Indian Patents
Title of Invention

BENZAMIDE COMPOUNDS
Abstract Novel benzamide compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are used in vitro or in vivo for preventing or treating coagulation disorders.
Full Text BENZAMIDE COMPOUNDS
Field of the Invention
This invention relates to novel compounds which are potent and highly
selective inhibitors of isolated factor Xa or when assembled in the prothrombinase
complex. These compounds show selectivity for factor Xa versus other proteases of
the coagulation (e.g. thrombin, fVIIa, fIXa) or the fibrinolytic cascades (e.g.
plasminogen activators, plasmin). In another aspect, the present invention relates to
novel monoamidino-containing compounds, their pharmaceutically acceptable salts,
and pharmaceutically acceptable compositions thereof which are useful as potent and
specific inhibitors of blood coagulation in mammals. In yet another aspect, the
invention relates to methods for using these inhibitors as therapeutic agents for disease
states in mammals characterized by coagulation disorders.
Background of the Invention
Hemostasis, the control of bleeding, occurs by surgical means, or by the
physiological properties of vasoconstriction and coagulation. This invention is
particularly concerned with blood coagulation and ways in which it assists in
maintaining the integrity of mammalian circulation after injury, inflammation,
disease, congenital defect, dysfunction or other disruption. Although platelets and
blood coagulation are both involved in thrombus formation, certain components of the
coagulation cascade are primarily responsible for the amplification or acceleration of
the processes involved in platelet aggregation and fibrin deposition.
Thrombin is a key enzyme in the coagulation cascade as well as in hemostasis.
Thrombin plays a central role in thrombosis through its ability to catalyze the
conversion of fibrinogen into fibrin and through its potent platelet activation activity.
Direct or indirect inhibition of thrombin activity has been the focus of a variety of
recent anticoagulant strategies as reviewed by Claeson, G., "Synthetic Peptides and
Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the

Blood Coagulation System", Blood Coag. Fibrinol. 5, 411-436 (1994). Several
classes of anticoagulants currently used in the clinic directly or indirectly affect
thrombin (i.e. heparins, low-molecular weight heparins, heparin-like compounds and
coumarins).
A prothrombinase complex, including Factor Xa (a serine protease, the
activated form of its Factor X precursor and a member of the calcium ion binding,
gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation
glycoprotein family), converts the zymogen prothrombin into the active procoagulant
thrombin. Unlike thrombin, which acts on a variety of protein substrates as well as at
a specific receptor, factor Xa appears to have a single physiologic substrate, namely
prothrombin. Since one molecule of factor Xa may be able to generate up to 138
molecules of thrombin (Elodi et al., Thromb. Res. 15, 617-619 (1979)), direct
inhibition of factor Xa as a way of indirectly inhibiting the formation of thrombin may
be an efficient anticoagulant strategy. Therefore, it has been suggested that
compounds which selectively inhibit factor Xa may be useful as in vitro diagnostic
agents, or for therapeutic administration in certain thrombotic disorders, see e.g., WO
94/13693.
Polypeptides derived from hematophagous organisms have been reported
which are highly potent and specific inhibitors of factor Xa. United States Patent
4,588,587 describes anticoagulant activity in the saliva of the Mexican leech,
Haementeria officinalis. A principal component of this saliva was shown to be the
polypeptide factor Xa inhibitor, antistasin (ATS), by Nutt, E. et al., "The Amino Acid
Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal
Structure", J. Biol. Chem., 263, 10162-10167 (1988). Another potent and highly
specific inhibitor of Factor Xa, called tick anticoagulant peptide (TAP), has been
isolated from the whole body extract of the soft tick Ornithidoros moubata, as
reported by Waxman, L., et al, "Tick Anticoagulant Peptide (TAP) is a Novel
Inhibitor of Blood Coagulation Factor Xa" Science, 248, 593-596 (1990).
Factor Xa inhibitory compounds which are not large polypeptide-type
inhibitors have also been reported including: Tidwell, R.R. et al., "Strategies for
Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin
Inhibitors", Thromb. Res., 12, 339-349 (1980); Turner, A.D. et al., "p-Amidino Esters
as Irreversible Inhibitors of Factor IXa and Xa and Thrombin", Biochemistry, 25.,
4929-4935 (1986); Hitomi, Y. et al., "Inhibitory Effect of New Synthetic Protease
Inhibitor (FUT-175) on the Coagulation System", Haemostasis, 11, 164-168 (1985);

Sturzebecher, J. et al., "Synthetic Inhibitors of Bovine Factor Xa and Thrombin.
Comparison of Their Anticoagulant Efficiency", Thromb. Res., 54,245-252 (1989);
Kam, CM. et al., "Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood
Coagulation Serine Proteases: New Anticoagulants", Biochemistry, 22, 2547-2557
(1988); Hauptmann, J. et al., "Comparison of the Anticoagulant and Antithrombotic
Effects of Synthetic Thrombin and Factor Xa Inhibitors", Thromb. Haemost., 63, 220-
223 (1990); and the like.
Others have reported Factor Xa inhibitors which are small molecule organic
compounds, such as nitrogen containing heterocyclic compounds which have amidino
substituent groups, wherein two functional groups of the compounds can bind to
Factor Xa at two of its active sites. For example, WO 98/28269 describes pyrazole
compounds having a terminal C(=NH)-NH2 group; WO 97/21437 describes
benzimidazole compounds substituted by a basic radical which are connected to a
naththyl group via a straight or branched chain alkylene,-C(=O) or -S(=O)2 bridging
group; WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino-
piperidine and 4-phenoxy-N-alkylamidino-piperidine group connected to a 3-
amidinophenyl group via a carboxamidealkyleneamino bridge; and EP 798295
describes compounds having a 4-phenoxy-N-alkylamidino-piperidine group
connected to an amidinonaphthyl group via a substituted or unsubstituted sulfonamide
or carboxamide bridging group.
There exists a need for effective therapeutic agents for the regulation of
hemostasis, and for the prevention and treatment of thrombus formation and other
pathological processes in the vasculature induced by thrombin such as restenosis and
inflammation. In particular, there continues to be a need for compounds which
selectively inhibit factor Xa or its precursors. Compounds that have different
combinations of bridging groups and functional groups than compounds previously
discovered are needed, particularly compounds which selectively or preferentially
bind to Factor Xa. Compounds with a higher degree of binding to Factor Xa than to
thrombin are desired, especially those compounds having good bioavailability and/or
solubility.
Summary of the Invention
The present invention relates to novel compounds which inhibit factor Xa,
their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug
derivatives, and pharmaceutically acceptable compositions thereof which have

particular biological properties and are useful as potent and specific inhibitors of
blood coagulation in mammals. In another aspect, the invention relates to methods of
using these inhibitors as diagnostic reagents or as therapeutic agents for disease states
in mammals characterized by undesired thrombosis or which have coagulation
disorders, such as in the treatment or prevention of any thrombotically mediated acute
coronary or cerebrovascular syndrome, any thrombotic syndrome occurring in the
venous system, any coagulopathy, and any thrombotic complications associated with
extracorporeal circulation or instrumentation, and for the inhibition of coagulation in
biological samples.
In certain embodiments, this invention relates to novel compounds which are
potent and highly selective inhibitors of isolated factor Xa when assembled in the
prothrombinase complex. These compounds show selectivity for factor Xa versus
other proteases of the coagulation cascade (e.g. thrombin, etc.) or the fibrinolytic
cascade, and are useful as diagnostic reagents as well as antithrombotic agents.
In one embodiment, the present invention relates to a compound according to
the formula:
wherein:
A is selected from:
(a) C1-C6-alkyl;
(b) C3-C8-cycloalkyI;
(c)

(d) phenyl, which is independently substituted with 0-2 R substitutuents;
(e) naphthyl, which is independently substituted with 0-2 R substitutuents;
and
a monocyclic or fused bicyclic heterocyclic ring system having from 5
to 10 ring atoms, wherein 1-4 ring atoms of the ring system are

selected from N, O and S, and wherein the ring system may be
substituted with 0-2 R substitutuents;
R is selected from:

m is an integer of 0-2;
R1, R2, R3 and R4 are independently selected from the group consisting of:
H, -OR5, -N(-R5, -R6), -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-C0-4alkylC3-8cycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from
1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties
may be independently replaced with a member selected from the group
consisting of halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-C0-4alkylC3-9Cycloalkyl, -CN, and -NO2; or
R1 and R2, or R2 and R3 taken together can form a 3-8 membered cycloalkyl or
a heterocyclic ring system, wherein the heterocyclic ring system may have
from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain
from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen
atoms on the heterocyclic ring system may be independently replaced with a
member selected from the group consisting of halo, C1-C4-alkyl, -CN -C1.
4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3-8Cycloalkyl and -
NO2;

R5 and R6 are independently selected from the group consisting of:
H, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
gCycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from 1-4
hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be
independently replaced with a member selected from the group consisting of
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -CN, and -NO2; or
R5 and R6 taken together can form a 3-8 membered cycloalkyl or a
heterocyclic ring system, wherein the heterocyclic ring system may have from
3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from
1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms
on the heterocyclic ring system may be independently replaced with a member
selected from the group consisting of halo, -C1-C4-alkyl, -CN -C1-4alkyl, -C2.
6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3-8cycloalkyl and -NO2;
Q is a member selected from the group consisting of:
a direct link, -CH2-, -C(=O)-, -O-, -N(R7)-, -N(R7)CH2-, - CH2N(R7) -, -
C(=NR7)-, -C(=O)-N(R7)-, -N(R7)-C(=O)-, -S-, -SO-, -SO2-, -SO2-N(R7)- and -
N(R7)-SO2-;
R7 is selected from:
H, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
gCycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from 1-4
hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be
independently replaced with a member selected from the group consisting of
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -CN, and -NO2;
D is a direct link or is a member selected from the group consisting of:
(a) phenyl, which is independently substituted with 0-2 Rla substitutuerits;
(b) naphthyl, which is independently substituted with 0-2 R1a
substitutuents; and
(c) a monocyclic or fused bicyclic heterocyclic ring system having from 5
to 10 ring atoms, wherein 1-4 ring atoms of the ring system are

selected from N, O and S, and wherein the ring system may be
subsituted from 0-2 Rla substitutuents;
Rla is selected from:
halo, -C1-4alkyl, -C2.6alkenyl, -C2.6alkynyl, -C3_8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -CN, -NO2, -(CH2)nNR2aR3a, -(CH2)nCO2R2a, -(CH2)nCONR2aR3a,
-SO2NR2lR3a, -SO2R2a, -CF3, -OR2a, and a 5-6 membered aromatic heterocyclic
system containing from 1-4 heteroatoms selected from N, O and S, wherein
from 1-4 hydrogen atoms on the aromatic heterocyclic system may be
independently replaced with a member selected from the group consisting of
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -CN and -NO2.
R2a and R3a are independently selected from the group consisting of:
H, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
gcycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from 1-4
hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be
independently replaced with a member selected from the group consisting of
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3_8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -CN and -NO2;
n is an integer of 0-2;
E is a direct link or a member selected from the group consisting of:

R8 is a member selected from the group consisting of:
R2b and R3b are each a member independently selected from the group consisting of:
H, -C1-4-alkyl, -C0-4-alkyl-aryl; -C0-4-alkyl-heterocyclic group, and R2b and R3b
together with the N atom to which they are attached can form a 5-8 membered

heterocyclic ring containing 1-4 heteroatoms selected from N, O and S,
wherein the heterocyclic ring may be substituted with 0-2 Rlc groups;
Rlc is a member selected from the group consisting of:

R2c and R3c are each independently a member selected from the group consisting of:
H; -C1-4-alkyl and -C1-4-alkyl-aryl;
q is an integer of 0-2;
G is a member selected from the group consisting of:
(a) C2-alkenyl or C3_8-cycloalkenyl, wherein the alkenyl and cycloalkenyl
attachment points are the alkenyl carbon atoms and wherein the -C2-
alkenyl or -C3-8-cycloalkenyl are substituted with 0-4 Rld groups;
(b) a phenylene group wherein the ring carbon atoms of the phenylene
group are substituted with 0-4 R1d groups;
(c) a 3-8 membered a saturated, partially unsaturated or aromatic
monocyclic- heterocyclic ring system containing 1-4 heteroatoms
selected from N, O and S, wherein 0-2 ring atoms of the heterocyclic
ring may be substituted with 0-4 RId groups; and,
(d) an 8-10 membered fused heterocyclic bicyclic ring system, containing
1-4 heteroatoms selected from N, O and S, wherein 0-2 ring atoms of
the fused bicyclic ring system may be substituted with 0-4 Rld groups;
Rld is a member selected from the group consisting of:


-N(R5a)-C(=O)-R2d; -N(R5a)-SO2-R2d; -(CH2V6-C(=O)-O-R2d; -(CH2)0
6-C(=O)-N(R2d,R3d); -(CH2)(,6-C(=NR2d)-N(R3d,R4d); -(CH2)0.6-
N(R5a)C(=NR2d)-N(R3d,R4d); a -(CH2)0.6-N(R3d)C5.6 membered saturated,
partially unsaturated or aromatic heterocyclic ring containing 1-4 heteroatoms
selected from N, O and S, and a -(CH2)0-6-5-6 membered saturated, partially
unsaturated or aromatic heterocyclic ring containing 1-4 heteroatoms selected
from N, O and S;
R5a R2d, R3d and R4d are each independently a member selected from the group
consisting of:
H, C1-6-alkyl and C1-6-alkylaryl, -CN; -NO2; carbocylic aryl, -CN; -NO2; or
R2d and R3d taken together with the N atoms they are independently attached
form a 5-7 membered saturated, partially unsaturated or aromatic heterocyclic
ring; or
R3d and R4d taken together with the N atom to which they are attached form a
5-8 membered saturated, partially unsaturated or aromatic heterocyclic ring
containing 1-4 heteroatoms selected from N, O and S;
J is a direct link or is a member selected from the group consisting of:
-N(-R9)-C(=O)-; -C(=O)-N(-R9)-; -O-; -S-; -SO-; -SO2-; -CH2-; -N(-R9)-; and
-N(-R9)-SO2-;
R9 is a member selected from the group consisting of:
H; -C1-4-alkyl; -C0-4-alkyl-carbocyclic aryl; -(CH2)-5-6 membered saturated,
partially unsaturated or aromatic heterocyclic ring containing l-4 heteroatoms
selected from N, O and S; -(CH2)1-6-C(=O)-O-C1-4-alkyl; and -(CH2)1
6-C(=O)-N(R6a,R6b);
R6a and R6b are each a member independently selected from the group consisting of:
H and -C1-6-alkyl;
X is a member selected from the group consisting of:
(a) phenyl substituted with 0-3 R1e groups;

(b) naphthyl substituted with 0-3 Rle groups and
(c) a 6-membered aromatic heterocyclic ring system containing 1-3 N
atoms and having 0-3 ring atoms substituted with 0-3 Rle groups; and
(d) an 8-10 membered fused aromatic heterocyclic bicyclic ring system
containing 1-4 heteroatoms selected from N, O and S and 0-3 ring
atoms of the fused heterocyclic bicyclic ring system are substituted
with 0-3 Rle groups;
R" is a member independently selected from the group consisting of:

R10, R2' and R3e are each independently a member selected from the group consisting
of:
H; -CM-alkyl; -CM-alkyl-O-R!»; -Co.2-alkyl-N(-Rlg, -R2g);-C,.
4-alkyl-carbocyclic aryl; -CM-alkyl-heterocyclic; and R10 and R2e, or R2e and
R3e together with the N atom to which they are attached can form 5-8
membered heterocyclic ring containing 1-4 heteroatoms selected from N, O
and S which can be substituted with 0-2 Rlg groups;
RIg and R2g are indepedently a member selected from the group of:
H; halo; -CM-alkyl, a carbocyclic aryl group ; a saturated, partially unsaturated
or aromatic heterocyclic group; -CN; -C(=O)-N(R3g)R4g; -C(=O)-OR3g; -NO2;
-(CH2)p-NR3gR4g; -SO2NR3gR4g; -SO2R3g; -CF3; and -(CH2)pOR3g;

p is an integer of 0-2;
R3g and R4g are each independently selected from the group consisting of:
H; C1-4-alkyl and -C0-4-alkyl-carbocyclic aryl;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
In certain aspects of this invention, compounds are provided which are useful
as diagnostic reagents. In another aspect, the present invention includes
pharmaceutical compositions comprising a pharmaceutically effective amount of the
compounds of this invention and a pharmaceutically acceptable carrier. In yet another
aspect, the present invention includes methods comprising using the above
compounds and pharmaceutical compositions for preventing or treating disease states
characterized by undesired thrombosis or disorders of the blood coagulation process
in mammals, or for preventing coagulation in stored blood products and samples.
Optionally, the methods of this invention comprise administering the pharmaceutical
composition in combination with an additional therapeutic agent such as an
antithrombotic and/or a thrombolytic agent and/or an anticoagulant.
Detailed Description of the Invention
Definitions
In accordance with the present invention and as used herein, the following
terms are defined with the following meanings, unless explicitly stated otherwise.
The term "alkenyl" refers to a trivalent straight chain or branched chain
unsaturated aliphatic radical. The term "alkinyl" (or "alkynyl") refers to a straight or
branched chain aliphatic radical that includes at least two carbons joined by a triple
bond. If no number of carbons is specified alkenyl and alkinyl each refer to radicals
having from 2-12 carbon atoms.
The term "alkyl" refers to saturated aliphatic groups including straight-chain,
branched-chain haying the number of carbon atoms specified, or if

no number is specified, having up to 12 carbon atoms. The term "cycloalkyl" as used
herein refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms
and preferably 3 to 7 carbon atoms.
As used herein, the terms "carbocyclic ring structure " and " C3-l6 carbocyclic
mono, bicyclic or tricyclic ring structure" or the like are each intended to mean stable
ring structures having only carbon atoms as ring atoms wherein the ring structure is a
substituted or unsubstituted member selected from the group consisting of: a stable
monocyclic ring which is aromatic ring ("aryl") having six ring atoms; a stable
monocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring; a stable
bicyclic ring structure having a total of from 7 to 12 ring atoms in the two rings
wherein the bicyclic ring structure is selected from the group consisting of ring
structures in which both of the rings are aromatic, ring structures in which one of the
rings is aromatic and ring structures in which both of the rings are non-aromatic; and a
stable tricyclic ring structure having a total of from 10 to 16 atoms in the three rings
wherein the tricyclic ring structure is selected from the group consisting of: ring
structures in which three of the rings are aromatic, ring structures in which two of the
rings are aromatic and ring structures in which three of the rings are non-aromatic. In
each case, the non-aromatic rings when present in the monocyclic, bicyclic or tricyclic
ring structure may independently be saturated, partially saturated or fully saturated.
Examples of such carbocyclic ring structures include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl,
[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),
2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or
tetrahydronaphthyl (tetralin). Moreover, the ring structures described herein may be
attached to one or more indicated pendant groups via any carbon atom which results
in a stable structure. The term "substituted" as used in conjunction with carbocyclic
ring structures means that hydrogen atoms attached to the ring carbon atoms of ring
structures described herein may be substituted by one or more of the substituents
indicated for that structure if such substitution(s) would result in a stable compound.
The term "aryl" which is included with the term "carbocyclic ring structure"
refers to an unsubstituted or substituted aromatic ring, substituted with one, two or
three substituents selected from loweralkoxy, loweralkyl, loweralkylamino, hydroxy,
halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl,

