl)furanyl
644 0CH(CH2CH2OH)C(O) NH 2-(5-indazol-6-yl)thienyl
645 0CH(CH2CH2OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl
646 0CH(CH2- 4-(2-
tetrazolyl)C(O) NH aminosulfonylphenyl)phenyl
647 0CH(CH2- 4-(2-aminosulfonylphenyl)-2-
tetrazolyl)C(O) NH pyridyl
648 0CH(CH2- 4-(2-methylaminosulfonyl-
tetrazolyl)C(O) NH phenyl)phenyl
649 0CH(CH2- 4-(2-ethylaminosulfonyl-
tetrazolyl)C(O) NH phenyl)-2-pyridyl
650 0CH (CH2- 2-aminosulfonyl-4-
tetrazolyl)C(O) NH cyclohexylphenyl
651 0CH (CH2- 3-aminosulfonyl-4-t-butyl-2-
tetrazolyl)C(O) NH pyridyl
652 0CH( CH2- 2-(5-indazol-5-yl)furanyl
tetrazolyl)C(O) NH
653 0CH(CH2- 2-(5-indazol-6-yl)thienyl
tetrazolyl)C(O) NH
654 0CH(CH2- 4-(2-tetrazolylphenyl)phenyl
tetrazolyl)C(O) NH
106
.. . . .
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WO98/01428 PCT~S97/1132S
Table 13
HN ~
H2N (\'t Z_A_B
EX n Z A-B
701 1 C(O) 4-(2-
aminosulfonylphenyl)phenyl
702 1 C(O)4-(2-aminosulfonylphenyl)-2-
pyridyl
703 1 C(O)4-(2-methylaminosulfonyl-
phenyl)phenyl
704 1 C(O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
705 1 C(O) 2-aminosulfonyl-4-
cyclohexylphenyl
706 1 C(O)3-aminosulfonyl-4-t-butyl-2-
pyridyl
707 1 C(O) 2-(5-indazol-5-yl)furanyl
708 1 C(O) 2-(5-indazol-6-yl)thienyl
709 1 C(O)4-(2-tetrazolylphenyl)phenyl
710 1 C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
711 1 C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
712 1 C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
713 1 C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
714 1 C(O)NH2-(5-indazol-5-yl)furanyl
715 1 C(O)NH2-(5-indazol-6-yl)thienyl
716 1 C(O)NH4-(2-tetrazolylphenyl)phenyl
717 1 NHC(O) 4-(2-
aminosulfonylphenyl)phenyl
107
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718 1 NHC(O~ 4-(2-aminosulfonylphenyl~-2-
pyridyl
719 1 NHC(O~ 4-(2-methylaminosulfonyl-
phenyl~phenyl
720 1 NHC(O~ 4-(2-ethylaminosulfonyl-
phenyl~-2-pyridyl
721 1 NHCtO~ 2-aminosulfonyl-4-
cyclohexylphenyl
722 1 NHC(O~ 3-aminosulfonyl-4-t-butyl-2-
pyridyl
723 1 NHC(O) 2-(5-indazol-5-yl~furanyl
724 1 NHC(O~ 2-(5-indazol-6-yl)thienyl
725 1 NHC(O)4-(2-tetrazolylphenyl~phenyl
726 1 SO2NH 4-(2-
aminosulfonylphenyl~phenyl
727 1 SO2NH 4-(2-aminosulfonylphenyl~-2-
pyridyl
728 1 SO2NH 4-(2-me~hylaminosulfonyl-
phenyl)phenyl
729 1 S02NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
730 1 S02NH 2-aminosulfonyl-4-
cyclohexylphenyl
731 1 S02NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
732 1 SO2NH 2-(5-indazol-S-yl)furanyl
733 1 SO2NH 2-(5-indazol-6-yl)thienyl
734 1 S02NH4-(2-tetrazolylphenyl)phenyl
735 0CH(CH2CH2OH)C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
736 0CH(CH2CH2OH)C(O~NH4-(2-aminosulfonylphenyl~-2-
pyridyl
737 0CH(CH2CH2OH~C(O)NH4-(2-methylaminosulfonyl-
phenyl~phenyl
738 0CH(CH2CH20H)C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
108
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739 oCH(CH2CH2OH)C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
740 0CH(CH2CH2OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
741 0CH(CH2CH2OH)C(O)NH 2-(5-indazol-5-yl)furanyl
742 0CH(CH2CH2OH)C(O)NH 2-(5-indazol-6-yl)thienyl
743 oCH(CH2CH2OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl
744 0CH(CH2- 4-(2-
tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl
745 0CH(CH2- 4-(2-aminosulfonylphenyl)-2-
tetrazolyl)C(O)NH pyridyl
746 0CH(CH2- 4-(2-methylaminosulfonyl-
tetrazolyl)C(O)NH phenyl)phenyl
747 0CH(CH2- 4-(2-ethylaminosulfonyl-
tetrazolyl)C(O)NH phenyl)-2-pyridyl
748 0CH(CH2- 2-aminosulfonyl-4-
tetrazolyl)C(O)NH cyclohexylphenyl
749 0CH(CH2- 3-aminosulfonyl-4-t-butyl-2-
tetrazolyl)C(O)NH pyridyl
750 0CH~CH2- 2-(5-indazol-5-yl)furanyl
tetrazolyl)C(O)NH
751 0CH(CH2- 2-(5-indazol-6-yl)thienyl
tetrazolyl)C(O)NH
752 0CH(CH2- 4-(2-tetrazolylphenyl)phenyl
tetrazolyl)C(O)NH
109
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Table 14
HN ~
H2N (~ Z_A_B
Ex n Z A-B
801 1 C(O) 4-(2-
aminosulfonylphenyl)phenyl
802 1 C(O)4-(2-aminosulfonylphenyl)-2-
pyridyl
803 1 C(O)4-(2-methylaminosulfonyl-
phenyl)phenyl
804 1 C(O)4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
805 1 C(O) 2-aminosulfonyl-4-
cyclohexylphenyl
806 1 C(O)3-aminosulfonyl-4-t-butyl-2-
pyridyl
807 1 C(O)2-(5-indazol-5-yl)furanyl
808 1 C(O)2-(5-indazol-6-yl)thienyl
809 1 C(O)4-(2-tetrazolylphenyl)phenyl
810 1 C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
811 1 C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