carboalkoxy and carboxamide, including but not limited to carbocyclic aryl,
heterocyclic aryl, and biaryl groups and the like, all of which may be optionally
substituted. Preferred aryl groups include phenyl, halophenyl, loweralkylphenyl,
napthyl, biphenyl, phenanthrenyl and naphthacenyl.
The term "arylalkyl" which is included with the term "carbocyclic aryl" refers
to one, two, or three aryl groups having the number of carbon atoms designated,
appended to an alkyl group having the number of carbon atoms designated. Suitable
arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl,
phenethyl, benzyhydryl, trityl, and the like, all of which may be optionally substituted.
As used herein, the term "heterocyclic ring" or "heterocyclic ring system" is
intended to mean a substituted or unsubstituted member selected from the group
consisting of stable monocyclic ring having from 5-7 members in the ring itself and
having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and
S; a stable bicyclic ring structure having a total of from 7 to 12 atoms in the two rings
wherein at least one of the two rings has from 1 to 4 hetero atoms selected from N, O
and S, including bicyclic ring structures wherein any of the described stable
monocyclic heterocyclic rings is fused to a hexane or benzene ring; and a stable
tricyclic heterocyclic ring structure having a total of from 10 to 16 atoms in the three
rings wherein at least one of the three rings has from 1 to 4 hetero atoms selected from
the group consisting of N, O and S. Any nitrogen and sulfur atoms present in a
heterocyclic ring of such a heterocyclic ring structure may be oxidized. Unless
indicated otherwise the terms "heterocyclic ring" or "heterocyclic ring system"
include aromatic rings, as well as non-aromatic rings which can be saturated, partially
saturated or fully saturated non-aromatic rings. Also, unless indicated otherwise the
term "heterocyclic ring system" includes ring structures wherein all of the rings
contain at least one hetero atom as well as structures having less than all of the rings
in the ring structure containing at least one hetero atom, for example bicyclic ring
structures wherein one ring is a benzene ring and one of the rings has one or more
hetero atoms are included within the term "heterocyclic ring systems" as well as
bicyclic ring structures wherein each of the two rings has at least one hetero atom.
Moreover, the ring structures described herein may be attached to one or more
indicated pendant groups via any hetero atom or carbon atom which results in a stable
structure. Further, the term "substituted" means that one or more of the hydrogen

atoms on the ring carbon atom(s) or nitrogen atom(s) of the each of the rings in the
ring structures described herein may be replaced by one or more of the indicated
substituents if such replacement(s) would result in a stable compound. Nitrogen
atoms in a ring structure may be quaternized, but such compounds are specifically
indicated or are included within the term "a pharmaceutically acceptable salt" for a
particular compound. When the total number of O and S atoms in a single
heterocyclic ring is greater than 1, it is preferred that such atoms not be adjacent to
one another. Preferably, there are no more that 1 O or S ring atoms in the same ring
of a given heterocyclic ring structure.
Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical
order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-
dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,
imidazolinyl, imidazolyl, lH-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pryidooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, 2H-pyrroIyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and
xanthenyl. Preferred heterocyclic ring structures include, but are not limited to,
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl,
benzimidazolyl, lH-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring
and spiro compounds containing, for example, the above heterocylic ring structures.

As used herein the term "aromatic heterocyclic ring system" has essentially the
same definition as for the monocyclic and bicyclic ring systems except that at least
one ring of the ring system is an aromatic heterocyclic ring or the bicyclic ring has an
aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring
structure.
The terms "halo" or "halogen" as used herein refer to Cl, Br, F or I
substituents. The term "haloalkyl", and the like, refer to an aliphatic carbon radicals
having at least one hydrogen atom replaced by a Cl, Br, F or I atom, including
mixtures of different halo atoms. Trihaloalkyl includes trifluoromethyl and the like as
preferred radicals, for example.
The term "methylene" refers to -CH2-.
The term "pharmaceutically acceptable salts" includes salts of compounds
derived from the combination of a compound and an organic or inorganic acid. These
compounds are useful in both free base and salt form. In practice, the use of the salt
form amounts to use of the base form; both acid and base addition salts are within the
scope of the present invention.
"Pharmaceutically acceptable acid addition salt" refers to salts retaining the
biological effectiveness and properties of the free bases and which are not biologically
or otherwise undesirable, formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic
acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, p-toluenesulfonic acid, salicyclic acid and the like.
"Pharmaceutically acceptable base addition salts" include those derived from
inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium,
iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are
the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from
pharmaceutically acceptable organic nontoxic bases include salts of primary,

secondary, and tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines and basic ion exchange resins, such as
isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine,
ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine,
arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine,
ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine,
piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred
organic nontoxic bases are isopropylamine, diethylamine, ethanolamine,
trimethamine, dicyclohexylamine, choline, and caffeine.
"Biological property" for the purposes herein means an in vivo effector or
antigenic function or activity that is directly or indirectly performed by a compound of
this invention that are often shown by in vitro assays. Effector functions include
receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any
carrier binding activity, any hormonal activity, any activity in promoting or inhibiting
adhesion of cells to an extracellular matrix or cell surface molecules, or any structural
role. Antigenic functions include possession of an epitope or antigenic site that is
capable of reacting with antibodies raised against it.
In the compounds of this invention, carbon atoms bonded to four non-identical
substituents are asymmetric. Accordingly, the compounds may exist as
diastereoisomers, enantiomers or mixtures thereof. The syntheses described herein
may employ racemates, enantiomers or diastereomers as starting materials or
intermediates. Diastereomeric products resulting from such syntheses may be
separated by chromatographic or crystallization methods, or by other methods known
in the art. Likewise, enantiomeric product mixtures may be separated using the same
techniques or by other methods known in the art. Each of the asymmetric carbon
atoms, when present in the compounds of this invention, may be in one of two
configurations (R or S) and both are within the scope of the present invention.
Preferred Embodiments
In a preferred embodiment the present invention provides a compound
according to the formula:
A-Q-D-E-G-J-X
wherein:

A is selected from:
(a) C1-C6-alkyl;
(b) C1-C8-cycloalkyl;
(c) -N(R',R2), N(R1,R2)-C(=NR3)-, N(R1,R2)-C(=NR3)-N(R4)-, R1-
C(=NR3)-, R'-C(=NR3)-N(R4)-;
(d) phenyl, which is independently substituted with 0-2 R substitutuents;
(e) naphthyl, which is independently substituted with 0-2 R substitutuents;
and
(f) a monocyclic or fused bicyclic heterocyclic ring system having from 5
to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
selected from N, O and S, and wherein the ring system may be
substituted with 0-2 R substitutuents;
R is selected from:

m is an integer of 0-2;
R1, R2, R3 and R4 are independently selected from the group consisting of:
H, -OR5, -N(-R5, -R6), -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-C0-4alkylC3-8cycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from

1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties
may be independently replaced with a member selected from the group
consisting of halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-C0-4alkylC3-8cycloalkyl, -CN, and -NO2; or
R1 and R2, or R2 and R3 taken together can form a 3-8 membered cycloalkyl or
a heterocyclic ring system, wherein the heterocyclic ring system may have
from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain
from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen
atoms on the heterocyclic ring system may be independently replaced with a
member selected from the group consisting of halo, C1-C4-alkyl, -CN -C1.
4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3-8cycloalkyl and -
NO2;
R5 and R6 are independently selected from the group consisting of:
H, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from 1-4
hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be
independently replaced with a member selected from the group consisting of
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3-
8cycloalkyl, -CN, and -NO2; or
R5 and R6 taken together can form a 3-8 membered cycloalkyl or a
heterocyclic ring system, wherein the heterocyclic ring system may have from
3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from
1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms
on the heterocyclic ring system may be independently replaced with a member
selected from the group consisting of halo, C1-C4-alkyl, -CN -C1-4alkyl, -C2.
6alkenyl, -C2.6alkynyl, -C3.8cycloalkyl, -C0-4alkylC3-8cycloalkyl and -NO2;
Q is a member selected from the group consisting of:
a direct link, -CH2-, -C(=O)-, -O-, -N(R7)-, -N(R7)CH2-, - CH2N(R7) -, -
C(=NR7)-, -C(=O)-N(R7), -N(R7)-C(=O)-, -S-, -SO-, -SO2-, -SO2-N(R7)- and -
N(R7)-SO2-;

R7 is selected from:
H, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from 1-4
hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be
independently replaced with a member selected from the group consisting of
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -CN, and -NO2;
D is a direct link or is a member selected from the group consisting of:
(a) phenyl, which is independently substituted with 0-2 R1a substitutuents;
(b) naphthyl, which is independently substituted with 0-2 R1a
substitutuents; and
(c) a monocyclic or fused bicyclic heterocyclic ring system having from 5
to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
selected from N, O and S, and wherein the ring system may be
subsituted from 0-2 R1a substitutuents;
Rla is selected from:
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -CN, -NO2, -(CH2)nNR2aR3a -(CH2)nCO2R2a, -(CH2)nCONR2aR3a,
-SO2NR2aR3a, -SO2R2a, -CF3, -OR2a, and a 5-6 membered aromatic heterocyclic
system containing from 1-4 heteroatoms selected from N, O and S, wherein
from 1-4 hydrogen atoms on the aromatic heterocyclic system may be
independently replaced with a member selected from the group consisting of
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
gcycloalkyl, -CN and -NO2.
R2a and R3a are independently selected from the group consisting of:
H, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
gcycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from 1-4
hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be
independently replaced with a member selected from the group consisting of

halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -CN and -NO2;
n is an integer of 0-2;
E is a direct link or a member selected from the group consisting of:

R8 is a member selected from the group consisting of:

R2b and R3b are each a member independently selected from the group consisting of:
H, -C1-4-alkyl, -C0-4-alkyl-aryl; -C0-4-alkyl-heterocyclic group, and R2b and R3b
together with the N atom to which they are attached can form a 5-8 membered
heterocyclic ring containing 1-4 heteroatoms selected from N, O and S,
wherein the heterocyclic ring may be substituted with 0-2 Rlc groups;
Rlc is a member selected from the group consisting of:
R2c and R3c are each independently a member selected from the group consisting of:
H; -C1-4-alkyl and -C1-4-alkyl-aryl;
q is an integer of 0-2;
G is a member selected from the group consisting of:
(a) C2-alkenyl or C3.8-cycloalkenyl, wherein the alkenyl and cycloalkenyl
attachment points are the alkenyl carbon atoms and wherein C2-alkenyl
or C3-8-cycloalkenyl are substituted with 0-4 Rld groups;

(b) a phenylene group wherein the ring carbon atoms of the phenylene
group are substituted with 0-4 Rld groups;
(c) a 3-8 membered a saturated, partially unsaturated or aromatic
monocyclic- heterocyclic ring system containing 1-4 heteroatoms
selected from N, O and S, wherein 0-4 ring atoms of the heterocyclic
ring may be substituted with 0-4 Rld groups; and,
(d) an 8-10 membered fused heterocyclic bicyclic ring system, containing
1-4 heteroatoms selected from N, O and S, wherein 0-4 ring atoms of
the fused bicyclic ring system may be substituted with 0-4 Rld groups;
Rld is a member selected from the group consisting of:

directly by its nitrogen atom to a carbon atom of a 5 to 6 membered saturated,
partially unsaturated or aromatic heterocyclic ring containing 1-4 heteroatoms
selected from N, O and S, and a -(CH2)0-6- group attached to a 5-6 membered
saturated, partially unsaturated or aromatic heterocyclic ring containing 1-4
heteroatoms selected from N, O and S;
R5a, R2d, R3d and R4d are each independently a member selected from the group
consisting of:
H, C1-6-alkyl and C1-6-alkylaryl, -CN; -NO2; carbocylic aryl, -CN; -NO2; or
R2d and R3d taken together with the N atoms ther are independently attached
form a 5-7 membered saturated, partially unsaturated or aromatic heterocyclic
ring; or

R3d and R4d taken together with the N atom to which they are attached form a
5-8 membered saturated, partially unsaturated or aromatic heterocyclic ring
containing 1-4 heteroatoms selected from N, O and S;
J is a direct link or is a member selected from the group consisting of:
-N(-R9)-C(=O)-; -C(=O)-N(-R9)-; -O-; -S-; -SO-; -SO2-; -CH2-; -N(-R9)-; and
-N(-R9)-SO2-;
R9 is a member selected from the group consisting of:
H; -C1-4-alkyl; -C0-4-alkyl-carbocyclic aryl; -(CH2)0-4-5-6 membered saturated,
partially unsaturated or aromatic heterocyclic ring containing 1 -4 heteroatoms
selected from N, O and S; -(CH2)1-6-C(=O)-O-C1-4-alkyl; and -(CH2)1-
6-C(=O)-N(R6a, R6b);
R6a and R6b are each a member independently selected from the group consisting of:
H and -C1-6-alkyl;
X is a member selected from the group consisting of:
(a) phenyl substituted with 0-3 R1e groups;
(b) naphthyl substituted with 0-3 Rle groups and
(c) a 6-membered aromatic heterocyclic ring system containing 1-3 N
atoms and having 0-3 ring atoms substituted with 0-3 Rle groups; and
(d) an 8-10 membered fused aromatic heterocyclic bicyclic ring system
containing 1-4 heteroatoms selected from N, O and S and 0-3 ring
atoms of the fused heterocyclic bicyclic ring system are substituted
with 0-3 Rle groups;
Rle is a member independently selected from the group consisting of:



R10, R2e and R3e are each independently a member selected from the group consisting
of:
H; -C1-4-alkyl; -C0-2-alkyl-O-R1g; -C0-2-alkyl-N(-R1g, -R2g);-C1-
4-alkyl-carbocyclic aryl; -C1-4-alkyl-heterocyclic; and R10 and R2e, or R2e and
R3e together with the N atom to which they are attached can form 5-8
membered heterocyclic ring containing 1-4 heteroatoms selected from N, O
and S which can be substituted with 0-2 Rlg groups;
Rlg and R2g are indepedently a member selected from the group of:
H; halo; -C1-4-alkyl, a carbocyclic aryl group ; a saturated, partially unsaturated
or aromatic heterocyclic group; -CN; -C(=O)-N(R3g)R4g; -C(=O)-OR3g; -NO2;
-(CH2),-NR3gK4g; -SO2NR3gR4g; -SO2R3g; -CF3; and -(CH2)pOR3g;
p is an integer of 0-2;
R3g and R4g are each independently selected from the group consisting of:
H; C1-4-alkyl and -C0-4-alkyl-carbocyclic aryl;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
In a further preferred embodiment the present invention provides a compound
according to the formula:
A-Q-D-E-G-J-X
wherein:
A is selected from:
(a) C1-C6-alkyl;

(b) C3-C8-cycloalkyl;
(c) -N(R1,R2), N(R1,R2)-C(=NR3)-, N(R1,R2)-C(=NR3)-N(R4)-, R1-
C(=NR3)-, R1-C(=NR3)-N(R4)-;
(d) phenyl, which is independently substituted with 0-2 R substitutuents;
(e) naphthyl, which is independently substituted with 0-2 R substitutuents;
and
(f) monocyclic or fused bicyclic heterocyclic ring system having from 5 to
10 ring atoms, wherein 1-4 ring atoms of the ring system are selected
from N, O and S, and wherein the ring system may be substituted with
0-2 R substitutuents;
R is selected from:
H, halo, -CN, -CO2R1, -C(=O)-N(R1, R2), -(CH2)m-CO2R1, -(CH2)m-
C(O)-N(R1, R2), -NO2, -SO2N(R1, R2), -SO2R1, -(CH2)mNR1R2, -(CH2)m-
C(=NR3)-R1, -(CH2)m-C(=NR3)-N(R1,R2), -(CH2)in-N(R4)-C(=NR3)-N(R1,R2), -
(CH2)mNR1- group attached to a 3-6 membered heterocylic ring having from 1
to 3 heteroatoms selected from the group consisting of N, O and S, -C1-4alkyl,
-C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3-8cycloalkyl, -CF3, -OR2,
and a 5-6 membered heterocyclic aromatic or partially saturated system,
including imidazoline, containing from 1-4 heteroatoms selected from N, O
and S, wherein from 1-4 hydrogen atoms on the heterocyclic system may be
independently replaced with a member selected from the group consisting of
halo, -methyl, -C2-C4-alkyl, -CN, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-C0-4alkylC3-8Cycloalkyl and -NO2;
m is an integer of 0-2;
R1, R2, R3 and R4 are independently selected from the group consisting of:
H, -OR5, -N(-R5, -R6), -C1-4alkyl, -C2-6alkenyl, -C2-8alkynyl, -C3-8cycloalkyl,
-C0-4alkylC3-8cycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from
1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties

may be independently replaced with a member selected from the group
consisting of halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl,
-C0-4alkylC3-8cycloalkyl, -CN, and -NO2; or
R1 and R2, or R2 and R3 taken together can form a 3-8 membered cycloalkyl or
a heterocyclic ring system, wherein the heterocyclic ring system may have
from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain
from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen
atoms on the heterocyclic ring system may be independently replaced with a
member selected from the group consisting of halo, C1-C4-alkyl, -CN -C1-
4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3-8cycloalkyl and -
NO2;
R5 and R6 are independently selected from the group consisting of:
H, -C1-4aIkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from 1-4
hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be
independently replaced with a member selected from the group consisting of
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
gcycloalkyl, -CN, and -NO2; or
R5 and R6 taken together can form a 3-8 membered cycloalkyl or a
heterocyclic ring system, wherein the heterocyclic ring system may have from
3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from
1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms
on the heterocyclic ring system may be independently replaced with a member
selected from the group consisting of halo, C1-C4-alkyl, -CN -C1-4alkyl, -C2.
6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3-8cycloalkyl and -NO2;
Q is a member selected from the group consisting of:
a direct link, -CH2-, -C(=O)-, -O-, -NH-, -NMe-, -NHCH2-, -NMeCH2-, -
CH2NH-, -C(=NH)-, -C(=O)-NH-, -NH-C(=O)-, -CH2NMe-, -C(=NMe)-;
D is a direct link or is a member selected from the group consisting of:
(a) phenyl, which is independently substituted with 0-2 R1a substitutuents;