812 1 C(O~NH4-(2-methylaminosulfonyl-
phenyl~phenyl
813 1 C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
814 1 C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
815 1 C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
816 1 C(O)NH2-(5-indazol-5-yl)furanyl
817 1 C(O)NH2-(5-indazol-6-yl)thienyl
110
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818 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl
819 1 NHC(O) 4- (2-
aminosulfonylphenyl)phenyl
820 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-
pyridyl
821 1 NHC(O) 4-(2-methylaminosulfonyl-
phenyl)phenyl
822 1 NHC(O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
823 1 NHC(O) 2-aminosulfonyl-4-
cyclohexylphenyl
824 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-
pyridyl
825 1 NHC(O) 2-(5-indazol-5-yl)furanyl
826 1 NHC(O) 2-(5-indazol-6-yl)thienyl
827 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl
828 1 SO2NH 4-(2-
aminosulfonylphenyl)phenyl
829 1 SO2NH 4-(2-aminosulfonylphenyl)-2-
pyridyl
830 1 SO2NH 4-(2-methylaminosulfonyl-
phenyl)phenyl
831 1 SO2NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
832 1 S02NH 2-aminosulfonyl-4-
cyclohexylphenyl
833 1 S02NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
834 1 SO2NH 2-(5-indazol-5-yl)furanyl
835 1 SO2NH 2-(5-indazol-6-yl)thienyl
836 1 SO2NH 4-(2-tetrazolylphenyl)phenyl
837 0CH(CH2CH2OH)C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
838 0CH(CH2CH2OH)C(O)NH4-(2- aminosulfonylphenyl)-2-
pyridyl
111
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839 0 CH(CH2CH2OH)C~O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
840 0 CH(CH2CH2OH)C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
841 0 CH(CH2CH2OH)C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
842 0 CH(CH2CH2OH)C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
843 0 CH(CH2CH2OH)C(O)NH2-(5-indazol-5-yl)furanyl
844 0 CH(CH2CH~OH)C(O)NH2-(5-indazol-6-yl)thienyl
845 0 CH(CH2CH20H)C(O)NH4-(2-tetrazolylphenyl)phenyl
846 0 CH(CH2- 4-(2-
tetrazolyl)C(O)NHaminosulfonylphenyl)phenyl
847 0 CH(CH2- 4-(2-aminosulfonylphenyl)-2-
tetrazolyl)C(O)NH pyridyl
848 0 CH(CH2- 4-(2-methylaminosulfonyl-
tetrazolyl)C(O)NH phenyl)phenyl
849 0 CH(CH2- 4-(2-ethylaminosulfonyl-
tetrazolyl)C(O)NH phenyl)-2-pyridyl
850 0 CH(CH2- 2-aminosulfonyl-4-
tetrazolyl)C(O)NHcyclohexylphenyl
851 0 CH(CH2- 3-aminosulfonyl-4-t-butyl-2-
tetrazolyl)C(O)NH pyridyl
852 0 CH(CH2- 2-(5-indazol-5-yl)furanyl
tetrazolyl)C(O)NH
853 0 CH(CH2- 2-(5-indazol-6-yl)thienyl
tetrazolyl)C(O)NH
854 0 CH(CH2- 4-(2-tetrazolylphenyl)phenyl
tetrazolyl)C(O)NH
112
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Table 15
HN~
H2N (\~ Z--A--B
Ex n Z A-s
901 1 C(O) 4-(2-
aminosulfonylphenyl)phenyl
902 1 C(O)4-(2-aminosulfonylphenyl)-2-
pyridyl
903 1 C(O)4-(2-methylaminosulfonyl-
phenyl)phenyl
904 1 C(O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
905 1 C(O) 2-aminosulfonyl-4-
cyclohexylphenyl
906 1 C(O)3-aminosulfonyl-4-t-butyl-2-
pyridyl
907 1 C(O) 2-(5-indazol-5-yl)furanyl
908 1 C(O) 2-(5-indazol-6-yl)thienyl
909 1 C(O)4-(2-tetrazolylphenyl)phenyl
910 1 C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
911 1 C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
912 1 C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
913 1 C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
914 1 C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
915 1 C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
916 1 C(O)NH2-(5-indazol-5-yl)furanyl
917 1 C(O)NH2-(5-indazol-6-yl)thienyl
113
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918 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl
919 1 NHC(O) 4-(2-
aminosulfonylphenyl)phenyl
920 1 NHC(O) 4-( 2-aminosulfonylphenyl)-2-
pyridyl
921 1 NHC~O~ 4-(2-methylaminosulfonyl-
phenyl)phenyl
922 1 NHC(O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
923 1 NHC(O) 2-aminosulfonyl-4-
cyclohexylphenyl
924 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-
pyridyl
925 1 NHC(O) 2-(5-indazol-5-yl)furanyl
926 1 NHC(O) 2-(5-indazol-6-yl)thienyl
927 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl
928 1 SO2NH 4-(2-
aminosulfonylphenyl)phenyl
929 1 S02NH 4-(2-aminosulfonylphenyl)-2-
pyridyl
930 1 SO2NH 4-(2-methylaminosulfonyl-
phenyl)phenyl
931 1 SO2NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
932 1 SO2NH 2-aminosulfonyl-4-
cyclohexylphenyl
933 1 SO2NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
934 1 S02NH 2-(5-indazol-5-yl)furanyl
935 1 SO2NH 2-(5-indazol-6-yl)thienyl
936 1 SO2NH 4-(2-tetrazolylphenyl)phenyl
937 3 CH(CH2CH20H)C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
938 0 CH(CH2CH20H)C(O)NH 4-(2-aminosulfonylphenyl)-2-
pyridyl
114
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939 0 CH(CH2CH2OH)C(O~NH4-( 2-methylaminosulfonyl-
phenyl)phenyl
940 0 CH(CH2CH20H)C(O~NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
941 0 CH(CH2CH2OH)C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
942 0 CH(CH2CH20H)C(O) NH3 -aminosulfonyl-4-t-butyl-2-
pyridyl
943 o CH(CH2CH2OH)C(O)NH2-(5-indazol-5-yl)furanyl
944 o CH(CH2CH2OH)C(O~NH2-(5-indazol-6-yl)thienyl
945 o CH(CH2CH20H)C(O)NH4-(2-tetrazolylphenyl)phenyl
946 0 CH(CH2- 4-(2-
tetrazolyl)C(O) NHaminosulfonylphenyl)phenyl
947 0 CH (CH2- 4-(2-aminosulfonylphenyl)-2-
tetrazolyl)C(O)NH pyridyl
948 0 CH(CH2- 4-(2-methylaminosulfonyl-
tetrazolyl)C(O) NH phenyl)phenyl
949 0 CH(CH2- 4-(2-ethylaminosulfonyl-
tetrazolyl)C(O)NH phenyl)-2-pyridyl
950 0 CH (CH2- 2-aminosulfonyl-4-
tetrazolyl)C(O) NH cyclohexylphenyl
951 0 CH(CH2- 3 -aminosulfonyl-4-t-butyl-2-
tetrazolyl)C(O) NH pyridyl
952 0 CH(CH2- 2-(5-indazol-5-yl)furanyl
tetrazolyl)C(O) NH
95 3 0 CH(CH2- 2-(5-indazol-6-yl)thienyl
tetrazolyl)C(O) NH
954 0 CH(CH2- 4-(2-tetrazolylphenyl)phenyl
tetrazolyl)C(O) NH
115
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WO98/01428
~able 16
HN~_~
H2N (~'~Z--A--B
Ex n Z A-B
1001 1 C(O) 4-(2-
aminosulfonylphenyl)phenyl
1002 1 C(O)4-(2-aminosulfonylphenyl)-2-
pyridyl
1003 1 C(O)4-(2-methylaminosulfonyl-
phenyl)phenyl
1004 1 C(O)4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1005 1 C(O) 2-aminosulfonyl-4-
cyclohexylphenyl
1006 1 C(O)3-aminosulfonyl-4-t-butyl-2-
pyridyl
1007 1 C(O)2-(5-indazol-5-yl)furanyl
1008 1 C(O)2-(5-indazol-6-yl)thienyl
1009 1 C(O)4-(2-tetrazolylphenyl)phenyl
1010 1 C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
1011 1 C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
1012 1 C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
1013 1 C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1014 1 C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
1015 1 C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
1016 1 C(O)NH2-(5-indazol-5-yl)furanyl
1017 1 C(O)NH2-(5-indazol-6-yl)thienyl
116
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1018 1 C(O)NH4-(2-tetrazolylphenyl)phenyl
1019 1 NHC(O) 4-(2-
aminosulfonylphenyl)phenyl
1020 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-
pyridyl
1021 1 NHC(O) 4-(2-methylaminosulfonyl-
phenyl)phenyl
1022 1 NHC~O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1023 1 NHC(O) 2-aminosulfonyl-4-
cyclohexylphenyl
1024 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-
pyridyl
1025 1 NHC(O) 2-(5-indazol-5-yl)furanyl
1026 1 NHC(O) 2-(5-indazol-6-yl)thienyl
1027 1 NHC(O)4-(2-tetrazolylphenyl)phenyl
1028 1 SO2NH 4-(2-
aminosulfonylphenyl)phenyl
1029 1 SO2NH 4-(2-aminosulfonylphenyl)-2-
pyridyl
1030 1 SO2NH 4-(2-methylaminosulfonyl-
phenyl)phenyl
1031 1 SO2NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1032 1 SO2NH 2-aminosulfonyl-4-
cyclohexylphenyl
1033 1 SO2NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
1034 1 SO2NH 2-(5-indazol-5-yl)furanyl
1035 1 SO2NH 2-(5-indazol-6-yl)thienyl
1036 1 SO2NH4-(2-tetrazolylphenyl)phenyl
1037 0 CH(CH2CH2OH)C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
1038 0 CH(CH2CH2OH)C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
117
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1039 0CH(CH2CH20H)C~O)NH4-(2-methylaminosulfonyl-
~henyl)phenyl
1040 0CH~CH2CH2OH) C~O)NH4-~2-ethylaminosulfonyl-
phenyl~-2-pyridyl
1041 0CH~CH2CH2OH)C(O)NH2-aminosulfonyl-4-
cyclohexylphenyl
1042 0CH(CH2CH2OH)C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
1043 0CH(CH2CH2OH)C(O)NH2-(5-indazol-5-yl~furanyl
1044 0CH(CH2CH2OH)C(O)NH2-(5-indazol-6-yl~thienyl
1045 0CH(CH2CH2OH)C(O)NH4-(2-tetrazolylphenyl~phenyl
1046 0CH~CH2- 4-~2-
tetrazolyl)C~O) NHaminosulfonylphenyl)phenyl
1047 oCH~CH2- 4-~2-aminosulfonylphenyl)-2-
tetrazolyl)C~O) NH pyridyl
1048 0CH~CH2- 4-~2-methylaminosulfonyl-
tetrazolyl)C~O~ NHphenyl)phenyl
1049 0CH~CH2- 4-~2-ethylaminosulfonyl-
tetrazolyl)C~O) NHphenyl)-2-pyridyl
1050 0CH(CH2- 2-aminosulfonyl-4-
tetrazolyl)C(O)NHcyclohexylphenyl
1051 0CH(CH2- 3-aminosulfonyl-4-t-butyl-2-