(b) naphthyl, which is independently substituted with 0-2 R1a
substitutuents; and
a monocyclic or fused bicyclic heterocyclic ring system having from 5
to 10 ring atoms, wherein 1-4 ring atoms of the ring system are
selected from N, O and S, and wherein the ring system may be
subsituted from 0-2 R1a substitutuents;
R1a is selected from:
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -CN, -NO2, -(CH2)nNR2aR3a -(CH2)nCO2R2a -(CH2)nCONR2aR3a
-SO2NR2aR3a, -SO2R2a, -CF3, -OR2a, and a 5-6 membered aromatic heterocyclic
system containing from 1-4 heteroatoms selected from N, O and S, wherein
from 1-4 hydrogen atoms on the aromatic heterocyclic system may be
independently replaced with a member selected from the group consisting of
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -CN and -NO2.
R2a and R3a are independently selected from the group consisting of:
H, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
8cycloalkyl, -C0-4alkylphenyl and -C0-4alkylnaphthyl, wherein from 1-4
hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be
independently replaced with a member selected from the group consisting of
halo, -C1-4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycloalkyl, -C0-4alkylC3.
gcycloalkyl, -CN and -NO2;
n is an integer of 0-2;
E is a member selected from the group consisting of:
a direct link, -O-, -NH-, -CH2NH-, -NHCH2-, -NMe-, -NH-C(=O)-NH-, -
C(=O)-NH-, -NH-C(=0)-;
G is a member selected from the group consisting of:
(a) a C2-alkenyl group or a C3-8-cycloalkenyl group, wherein the alkenyl
group and cycloalkenyl group attachment points are the alkenyl carbon

atoms and wherein the C2-alkenyl group or C3-8-cycloalkenyl group is
substituted with 0-4 Rld groups;
(b) a phenylene group wherein the ring carbon atoms of the phenylene
group arc substituted with 0-4 Rld groups;
(c) a 3-8 membered a saturated, partially unsaturated or aromatic
monocyclic- heterocyclic ring system containing 1-4 heteroatoms
selected from N, O and S, wherein 0-4 ring atoms of the heterocyclic
ring may be substituted with 0-4 Rld groups; and,
(d) an 8-10 membered fused heterocyclic bicyclic ring system, containing
1-4 heteroatoms selected from N, O and S, wherein 0-4 ring atoms of
the fused bicyclic ring system may be substituted with 0-4 Rld groups;
Rld is a member selected from the group consisting of:

attached via the nitrogen atom to a carbon atom of a 5 to 6 membered
saturated, partially unsaturated or aromatic heterocyclic ring containing 1-4
heteroatoms selected from N, O and S, and a -(CH2)0-6- group attached to a 5-6
membered saturated, partially unsaturated or aromatic heterocyclic ring
containing 1-4 heteroatoms selected from N, O and S;
R5a, R2d, R3d and R4d are each independently a member selected from the group
consisting of:
H, C1-6-alkyl and C1-6-alkylaryl, -CN; -NO2; carbocylic aryl, -CN; -NO2; or

R2d and R3d taken together with the N atoms ther are independently attached
form a 5-7 membered saturated, partially unsaturated or aromatic heterocyclic
ring; or
R3d and R4d taken together with the N atom to which they are attached form a
5-8 membered saturated, partially unsaturated or aromatic heterocyclic ring
containing 1-4 heteroatoms selected from N, O and S;
J is a member selected from the group consisting of:
a direct link, -O-, -NH-, -NMe-, -C(=O)-NH-, -NH-C(=O)-;
X is a member selected from the group consisting of:
(a) phenyl substituted with 0-3 Rlc groups;
(b) naphthyl substituted with 0-3 R1e groups and
(c) a 6-membered aromatic heterocyclic ring system containing 1-3 N
atoms and having 0-3 ring atoms substituted with 0-3 Rle groups; and
(d) an 8-10 membered fused aromatic heterocyclic bicyclic ring system
containing 1-4 heteroatoms selected from N, O and S and 0-3 ring
atoms of the fused heterocyclic bicyclic ring system are substituted
with 0-3 R1e groups;


R10, R2e and R3c are each independently a member selected from the group consisting
of:
H; -C1-4-alkyl; -C1-2-alkyl-O-Rlg; -C0-2-alkyl-N(-R1g, -R2g);-C1.
4-alkyl-carbocyclic aryl; -C1-4-alkyl-heterocyclic; and R10 and R2e, or R2e and
R3e together with the N atom to which they are attached can form 5-8
membered heterocyclic ring containing 1-4 heteroatoms selected from N, O
and S which can be substituted with 0-2 Rlg groups;
R1g and R2g are indepedently a member selected from the group of:
H; halo; -C1-4-alkyl, a carbocyclic aryl group; a saturated, partially unsaturated
or aromatic heterocyclic group; -CN; -C(=O)-N(R3g,R4g); -C(=O)-OR3g; -NO2;
-(CH2)p-NR3gR4g; -SO2NR3gR4g; -SO2R3g; -CF3; and -(CH2)pOR3g;
p is an integer of 0-2;
R3g and R4g are each independently selected from the group consisting of:
H; C1-4-alkyl and -C0-4-alkyl-carbocyclic aryl;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
In a still further preferred embodiment the present invention provides a
compound according to the formula:
A-Q-D-E-G-J-X
wherein:
A is a member selected from the group consisting of:








and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
In another further preferred embodiment the present invention provides a
compound according to the formula:









In another preferred embodiment the present invention provides a compound
according to the formula:

wherein:
J is a member selected from the group consisting of:
-NHC(=O)-, -C(=O)NH-;
X is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.












Rle is a member selected from the group of:
F, -Cl, -Br, -OH, -Me and -OMe;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.
In another preferred embodiment the present invention provides a compound
of the following formulae, which illustrate the compounds having preferred
substituents for G, particularly when G is a pyrazole ring structure.


wherein:
R is a member selected from the group of:
-SO2-NH2, and -SO2Me;
Rla is a member selected from the group of:
H, -F, -Cl and Br;
Rld is a member selected from the group consisting of:
-H, -CH3, -CF3, -CN, -SO2NH2 and -SO2CH3; and
Rle is a member selected from the group of:
-Cl and -Br;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.

In another preferred embodiment the present invention provides a compound
of the following formulae, which illustrate the compounds having preferred
substituents for A-Q taken collectively when the remainder of the compound structur
has the one of the following two formulae:

and all pharmaceutically acceptable isomers, salts, hydrates, solvates and
prodrug derivatives thereof.









This invention also encompasses all pharmaceutically acceptable isomers,
salts, hydrates, solvates, and prodrug derivatives of the preferred compounds. In
addition, the preferred compounds can exist in various isomeric and tautomeric forms,
and all such forms are meant to be included in the invention, along with
pharmaceutically acceptable salts, hydrates, solvates, and prodrug derivatives of such
isomers and tautomers.
The compounds of this invention may be isolated as the free acid or base or
converted to salts of various inorganic and organic acids and bases. Such salts are
within the scope of this invention. Non-toxic and physiologically compatible salts are
particularly useful although other less desirable salts may have use in the processes of
isolation and purification.
A number of methods are useful for the preparation of the salts described
above and are known to those skilled in the art. For example, the free acid or free
base form of a compound of one of the formulas above can be reacted with one or
more molar equivalents of the desired acid or base in a solvent or solvent mixture in
which the salt is insoluble, or in a solvent like water after which the solvent is
removed by evaporation, distillation or freeze drying. Alternatively, the free acid or
base form of the product may be passed over an ion exchange resin to form the
desired salt or one salt form of the product may be converted to another using the
same general process.
Prodrug Derivatives of Compounds
This invention also encompasses prodrug derivatives of the compounds
contained herein. The term "prodrug" refers to a pharmacologically inactive
derivative of a parent drug molecule that requires biotransformation, either
spontaneous or enzymatic, within the organism to release the active drug. Prodrugs
are variations or derivatives of the compounds of this invention which have groups
cleavable under metabolic conditions. Prodrugs become the compounds of the
invention which are pharmaceutically active in vivo, when they undergo solvolysis
under physiological conditions or undergo enzymatic degradation. Prodrug
compounds of this invention may be called single, double, triple etc., depending on
the number of biotransformation steps required to release the active drug within the
organism, and indicating the number of functionalities present in a precursor-type

form. Prodrug forms often offer advantages of solubility, tissue compatibility, or
delayed release in the mammalian organism (see, Bundgard, Design of Prodrugs, pp.
7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of
Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA, 1992).
Prodrugs commonly known in the art include acid derivatives well known to
practitioners of the art, such as, for example, esters prepared by reaction of the parent
acids with a suitable alcohol, or amides prepared by reaction of the parent acid
compound with an amine, or basic groups reacted to form an acylated base derivative.
Moreover, the prodrug derivatives of this invention may be combined with other
features herein taught to enhance bioavailability.
As mentioned above, the compounds of this invention find utility as
therapeutic agents for disease states in mammals which have disorders of coagulation
such as in the treatment or prevention of unstable angina, refractory angina,
myocardial infarction, transient ischemic attacks, thrombotic stroke, embolic stroke,
disseminated intravascular coagulation including the treatment of septic shock, deep
venous thrombosis in the prevention of pulmonary embolism or the treatment of
reocclusion or restenosis of reperfused coronary arteries. Further, these compounds
are useful for the treatment or prophylaxis of those diseases which involve the
production and/or action of factor Xa/prothrombinase complex. This includes a
number of thrombotic and prothrombotic states in which the coagulation cascade is
activated which include but are not limited to, deep venous thrombosis, pulmonary
embolism, myocardial infarction, stroke, thromboembolic complications of surgery
and peripheral arterial occlusion.
Accordingly, a method for preventing or treating a condition in a mammal
characterized by undesired thrombosis comprises administering to the mammal a
therapeutically effective amount of a compound of this invention. In addition to the
disease states noted above, other diseases treatable or preventable by the
administration of compounds of this invention include, without limitation, occlusive
coronary thrombus formation resulting from either thrombolytic therapy or
percutaneous transluminal coronary angioplasty, thrombus formation in the venous
vasculature, disseminated intravascular coagulopathy, a condition wherein there is
rapid consumption of coagulation factors and systemic coagulation which results in
the formation of life-threatening thrombi occurring throughout the microvasculature

leading to widespread organ failure, hemorrhagic stroke, renal dialysis, blood
oxygenation, and cardiac catheterization.
The compounds of the invention also find utility in a method for inhibiting the
coagulation biological samples, which comprises the administration of a compound of
the invention.
The compounds of the present invention may also be used in combination with
other therapeutic or diagnostic agents. In certain preferred embodiments, the
compounds of this invention may be coadministered along with other compounds
typically prescribed for these conditions according to generally accepted medical
practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics,
including platelet aggregation inhibitors, tissue plasminogen activators, urokinase,
prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of the
present invention may act in a synergistic fashion to prevent reocclusion following a
successful thrombolytic therapy and/or reduce the time to reperfusion. These
compounds may also allow for reduced doses of the thrombolytic agents to be used
and therefore minimize potential hemorrhagic side-effects. The compounds of this
invention can be utilized in vivo, ordinarily in mammals such as primates, (e.g.
humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
The biological properties of the compounds of the present invention can be
readily characterized by methods that are well known in the art, for example by the in
vitro protease activity assays and in vivo studies to evaluate antithrombotic efficacy,
and effects on hemostasis and hematological parameters, such as are illustrated in the
examples.
Diagnostic applications of the compounds of this invention will typically
utilize formulations in the form of solutions or suspensions. In the management of
thrombotic disorders the compounds of this invention may be utilized in compositions
such as tablets, capsules or elixirs for oral administration, suppositories, sterile
solutions or suspensions or injectable administration, and the like, or incorporated intc
shaped articles. Subjects in need of treatment (typically mammalian) using the
compounds of this invention can be administered dosages that will provide optimal
efficacy. The dose and method of administration will vary from subject to subject and

be dependent upon such factors as the type of mammal being treated, its sex, weight,
diet, concurrent medication, overall clinical condition, the particular compounds
employed, the specific use for which these compounds are employed, and other
factors which those skilled in the medical arts will recognize.
Formulations of the compounds of this invention are prepared for storage or
administration by mixing the compound having a desired degree of purity with
physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in
sustained release or timed release formulations. Acceptable carriers or diluents for
therapeutic use are well known in the pharmaceutical field, and are described, for
example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R.
Gennaro edit. 1985). Such materials are nontoxic to the recipients at the dosages and
concentrations employed, and include buffers such as phosphate, citrate, acetate and
other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less
than about ten residues) peptides such as polyarginine, proteins, such as serum
albumin, gelatin, or immunoglobulins, hydrophilic polymers such as
polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or
arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose
or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar
alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic
surfactants such as Tween, Pluronics or polyethyleneglycol.
Dosage formulations of the compounds of this invention to be used for
therapeutic administration must be sterile. Sterility is readily accomplished by
filtration through sterile membranes such as 0.2 micron membranes, or by other
conventional methods. Formulations typically will be stored in lyophilized form or as
an aqueous solution. The pH of the preparations of this invention typically will be 3-
11, more preferably 5-9 and most preferably 7-8. It will be understood that use of
certain of the foregoing excipients, carriers, or stabilizers will result in the formation
of cyclic polypeptide salts. While the preferred route of administration is by injection,
other methods of administration are also anticipated such as orally, intravenously
(bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally,
transdermally or intraperitoneally, employing a variety of dosage forms such as
suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations
and topical formulations such as ointments, drops and dermal patches. The

compounds of this invention are desirably incorporated into shaped articles such as
implants which may employ inert materials such as biodegradable polymers or
synthetic silicones, for example, Silastic, silicone rubber or other polymers
commercially available.
The compounds of the invention may also be administered in the form of
liposome delivery systems, such as small uni lamellar vesicles, large unilamellar
vesicles and multilamellar vesicles. Liposomes can be formed from a variety of
lipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of this invention may also be delivered by the use of
antibodies, antibody fragments, growth factors, hormones, or other targeting moieties,
to which the compound molecules are coupled. The compounds of this invention may
also be coupled with suitable polymers as targetable drug carriers. Such polymers can
include polyvinylpyrrolidinone, pyran copolymer, polyhydroxy-propyl-
methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-
polylysine substituted with palmitoyl residues. Furthermore, compounds of the
invention may be coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example polylactic acid, polyglycolic acid,
copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
Polymers and semipermeable polymer matrices may be formed into shaped articles,
such as valves, stents, tubing, prostheses and the like.
Therapeutic compound liquid formulations generally are placed into a
container having a sterile access port, for example, an intravenous solution bag or vial
having a stopper pierceable by hypodermic injection needle.
Therapeutically effective dosages may be determined by either in vitro or in
vivo methods. For each particular compound of the present invention, individual
determinations may be made to determine the optimal dosage required. The range of
therapeutically effective dosages will be influenced by the route of administration, the
therapeutic objectives and the condition of the patient. For injection by hypodermic
needle, it may be assumed the dosage is delivered into the body's fluids. For other

routes of administration, the absorption efficiency must be individually determined for
each compound by methods well known in pharmacology. Accordingly, it may be
necessary for the therapist to titer the dosage and modify the route of administration as
required to obtain the optimal therapeutic effect. The determination of effective
dosage levels, that is, the dosage levels necessary to achieve the desired result, will be
readily determined by one skilled in the art. Typically, applications of compound are
commenced at lower dosage levels, with dosage levels being increased until the
desired effect is achieved.
The compounds of the invention can be administered orally or parenterally in
an effective amount within the dosage range of about 0.1 to 100 mg/kg, preferably
about 0.5 to 50 mg/kg and more preferably about 1 to 20 mg/kg on a regimen in a
single or 2 to 4 divided daily doses and/or continuous infusion.
Typically, about 5 to 500 mg of a compound or mixture of compounds of this
invention, as the free acid or base form or as a pharmaceutically acceptable salt, is
compounded with a physiologically acceptable vehicle, carrier, excipient, binder,
preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical
practice. The amount of active ingredient in these compositions is such that a suitable
dosage in the range indicated is obtained.
Typical adjuvants which may be incorporated into tablets, capsules and the
like are binders such as acacia, com starch or gelatin, and excipients such as
microcrystalline cellulose, disintegrating agents like com starch or alginic acid,
lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose,
or flavoring agents. When a dosage form is a capsule, in addition to the above
materials it may also contain liquid carriers such as water, saline, or a fatty oil. Other
materials of various types may be used as coatings or as modifiers of the physical
form of the dosage unit. Sterile compositions for injection can be formulated
according to conventional pharmaceutical practice. For example, dissolution or
suspension of the active compound in a vehicle such as an oil or a synthetic fatty
vehicle like ethyl oleate, or into a liposome may be desired. Buffers, preservatives,
antioxidants and the like can be incorporated according to accepted pharmaceutical
practice.

Preparation of Compounds
The compounds of the present invention may be synthesized by either solid or
liquid phase methods described and referenced in standard textbooks, or by a
combination of both methods. These methods are well known in the art. See,
Bodanszky, "The Principles of Peptide Synthesis", Hafner, et at., Eds., Springer-
Verlag, Berlin, 1984.
Starting materials used in any of these methods are commercially available
from chemical vendors such as Aldrich, Sigma, Nova Biochemicals, Bachem
Biosciences, and the like, or may be readily synthesized by known procedures.
Reactions are carried out in standard laboratory glassware and reaction vessels
under reaction conditions of standard temperature and pressure, except where
otherwise indicated.
During the synthesis of these compounds, the functional groups of the amino
acid derivatives used in these methods are protected by blocking groups to prevent
cross reaction during the coupling procedure. Examples of suitable blocking groups
and their use are described in "The Peptides: Analysis, Synthesis, Biology", Academic
Press, Vol. 3 (Gross, et al., Eds., 1981) and Vol. 9 (1987), the disclosures of which are
incorporated herein by reference.
Compounds according to the invention can be synthesized utilizing procedures
well known in the art. The reaction products are isolated and purified by conventional
methods, typically by solvent extraction into a compatible solvent. The products may
be further purified by column chromatography or other appropriate methods.
Compositions and Formulations
The compounds of this invention may be isolated as the free acid or base or
converted to salts of various inorganic and organic acids and bases. Such salts are
within the scope of this invention. Non-toxic and physiologically compatible salts are
particularly useful although other less desirable salts may have use in the processes of
isolation and purification.

A number of methods are useful for the preparation of the salts described
above and are known to those skilled in the art. For example, reaction of the free acid
or free base form of a compound of the structures recited above with one or more
molar equivalents of the desired acid or base in a solvent or solvent mixture in which
the salt is insoluble, or in a solvent like water after which the solvent is removed by
evaporation, distillation or freeze drying. Alternatively, the free acid or base form of
the product may be passed over an ion exchange resin to form the desired salt or one
salt form of the product may be converted to another using the same general process.

A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg,
preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from
about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compounds of this
invention may be administered several times daily, and other dosage regimens may
also be useful.

In practicing the methods of this invention, the compounds of this invention
may be used alone or in combination, or in combination with other therapeutic or
diagnostic agents. In certain preferred embodiments, the compounds of this
inventions may be coadministered along with other compounds typically prescribed
for these conditions according to generally accepted medical practice, such as
anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet
aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase,
streptokinase, heparin, aspirin, or warfarin. The compounds of this invention can be
utilized in vivo, ordinarily in mammals such as primates, such as humans, sheep,
horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.