tetrazolyl)C(O) NH pyridyl
1052 0CH(CH2- 2-~ 5- indazol-5-yl)furanyl
tetrazolyl)C~O)NH
1053 0CH~CH2- 2-(5-indazol-6-yl)thienyl
tetrazolyl)C~O) NH
1054 0CH~CH2- 4-(2-tetrazolylphenyl)phenyl
tetrazolyl)C~O) NH
118
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Table 17
HN~
(\~ Z_A_B
EX n Z Rl A-B
1101 1 C(O) H3-acetyl-4-benzylpiperidine
1102 1 C(O) H4-(4-fluorobenzyl)piperidine
1103 1 C (O) H4-(2,3-difluorobenzyl)
piperidine
1104 1 C(O) H4-(2-chloro-4-fluorobenzyl)
piperidine
1105 1 C(O)CH2CH2OH3-acetyl-4-benzylpiperidine
110 6 1 C ( O )CH2CH2OH4-~3-fluorobenzyl)piperidine
110 7 1 C ( O )CH2CH2 OH4-(4-fluorobenzyl)piperidine
1108 1 C(O)CH2CH2OH4-(2,3-difluorobenzyl)
piperidine
1109 1 C(O)CH2CH2OH4-(2-chloro-4-fluorobenzyl)
piperidine
1110 1 C(O) CH2OCH34-benzylpiperidine
1111 1 C(O) CH2OCH33-acetyl-4-benzylpiperidine
1112 1 C(O) CH2OCH34-(3-fluorobenzyl)piperidine
1113 1 C(O) CH2OCH34-(4-fluorobenzyl)piperidine
1114 1 C(O) CH2OCH34-(2,3-difluorobenzyl)
piperidine
1115 1 C(O) CH2OCH34-(2-chloro-4-fluorobenzyl)
piperidine
1116 1 C (O)CH2CH2-4-benzylpiperidine
tetrazolyl
1117 1 C (O)CH2CH2-3-acetyl-4-benzylpiperidine
tetrazolyl
1118 1 C (O)CH2CH2-4-(3-fluorobenzyl)piperidine
tetrazolyl
119
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1119 1 C(O) CH2CH2-4-(4-fluorobenzyl)piperidine
tetrazolyl
1120 1 C(O) CH2CH2-4-(2,3-difluorobenzyl)
tetrazolylpiperidine
1121 1 C(O) CH2CH2-4-(2-chloro-4-fluorobenzyl)
tetrazolylpiperidine
1122 1C(O)NH H3-acetyl-4-benzylpiperidine
1123 1C(O)NH H4-(3-fluorobenzyl)piperidine
1124 1C(O)NH H4-(4-fluorobenzyl)piperidine
1125 1C(O)NH H4-(2,3-difluorobenzyl)
piperidine
1126 1C(O)NH H4-(2-chloro-4-fluorobenzyl)
piperidine
1127 1C(O)NHCH2CH2OH4-benzylpiperidine
1128 1C(O)NHCH2CH2OH3-acetyl-4-benzylpiperidine
1129 1C(O)NHCH2CH2OH4-(3-fluorobenzyl)piperidine
1130 1C(O)NHCH2CH2OH4-(4-fluorobenzyl)piperidine
1131 1C(O)NHCH2CH2OH4-(2,3-difluorobenzyl)
piperidine
1132 1C(O)NHCH2CH2OH4-(2-chloro-4-fluorobenzyl)
piperidine
1133 1C(O)NH CH2OCH34-benzylpiperidine
1134 1C(O)NH CH2OCH33-acetyl-4-benzylpiperidine
1135 1C(O)NH CH2OCH34-(3-fluorobenzyl)piperidine
1136 1C(O)NH CH2OCH34-(4-fluorobenz~l)piperidine
1137 1C(O)NH CH2OCH34-(2,3-difluorobenzyl)
piperidine
1138 1C(O)NH CH2OCH34-(2-chloro-4-fluorobenzyl)
piperidine
1139 1C(O)NH CH2CH2-4-benzylpiperidine
tetrazolyl
1140 1C(O)NH CH2CH2-3-acetyl-4-benzylpiperidine
tetrazolyl
1141 1C(O)NH CH2CH2-4-(3-fluorobenzyl)piperidine
tetrazolyl
120
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1142 1C(O)NHCH2CH2-4-(4-fluorobenzyl~piperidine
tetrazolyl
1143 1C(O)NHCH2CH2-4-(2,3-difluorobenzyl)
tetrazolylpiperidine
1144 1C(O)NHCH2CH2-4-(2-chloro-4-fluorobenzyl)
tetrazolylpiperidine
1145 1 SO2NH H 4-benzylpiperidine
1146 1 SO2NH H3-acetyl-4-benzylpiperidine
1147 1 SO2NH H4-(3-fluorobenzyl)piperidine
1148 1 SO2NH H4-(4-fluorobenzyl)piperidine
1149 1 SO2NH H4-(2,3-difluorobenzyl)
piperidine
1150 1 SO2NH H4-(2-chloro-4-fluorobenzyl)
piperidine
1151 1 SO2NHCH2CH2OH4-benzylpiperidine
1152 1 SO2NHCH2CH2OH3-acetyl-4-benzylpiperidine
1153 1 SO2NHCH2CH2OH4-(3-fluorobenzyl)piperidine
1154 1 SO2NHCH2CH2OH4-(4-fluorobenzyl)piperidine
1155 1 SO2NHCH2CH2OH4-(2,3-difluorobenzyl)
piperidine
1156 1 SO2NHCH2CH2OH4-(2-chloro-4-fluorobenzyl)
piperidine
1157 1 S02NHCH20CH34-benzylpiperidine
1158 1 S02NHCH20CH33-acetyl-4-benzylpiperidine
1159 1 SO2NHCH2OCH34-(3-fluorobenzyl)piperidine
1160 1 SO2NHCH2OCH34-(4-fluorobenzyl)piperidine
1161 1 S02NHCH20CH34-(2,3-difluorobenzyl)
piperidine
1162 1 SO2NHCH2OCH34-(2-chloro-4-fluorobenzyl)
piperidine
1163 1 S02NHCH2CH2-4-benzylpiperidine
tetrazolyl
1164 1 S02NHCH2CH2-3-acetyl-4-benzylpiperidine
tetrazolyl
1165 1 SO2NHCH2CH2-4-(3-fluorobenzyl)piperidine
tetrazolyl
121
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1166 1 S02NH CH2CH2-4-(4-fluorobenzyl)piperidine
tetrazolyl
1167 1 SO2NH CH2CH2-4-(2,3-difluorobenzyl)
tetrazolyl piperidine
1168 1 S02NH CH2CH2-4-(2-chloro-4-fluorobenzyl)
tetrazolyl piperidine
122
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WO98/01428
Table 18
H ~N~ ~
(\~ Z_A_B
Ex n Z Rl A-B
1201 1 C(O) H 4-benzylpiperidine
1202 1 C(O) H3-acetyl-4-benzylpiperidine
1203 1 C(O) H4-(3-fluorobenzyl)piperidine
1204 1 C(O) H4-(4-fluorobenzyl)piperidine
1205 1 C(O) H4-(2,3-difluorobenzyl)
piperidine
1206 1 C(O) H4-(2-chloro-4-fluorobenzyl)
piperidine
1207 1 C(O)CH2CH2OH4-benzylpiperidine
1208 1 C(O)CH2CH2OH3-acetyl-4-benzylpiperidine
1209 1 C(O)CH2CH2OH4-(3-fluorobenzyl)piperidine
1210 1 C(O)CH2CH2OH4-(4-fluorobenzyl)piperidine
1211 1 C(O)CH2CH2OH4-(2,3-difluorobenzyl)
piperidine
1212 1 C(O)CH2CH2OH4-(2-chloro-4-fluorobenzyl)
piperidine
1213 1 C(O) CH2OCH34-benzylpiperidine
1214 1 C(O) CH2OCH33-acetyl-4-benzylpiperidine
1215 1 C(O) CH2OCH34-(3-fluorobenzyl)piperidine
1216 1 C(O) CH2OCH34-(4-fluorobenzyl)piperidine
1217 1 C(O) CH2OCH34-(2,3-difluorobenzyl)
piperidine
1218 1 C(O) CH2OCH34-(2-chloro-4-fluorobenzyl)
piperidine
1219 1 C(O) CH2CH2-4-benzylpiperidine
tetrazolyl
1220 1 C(O) CH2CH2-3-acetyl-4-benzylpiperidine
tetrazolyl
123
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1221 1 C(O) CH2CH2-4-(3-fluorobenzyl)piperidine
tetrazolyl
1222 1 C(O) CH2CH2-4-(4-fluorobenzyl)piperidine
tetrazolyl
1223 1 C(O) CH2CH2-4-(2,3-difluorobenzyl)
tetrazolylpiperidine
1224 1 C(O) CH2CH2-4-(2-chloro-4-fluorobenzyl)
tetrazolylpiperidine
1225 1 C(O)NH H 4-benzylpiperidine
1226 1 C(O)NH H3-acetyl-4-benzylpiperidine
1227 1 C(O)NH H4-(3-fluorobenzyl)piperidine
1228 1 C(O)NH H4-(4-fluorobenzyl)piperidine
1229 1 C(O)NH H4-(2,3-difluorobenzyl)
piperidine
1230 1 C(O)NH H4-(2-chloro-4-fluorobenzyl)
piperidine
1231 1 C(O)NH CH2CH2OH4-benzylpiperidine
1232 1 C(O)NH CH2CH20H3-acetyl-4-benzylpiperidine
1233 1 C(O)NH CH2CH2OH4-(3-fluorobenzyl)piperidine
1234 1 C(O)NH CH2CH2OH4-(4-fluorobenzyl)piperidine
1235 1 C(O)NH CH2CH2OH4-(2,3-difluorobenzyl~
piperidine
1236 1 C(O)NH CH2CH2OH4-(2-chloro-4-fluorobenzyl)
piperidine
1237 1 C(O)NH CH2OCH34-benzylpiperidine
1238 1 C(O)NH CH2OCH33-acetyl-4-benzylpiperidine
1239 1 C(O)NH CH2OCH34-(3-fluorobenzyl)piperidine
1240 1 C(O)NH CH2OCH34-(4-fluorobenzyl)piperidine
1241 1 C(O)NH CH2OCH34-(2,3-difluorobenzyl)
piperidine
1242 1 C(O)NH CH2OCH34-(2-chloro-4-fluorobenzyl)
piperidine
1243 1 C(O)NH CH2CH2-4-benzylpiperidine
tetrazolyl
1244 1 C(O)NH CH2CH2-3-acetyl-4-benzylpiperidine
tetrazolyl
124
. , . ~ , ~
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1245 1C(O)NH CH2CH2-4-(3-fluorobenzyl)piperidine
tetrazolyl
1246 1C(O) NH CH2CH2-4-(4-fluorobenzyl)piperidine
tetrazolyl
1247 1C(O)NH CH2CH2-4-(2,3-difluorobenzyl)
tetrazolyl piperidine
1248 1C(O)NH CH2CH2-4-(2-chloro-4-fluorobenzyl)
tetrazolyl piperidine
1249 1SO2NH H 4-benzylpiperidine
1250 1SO2NH H3-acetyl-4-benzylpiperidine
1251 1S02NH H4-(3-fluorobenzyl)piperidine
1252 1SO2NH H4-(4-fluorobenzy~)piperidine
1253 1S02NH H4-(2,3-difluorobenzyl)
piperidine
1254 1S02NH H4-(2-chloro-4-fluorobenzyl)
piperidine
1255 1SO2NH CH2CH2OH4-benzylpiperidine
1256 1SO2NH CH2CH2OH3-acetyl-4-benzylpiperidine
1257 1SO2NH CH2CH2OH4-(3-fluorobenzyl)piperidine
1258 1SO2NH CH2CH2OH4-(4-fluorobenzyl)piperidine
1259 1SO2NH CH2CH2OH4-(2,3-difluorobenzyl)
piperidine
1260 1SO2NH CH2CH2OH4-(2-chloro-4-fluorobenzyl)
piperidine
1261 1S02NH CH20CH34-benzylpiperidine
1262 1SO2NH CH2OCH33-acetyl-4-benzylpiperidine
1263 1SO2NH CH2OCH34-(3-fluorobenzyl)piperidine
1264 1SO2NH CH2OCH34-(4-fluorobenzyl)piperidine
1265 1SO2NH CH2OCH34-(2,3-difluorobenzyl)
piperidine
1266 1SO2NH CH2OCH34-(2-chloro-4-fluorobenzyl)
piperidine
1267 1S02NH CH2CH2-4-benzylpiperidine
tetrazolyl
1268 1SO2NH CH2CH2-3-acetyl-4-benzylpiperidine
tetrazolyl
125
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1269 1 S02NHCH2cH2-4-(3-fluorobenzyl)piperidine
tetrazolyl
1270 1 S02~HCH2CH2-4-(4-fluorobenzyl)piperidine
tetrazolyl
1271 1 S02NHCH2CH2-4-(2,3-difluorobenzyl)
tetrazolyl piperidine
1272 1 S02NHCH2CH2-4-(2-chloro-4-fluorobenzyl)
tetrazolyl piperidine
126
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WO 98101428
Table 19
H2N~l~N
(\'t Z_A_B
EX n Z R1 A-B
1301 1 C(O) H 4-benzylpiperidine
1302 1 C(O) H3-acetyl-4-benzylpiperidine
1303 1 C(O) H4-(3-fluorobenzyl)piperidine
1304 1 C(O) H4-(4-fluorobenzyl)piperidine
1305 1 C(O) H4-(2,3-difluorobenzyl)
piperidine
1306 1 C(O) H4-(2-chloro-4-fluorobenzyl
piperidine
1307 1 C(O)CH2CH2OH4-benzylpiperidine
1308 1 C(O)CH2CH2OH3-acetyl-4-benzylpiperidine
1309 1 C(O)CH2CH2OH4-(3-fluorobenzyl)piperidine
1310 1 C(O)CH2CH2OH4-(4-fluorobenzyl)piperidine
1311 1 C(O)CH2CH2OH4-(2,3-difluorobenzyl)
piperidine
1312 1 C(O)CH2CH2OH4-(2-chloro-4-fluorobenzyl)
piperidine
1313 1 C(O) CH~OCH34-benzylpiperidine
1314 1 C(O) CH2OCH33-acetyl-4-benzylpiperidine
1315 1 C(O) CH2OCH34-(3-fluorobenzyl)piperidine
1316 1 C(O) CH2OCH34-(4-fluorobenzyl)piperidine