The preferred compounds of the present invention are characterized by their
ability to inhibit thrombus formation with acceptable effects on classical measures of
coagulation parameters, platelets and platelet function, and acceptable levels of
bleeding complications associated with their use. Conditions characterized by
undesired thrombosis would include those involving the arterial and venous
vasculature.

With respect to the coronary arterial vasculature, abnormal thrombus
formation characterizes the rupture of an established atherosclerotic plaque which is
the major cause of acute myocardial infarction and unstable angina, as well as also
characterizing the occlusive coronary thrombus formation resulting from either
thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA).
With respect to the venous vasculature, abnormal thrombus formation
characterizes the condition observed in patients undergoing major surgery in the lower
extremities or the abdominal area who often suffer from thrombus formation in the
venous vasculature resulting in reduced blood flow to the affected extremity and a
predisposition to pulmonary embolism. Abnormal thrombus formation further
characterizes disseminated intravascular coagulopathy commonly occurs within both
vascular systems during septic shock, certain viral infections and cancer, a condition
wherein there is rapid consumption of coagulation factors and systemic coagulation
which results in the formation of life-threatening thrombi occurring throughout the
microvasculature leading to widespread organ failure.
The compounds of this present invention, selected and used as disclosed
herein, are believed to be useful for preventing or treating a condition characterized by
undesired thrombosis, such as (a) the treatment or prevention of any thrombotically
mediated acute coronary syndrome including myocardial infarction, unstable angina,
refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy
or post-coronary angioplasty, (b) the treatment or prevention of any thrombotically
mediated cerebrovascular syndrome including embolic stroke, thrombotic stroke or
transient ischemic attacks, (c) the treatment or prevention of any thrombotic syndrome
occurring in the venous system including deep venous thrombosis jr pulmonary
embolus occurring either spontaneously or in the setting of malignancy, surgery or
trauma, (d) the treatment or prevention of any coagulopathy including disseminated
intravascular coagulation (including the setting of septic shock or other infection,
surgery, pregnancy, trauma or malignancy and whether associated with multi-organ
failure or not), thrombotic thrombocytopenic purpura, thromboangiitis obliterans, or
thrombotic disease associated with heparin induced thrombocytopenia, (e) the
treatment or prevention of thrombotic complications associated with extracorporeal
circulation (e.g. renal dialysis, cardiopulmonary bypass or other oxygenation

procedure, plasmapheresis), (f) the treatment or prevention of thrombotic
complications associated with instrumentation (e.g. cardiac or other intravascular
catheterization, intra-aortic balloon pump, coronary stent or cardiac valve), and (g)
those involved with the fitting of prosthetic devices.
Anticoagulant therapy is also useful to prevent coagulation of stored whole
blood and to prevent coagulation in other biological samples for testing or storage.
Thus the compounds of this invention can be added to or contacted with any medium
containing or suspected to contain factor Xa and in which it is desired that blood
coagulation be inhibited, e.g., when contacting the mammal's blood with material
such as vascular grafts, stents, orthopedic prostheses, cardiac stents, valves and
prostheses, extra corporeal circulation systems and the like.
Without further description, it is believed that one of ordinary skill in the art
can, using the preceding description and the following illustrative examples, make and
utilize the compounds of the present invention and practice the claimed methods.
EXAMPLES
Examples of Chemical Production Process General Reaction Schemes

















Step 1: To a solution of 2-fluoro nitrobenzene (1.41 g, 10 mmol, 1.0 equiv) and 3-
hydroxybenzonitrile (1.19 g, 1.0 equiv) in 10 mL of DMF was added K2CO3 (2.76 g, 2
equiv). After stirring at 60°C for 3 h, the mixture was diluted with EtOAc and washed
with H2O. The organic layer was dried over MgSO4, filtered and evaporated to give 3-
(2-nitrophenoxy)benzonitrile (2.38 g, 99%). MS found for C13H9N2O3(M+H)+: 241.
Step 2: A solution of 3-(2-nitrophenoxy)benzonitrile (1.21 g, 5 mmol, 1.0 equiv) in
30 mL of EtOH was treated with SnCl22H2O (3.38 g, 3 equiv) at reflux for 4 h. The
volatile was evaporated and the residue was redissolved in EtOAc, washed with
saturated aqueous NaHCO3 and 1N NaOH. The organic layer was dried over MgSO4,
filtered and evaporated to give 3-(2-aminophenoxy)benzonitrile (1.04 g, 99%). MS
found for C13H11N2O (M+H)+: 211.
Step 3: A mixture of 3-(2-aminophenoxy)benzonitrile (210 mg, 1 mmol, 1.0 equiv), 4-
[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1 equiv), Bop reagent (880
mg, 2 equiv) and TEA (1.39 mL, 10 equiv) in 3 mL of DMF was stirred at rt
overnight. The mixture was diluted with EtOAc, washed with H2O. The organic layer
was dried over MgSO4, filtered and evaporated. Flash chromatography on silica gel
gave 3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)phenoxy)benzonitrile
(300 mg, 57%). MS found for C30H28N3O4S (M+H)+: 526.
Step 4: A stream of HCl(g) was bubbled through a 0°C solution of 3-(2-(4-[(2-t-
butylaminosulfonyl)phenyl]benzoylamino)phenoxy)benzonitrile (53 mg, 0.1 mmol) in
5 mL of methanol until saturation. The mixture was stirred at rt overnight and
evaporated. The resulting residue was treated with ammonium acetate (39 mg, 5

equiv) in 10 ml methanol at reflux temperature for 2 h. The solvent was removed at
reduced pressure and the crude benzamidine was purified by HPLC (C18 reversed
phase) eluting with 0.5% TFA in H2O/CH3CN to give 3-(2-(4-[(2-
aminosulfonyl)phenyl]benzoylamino) phenoxy)benzamidine (40 mg, 83%). MS found
for C26H23N4O4S (M+H)+: 487.

Step 1: A mixture of 3-(2-amino-4-fluorophenoxy)benzonitrile (230mg, 1 mmol, 1.0
equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic chloride (349 mg, 1 equiv),
pyridine (3 mL) in 10 mL of dichloromethane was stirred at rt overnight, washed with
H2O. The organic layer was dried over MgSO4, filtered and evaporated. Flash
chromatography on silica gel gave 3-(4-fluoro-2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) benzonitrile (495 mg,
91%). MS found for C30H27FNjO4S (M+H)+: 544.
Step 2: A stream of HCl(g) was bubbled through a 0°C solution of 3-(4-fluoro-2-(4-
[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) benzonitrile (55 mg,
0.1 mmol) in 5 mL of methanol until saturation. The mixture was stirred at rt
overnight and evaporated. The resulting residue was treated with ammonium acetate
(39 mg, 5 equiv) in 10 ml methanol at reflux temperature for 2 h. The solvent was
removed at reduced pressure and the crude benzamidine was purified by HPLC (C18
reversed phase) eluting with 0.5% TFA in H2O/CH3CN to give 3-(4-fluoro-2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) benzamidine (39 mg, 77%).
MS found for C26H22FN4O4S (M+H)+: 505.


Step 1: A mixture of 3-(2-amino-4-trifluoromethylphenoxy)benzonitrile (280 mg, 1
mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic chloride (349 mg, 1
equiv), pyridine (3 mL) in 10 mL of dichloromethane was stirred at rt overnight,
washed with H2O. The organic layer was dried over MgSO4, filtered and evaporated.
Flash chromatography on silica gel gave 3-(4-trifluoromethyl-2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) benzonitrile (529 mg,
89%). MS found for C31H27F3N3O4S (M+H)+: 594.
Step 2: A stream of HCl(g) was bubbled through a 0°C solution of 3-(4-
trifluoromethyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)
benzonitrile (59 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture was
stirred at rt overnight and evaporated. The resulting residue was treated with
ammonium acetate (39 mg, 5 equiv) in 10 ml methanol at reflux temperature for 2 h.
The solvent was removed at reduced pressure and the crude benzamidine was purified
by HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN to give 3-(4-
trifluoromethyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)
benzamidine (35 mg, 63%). MS found for C27H22F3N4O4S (M+H)+: 555.


Step 1: A mixture of 3-(2-amino-4-methylsulfonylphenoxy)benzonitrile (290 mg, 1
mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic chloride (349 mg, 1
equiv), pyridine (3 mL) in 10 mL of dichloromethane was stirred at rt overnight,
washed with H2O. The organic layer was dried over MgSO4, filtered and evaporated.
Flash chromatography on silica gel gave 3-(4-methylsulfonyl-2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) benzonitrile (429 mg,
71%). MS found for C3lH30N3O6S2 (M+H)+: 604.
Step 2: A stream of HCl(g) was bubbled through a 0°C solution of 3-(4-
methylsulfonyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)
benzonitrile (60 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture was
stirred at rt overnight and evaporated. The resulting residue was treated with
ammonium acetate (39 mg, 5 equiv) in 10 ml methanol at reflux temperature for 2 h.
The solvent was removed at reduced pressure and the crude benzamidine was purified
by HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN to give 3-(4-
methylsulfonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)
benzamidine (27 mg, 47%). MS found for C27H2SN4O6S2 (M+H)+: 565.



Step 1: A solution of 3-(5-methoxy-2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino) phenoxy) benzamidine (52 mg, 0.1
mmol, 1 equiv) in 5 mL of methylene chloride was treated with BBr3 (1 M in
dichloromethane, 0.5 mL, 5 equiv) overnight. The reaction was quenched with water
carefully and after the volatile was evaporated, the aqueous residue was purified by
HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN to give 3-(5-
hydroxy-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)
benzamidine. (41 mg, 82%). MS found for C26H23N4O6S (M+H)+: 503.


Step 1: A mixture of 3-(2-amino-4-methoxycarbonylphenoxy)benzonitrile (270 mg, 1
mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic chloride (349 mg, 1
equiv), pyridine (3mL) in 10 mL of dichloromethane was stirred at rt overnight,
washed with H2O. The organic layer was dried over MgSO4, filtered and evaporated.
Flash chromatography on silica gel gave 3-(4-methoxycarbonyl-2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) benzonitrile (502 mg,
86%). MS found for C32H30N3O6S (M+H)+: 584.
Step 2: A stream of HCl(g) was bubbled through a 0°C solution of 3-(4-
methoxycarbonyl-2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) benzonitrile (58 mg, 0.1
mmol) in 5 mL of methanol until saturation. The mixture was stirred at rt overnight
and evaporated. The resulting residue was treated with ammonium acetate (39 mg, 5
equiv) in 10 ml methanol at reflux temperature for 2 h. The solvent was removed at
reduced pressure and the crude benzamidine was purified by HPLC (C18 reversed
phase) eluting with 0.5% TFA in H2O/CH3CN to give 3-(4-methoxycarbonyl-2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) benzamidine (29.5 mg, 54%).
MS found for C28H25N«O6S (M+H)+: 545.

A solution of 3-(4-methoxycarbonyl-2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) benzamidine (10.9 mg, 0.02
mmol, 1.0 equiv) in 5 mL of methanol was treated with IN LiOH (2 mL) at rt for 2 h.

Methanol was evaporated, the aqueous residue was subjected to HPLC with 0.5%
TFA in H2O/CH3CN to give 3-(4-hydroxycarbonyl-2-(4-[(2-
aminosulfonyl)phenyl3phenylcarbonylamino)phenoxy) benzamidine (8.9 mg, 84%).
MS found for C27H23N4O6S (M+H)+: 531.

Step 1: A mixture of 3-(2-amino-phenylamino)benzonitrile (196 mg, 1 mmol, 1.0
equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic chloride (349 mg, 1 equiv),
pyridine (3 mL) in 10 mL of dichloromethane was stirred at it overnight, washed with
H2O. The organic layer was dried over MgSO4, filtered and evaporated. Flash
chromatography on silica gel gave 3-(2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylcarbonylamino) phenylamino) benzonitrile (226
mg, 43%). MS found for C30H29N4O3S (M+H)+: 525.
Step 2: A stream of HCl(g) was bubbled through a 0°C solution of 3-(2-(4-[(2-t-
butylaminosulfony1)phenyl]phenylcarbonylamino)pheylamino) benzonitrile (53 mg,
0.1 mmol) in 5 mL of methanol until saturation. The mixture was stirred at rt
overnight and evaporated. The resulting residue was treated with ammonium acetate
(39 mg, 5 equiv) in 10 ml methanol at reflux temperature for 2 h. The solvent was
removed at reduced pressure and the crude benzamidine was purified by HPLC (C18
reversed phase) eluting with 0.5% TFA in H2O/CH3CN to give 3-(2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)pheylamino) benzamidine (27 mg, 55%).
MS found for C26H24N5O3S (M+H)+: 486.


Step 1: A mixture of 7-(2-aminophenoxy)isoquinoline (237 mg, 1 mmol, 1.0 equiv),
4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1 equiv), Bop reagent (880
mg, 2 equiv) and TEA (1.39 mL, 10 equiv) in 3 mL of DMF was stirred at rt
overnight. The mixture was diluted with EtOAc, washed with H2O. The organic layer
was dried over MgSO4, filtered and evaporated. Flash chromatography on silica gel
gave 7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)phenoxy)isoquinoline
(469 mg, 85%). MS found for C32H30N3O4S (M+H)+: 552.
Step 2: A solution of 7-(2-(4-[(2-t-
butylaminosulfonyl)phenyl]benzoylamino)phenoxy) isoquinoline (110 mg, 0.2 mmol,
1 equiv) in 5 mL of acetone was treated with mCPBA (113 mg, 57%, 1.5 equiv) until
HPLC showed complete reaction. Acetone was evaporated, the residue was
partetioned between methylene chloride and saturated aqueous NaHCO3. The organic
layer was dried ove MgSO4 and used in the next step directly.
Step 3: The compound obtained in step 2 in 5 mL of pyridine was treated with tosyl
chloride (46 mg, 1.2 equiv) at rt overnight and pyridine was removed under reduced
pressure. The residue was reacted with 5 mL of ethanolamine for 12 h, and partitioned
between methylene chloride and water. The organic layer was dried over MgSO4,
filtered, evaporated and refluxed in 3 mL of trifluoroacetic acid for 30 min. After
removing TFA, the crude was purified by HPLC (C18 reversed phase) eluting with
0.5% TFA in H2O/CH3CN to give 7-(2-(4-[(2-
aminosulfonyl)phenyl]benzoylamino)phenoxy)-l-aminoisoquinoline (43 mg, 42%).
MS found for C28H23N4O4S (M+H)+: 511.


Step 1: A mixture of 7-(2-amino-4-fluorophenoxy)isoquinoline (255 mg, 1 mmol, 1.0
equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1 equiv), Bop
reagent (880 mg, 2 equiv) and TEA (1.39 mL, 10 equiv) in 3 mL of DMF was stirred
at rt overnight. The mixture was diluted with EtOAc, washed with H2O. The organic
layer was dried over MgSO4, filtered and evaporated. Flash chromatography on silica
gel gave 7-(2-(4- [(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-fluorophenoxy)
isoquinoline (467 mg, 82%). MS found for C32H29FN3O4S (M+H)+: 570.
Step 2: A solution of 7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-
fluorophenoxy) isoquinoline (114, 0.2 mmol, 1 equiv) in 5 mL of acetone was treated
with mCPBA (113 mg, 57%, 1.5 equiv) until HPLC showed complete reaction.
Acetone was evaporated, the residue was partetioned between methylene chloride and
saturated aqueous NaHCO3. The organic layer was dried ove MgSO4 and used in the
next step directly.
Step 3: The compound obtained in step 4 in 5 mL of pyridine was treated with tosyl
chloride (46 mg, 1.2 equiv) at rt overnight and pyrine was removed under reduced
pressure. The residue was reacted with 5 mL of ethanolamine for 12 h, and partitioned
between methylene chloride and water. The organic layer was dried over MgSO4,
filtered, evaporated and refluxed in 3 mL of trifluoroacetic acid for 30 min. After
removing TFA, the crude was purified by HPLC (C18 reversed phase) eluting with
0.5% TFA in H2O/CH3CN to give 7-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)-


Step 1: A mixture of 7-(2-amino-4-trifluoromethylphenoxy)isoquinoline (305 mg, 1
mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1 equiv),
Bop reagent (880 mg, 2 equiv) and TEA (1.39 mL, 10 equiv) in 3 mL of DMF was
stirred at rt overnight. The mixture was diluted with EtOAc, washed with H2O. The
organic layer was dried over MgSO4, filtered and evaporated. Flash chromatography
on silica gel gave 7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-
trifluoromethylphenoxy) isoquinoline (360 mg, 58%). MS found for C33H29F3N3O4S
(M+H)+: 620.
Step 2: A solution of 7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-
trifluoromethylphenoxy) isoquinoline (124 mg, 0.2 mmol, 1 equiv) in 5 mL of acetone
was treated with mCPBA (113 mg, 57%, 1.5 equiv) until HPLC showed complete
reaction. Acetone was evaporated, the residue was partetioned between methylene
chloride and saturated aqueous NaHCO,. The organic layer was dried ove MgSO4 and
used in the next step directly.
Step3: The compound obtained in step 4 in 5 mL of pyridine was treated with tosyl
chloride (46 mg, 1.2 equiv) at rt overnight and pyrine was removed under reduced
pressure. The residue was reacted with 5 mL of ethanolamine for 12 h, and partitioned
between methylene chloride and water. The organic layer was dried ove MgSO4,
filtered, evaporated and refluxed in 3 mL of trifluoroacetic acid for 30 min. After

removing TFA, the crude was purified by HPLC (C18 reversed phase) eluting with
0.5% TFA in H2O/CH3CN to give 7-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)-
4-trifluoromethylphenoxy)l-aminoisoquinoline (64 mg, 52%). MS found for
C29H22F3N4O4S (M+H)+: 579.

Step 1: A mixture of 7-(2-amino-4-methylsulfonylphenoxy)isoquinoline (315 mg, 1
mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1 equiv),
Bop reagent (880 mg, 2 equiv) and TEA (1.39 mL, 10 equiv) in 3 mL of DMF was
stirred at it overnight. The mixture was diluted with EtOAc, washed with H2O. The
organic layer was dried over MgSO4, filtered and evaporated. Flash chromatography
on silica gel gave 7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-
methlsulfonylphenoxy) isoquinoline (460 mg, 73%). MS found for C33H32N3O6S2
(M+H)+: 630.
Step 2: A solution of 7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-
methlsulfonylphenoxy) isoquinoline (126 mg, 0.2mmol, 1 equiv) in 5 mL of acetone
was treated with mCPBA (113 mg, 57%, 1.5 equiv) until HPLC showed complete
reaction. Acetone was evaporated, the residue was partetioned between methylene
chloride and saturated aqueous NaHCO3. The organic layer was dried ove MgSO4 and
used in the next step directly.
Step 3: The compound obtained in step 4 in 5 mL of pyridine was treated with tosyl
chloride (46 mg, 1.2 equiv) at rt overnight and pyrine was removed under reduced

pressure. The residue was reacted with 5 mL of ethanolamine for 12 h, and partitioned
between methylene chloride and water. The organic layer was dried over MgSO4,
filtered, evaporated and refluxed in 3 mL of trifluoroacetic acid for 30 min. After
removing TFA, the crude was purified by HPLC (C18 reversed phase) eluting with
0.5% TFA in H2O/CH3CN to give 7-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)-
4-methylsulfony!phenoxy)l-aminoisoquinoline (94 mg, 80%). MS found for
C29H25N4O6S2 (M+H)+: 589.

Step 1: A solution of 2-fluoro-5-nitrobenzoic acid (1.85 g, 10 mmol, 1.33 equiv) in
thionyl chloride (5 mL) was refluxed for 2 h and evaporated. The residue was
redissolved in 20 mL of methylene chloride and to the solution were added 4-[(2-t-
butylaminosulfonyl)phenyl]aniline (2.0 g, 1.0 equiv) and 5 mL of pyridine. After
stirring at rt overnight, the volatile was evaporated. Flash chromatography on silica
gel l-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl)-2-fluoro-5-
nitrobenzene (2.9 g, 99%). MS found for C23H23FN3O5S (M+H)+: 472.
Step 2: To a solution of l-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl)-
2-fluoro-5-nitrobenzene (1.18 g, 0.25 mmol, 1.0 equiv) and 3-hydroxybenzonitrile
(298 mg, 1.0 equiv) in 10 mL of DMF was added K2CO3 (691 mg, 2 equiv). After
stirring at 60°C for 3 h, the mixture was diluted with StOAc and washed with H2O.
The organic layer was dried over MgSO4, filtered, evaporated and chromatographied
to give 3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-
nitrophenoxy) benzonitrile(950 g, 63%). MS found for C30H27N4O6S (M+H)+: 571.

Step 3: A stream of HCl(g) was bubbled through a 0°C solution of 3-(2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-nitrophenoxy)benzonitrile (57
mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture was stirred at rt
overnight and evaporated. The resulting residue was treated with ammonium acetate
(39 mg, 5 equiv) in 10 ml methanol at reflux temperature for 2 h. The solvent was
removed at reduced pressure and the crude was purified by HPLC (C18 reversed
phase) eluting with 0.5% TFA in H2O/CH3CN to 3-(2-(4-[(2-
aminosulfonyl)phenyl]phenylaminocarbonyl-4-nitrophenoxy) benzamidine (24 mg,
45%). MS found for C24H22N5O6S (M+H)+: 532.

A mixure of 3-(2-(4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl-4-nitrophenoxy)
benzamidine (53 mg, 0.1 mmol, 1 equiv), 5 mL of IN HC1, 5 mg of Pd/C (10%) in 10
mL of methanol was stirred at rt under 1 atm H2 atomosphere overnight. After
filtration through a thin layer of Celite and removal of the volatile, the aqueous
residue was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in
H2O/CH3CN to 3-(2-(4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl-4-
aminophenoxy) benzamidine (31 mg, 66%). MS found for C26H24N5O4S (M+H)+: 502.


Step 1: A mixure of 3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylammocarbonyl-4-
nitrophenoxy) benzonitrile (570 mg, 1 mmol, 1 equiv) and SnCl2.2H2O (677 mg, 3
equiv) in 25 mL of EtOAc was refluxed for 2 h. The reaction was quenched with sat.
NaHCO3. The organic layer was separated and dried over MgSO4, filtered and
evaporated to give 3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-
aminophenoxy) benzonitrile (45 mg, 83%). MS found for C30H29N4O4S (M+H)+: 541.
Step 2: A mixure of t-BuNO2 (21 mg, 0.1 mmol, 2 equiv), CuCl (20 mg, 2 equiv) in 5
mL of acetonitrile was refluxed for 10 min. To the solution was added 3-(2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylarninocarbonyl-4-aminophenoxy) benzonitrile (54
mg, 0.1 mmol, 1 equiv). The mixture was refluxed for 1h and evaporated. Flash
chromatography with 1:2 EtOAc/hexane to give [(2-t-
butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-chlorophenoxy) benzonitrile (43
mg, 77%)MS found for C30H27C1N3O4S (M+H)+: 561.
Step 3: A stream of HCl(g) was bubbled through a 0°C solution of 3-(2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-chlorophenoxy) benzonitrile (56
mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture was stirred at rt
overnight and evaporated. The resulting residue was treated with ammonium acetate
(40 mg, 5 equiv) in 10 ml methanol at reflux temperature for 2 h. The solvent was
removed at reduced pressure and the crude was purified by HPLC (C18 reversed
phase) eluting with 0.5% TFA in H2O/CH3CN to 3-(2-(4-[(2-
aminosulfonyl)phenyl]phenylaminocarbonyl-4-chlorophenoxy) benzamidine (47 mg,
84%). MS found for C26H22C1N4O4S (M+H)+: 521.


This compound is prepared according to the procedure described in example 19. MS
found for C26H22BrN4O4S (M+H)+: 565.

A mixture of 2-bromo-6-(2-aminophenoxy) naphthalene (314 mg, 1 mmol, 1.0 equiv),
4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride (349 mg, 1 equiv), pyridine (3
mL) in 10 mL of dichloromethane was stirred at rt overnight, washed with H2O. The
organic layer was dried over MgSO4, filtered, evaporated and refluxed in 2 mL of
trifiuoroacetic acid for 30 min. TFA was then evaporated and HPLC (C18 reversed
phase) eluting with 0.5% TFA in H2O/CH3CN gave 2-bromo-6-(2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy naphthalene (378 mg, 66%).
MS found for C29H22BrN2O4S (M+H)+: 573.


A mixture of 3-methoxycarbonyl-2-(2-aminophenoxy) (294 mg, 1 mmol, 1.0 equiv),
4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride (349 mg, 1 equiv), pyridine (3
mL) in 10 mL of dichloromethane was stirred at rt overnight, washed with H2O. The
organic layer was dried over MgSO4, filtered, evaporated and refluxed in 2 mL of
trifluoroacetic acid for 30 min. TFA was then evaporated and HPLC (C18 reversed
phase) eluting with 0.5% TFA in H2O/CH3CN gave 3-methoxycarbonyl-2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy naphthalene (420 mg, 76%).
MS found for C31H25N2O6S (M+H)+: 553.

A solution of 3-methoxycarbonyl-2-(4-methylsulfonyl-2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) naphthalene (55 mg, 0.1
mmol, 1.0 equiv) in 5 mL of methanol was treated with 1N LiOH (2 mL) at rt for 2 h.

Methanol was evaporated, the aqueous residue was subjected to HPLC with 0.5%
TFA in H2O/CH3CN to give 3-hydroxycarbonyl-2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy naphthalene (47 mg, 88%). MS
found for C30H23N2O6S (M+H)+: 539.

Step 1: A solution of 3-methoxycarbonyl-2-(4-methylsulfonyl-2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) naphthalene (40 mg,
0.066 mmol) in 5 mL of methanol was treated with 1N LiOH (2 mL) at rt for 2 h.
Methanol was evaporated, and acidified with IN HC1 until PH ~ 1-2. The product (39
mg, 100%), 3-hydroxycarbonyl-2-(4-methylsulfonyl-2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) naphthalene, was
extracted with EtOAc, dried over MgSO4, filtered and evaporated. MS found for
C34H31N2O6S (M+H)+: 595.
Step 2: A solution of 3-hydroxycarbonyl-2-(4-methylsulfonyl-2-(4-[(2-t-
buty1aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy) naphthalene (39 mg,
0.066 mmol) was refluxed in 3 mL of thionyl chloride for 2 h and evaporated. The
residue was then stirred in 5 mL of 2M ammonia in methanol overnight. The volatile
was evaporated and the residue was refluxed in 2 mL of trifluoroacetic acid overnight
to give the product 3-aminocarbonyl-2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy naphthalene (14 mg, 39%) after
HPLC (C18 reversed phase, eluting with 0.5% TFA in H2O/CH3CN). MS found for
C30H24N3O5S (M+H)+: 538.


A mixture of 2-(2-aminophenoxy)-3-methoxycarbonyl-6-bromo naphthalene (372 mg,
1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride (349 mg, 1
equiv), pyridine (3 mL) in 10 mL of dichloromethane was stirred at rt overnight,
washed with H2O. The organic layer was dried over MgSO4, filtered, evaporated and
refluxed in 2 mL of trifluoroacetic acid for 30 min. TFA was then evaporated and
HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN gave 3-
methoxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy-6-
bromo naphthalene (423 mg, 67%). MS found for C31H24BrN2O6S (M+H)+: 631.


A solution of 3-methoxycarbonyl-2-(4-methylsulfonyl-2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)-6-bromo naphthalene (63 mg,
0.1 mmol, 1.0 equiv) in 5 mL of methanol was treated with 1N LiOH (2 mL) at rt for
2 h. Methanol was evaporated, the aqueous residue was subjected to HPLC with 0.5%
TFA in H2O/CH3CN to give 3-hydroxycarbonyl-2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy-6-bromo naphthalene (47 mg,
78%). MS found for C30H22BrN2O6S (M+H)+: 617.

Step 1: A solution of 2-ntrobenzoyl chloride (3.70 g, 20 mmol, 1.0 equiv), 2-amino-5-
bromopyridine (3.50 g, 1.0 equiv), pyridine (10 mL) in 25 mL of methylene chloride
was stirred overnight. The volatile was evaporated, flash chromatography on silica gel
gave N-(5-bromo-2-pyridinyl)-(2-nitro)phenylcarboxamide (5.02 g, 77%). MS found
for C12H9BrN3O3 (M+H)+: 322.
Step 2: A solution of N-(5-bromo-2-pyridinyl)-(2-nitro)phenylcarboxamide (1.0 g, 3.1
mmol, 1.0 equiv) in 30 mL of EtOAc was treated with SnCl22H2O (2.80 g, 4 equiv)
at reflux for 4 h. The volatile was evaporated and the residue was redissolved in
EtOAc, washed with saturated aqueous NaHCO3 and 1N NaOH. The organic layer
was dried over MgSO4, filtered and evaporated to N-(5-bromo-2-pyridinyl)-(2-
amino)phenylcarboxamide (0.89 g, 98%). MS found for Cl2H11BrN3O (M+H)+: 292.
Step 3: A mixture of N-(5-bromo-2-pyridinyl)-(2-amino)phenylcarboxamide (292 mg,
1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride (349 mg, 1
equiv), pyridine (3 mL) in 10 mL of dichloromethane was stirred at rt overnight,

washed with H2O. The organic layer was dried over MgSO4, filtered, evaporated and
refluxed in 2 mL of trifluoroacetic acid for 30 min; TFA was then evaporated and
HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN gave N-(5-
bromo-2-pyridinyl)-(2-4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenylcarboxamide (470 mg, 85%). MS
found for C25H20BrN4O4S (M+H)+: 551.

A mixture of N-(5-chloro-2-pyridinyl)-(2-amino)phenylcarboxamide (247 mg, 1
mmol, 1.0 equiv), 4-[(2-t-burylarninosulfonyl)phenyl]benzoyl chloride (349 mg, 1
equiv), pyridine (3 mL) in 10 mL of dichloromethane was stirred at rt overnight,
washed with H2O. The organic layer was dried over MgSO4, filtered, evaporated and
refluxed in 2 mL of trifluoroacetic acid for 30 min. TFA was then evaporated and
HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN gave N-(5-
chloro-2-pyridinyl)-(2-4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)phenylcarboxarnide (370 mg, 73%). MS
found for C25H20ClN4O4S (M+H)+: 507.


Step 1: To a mixture of 2-bromothioanisole (4.8g, 23.6mmol), 4-
carboxybenzeneboronic acid (3.92g, 23.6mmol) and 2M K2CO3 (35.5mmol, 71mmol)
in dioxane (20ml) was added dichlorobis(triphenylphosphine)palladium (II) (415mg,
0.6mmol) under Ar. It was refluxed for 2hrs. After the removal of the solvent, the
residue was neutralized by 1N HC1 and extracted with dichloromethane. The organic
layer was dried over MgSO4 and concentrated in vacuo to give 4-[(2-
methylthio)phenyl]benzoic acid (5.9g, 100%). ES-MS (M+H)+=245.
Step 2: To a solution of 4-[(2-methylthio)phenyl]benzoic acid (3.43g, 14mmol) in
H2O (10ml) and acetone (20ml) was added oxone monopersulfate (34.6g, 56mmol).
The mixture was stirred at r.t. overnight. After the removal of the solvent, the residue
was extracted with ethyl acetate. The organic layer was dried over MgSO4 and
concentrated in vacuo to give 2.16g (63%) 4-[(2-methylsulfonyl)phenyl]benzoic acid.
ES-MS (M+H)+=277.
Step 3: To a solution of 4-[(2-methylsulfonyl)phenyl]benzoic acid (552mg, 2mmol) in
dichlpromethane (5ml) was added oxalyl chloride (350ul, 4mmol) and 2 drops of
DMF. The mixture was stirred at r.t. for 2 hrs. After the removal of the solvent in
vacuo, the residue was dissolved in dichloromethane (5ml), N-(5-bromo-2-pyridinyl)-
(2-amino)phenylcarboxamide (700mg, 2.4mmol), pyridine (486ul, 6mmol) and
catalytic amount of DMAP were added. The mixture was stirred at r.t. overnight.
After the removal of the solvent, the residue was purified by flash column (30% ethyl
acetate/hexane) and then preparative HPLC to get 414mg (38%) of N-(5-bromo-2-
pyridinyl)-(2-(4-[(2-

methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide. ES-MS M+=550,
(M+2)+=552.

To a solution of 4-[(2-methylsulfonyl)phenyl]benzoic acid (280 mg, 1 mmol) in
dichloromethane (5ml) was added oxalyl chloride (175 ul, 2 mmol) and 2 drops of
DMF. The mixture was stirred at r.t. for 2 hrs. After the removal of the solvent in
vacuo, the residue was dissolved in dichloromethane (5ml), N-(5-chloro-2-pyridinyl)-
(2-amino)phenylcarboxamide (297mg, 1.2 mmol), pyridine (243ul, 3 mmol) and
catalytic amount of DMAP were added. The mixture was stirred at r.t. overnight.
After the removal of the solvent, the residue was purified by flash column (30% ethyl
acetate/hexane) and then preparative HPLC to get 95 mg (20%) of N-(5-chloro-2-
pyridinyl)-(2-(4-[(2-
methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide. ES-MS
M+=505.5, (M+2)+=507.5.


A sample of 4-[(2-methylsulfonyl)phenyl]benzoic acid (280 mg, 1 mmol, 1 equiv)
was refluxed with 2 mL of thionyl chloride for 2 h and evaporated. The residue was
dissolved in 5 mL of dichloromethane, N-(4-bromo-2-methoxycarbonyphenyl)-(2-
amino)phenylcarboxamide (348 mg,l equiv), pyridine (3 mL) were added. The
mixture was stirred at r.t. overnight. After the removal of the solvent, the residue was
purified by flash column to give 480 mg (79%) of N-(4-bromo-2-
methoxycarbonyphenyl)-(2-(4-[(2-
methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide. MS found for
C29H24BrN2O6S (M+H)+: 607.

A sample of 4-[(2-methylsulfonyl)phenyl]benzoic acid (280 mg, 1 mmol, 1 equiv)
was refluxed with 2 mL of thionyl chloride for 2 h and evaporated. The residue was
dissolved in 5 mL of dichloromethane, N-(4-chloro-2-methoxycarbonyphenyl)-(2-
amino)phenylcarboxamide (304 mg,l equiv), pyridine (3 mL) were added. The
mixture was stirred at r.t. overnight. After the removal of the solvent, the residue was
purified by flash column to give 479 mg (85%) of N-(4-chloro-2-
methoxycarbonyphenyl)-(2-(4-[(2-
methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide. MS found for
C29H24C1N2O6S (M+H)+: 563.


Step 1: A solution of 2-aminopyridine-3-carboxylic acid (138 mg, 1 mmol) in 10 mL
of methanol was treated with thionyl chloride in portions until complete reaction. The
solvent was evaporated and the residue was dissolved in 10 mL of pyridine. To the
solution were added 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid and POC13. The
resulting mixture was stirred at rt overnight, quenched by slow addition of water, and
extracted with EtOAc. The organic layer was dried over MgSO4, filtered and flash
chromatographied to give methyl 2-(4-[(2-t-
butylaminosul fonyl)phenyl]phenylcarbonyl)aminopyridine-3 -carboxylate (243 mg,
52%). MS found for C24H26N3O5S (M+H)+: 468.
Step 2: To A solution of 2-amino-5-bromopridine (45 mg, 4.0 equiv) in 5 mL of
methylene chloride treated with AlMe3 (2M in hexane, 0.65 mL, 20 equiv) for 30 min
was added methyl 2-(4-[(2-t-
butylaminosulfonyl)phenyl]phenylcarbonyl)aminopyridine-3-carboxylate(30mg,
0.064 mmol, 1 equiv). The mixture was stirred at rt overnight, quenched with
saturated aqueous potassium sodium tartrate. The organic layer was dried over
MgSO4, filtered, evaporated and refluxed in 2 mL of trifluoroacetic acid for 30 min.
TFA was then evaporated and HPLC (C18 reversed phase) eluting with 0.5% TFA in
H2O/CH3CN gave N-(5-bromo-2-pyridinyl)-(2-4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-3-carboxamide (17 mg, 48%).
MS found for C24HI9BrN5O4S (M+H)+: 552.


To A solution of 2-amino-5-chloropridine (32 mg, 4.0 equiv) in 5 mL of methylene
chloride treated with AlMe3 (2M in hexane, 0.65 mL, 20 equiv) for 30 min was added
methyl 2-(4- [(2-t-buty laminosulfonyl)phenyl]phenylcarbonyl)aminopyridine-3 -
carboxylate (30 mg, 0.064 mmol, 1 equiv). The mixture was stirred at rt overnight,
quenched with saturated aqueous potassium sodium tartrate. The organic layer was
dried over MgSO4, filtered, evaporated and refluxed in 2 mL of trifluoroacetic acid for
30 min. TFA was then evaporated and HPLC (C18 reversed phase) eluting with 0.5%
TFA in H2O/CH3CN gave N-(5-chloro-2-pyridinyl)-(2-4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-3-carboxamide (21 mg, 66%).
MS found for C24H19C1N5O4S (M+H)+: 508.


To A solution of 2-amino-5-brornopridine (69.2 mg, 4.0 equiv) in 5 mL of methylene
chloride treated with AlMe3 (2M in hexane, 1 mL, 20 equiv) for 30 min was added 3-
(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonyl)aminopyridine-2-carboxylate
(46.7 mg, 1 equiv). The mixture was stirred at rt overnight, quenched with saturated
aqueous potassium sodium tartrate. The organic layer was dried over MgSO4, filtered,
evaporated and refluxed in 2 mL of trifluoroacetic acid for 30 min. TFA was then
evaporated and HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN
gaveN-(5-bromo-2-pyridinyl)-(3-4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-2-carboxamide (29 mg, 53%).
MS found for C24H19BrN5O4S (M+H)+: 552.