1317 1 C(O) CH2OCH34-(2,3-difluorobenzyl)
piperidine
1318 1 C(O) CH2OCH34-(2-chloro-4-fluorobenzyl)
piperidine
1319 1 C(O) CH2CH2-4-benzylpiperidine
tetrazolyl
1320 1 C(O) CH2CH2-3-acetyl-4-benzylpiperidine
tetrazolyl
127
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1321 1 C(O) CH2CH2-4-~3-fluorobenzyl)piperidine
tetrazolyl
1322 1 C(O) CH2CH2-4-(4-fluorobenzyl)piperidine
tetrazolyl
1323 1 C(O) CH2CH2-4-(2,3-difluorobenzyl)
tetrazolylpiperidine
1324 1 C(O) CH2CH2-4-(2-chloro-4-fluorobenzyl)
tetrazolylpiperidine
1325 1 C(O)NH H 4-benzylpiperidine
1326 1 C(O)NH H3-acetyl-4-benzylpiperidine
1327 1 C(O)NH H4-(3-fluorobenzyl)piperidine
1328 1 C(O)NH H4-(4-fluorobenzyl)piperidine
1329 1 C(O)NH H4-(2,3-difluorobenzyl)
piperidine
1330 1 C(O)NH H4-(2-chloro-4-fluorobenzyl)
piperidine
1331 1 C(O)NH CH2CH2OH4-benzylpiperidine
1332 1 C(O)NH CH2CH2OH3-acetyl-4-benzylpiperidine
1333 1 C(O)NH CH2CH2OH4-(3-fluorobenzyl)piperidine
1334 1 C(O)NH CH2CH2OH4-(4-fluorobenzyl)piperidine
1335 1 C(O)NH CH2CH2OH4-(2,3-difluorobenzyl)
piperidine
1336 1 C(O)NH CH2CH2OH4-(2-chloro-4-fluorobenzyl)
piperidine
1337 1 C(O)NH CH2OCH34-benzylpiperidine
1338 1 C(O)NH CH2OCH33-acetyl-4-benzylpiperidine
1339 1 C(O)NH CH2OCH34-(3-fluorobenzyl)piperidine
1340 1 C(O)NH CH2OCH34-(4-fluorobenzyl)piperidine
1341 1 C(O)NH CH2OCH34-(2,3-difluorobenzyl)
piperidine
1342 1 C(O)NH CH2OCH34-(2-chloro-4-fluorobenzyl)
piperidine
1343 1 C(O)NH CH2CH2-4-benzylpiperidine
tetrazolyl
1344 1 C(O)NH CH2CH2-3-acetyl-4-benzylpiperidine
tetrazolyl
128
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1345 1C(O)NH CH2CH2-4-(3-fluorobenzyl)piperidine
tetrazolyl
1346 1C(O) NHCH2CH2 -4-(4-fluorobenzyl)piperidine
tetrazolyl
1347 1C(O)NH CH2CH2-4-~2,3-difluorobenzyl)
tetrazolylpiperidine
1348 1C(O)NH CH2CH2-4-(2-chloro-4-fluorobenzyl)
tetrazolylpiperidine
1349 1 SO2NH H 4-benzylpiperidine
1350 1 SO2NH H3-acetyl-4-benzylpiperidine
1351 1 SO2NH H4-(3-fluorobenzyl)piperidine
1352 1 SO2NH H4-(4-fluorobenzyl)piperidine
1353 1 SO2NH H4-(2,3-difluorobenzyl)
piperidine
1354 1 S02NH H4-(2-chloro-4-fluorobenzyl)
piperidine
1355 1 S02NHCH2CH20H4-benzylpiperidine
1356 1 S02NHCH2CH20H3-acetyl-4-benzylpiperidine
1357 1 SO2NHCH2CH2OH4-(3-fluorobenzyl)piperidine
1358 1 SO2NHCH2CH2OH4-(4-fluorobenzyl)piperidine
1359 1 S02NHCH2CH20H4-(2,3-difluorobenzyl)
piperidine
1360 1 S02NHCH2CH20H4-(2-chloro-4-fluorobenzyl)
piperidine
1361 1 SO2NH CH2OCH34-benzylpiperidine
1362 1 SO2NH CH2OCH33-acetyl-4-benzylpiperidine
1363 1 S02NH CH20CH34-(3-fluorobenzyl)piperidine
1364 1 SO2NH CH2OCH34-(4-fluorobenzyl)piperidine
1365 1 S02NH CH20CH34-(2,3-difluorobenzyl)
piperidine
1366 1 SO2NH CH2OCH34-(2-chloro-4-fluorobenzyl)
piperidine
1367 1 SO2NH CH2CH2-4-benzylpiperidine
tetrazolyl
1368 1 SO2NH CH2CH2-3-acetyl-4-benzylpiperidine
tetrazolyl
129
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1369 1 S02NHCH2CH2-4-(3-fluorobenzyl)piperidine
tetrazolyl
1370 1 S02NHCH2CH2-4-(4-fluorobenzyl)piperidine
tetrazolyl
1371 1 SO2NHCH2CH2-4-(2,3-difluorobenzyl)
tetrazolyl piperidine
1372 1 SO2NHCH2CH2-4-(2-chloro-4-fluorobenzyl)
tetrazolyl piperidine
130
CA 022~9~73 1999-0l-06
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Table 20
HN~ ~
H2N (~Z--A--B
Ex n Z A-B
1401 1 C(O) 4-(2-
aminosulfonylphenyl)phenyl
1402 1 C(O)4-(2-aminosulfonylphenyl)-2-
pyridyl
1403 1 C(O)4-(2-methylaminosulfonyl-
phenyl)phenyl
1404 1 C(O)4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1405 1 C(O) 2-aminosulfonyl-4-
cyclohexylphenyl
1406 1 C(O)3-aminosulfonyl-4-t-butyl-2-
pyridyl
1407 1 C~O)2-(5-indazol-5-yl)furanyl
1408 1 C(O)2-(5-indazol-6-yl)thienyl
1409 1 C(O)4-(2-tetrazolylphenyl)phenyl
1410 1 C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
1411 1 C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
1412 1 C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
1413 1 C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1414 1 C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
1415 1 C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
1416 1 C(O)NH2-(5-indazol-5-yl)furanyl
1417 1 C(O)NH2-(5-indazol-6-yl)thienyl
131
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1418 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl
1419 1 NHC(O) 4-(2-
aminosulfonylphenyl)phenyl
1420 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-
pyridyl
1421 1 NHC(O) 4-(2-methylaminosulfonyl-
phenyl)phenyl