To A solution of 2-amino-5-chloropridine (51.2 mg, 4.0 equiv) in 5 mL of methylene
chloride treated with AlMe3 (2M in hexane, 1 mL, 20 equiv) for 30 min was added 3-
(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonyl)aminopyridine-2-carboxylate
(46.7 mg, O.lmmol, 1 equiv). The mixture was stirred at rt overnight, quenched with
saturated aqueous potassium sodium tartrate. The organic layer was dried over
MgSO4, filtered, evaporated and refluxed in 2 mL of trifluoroacetic acid for 30 min.
TFA was then evaporated and HPLC (C18 reversed phase) eluting with 0.5% TFA in
H2O/CHjCN gave N-(5-chloro-2-pyridinyl)-(2-4-[(2-
aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-3-carboxamide (33 mg, 64%).
MS found for C24H19C1N5O4S (M+H)+: 508.


Step 1: A mixture of methyl 2-aminobenzoate (150 mg, 1 mmol, 1.0 equiv), 4-[(2-
methylsulfonyl)phenyl]benzoic chloride (294 mg, 1 equiv), pyridine (3 mL) in 10 mL
of dichloromethane was stirred at it overnight, washed with H2O. The organic layer
was dried over MgSO4, filtered and evaporated. Flash chromatography on silica gel
gave methyl 2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)aminobenzoate (250 mg,
54%). MS found for C25H27N2O5S (M+H)+: 467.
Step 2: To a solution of 4-bromo-2-ntroaniline (43.4 mg, 0.2 mmol, 2.0 equiv) in 5
mL of methylene chloride treated with AlMe3 (2M in hexane, 0.3 mL, 6 equiv) for 30

The compound N-(4-methoxyphenyl)-N'-(4-[(2-tert-butylaminosulfonyl)phenyl]
phenyl)-maleamic amide (40 mg, 79 mol) was dissolved in TFA (3 mL). It was
allowed to stand at room temperature overnight. TFA was removed in vacuo. The
residue was purified by HPLC using a gradient of 5% CH3CN in H2O (containing
0.1% TFA) to 95% CH3CN over 60 min. Fractions containing the desired product
were pooled, and lyophilized to give a powder (18 mg, yield: 51%). MS 452 (M + H)
and 474 (M + Na). 1H NMR (CDC13) 11.40 (br.s, 1H), 10.28 (br.s, 1H), 8.12 (d, 1H,
J = 8 Hz), 7.72 (d, 2H, J = 8 Hz), 7.60 - 7.20 (m, 9H), 6.86 (AB type, 2H), 6.45 (br.s,
2H), 3.79 (s, 3H).

To a solution of commercially available maleic acid monomethyl ester (277 mg, 2.13
mmol), 4-(2-tert-butylaminosulfonylphenyl)aniline (648 mg, 2.13 mmol) and
triethylamine (0.593 mL, 4.26 mmol) in CH2C12 (20 mL), BOP (1.13 g, 2.55 mmol)
was added. The mixture was stirred at room temperature overnight. More maleic acid
monomethyl ester (50 mg, 0.385 mmol) was added. It was stirred for 3 hours. The
CH2C12 solution was then washed with sat. NaHCO3, IN HC1 and sat. NaCl. The
solution was dried over Na2SO4, concentrated in vacuo. The residue was purified by a
silica gel column using a gradient of 10-40% EtOAc in hexane as solvents, to give the
titled compound (360 mg, yield: 41%). MS 361 (M + H - tBu) and 439 (M + Na).

min was added methyl 2-(4-[(2-
methylsulfonyl)phenyl]phenylcarbonyl)aminobenzoate (46.6 mg, 1 equiv). The
mixture was stirred at rt overnight, quenched with saturated aqueous potassium
sodium tartrate. The organic layer was dried over MgSO4, filtered and evaporated.
Flash chromatography on silica gel gave N-(4-bromo-2-nitrophenyl)-(2-(4-[(2-
methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide (5 mg, 9%). MS
found for C27H21BrN3O6S (M+H)+: 594.

A. Preparation of N-(4-methoxyphenyl)-N'-(4-[(2-tert-butylaminosulfonyl)phenyl]
phenyl)-maleamic amide.
To a solution of commercially available N-(4-methoxyphenyl)maleamic acid (100 mg,
0.452 mmol), triethylamine (0.126 mL, 0.906 mmol) and 4-(2-tert-
butylaminosulfonylphenyl)aniline (138 mg, 0.454 mmol) in anhydrous DMF (5 mL),
BOP (260 mg, 0.588 mmol) was added. The mixture was stirred at room temperature
overnight. Water and EtOAc were added. The organic phase was separated, washed
with H2O, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The
residue was purified by HPLC using a gradient of 20% CH3CN in H2O (containing
0.1% TFA) to 100% CH3CN over 80 min. Fractions containing the desired product
were pooled, and lyophilized to give a powder (70 mg, yield: 31%). MS 508 (M + H).
B. Preparation of N-(4-methoxyphenyl)-N'-(4-[(2-aminosulfonyl)phenyl]phenyl)-
maleamic amide.

B. Preparation of N-(4-bromophenyl)-N'-(4-[(2-aminosulfonyl)phenyl]phenyl)-
maleamic amide.
To a solution of 4-bromoaniline (93 mg, 0.543 mmol) in CH2C12 (5 mL) at room
temperature, trimethylaluminum (0.82 mL, 2.0 M in hexane, 1.64 mmol) was added
dropwise. After the solution was stirred for 30 min at room temperature, compound
N-(4-[(2-tert-butylaminosulfonyl)phenyl] phenyl)maleamic methyl ester (113 mg,
0.272 mmol) was added. The mixture was stirred at room temperature for 2 days. The
solution was neutralized with 1N HC1 to pH 2-3. Water and CH2C12 were added, and
organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue
was dissolved in TFA (4 mL). It was allowed to stand at room temperature overnight.
TFA was removed in vacuo. The residue was purified by HPLC using a gradient of
5% CH3CN in H2O (containing 0.1% TFA) to 95% CH3CN over 60 min. Fractions
containing the desired product were pooled, and lyophilized to give a powder (8 mg,
yield: 6%). MS 500 and 502 (M + H), 522 and 524 (M + Na). 1H NMR (CD3OD)
8.09 (d, 1H, J = 8 Hz), 7.68 (d, 2H, J = 8 Hz), 7.64 - 7.28 (m, 9H), 6.45 (AB type,
2H).

A. Preparation of N-(5-bromopyridin-2-yl)-methylmaleimide.
A mixture of citraconic anhydride (1.00 mL, 11.1 mmol) and 2-amino-5-
bromopyridine (1.93 g, 11.2 mmol) in toluene (60 mL) was heated to reflux overnight.

The solution was cooled down, filtered. The filtrate was concentrated in vacuo to give
a solid (2.10 g, yield: 71%). MS 267 and 269 (M + H).
B. Preparation of N1-(5-bromopyridin-2-yl)-N4-(4-[(2-aminosulfonyl)phenyl] phenyl)-
2-methylmaleamic amide and N1-(5-bromopyridin-2-yl)-N4-(4-[(2-
ammosulfonyl)phenyl]phenyl)-3-methylmaIeamic amide.
To the solution of 4-(2-aminosulfonyIphenyl)aniline (0.170 g, 0.685 mmol) in
CH2C12 (10 mL) at room temperature, trimethylaluminum (2.0 M in hexane, 2.00
mL, 4.00 mmol) was added dropwise, during which time, white gel-like precipitates
came out the solution. It was stirred for 30 min. A solution of N-(5-brornopyridin-2-
yl)-methylmaleimide (0.122 g, 0.457 mmol) in CH2C12 (5 mL) was added. It was
stirred for 1 hour, during which time the precipitates started to dissolve, and the
solution became clear. It was stirred for another 2 hours. 1N HC1 was added to
neutralize the solution to pH 2-3, which resulted in precipitation. The precipitates
were collected by filtration, dried on vacuum. The precipitates (75 mg, yield: 32%)
were a mixture of 2-methyl and 3-methylmaleamic amide isomers in a ratio of 1 : 5.
MS 515 and 517 (M + H), 537 and 539 (M + Na).

Step 1: A solution of 2-amino-4-nitrobenzoic acid (182 mg, 1 mmol, 1 equiv) in 10
mL of methanol was treated with thionyl chloride in portions until complete reaction.
The solvent was evaporated and the residue was dissolved in 10 mL of pyridine. To
the solution were added 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1

equiv) and POC13 (0.93 mL, 10 equiv). The resulting mixture was stirred at rt
overnight, quenched by slow addition of water, and extracted with EtOAc. The
organic layer was dried over MgSO4, filtered and flash chromatographied to give
methyl 2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonyl)amino-4-nitrobenzoate
(430 mg, 84%). MS found for C25H26N3O7S (M+H)+: 512.
Step 2: To A solution of 2-amino-5-bromopridine (135 mg, 4.0 equiv) in 5 mL of
methylene chloride treated with AlMe3 (2M in hexane, 1 mL, 10 equiv) for 30 min
was added methyl 2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonyl)amino-4-
nitrobenzoate (100 mg, 0.2 mmol, 1 equiv). The mixture was stirred at rt overnight,
quenched with saturated aqueous potassium sodium tartrate. The organic layer was
dried over MgSO4, filtered, evaporated and refluxed in 2 mL of trifluoroacetic acid for
30 min. TFA was then evaporated and HPLC (C18 reversed phase) eluting with 0.5%
TFA in H2O/CH3CN gave N-(5-bromo-2-pyridinyl)-(2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-nitrophenylcarboxamide(42mg,
36%). MS found for C25H19BrN5O6S (M+H)+: 596.



A solution of N-(5-bromo-2-pyridinyl)-(2-(4-[(2-t-
butylsulfonyl)phenyl]phenylcarbonyl) amino)-4-nitrophenylcarboxamide (65 mg, 0.1
mmol, 1 equiv) in 10 mL of EtOAc was treated with SnCl22H2O (90 m g, 4 equiv) at
reflux for 4 h. The volatile was evaporated and the residue was redissolved in EtOAc,
washed with saturated aqueous NaHCO3 and 1N NaOH. The organic layer was dried
over MgSO4, filtered and evaporated to give N-(5-bromo-2-pyridinyl)-(2-(4-[(2-t-
butylsulfonyl)phenyl]phenylcarbonyl) amino)-4-aminophenyl carboxamide, which
was refluxed with 2 mL of TFA for 1h. After removal of TFA by rotavap, the residue
was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN
to give N-(5-bromo-2-pyridinyl)-(2-(4-[(2-
aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-aminophenylcarboxamide (47 mg,
84%). MS found for C25H21BrN5O4S (M+H)+: 566.

This compound was prepared according to the procedure described in example 50. MS
found for C25H2IC1N5O4S (M+H)+: 522.

A solution of N-(5-bromo-2-pyridinyl)-(2-(4-[(2-t-
butylsulfonyl)phenyl]phenylcarbonyl) amino)-4-aminophenyl carboxamide (62 mg,
O.1mmol, 1 equiv) in 3 mL of CH2C12 was treated with MsCl (23 mg, 2 equiv) and
TEA (0.5 mL) at rt for 4 h. The mixture was washed with water and dried over
MgSO4, filtered and evaporated. The residue was refluxed with 2 mL of TFA for 1h.
After removal of TFA by rotavap, the residue was purified by HPLC (C18 reversed
phase) eluting with 0.5% TFA in H2O/CH3CN to give N-(5-bromo-2-pyridinyl)-(2-(4-
[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-
methylsulfonylaminophenylcarboxamide (33 mg, 52%). MS found for
C26H23BrN5O6S2 (M+H)+: 644.




Step 1: A mixture of N-(5-bromo-2-pyridinyl)-(2-amino)phenylcarboxarnide (292 mg,
1 mmol, 1.0 equiv), 4-cyano benzoyl chloride (165 mg, 1 equiv), pyridine (3 mL) in
10 mL of dichloromethane was stirred at rt overnight, washed with H2O. The organic
layer was dried over MgSO4, filtered, evaporated to give N-(5-bromo-2-pyridinyl)-(2-
(4-cyanophenylcarbonyl)amino)-phenylcarboxamide (349 mg, 70%). MS found for
C20H14BrN4O2 (M+H)+: 421.

Step 2: A stream of HCl(g) was bubbled through a 0°C solution of N-(5-bromo-2-
pyridinyl)-(2-(4-cyanophenylcarbonyl)amino)-phenylcarboxamide (49 mg, 0.1 mmol)
in 5 mL of methanol until saturation. The mixture was stirred at rt overnight and
evaporated. The resulting residue was treated with ammonium acetate (40 mg) in 10
ml methanol at reflux temperature for 2 h. The solvent was removed at reduced
pressure and the crude benzamidine was purified by HPLC (C18 reversed phase)
eluting with 0.5% TFA in H2O/CH3CN to give N-(5-bromo-2-pyridinyl)-(2-(4-
amidinophenylcarbonyl)arnino)-phenylcarboxamide (31 mg, 70%). MS found for
C20H17BrN5O2(M+H)+: 438.








resulting residue was treated with ethylene diamine (40 mg) in 10 ml methanol at
reflux temperature for 2 h. The solvent was removed at reduced pressure and the
crude benzamidine was purified by HPLC (C18 reversed phase) eluting with 0.5%
TFA in H2O/CH3CN to give N-(5-bromo-2-pyridinyl)-(2-(4-(2-
imidazolinyl)phenylcarbonyl)amino)-phenylcarboxamide (41 mg, 89%). MS found
for C22H19BrN5O2(M+H)+: 464.











A mixure of 3-(2-(4-[(2-t-
butylaminosulfonyl)phenyl]benzoylamino)phenoxy)benzonitrile (53 mg, 0.1 mmol)
(53 mg, 0.1 mmol, 1 equiv), 5 mg of Pd/C (10%) in 10 mL of methanol was stirred at
rt under 1 atm H2 atomosphere overnight. After filtration through a thin layer of Celite
and removal of the volatile, residue was refluxed in 2 mL of TFA for 1h, and purified
by HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN to 3-(2-(4-[(2-
aminosulfonyl)phenyl]benzoylamino) phenoxy)benzylamine (13 mg, 27%). MS found
for C26H24N3O4S (M+H)+: 474.

Step 1: To a solution of 2-amino-5-chloropyridine (328mg, 2.55mmol) in
tetrahydrofuran (5ml) was 0.5M potassium bis(trimethylsilyl)amide in toluene (10ml,
5.05mmol) dropwise at -78 °C. After stirred for additional 0.5hr at -78 °C, the mixture
was added 5-chloroisatoic anhydride (0.5g, 2.55mmol) at -78 °C. The mixture was
warmed up to r.t gradually and stirred overnight. After quenched by saturated
ammonium chloride solution, the mixture was extracted by ethyl acetate. The organic
layer was dried over magnesium sulfate and concentrated to give (2-amino-5-
chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide (0.7 lg. 100%). MS found for
C12H9C12N3O M+=282, (M+2)+=284.

Step 2: To a solution of the compound of (2-amino-5-chlorophenyl)-N-(5-chloro(2-
pyridyl))carboxamide (0.71g, 2.52mmol) in dichloromethane (10ml) was added 3-
cyanobenzoly chloride (417mg, 2.52mmol) and pyridine (0.61 lml, 7.55mmol). The
mixture was stirred at r.t. overnight. The precipitate was filtered and washed with
dichloromethane to give N-{4-chIoro-2-[N-(5-chloro(2-
pyridyl))carbamoyl]phenyl}(4-cyanophenyl)carboxamide as a solid (683mg, 66%).
MS found for C20H12C12N4O2 M+=411, (M+2)+=413.
Step 3: To a solution of the compound of N-{4-chloro-2-[N-(5-chloro(2-
pyridyl))carbamoyl]phenyl}(4-cyanophenyl)carboxamide (683mg, 1.66mmol) in
anhydrous pyridine (10ml) and triethyl amine (lml) was saturated with hydrogen
sulfide gas at 0 °C. The mixture was stirred at r.t. overnight. After the evaporated the
solvent, the residue was dissolved in anhydrous acetone (5ml) and iodomethane (lml,
16.6mmol) was added. The mixture was stirred under reflux condition for 2 hrs. After
the evaporation of solvent, the residue was dissolved in anhydrous methanol (5ml)
and added a solution of N-methylethylenediamine (0.732ml, 8.3mmol) and acetic acid
(1.5ml) in anhydrous methanol (5ml).The mixture was stirred under reflux condition
for 2 hrs. After the evaporation of solvent, the crude residue was purified by RP-
HPLC to giveN-{4-chloro-2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(l-
methyl(2-imidazolin-2-yl))phenyl]carboxamide as a white powder. MS found for
C23H19C12N5O2 M+=468 (M+2)+=470.





Step l: To a solution of 5-methyl-2-nitrobenzoic acid (1g, 5.52mmol) in
dichloromethane (5ml) was added oxalyl chloride (0.964ml, 11.04mmol) and a few
drops of dimethylformamide. The mixture was stirred at r.t. for 2 hrs. After the
evaporation of the solvent, the residue was dissolved in dichloromethane (5ml). 2-
amino-5-chloropyridine (852mg, 6.62mmol) and pyridine (1.34ml, 16.56mmol) were

added to the solution, The mixture was stirred at r.t. overnight. After the evaporation
of the solvent, the crude residue was purified by silica gel column chromatography
using solvent system 25% ethyl acetate in hexane as eluent to give N-(5-chloro(2-
pyridyl))(5-methyl-2-nitrophenyl)carboxamide as a solid (1.48g, 92%). MS found for
C13H10C1N3O3 M+=291, (M+2)+=293.
Step 2: To a solution of the compound of N-(5-chloro(2-pyridyl))(5-methyl-2-
nitrophenyl)carboxamide (1.48g, 5.1mmol) in methanol (10ml) was added 5% Pt/C
(1.48g, 0.19mmol). The mixture was applied hydrogen balloon at r.t.for 2 hrs. After
the filtration by Celite, the filtrate was concentrated to give (2-aminophenyl)-N-(2-
pyridyl)carboxamide, C, chloride, N (1.36g, 100%). MS found for C13H12C1N3O
M+=262, (M+2)+=264.
Step 3: To a solution of the compound of (2-aminophenyl)-N-(2-pyridyl)carboxamide,
C, chloride, N (1.36g, 5.2mmol) in dichloromethane (10ml) was added 3-
cyanobenzoly chloride (860mg, 5.2mmol) and pyridine (1.26ml, 15.6mmol). The
mixture was stirred at r.t. overnight. After the evaporation of the solvent, the crude
residue was purified by silica gel column chromatography using solvent system 25%
ethyl acetate in hexane as eluent to give N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-
rnethylphenyl}(4-cyanophenyl)carboxamide as a solid (830mg, 41%). MS found for
C21H15C1N4O2 M+=390, (M+2)+=392.
Step 4: To a lotion of the compound of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-
methylphenyl}(4-cyanophenyl)carboxamide (830mg, 2.1mmol) in anhydrous
methanol (5ml) and ethyl acetate (10ml) was saturated with hydrogen chloride gas at
0 °C. The mixture was stirred at r.t. overnight. After the evaporated the solvent, the
residue was dissolved in anhydrous methanol (5ml) and N-methylethylenediamine
(0.926ml, 10.5mmol) was added. The mixture was stirred under reflux condition for 2
hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to
giveN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}[4-(l-methyl(2-
imidazolin-2-yl))phenyl]carboxamide as a white powder. MS found for
C24H22C1N5O2 M+=448, (M+2)+=450.




Step l: To a solution of 3,4,5-trimethoxy-2-nitrobenzoic acid (0.5g, 1.95mmol) in
dichloromethane (5ml) was added oxalyl chloride (0.34ml, 3.9mmol) and a few drops
of dimethylformamide. The mixture was stirred at r.t. for 2 hrs. After the evaporation
of the solvent, the residue was dissolved in dichloromethane (5ml). 2-amino-5-
bromopyridine (0.81g, 4.7mmol) and pyridine (0.94ml, 11.7mmol) were added to the
solution. The mixture was stirred at r.t. overnight. After the evaporation of the solvent,
the crude residue was purified by silica gel column chromatography using solvent
system 25% ethyl acetate in hexane as eluent to give N-(5-bromo(2-pyridyl))(3,4,5-
trimethoxy-2-nitrophenyl)carboxamide as a solid (790mg, 98%). MS found for
C15H14BrN3O6 M+=412, (M+2)+=414.
Step 2: To a solution of the compound of N-(5-bromo(2-pyridyl))(3,4,5-trimethoxy-2-
nitrophenyl)carboxamide (790mg, 1.92mmol) in ethyl acetate (5ml) was added tin
chloride (II) hydrate (1.73g, 7.67mrnol). The mixture was stirred under reflux
condition for 2 hrs. After filtered by Celite, the filtrate was added 1N sodium
hydroxide solution and extracted with ethyl acetate. The organic layer was dried over
magnesium sulfate and concentrated to give (2-amino-3,4,5-trimethoxyphenyl)-N-(5-
bromo(2-pyridyl))carboxamide (570mg, 77%). MS found for C15H16BrN3O4
M+=382, (M+2)+=384.
Step 3:.To a solution of the compound of (2-amino-3,4,5-trimethoxyphenyl)-N-(5-
bromo(2-pyridyl))carboxamide (570mg, 1.49mmol) in dichloromethane (5ml) was
added 3-cyanobenzoly chloride (247mg, 1.49mmol) and pyridine (0.362ml,
4.48mmol). The mixture was stirred at r.t. overnight. After the evaporation of the
solvent, the crude residue was purified by silica gel column chromatography using

solvent system 25% ethyl acetate in hexane as eluent to give N-{6-[N-(5-bromo(2-
pyridyl))carbamoyl]-2,3,4-trimethoxyphenyl}(4-cyanophenyl)carboxamide as a solid
(680mg, 69%). MS found for C23H19BrN4O5 M+=511, (M+2)+=513.
Step 4: To a slotion of the compound of N-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-
2,3,4-trimethoxyphenyl}(4-cyanophenyl)carboxamide (680mg, 1.33mmol) in
anhydrous methanol (5ml) and ethyl acetate (10ml) was saturated with hydrogen
chloride gas at 0 °C. The mixture was stirred at r.t. overnight. After the evaporated the
solvent, the residue was dissolved in anhydrous methanol (5ml) and N-
methylethylenediamine (0.586ml, 6.65mmol) was added. The mixture was stirred
under reflux condition for 2 hrs. After the evaporation of solvent, the crude residue
was purified by RP-HPLC to give N-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-2,3,4-
trimethoxyphenyl}[4-(l-methyl(2-imidazolin-2-yl))phenyl]carboxamide as a white
powder (240mg, 32%). MS found for C26H26BrN5O5 M+=568, (M+2)+=570.



Step 1: To a solution of 4-{2-{[(tert-butyl)amino}sulfonyl}phenyl}benzoic acid
(167mg, 0.5mmol) in dichloromethane (5ml) was added oxalyl chloride (0.09ml,
lmmol) and a few drops of dimethylformamide. The mixture was stirred at r.t. for 2
hrs. After the evaporation of the solvent, the residue was dissolved in dichloromethane
(5ml). The compound of (2-amino-5-chlorophenyl)-N-(5-chloro(2-
pyridyl))carboxamide (0.17g, 0.6mmol) and pyridine (0.122ml, 1.5mmol) were added
to the solution. The mixture was stirred at r.t. overnight. The solvent was evaporated
to give (2- {[4-(2- {[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-carbonylamino} -5-
chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide. MS found for C29H26C12N4O4S
M+=597, (M+2)+=599.
Step 2: The mixture of the compound of (2-{[4-(2-{[(tert-
butyl)amino]sulfonyl}phenyl)phenyl] carbonylamino}-5-chlorophenyl)-N-(5-
chloro(2-pyridyl))carboxamideexample 12 (0.5mmol) in trifluoroacetic acid (5ml)
was stirred at r.t. for 5hrs. After the evaporation of solvent, the crude residue was
purified by RP-HPLC to give
N-(5-chloro(2-pyridyl))(5-chloro-2-{[4-(2-sulfamoylphenyl)-
phenyl]carbonylamino}phenyl)-carboxamide as a white powder (68mg, 25%). MS
found for C25H18C12N4O4S
M+=541,(M+2)+=543.


A stream of H2S (g) was bubbled through a 0 °C solution of N-{2-[N-(5-chIoro(2-
pyridyl))carbamoyl]phenyl} [4-(2-cyanophenyl)phenyl]carboxamide (100 mg, 0.22
mmol, 1.0 equiv.) in 9 mL pyridine and 1 mL NEt3 until saturation. The mixture was
stirred at rt for 1 day and evaporated. The resulting residue was treated with Mel (94
mg, 0.663 mmol, 3.0 equiv.) in 10 mL acetone at reflux temperature for 1 hr and
concentrated to dryness. The resulting residue was treated with a mixture of NH4OAc
(340 mg, 4.42 mmol, 20 equiv.) in 0.5 mL acetic acid and 2 mL methanol at 50 °C for
2 days. The solvent was removed at reduced pressure and the crude benzamidine was
purified by HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN to
give 2-[4-(N-{2-[N-(5-chloro-2-
pyridyl)carbamoyl]phenyl}carbamoyl)phenyl]benzenecarboxamidine (15 mg, 15%).
MS found for C26H20ClN5O2 (M+H)+: 470.




This compound was ontained as on of the side product in Example 157.
MS found for C26H19C1N4O3 (M+H)+: 471

A mixture of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(2-
cyanophenyl)phenyl] carboxamide (200 mg, 0.442 mmol, 1.0 equiv.), cobalt chloride
(86 mg, 0.664 mmol, 1.5 equiv.) and sodium borohydride (50 mg, 1.33 mmol, 3.0
equiv.) in DMF (15 mL) was stirred at 0 °C to rt for 3 days. The reaction was
quenched with ice cubes, diluted with DCM (100 mL) and filtered through celite. The
filtrate was washed with saturated aqueous NaHCO3. The organic layer was dried
over MgSO4, filtered, evaporated and HPLC (C18 reversed phase) eluting with 0.1%
TFA in H2O/CH3CN gave {4-[2-(aminomethyl)phenyl]phenyl}-N-{2-[N-(5-chloro(2-
pyridyl))carbamoyl]phenyl} carboxamide (87 mg, 43%). MS found for C26H21C1N4O2
(M+H)+: 457.


A mixture of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-
cyanophenyl)carboxamide (1 g, 2.6 mmol, 1.0 equiv.), cobalt chloride (0.5 g, 3.85
mmol, 1.5 equiv.) and sodium borohydride (0.295 g, 7.8 mmol, 3.0 equiv.) in DMF
(20 mL) was stirred at 0 °C to rt for 2.5 hr. The reaction was quenched with ice cubes,
diluted with ethyl acetate (100 mL) and filtered through celite. The filtrate was
washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4,
filtered, evaporated and HPLC (C18 reversed phase) eluting with 0.1% TFA in
H2O/CH3CN gave [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-
pyridyl))carbamoyl]phenyl}carboxamide (320 mg, 30%). MS found for
C20H17C1N402(M+H)+:381.


A mixture of [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-
pyridyl))carbamoyl]phenyl}carboxamide (80 mg, 0.21 mmol), 2-methylthio-2-
imidazoline hydriodide (77 mg, 0.315 mmol, 1.5 equiv.) and triethyl amine (0.5 mL)
in 1 mL DMF was stirred at room temperature overnight, concentrated to dryness and
HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN gave N-{2-[N-(5-
chloro(2-pyridyl))carbamoyl]phenyl}{4-[(2-imidazolin-2-
ylamino)methyl]phenyl}carboxamide (13.5 mg, 15%). MS found for C23H21C1N6O2
(M+H)+: 449

Step 1: To the boiling solution of 2-methylthio-2-imidazoline hydriodide (1 g, 8.4
mmol) in methanol (10 mL) was added Mel (0.78 mL, 12.6 mmol, 1.5 equiv.)
dropwise. The reaction mixture was stirred at reflux temperature for 1 hr,
concentrated and crystallized with ether to give l-methyl-2-methylthio-2-imidazoline
(1.1 g, 100%).
MS found for C5H10N2S (M+H)+: 131.
Step 2: A mixture of [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-
pyridyl))carbarnoyl]phenyl}carboxamide (74 mg, 0.195 mmol), l-methyl-2-
methylthio-2-imidazoline (25 mg, 0.195 mmol), NEt3 (2 mL) and pyridine (5 mL)
was stirred at 80 °C overnight, concentrated and HPLC (C18 reversed phase)eluting
with 0.1% TFA in H2O/CH3CN gave N-{2-[N-(5-chloro(2-
pyridyl))carbamoyl]phenyl}(4-{[(l-methyl(2-imidazolin-2-

yl))amino]methyl}phenyl)carboxamide (52 mg, 65%). MS found for C24H23C1N6O2
(M+H)+: 463.

Preparation of methyl 3-[(4-cyanophenyl)carbonylamino]thiophene-2-carboxy late
A mixture of 4-cyanobenzoyl chloride (1.0500g, 6.4 mmol), methyl 3-
aminothiophenecarboxylate (l.OOOOg, 6.4 mmol), and triethylamine (1 mL, 7.0 mmol)
in dichloromethane was stirred at room temperature for 18 hours. The mixture was
poured into a separatory funnel and washed by 1 N HC1. The organic layers were
combined, dried over MgSO4, concentrated in vacuo, and chromatographed through a
silica gel column to give the title compound 1.6588 g (91%). ES-MS 287 (M+l).
Preparation of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}(4-
cyanophenyl)carboxamide
A portion of 2-amino-5-chloropyridine (68.6 mg, 0.5 mmol) was treated with AlMe3
(0.8 mL, 1.6 mmol), followed by adding the product from step A (160 mg, 0.5 mmol).
The mixture was stirred at room temperature for 18 hours. The excess of AlMe3 was
killed by IN HC1 solution. The organic layers were combined, dried over MgSO4,
concentrated in vacuo, and chromatographed through a silica gel column to give the
title compound 0.1528 g (80%). ES-MS 383 (M+l).

Preparation of Example 163.
A mixture of the product from step B (0.1528 g, 0.4 mmol) and EtOH saturated with
HC1 was stirred at room temperature for 18 hours. The solvent was removed by a
rotovap. The crude oil was treated with 2 mL N-methylethylenediamine for 2 hours
until the reaction was complete. Prep HPLC was used to purity the final product. It
gave 0.1537 g (88%). ES-MS 440(M+l).

Example 164 was made by the procedure of Example 163. ES-MS 428(M+1).

Example 165 was made by the procedure of Example 163. ES-MS 400(M+l).


















Step 1: A solution of 2-amino-5-bromopyridine (0.200 g, 1.16 mmol 1.0 equiv), in 5
mls of methylene chloride, under argon, was treated with trimethylaluminum (0.312
mL, 2.0N in hexanes, 4.0 equiv) at room temperature for 30 min. To the solution was
added ethyl-3-methylpyrazole-5-carboxylate (0.356 g, 2.0 equiv). After 4hrs, the
volatile was evaporated, and the residue was redissolved into EtOAc, washed with

0.5N HC1, 0.2 N K2CO3, and saturated aqueous NaCl. The organic layer was dried
over Na2SO4, filtered, evaporated and purified via flash chromatography on silica gel
to give N-(5-bromo-2-pyridinyl)-(3-methyl)5-pyrazolecarboxamide (0.160 g, 49%).
MS found for C10H9BrN4O (M+H)+: 281, 283.
Step 2: A solution of N-(5-bromo-2-pyridinyl)-(3-methyI)5-pyrazolecarboxamide
(0.060 g, 0.213 mmol, 1.0 equiv) in 2 mL of acetonitrile was treated with triphosgene
(0.063 g, 1.0 equiv) at room temperature for 5min under argon. To the solution was
added 4-[(2-t-butylaminosulfonyl)phenyl]phenylamine (0.071 g, 1.1 equiv) After 1 hr,
the volatile was evaporated and the residue was redissolved into EtOAc, washed with
0.5N HC1, 0.2 N K2CO3, and saturated aqueous NaCl. The organic layer was dried
over Na2SO4, filtered, evaporated, purified via flash chromatography on silica gel and
then reacted in 2 mL of trifluoroacetic acid for 16 hrs at room temperature. TFA was
then evaporated and the residue was redissolved into EtOAc, washed with 0.5N HC1,
0.2 N K2CO3, and saturated aqueous NaCl. The organic layer was dried over Na2SO4,
filtered, evaporated, and triturated with diethyl ether to give N-(5-bromo-2-pyridinyl)-
(2-4-[(2-aminosulfonyl)phenyl] phenylaminocarbonyl)5-methyl-pyrazolcarboxamide
(0.0024 g, 2%). MS found for C23H19BrN6O4S (M+H)+: 555, 557.

Step 1: A solution of 5-fluoro-2-nitrobenzoic acid (10.0 g, 54 mmol, 1.0 equiv), 2-
amino-5-bromopyridine (12.2 g, 1.3 equiv), in 80 mL of pyridine was treated with
phosphorous oxychloride (25.3 g, 3.0 equiv) for 30 min. The volatile was evaporated

and the residue was redissolved into EtOAc, washed with 1N HC1, saturated aqueous
NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4,
filtered, and evaporated. The volatile was evaporated, and the product was triturated
with diethyl ether to give N-(5-bromo-2-pyridinyl)-(2-nitro)-5-
fluorophenylcarboxamide (12.5 g, 68%). MS found for C12H7BrFN3O3 (M+H)+: 340,
342.
Step 2: A solution of N-(5-bromo-2-pyridinyl)-(2-nitro)-5-flurophenylcarboxamide
(2.0 g, 5.88 mmol, 1.0 equiv) in 30 mL of EtOAc was treated with SnCl22H2O (5.90
g, 4 equiv) at reflux for 4 h. The volatile was evaporated and the residue was
redissolved in EtOAc, washed with saturated aqueous NaHCO3 and 1N NaOH. The
organic layer was dried over MgSO4, filtered and evaporated to N-(5-bromo-2-
pyridinyl)-(2-amino)-5-fluorophenylcarboxamide (1.79 g, 98%). MS found for
C12H9BrFN3O (M+H)+: 310, 312.
Step 3: A mixture of N-(5-bromo-2-pyridinyl)-(2-amino)-5-fluorophenylcarboxamide
(0.310 g, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride
(0.430 g, 1.3 equiv), pyridine (2 mL) in 10 mL of dichloromethane was stirred at rt
overnight The volatile was evaporated and the residue was redissolved into EtOAc,
washed with IN HC1, saturated aqueous NaHCO3 and saturated aqueous NaCl. The
organic layer was dried over Na2SO4, filtered, and evaporated. The intermediate was
reacted into 5 mL of trifluoroacetic acid at rt overnight. TFA was then evaporated and
the product was triturated with diethyl ether, and then with chloroform to give N-(5-
bromo-2-pyridinyl)-(2-4-[(2-arninosulfonyl)phenyl] phenylcarbonylamino)-5-
fluorophenylcarboxamide (120 mg, 21%). MS found for C25H18BrFN4O4S (M+H)+:
569,571.


This compound is prepared according to the procedure described in example 2 with
the exception of using zinc in acetic acid to reduce nitro-intermediate in step 2. The
final product was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in
H2O/CH3CN. MS found for C25H!8C1FN4O4S (M+H)+: 525, 527.

This compound is prepared according to the procedure described in example 2 with
the exception of using 5-acetamido-2-nitrobenzoic acid as the starting material in step
1. The final product was purified by HPLC (C18 reversed phase) eluting with 0.5%
TFA in H2O/CH3CN MS found for C27BrN5O5S (M+H)+: 608, 610.

This compound is prepared according to the procedure described in example 2 with
the exception of the following step 1b performed on the nitro-intermediate from step
1. The final product was purified by HPLC (C18 reversed phase) eluting with 0.5%
TFA in H2O/CH3CN MS found for C30H29BrN6O4S (M+H)+: 649, 651.


Step lb: A mixture of N-(5-bromo-2-pyridinyl)-(2-nitro)-5-fluorophenyIcarboxamide
(0.68 g, 2 mmol, 1.0 equiv), N-methylpiperazine (0.60 g, 3 equiv), and Cs2CO3 (1.30
g, 2 equiv) in 5 mL of dimethylformamide was stirred at 90°C overnight. Ethyl acetate
was added and washed with H2O. The organic layer was dried over Na2CO4, filtered,
evaporated, purified via flash chromatography on silica gel to give N-(5-bromo-2-
pyridinyl)-(2-nitro)-5-(4-N-methylpiperazine)phenylcarboxamide (0.54g, 65%). MS
found for C17H18BrN5O3 (M+H)+: 419, 421.
This compound is prepared according to the procedure described in example 5. The
final product was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in
H2O/CH3CNMS found for C28H21C1N6O4S (M+H)+: 573, 575.
Step 3: A mixture of 4-[(2-t-butylaminosulfonyl)phenyl]phenylamine (0.180 g, 1.2
equiv), N,N'-disuccinimidyl carbonate (0.154 g, 1.2 equiv), 4-methylmorpholine (0.5

mL) in 10 mL of acetonitrile was stirred at rt for 30 min. N-(5-bromo-2-pyridinyl)-(2-
amino)-5-fluorophenyIcarboxamide (0.155 g, 0.5 mmol, 1.0 equiv) was added and the
solution was stirred at rt for 3 hrs. The volatile was evaporated and the residue was
redissolved into EtOAc, washed with 1N HC1, saturated aqueous NaHCO3 and
saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and
evaporated. The intermediate was reacted into 5 mL of trifluoroacetic acid at rt
overnight. TFA was then evaporated and the product was purified by HPLC (C18
reversed phase) eluting with 0.5% TFA in H2O/CH3CN to give N-(5-bromo-2-
pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylaminocarbonylamino)-5-
fluorophenylcarboxamide (0.053 g, 18%). MS found for C25H19BrFN5O4S (M+H)+:
584, 586.