1422 1 NHC(O) 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridy~
1423 1 NHC(O) 2-aminosulfonyl-4-
cyclohexylphenyl
1424 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-
pyridyl
1425 1 NHC(O) 2-(5-indazol-5-yl)furanyl
1426 1 NHC(O) 2-(5-indazol-6-yl)thienyl
1427 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl
1428 1 S02NH 4-(2-
aminosulfonylphenyl)phenyl
1429 1 S02NH 4-(2-aminosulfonylphenyl)-2-
pyridyl
1430 1 S02NH 4-(2-methylaminosulfonyl-
phenyl)phenyl
1431 1 SO2NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1432 1 SO2NH 2-aminosulfonyl-4-
cyclohexylphenyl
1433 1 SO2NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
1434 1 S02NH 2-(5-indazol-5-yl)furanyl
1435 1 SO2NH 2-(5-indazol-6-yl)thienyl
1436 1 SO2NH 4-(2-tetrazolylphenyl)phenyl
1437 0 CH(CH2CH2OH)C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
1438 0 CH(CH2CH2OH)C(O)NH4-(2-aminosulfonylphenyl) -2-
pyridyl
132
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1439 0CH(CH2CH2OH)C(O)NH 4-(2-methylaminosulfonyl-
phenyl)phenyl
1440 0CH(CH2CH2OH)C(O)NH 4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1441 0CH~CH2CH2OH)C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
1442 0CH(CH2CH2OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-
pyridyl
1443 0CH(CH2CH2OH)C(O)NH 2-(5-indazol-5-yl)furanyl
1444 0CH(CH2CH2OH)C(O)NH 2-(5-indazol-6-yl)thienyl
1445 0CH(CH2CH2OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl
1446 0CH(CH2- 4-~2-
tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl
1447 0CH(CH2- 4-(2-aminosulfonylphenyl)-2-
tetrazolyl)C(O)NH pyridyl
1448 0CH(CH2- 4-(2-methylaminosulfonyl-
tetrazolyl)C(O)NH phenyl)phenyl
1449 0CH(CH2- 4-(2-ethylaminosulfonyl-
tetrazolyl)C(O)NH phenyl)-2-pyridyl
1450 0CH(CH2- 2-aminosulfonyl-4-
tetrazolyl)C(O)NH cyclohexylphenyl
1451 0CH(CH2- 3-aminosulfonyl-4-t-butyl-2-
tetrazolyl)C(O)NH pyridyl
1452 0CH(CH2- 2-(5-indazol-5-yl)furanyl
tetrazolyl)C(O)NH
1453 0CH(CH2- 2-(5-indazol-6-yl)thienyl
tetrazolyl)C(O)NH
1454 0CH(CH2- 4-(2-tetrazolylphenyl)phenyl
tetrazolyl)C(O)NH
133
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PCT~S97/1132S
WO98/01428
~able 21
N ~ '~ A
Ex Z' A-B
1501CH2C(O)NH 4-(2- -
aminosulfonylphenyl)phenyl
1502CH2C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
1503CH2C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
1504CH2C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1505CH2C(O)NH 2-aminosulfonyl-4-
cyclohexylphenyl
1506CH2C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
1507CH2C(O)NH2-(5-indazol-5-yl)furanyl
1508CH2C(O)NH2-(5-indazol-6-yl)thienyl
1509CH2C(O)NH4-(2-tetrazolylphenyl)phenyl
1510CH2CH2C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
1511CH2CH2C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
1512CH2CH2C(O)NH4-~2-tert-butylaminosulfonyl-
phenyl)phenyl
1513CH2CH2C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1514CH2CH2C(O)NH2-aminosulfonyl-4-
cyclohexylphenyl
1515CH2CH2C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
1516CH2CH2C(O)NH2-(5-indazol-5-yl)furanyl
1517CH2CH2C(O)NH2-(5-indazol-6-yl)thienyl
1518CH2CH2C(O)NH4-(2-tetrazolylphenyl)phenyl
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W098/01428
1519 SCH2C(O)NH 4-(2-
aminosulfonylphenyl)phenyl
1520 SCH2C(O)NH4-(2-aminosulfonylphenyl)-2-
pyridyl
1521 SCH2C(O)NH4-(2-methylaminosulfonyl-
phenyl)phenyl
1522 SCH2C(O)NH4-(2-ethylaminosulfonyl-
phenyl)-2-pyridyl
1523 SCH2C(O)NH2-aminosulfonyl-4-
cyclohexylphenyl
1524 SCH2C(O)NH3-aminosulfonyl-4-t-butyl-2-
pyridyl
1525 SCH2C(O)NH2-(5-indazol-5-yl)furanyl
1526 SCH2C(O)NH2-(5-indazol-6-yl)thienyl
1527 SCH2C(O)NH4-(2-tetrazolylphenyl)phenyl
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UtilitY
The compounds of this invention are useful as
anticoagulants for the treatment or prevention of
thromboembolic disorders in mammals. The term "thromboembolic
disorders" as used herein includes arterial or venous
cardiovascular or cerebrovascular thromboembolic disorders,
including, for example, unstable angina, first or recurrent
myocardial infarction, ischemic sudden death, transient
ischemic attack, stroke, atherosclerosis, venous thrombosis,
deep vein thrombosis, thrombophlebitis, arterial embolism,
coronary and cerebral arterial thrombosis, cerebral embolism,
kidney embolisms, and pulmonary embolisms. The anticoagulant
effect of compounds of the present invention is believed to be
due to inhibition of factor Xa or thrombin.
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 sodiumphosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5 %
PEG 8000. The Michaelis constant, Km, for substrate
hydrolysis was determined at 25~C using the method of
Lineweaver and Burk. Values o~ Ki were determined by allowing
0.2-0.5 nM human factor Xa (Enzyme Research Laboratories,
South Bend, IN) to react with the substrate (0.20 mM-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))
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where:
vO is the velocity of the control in the absence of
inhibitori
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 <5 ~m,
thereby confirming the utility of the compounds of the present
invention as effective Xa inhibitors.
The antithrombotic effect of compounds of the present
invention can be demonstrated in a rabbit arterio-venous tAV)
shunt thrombosis model. In this model, rabbits weighing 2-3
kg anesthetized with a mixture of xylazine (lO mg/kg i.m.) and
ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt
device is connected between the femoral arterial and the
femoral venous cannulae. The AV shunt device consists of a
piece of 6-cm tygon tubing which contains a piece of silk
thread. Blood will flow from the femoral artery via the AV-
shunt into the femoral vein. The exposure of flowing blood to
a silk thread will induce the formation of a significant
thrombus. After forty minutes, the shunt is disconnected and
the silk thread covered with thrombus is weighed. Test agents
or vehicle will be given (i.v., i.p., s.c., or orally) prior
to the opening of the AV shunt. 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
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. Specifically, the compounds have utility as drugs
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for the treatment of diseases arising from elevated thrombin
activity such as myocardial infarction, and as reagents used
as anticoagulants in the processing of blood to plasma for
diagnostic and other commercial purposes.
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, 18289-182g7 (l990),
herein incorporated by re~erence. 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
throm~bin inhibition. Human thrombin (Enzyme Research
Laboratories, Inc., South Bend, IN) at a concentration of 0.2
nM in O.lO 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 st~n~rd
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 ~m, 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.
The compounds are adm~inistered to a m~mm~l in a
therapeutically effective amount. By "therapeutically
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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 ~ ministered 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
antagonists and thromboxane-A2-synthetase inhibitors, as well
as pharmaceutically acceptable salts or prodrugs thereof.
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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
tissue plasminogen activator, anistreplase, urokinase or
streptokinase, including pharmaceutically acceptable salts or
prodrugs thereof. The term anistreplase, as used herein,
refers to anisoylated plasminogen streptokinase activator
complex, as described, for example, in European Patent
Application No. 028,489, the disclosure of which is hereby
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CA 022~9~73 1999-01-06
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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.
Administration of the compounds of Formula I of the
invention in combination with such additional therapeutic
agent, may afford an efficacy advantage over the compounds and
agents alone, and may do so while permitting the use of lower
doses of each. A lower dosage minimizes the potential of side
effects, thereby providing an increased margin of safety.
The compounds of the present invention are also useful as
standard or reference compounds, for example as a qua~ity
standard or control, in tests or assays involving the
inhibition of factor Xa. Such compounds may be provided in a
commercial kit, for example, ~or 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
ccmpounds of the present invention. If production of pNA is
observed in the solutions containing test sample, but no
compound of the present invention, then one would conclude
factor Xa was present.
Dosaqe and Formulation
The compounds of this invention can be adminis~ered
in such oral dosage forms as tablets, capsules (each of which
includes sustained release or timed release formulations)~
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WO 98/01428
pills, powders, granules, el~xirs, tinctures, suspensions,
syrups, and emulsions. They may also be administered in
intravenous (bolus or infusion), intraperitoneal,
subcutaneous, or intramuscular form, all using dosage forms
well known to those of ordinary skill in the pharmaceutical
arts. They can be administered alone, but generally will be
administered with a pharmaceutical carrier selected on the -
basis of the chosen route of administration and standard
pharmaceutical practice.
The dosage regimen for the compounds of the present
invention will, of course, vary depending upon known factors,
such as the pharmacodynamic characteristics of the particular
agent and its mode and route of administration; the species,
age, sex, health, medical condition, and weight of the
recipient; the nature and extent of the symptoms; the kind of
concurrent treatment; the frequency of treatment; the route of
administration, the renal and hepatic function of the
patient,and the effect desired. A physician or veterinarian
can determine and prescribe the effective amount of the drug
required to prevent, counter, or arrest the progress of the
thromboembolic disorder.
By way of general guidance, the daily oral dosage of each
active ingredient, when used for the indicated effects, will
range between about 0.001 to 1000 mg/kg of body weight,
preferably between about 0.01 to 100 mg/kg of body weight per
day, and most preferably between about 1.0 to 20 mg/kg/day.
Intravenously~ the most preferred doses will range from about
1 to about 10 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 ~mlnjstered in
divided doses of two, three, or four times daily.
Compounds of this invention can be administered in
intranasal form via topical use of suitable intranasal
vehicles, or via transdermal routes, using transdermal skin
patches. When administered in the form of a transdermal
delivery system, the dosage ~min; stration will, of course, be
continuous rather than intermittent throughout the dosage
regimen.
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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 ~mi~i stration 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 li~uid 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
30 ~nmi ni 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.
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,
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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
ac-id, 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.
Li~uid dosage forms for oral ~mi ni stration can contain
coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous
dextrose (glucose), and related sugar solutions and glycols
such as propylene glycol or polyethylene glycols are suitable
carriers for parenteral solutions. Solutions for parenteral
administration preferably contain a water soluble salt of the
active ingredient, suitable stabilizing agents, and if
necessary, buffer substances- Antioxidizing agents such as
sodium bisulfite, sodium sulfite, or ascorbic acid, either
alone or combined, are suitable stabilizing agents. Also used
are citric acid and its salts and sodium EDTA. In addition,
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parenteral solutions can contain preservatives, such as
benzalkonium chloride, methyl- or propyl-paraben, and
chlorobutanol.
Suitable pharmaceutical carriers are described in
Remin~ton'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 containing 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.
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
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ce~lulose, 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 ~m;n; stered with the compound of Formula I,
generally the amount of each component in a typical daily
dosage and typical dosage form may be reduced relative to the
usual dosage of the agent when administered alone, in view of
the additive or synergistic effect of the therapeutic agents
when administered in combination.
Particularly when provided as a single dosage unit, the
potential exists for a chemical interaction between the
combined active ingredients. For this reason, when the
compound of Formula I and a second therapeutic agent are
combined in a single dosage unit they are formulated such that
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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;nimize 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 mi ni m; zing contact between
the components of combination products of the present
invention, whether administered in a single dosage form or
~m; ni stered in separate forms but at the same time by the
same manner, will be readily apparent to those skilled 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
scope of the appended claims, the invention may be practiced
otherwise that as specifically described herein.
147