Step 1: A mixture of N-(5-bromo-2-pyridinyl)-(2-amino)5-fluorophenylcarboxamide
(1.24 g, 4 mmol, 1.0 equiv), 4-cyano benzoyl chloride (0.792 g, equiv), and pyridine
(3 mL) in 15 mL of dichloromethane was stirred at rt overnight. The volatile was
evaporated and the residue was redissolved into EtOAc, washed with 1N HC1,
saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried
over Na3SO4, filtered, and evaporated to give N-(5-bromo-2-pyridinyl)-(2-(4-
cyanophenylcarbonyl)amino)5-fluorophenylcarboxamide (1.14 g, 65%). MS found for
C20Hl2BrFN4O2 (M+H)+: 439, 441.
Step 2: A mixture of N-(5-bromo-2-pyridinyl)-(2-(4-cyanophenylcarbonyl)amino)5-
fluorophenylcarboxamide (1.12 g, 2.56 mmol, 1.0 equiv), hydroxylamine-HC1 (0.213
g, 1.2 equiv), and triethylamine (1 mL) in 15 mL of ethyl alcohol was stirred at 50°C

overnight. The volatile was evaporated and the residue was redissolved into EtOAc,
washed with 1N HC1, saturated aqueous NaHCO3 and saturated aqueous NaCl. The
organic layer was dried over Na2SO4, filtered, and evaporated to give N-(5-bromo-2-
pyridinyl)-(2-(4-hydroxyamidinophenylcarbonyl)amino)5-fluorophenylcarboxamide
(compound Example 194) (0.84 g, 70%). One third of this material was purified by
HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN to yield 0.20
grams (71%). MS found for C20H15BrFN5O3 (M+H)+: 472, 474.
Step 3: A mixture of N-(5-bromo-2-pyridinyl)-(2-(4-
hydroxyamidinophenylcarbonyl)amino)5-fluorophenylcarboxamide (0.56 g, 1.19
mmol, 1.0 equiv) and zinc dust (0.39 g, 5.0 equiv), in 10 mL of acetic acid was stirred
at rt for 45 min. The volatile was filtered and evaporated. The residue was purified by
HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN give N-(5-bromo-
2-pyridinyl)-(2-(4-amidinophenylcarbonyl)amino)5-fluorophenyl-carboxamide
(compound Example 195) (0.24 g, 44%).
MS found for C20H15BrFN5O2 (M+H)+: 456,458.

Step 1: A stream of HCl(g) was bubbled through a 0°C solution of N-(5-bromo-2-
pyridinyl)-(2-(4-cyanophenylcarbonyl)amino)5-fluorophenylcarboxamide (1.0 g, 2.3
mmol) in 30 mL of methanol until saturation. The mixture was stirred at rt overnight
and evaporated. One-fifth of the resulting residue was treated with (2-
aminoethyl)methylamine (0.10 g) in 10 ml methanol at rt overnight. The solvent was
removed at reduced pressure and the crude product was purified by HPLC (C18














To a solution of 4,5-dimethoxy-2-nitrobenzoic acid (2.2gm, 10mmol) and 2-amino-5-
bromopyridine (2.4gm, 14mmol) in anhydrous pyridine (50mL) at 0°C was added
POC13 (1.9mL, 20mmol). After stirring at room temperature for 30min, the reaction
was complete. The mixture was concentrated and diluted with EtOAc (200mL). The
organic solution was washed with brine, dried and evaporated to give intermediate
compound 1 (3.0gm, 80%). MS found for C14H12BrN3O5 (M+H)+: 382.00, 383.95.
A mixture of intermediate compound 1 (320mg, 0.83mmol) and SnCl2-2H2O (900mg,
4.0mmol) in EtOAc (10mL) was refluxed for 1 hour. Reduction completed. The solid
was filtered through a celite bed. The filtrate was diluted with EtOAc (50mL), and the
red solution was washed with 1N aq. NaOH solution (x3) and brine, dried and
evaporated to give intermediate compound 2 (230mg, 78%). MS found for
C14H14BrN3O3 (M+H)+: 352.00, 354.05.
To a solution of intermediate compound 2 (200mg, 0.57mmol) in a mixture of
pyridine (3mL) and DCM (10mL) was added 4-cyanobenzoyl chloride (140mg,
0.85mmol). Precipitate formed immediately and the reaction was complete. The solid
was collected by filtration and washed with DCM. After drying in vacco, the titled
compound was obtained as a yellow solid in 70% yield (190mg). MS found for
C22H17BrN4O4 (M+H)+: 481.00, 483.00.


To a solution of compound obtained in Example 259 (100mg, 0.20mmol) in 10%
Et3N/pyridine (10mL) at 0°C was bubbled dry H2S gas to saturation. The mixture was
stirred at ambient temperatures overnight, and the conversion was complete. The
solvent was removed to dryness, and the residue was suspended in anhydrous acetone
(lOmL), followed by addition of MeI (1mL). The reaction mixture was refluxed for 1
hour. The solvent was removed by rotary evaporation. To the residue was added
anhydrous MeOH (lOmL) and N-methylethylenediamine (ImL). The resulting
mixture was refluxed for 1 hour, concentrated and subjected to RP-HPLC purification
to give the title compound. MS found for C25H24BrN5O4 (M+H)+: 538.1, 540.1.

The title compound was obtained from the Example 259 compound according to the
procedure described in Example 2. MS found for C22H20BrN5O4 (M+H)+: 498.1,
500.0.


To the suspension of the compound Example 262 (100mg) in a mixture of anhydrous
MeOH (5mL) and EtOAc (5mL) at 0°C was bubbled anhydrous HC1 gas to saturation.
The mixture was stirred at ambient temperatures overnight. The conversion
completed. The solvent was evaporated to dryness. The residue was dissolved in
anhydrous MeOH (10mL), followed by addition of N-methylethylenediamine (lmL).
The resulting mixture was refluxed for 1 hour, concentrated and subjected to RP-
HPLC purification to give the title compound 263. MS found for C24H22C1N5O3
(M+H)+: 464.




















To a suspension of compound N-(5-chloro(2-pyridyl)){2-[(4-cyanophenyl)-
carbonylamino]-5-methoxyphenyl}carboxamide (500mg, 1.2mmol) in DCM (100mL)
at -78°C was added BBr3 (2mL). The mixture was stirred at ambient temperatures for
72 hours. The solid was collected by filtration and was washed by DCM and water,
dried under vacuum. The filtrate was concentrated and extracted with EtOAc. The
organic extract was washed with brine, dried and evaporated. The resulting solid was
combined with the solid obtained from filtration to give the title compound. Total
yield is 90% (430mg). MS found for C20H13ClN4O3 (M+H)+: 393.0.



(83mg, 0.25mmol) in DMF (1mL) at room temperature was added ethyl bromoacetate
(15p.L, 0.13mmol). The mixture was stirred for 1 hour before diluted with EtOAc
(20mL) and water (10mL). The organic layer was washed with brine dried and
evaporated to give 70mg of the crude compound, which was used without farther
purification. MS found for C24H19C1N4O5 (M+H)+: 479.0.

Example 286
4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-hydroxyphenyl}carbamoyl)-
benzenecarboxamidine

The title compound was obtained according to the procedure described in Example
282. MS found for C20Hl6ClN5O3 (M+H)+: 410.1.


To a solution of Example 284 (10mg) in MeOH (lmL) was added 50L of 1N aq.
LiOH solution. The mixture was stirred for 1 hour and purified by RP-HPLC to give
the title compound. MS found for C24H22C1N5O5 (M+H)+: 496.

WE CLAIM:
1. Benzamide compounds of the following formula:
A-Q-D-E-G-J-X
wherein:
A is -N(R1,R2) or -N(R1,R2)-C(=NR3)-, wherein R1, R2, and R3 are independently selected
from the group consisting of:
H, -OR5, -C1-4alkyl, -C0-4alkylC3-8cycloalkyl, wherein R5 is H or -C1-4alkyl;
or R1 and R2, or R2 and R3 taken together can form a heterocyclic ring system,
wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to
2 rings being in the ring system and may contain from 1-4 heteroatoms selected
from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring
system may be independently replaced with C1-C4-alkyl and wherein any sulfur
atom present may be oxidized;
Q is a direct link;
D is phenyl, which is independently substituted with 0-2 Rla substitutuents, wherein Rla
is halo;
E is -C(=O)-N(-R8)-, wherein R8 is H;
G is a phenylene group wherein the ring carbon atoms of the phenylene group are
substituted with 0-4 Rld groups, wherein Rld is a member selected from the group
consisting of:
H, halo, C1-6-alkyl, -CF3, -(CH2)0-6-OR2d, and -O-(CH2)1-6-C(=O)-O-R2d, wherein
R2d is H or C1-6-alkyl;
J is -C(=O)-N(-R9)-, wherein R9 is H;
X is a pyridine ring having 0-3 ring atoms substituted with 0-3 Rle groups, wherein Rle is
halo;
or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.
2. A compound as claimed in claim 1 having the following structure:


or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.
3. A compound as claimed in claim 1 having the following structure:

wherein:
A-Q is a member selected from the group of:


4. A compound as claimed in claim 3, wherein


or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.
6. A compound as claimed in claim 1 selected from the group consisting of:
N-(5-bromo-2-pyridinyl)-(2-(4-amidinophenylcarbonyl)amino)-phenylcarboxamide,
N-(5-bromo-2-pyridinyl)-(2-(4-(2-imidazolinyl)phenylcarbonyl)amino)-
phenylcarboxamide,
N-(5-bromo-2-pyridinyl)-(2-(4-(5-tetrazolyl)phenylcarbonyl)amino)-phenylcarboxamide,
N-(5-bromo-2-pyridinyl)-(2-(4[-[ 1,1 -doxo( 1,4-thiazaperhydroin-4-
yl))iminimethy]phenylcarbonyl)amino)-phenylcarboxamide,
N-(5-bromo-2-pyridinyl)-(2-(4-[l-oxo(l,4-thiazaperhydroin-4-
yl))iminimethy]phenylcarbonyl)amino)-phenylcarboxamide,
N-(5-bromo-2-pyridinyl)-(2-(4-amidinophenylcarbonyl)amino)5-
fluorophenylcarboxamide,
N-(5-bromo-2-pyridinyl)-(2-(4-(l-methyl-2-imadazolin-2-yl)phenylcarbonyl)amino)5-
fluorophenylcarboxamide,
(4,5-dimethoxy-2-{[4-(l-methyl(2-imidazolin-2-yl))phenyl]carbonylamino}phenyl)-N-
(5-bromo(2-pyridyl))carboxamide,
4-(N-{2-[N-(5-bromo(2-pyridyl))carbamoyl]-4,5-dimethoxyphenyl}carbamoyl)-
benzenecarboxamidine,
N-(5-chloro(2-pyridyl))(5-methoxy-2-{[4-(l-methyl(2-imidazolin-2-yl))phenyl]-
carbonylamino }phenyl)carboxamide,
4-(N- {2- [N-(5 -chloro(2-pyridyl))carbamoyl] -4-methoxyphenyl} carbamoyl)benzene-
carboxamidine,
N-(5-chloro(2-pyridyl))[2-({4-[imino(methylamino)methyl]phenyl}carbonylamino)-5-
methoxyphenyl]carboxamide,
[2-( {4- [(dimethylamino)iminomethyl]phenyl} carbonylamino)-5 -methoxyphenyl] -N-(5 -
chloro(2-pyridyl))carboxamide,
N-(5-chloro(2-pyridyl))(2-{[4-(iminopyrrolidinylmethyl)phenyl]carbonylamino}-5-
methoxyphenyl)carboxamide,
N-(5-chloro(2-pyridyl))(2-{[4-(iminopiperidylmethyl)phenyl]carbonylamino}-5-
methoxyphenyl)carboxamide,

N-(5-chloro(2-pyridyl))(2-{[4-(iminomorpholin-4-ylmethyl)phenyl]carbonylamin}-5-
methoxyphenyl)carboxamide,
N-(5-chloro(2-pyridyl))(2-{[4-(imino-l,4-thiazaperhydroin-4-
ylmethyl)phenyl]carbonylamino}-5-methoxyphenyl)carboxamide,
(2-{[4-(amino(hydroxyimino)methyl)phenyl]carbonylamino}-5-methoxyphenyl)-N-(5-
chloro(2-pyridyl))carboxamide,
N-(5-bromo(2-pyridyl))(5-methoxy-2-{[4-(l-methyl(2-imidazolin-2-
yl))phenyl]carbonylamino}phenyl)carboxamide,
4-(N-{2-[N-(5-bromo(2-pyridyl))carbamoyl]-4-
methoxyphenyl}carbamoyl)benzenecarboxamidine,
N-(5-bromo(2-pyridyl))[2-({4-[imino(methylamino)methyl]phenyl}carbonylamino)-5-
methoxyphenyl]carboxamide,
[2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-
bromo(2-pyridyl))carboxamide,
N-(5-chloro(2-pyridyl))(2-{[4-(iminopyrrolidinylmethyl)phenyl]carbonylamino}-5-
methoxyphenyl)carboxamide,
N-(5-bromo(2-pyridyl))(2-{[4-(iminopiperidylmethyl)phenyl]carbonylamino}-5-
methoxyphenyl)carboxamide,
N-(5-bromo(2-pyridyl))(2-{[4-(iminomorpholin-4-ylmethyl)phenyl]carbonylamino}-5-
methoxyphenyl)carboxamide,
N-(5-bromo(2-pyridyl))(2-{[4-(imino-l,4-thiazaperhydroin-4-
ylmethyl)phenyl] carbonylamino}-5-methoxyphenyl)carboxamide,
(2-{[4-(amino(hydroxyimino)methyl)phenyl]carbonylamino}-5-methoxyphenyl)-N-(5-
bromo(2-pyridyl))carboxamide,
methyl 2-[4-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-3-[N-(5-
chloro(2-pyridyl))carbamoyl]phenoxy]acetate,
(6-{[4-(amino(hydroxyimino)methyl)phenyl]carbonylamino}-3-hydroxyphenyl)-N-(5-
chloro(2-pyridyl))carboxamide, and
4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-hydroxyphenyl}carbamoyl)-
benzenecarboxamidine,
or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.

7. The compound as claimed in claim 1 selected from the group consisting of:



or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.
8. The compound as claimed in claim 1 selected from the group consisting of:

or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.
9. The compound as claimed in claim 1 selected from the group consisting of:


10. The compound as claimed in claim 1 selected from the group consisting of:



or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.
11. The compound as claimed in claim 1 selected from the group consisting of:

or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.
12. The compound as claimed in claim 1 selected from the group consisting of:


or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.
13. The compound as claimed in claim 1, which is a member selected from the group
consisting of:





or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.
14. The compound as claimed in claim 1, which is a member selected from the group
consisting of:


or a pharmaceutically acceptable tautomeric isomer, salt, hydrate or solvate thereof.
15. A compound as claimed in any one of claims 1-14 in the preparation of a
medicament for preventing or treating a condition in a mammal characterized by
undesired thrombosis.
16. A compound as claimed in claim 15, wherein the condition is selected from the
group consisting of:

acute coronary syndrome, myocardial infarction, unstable angina, refractory
angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-
coronary angioplasty, a thrombotically mediated cerebrovascular syndrome,
embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis,
deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated
intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis
obliterans, thrombotic disease associated with heparin-induced thrombocytopenia,
thrombotic complications associated with extracorporeal circulation, thrombotic"
complications associated with instrumentation, and thrombotic complications
associated with the fitting of prosthetic devices.
17. A compound as claimed in any one of claims 1-14 for inhibiting the coagulation of
biological samples.

Novel benzamide compounds, their salts and compositions related thereto
having activity against mammalian factor Xa are disclosed. The compounds are used
in vitro or in vivo for preventing or treating coagulation disorders.

Documents:

IN-PCT-2002-479-KOL-AMANDED CLAIMS.pdf

IN-PCT-2002-479-KOL-CORRESPONDENCE-1.1.pdf

IN-PCT-2002-479-KOL-CORRESPONDENCE.pdf

IN-PCT-2002-479-KOL-FORM 13-1.1.pdf

IN-PCT-2002-479-KOL-FORM 27.pdf

in-pct-2002-479-kol-granted-abstract.pdf

in-pct-2002-479-kol-granted-assignment.pdf

in-pct-2002-479-kol-granted-claims.pdf

in-pct-2002-479-kol-granted-correspondence.pdf

in-pct-2002-479-kol-granted-description (complete).pdf

in-pct-2002-479-kol-granted-examination report.pdf

in-pct-2002-479-kol-granted-form 1.pdf

in-pct-2002-479-kol-granted-form 13.pdf

in-pct-2002-479-kol-granted-form 18.pdf

in-pct-2002-479-kol-granted-form 3.pdf

in-pct-2002-479-kol-granted-form 5.pdf

in-pct-2002-479-kol-granted-gpa.pdf

in-pct-2002-479-kol-granted-reply to examination report.pdf

in-pct-2002-479-kol-granted-specification.pdf

in-pct-2002-479-kol-granted-translated copy of priority document.pdf

IN-PCT-2002-479-KOL-OTHERS-1.1.pdf


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Patent Number 231456
Indian Patent Application Number IN/PCT/2002/479/KOL
PG Journal Number 10/2009
Publication Date 06-Mar-2009
Grant Date 04-Mar-2009
Date of Filing 17-Apr-2002
Name of Patentee MILLENNIUM PHARMACEUTICALS, INC. ,
Applicant Address 256 EAST GRAND AVENUE, SOUTH SAN FRANCISCO, CA
Inventors:
# Inventor's Name Inventor's Address
1 ZHANG PENGLIE 224 SERRANO DRIVE, SOUTH SAN FRANCISCO, CA 94132
2 WANG LINGYAN 224 BRENTWOOD DRIVE, SOUTH SAN FRANCISCO, CA 94080
3 GOLDMAN ERIC 1577 PERSHING DRIVE, #C, SAN FRANCISCO, CA 94129
4 LI WENHAO P.O. BOX 1993, SOUTH SAN FRANCISCO, CA 94083
5 ZUCKETT JINGMEI 130 BARNESON AVENUE, #1, SAN MATEO, CA 94402
6 SONG YONGHONG 1144 NIMITZ LANE, FOSTER CITY, CA 94404
7 SCARBOROUGH ROBERT 22 GREENBRIER COURT, HALF MOON BAY, CA 94019
8 ZHU BING-YAN 3325 ADELAIDE WAY, BELMONT, CA 94002
9 HUANG WENRONG 7723 HUNTRIDGE LANE, CUPERTINO, CA 95014
PCT International Classification Number C07C 311/00
PCT International Application Number PCT/US2000/25196
PCT International Filing date 2000-09-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/154,332 1999-09-17 U.S.A.
2 60/185,746 2000-02-29 U.S.A.